[Federal Register Volume 89, Number 88 (Monday, May 6, 2024)]
[Rules and Regulations]
[Pages 37286-37445]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2024-08935]



[[Page 37285]]

Vol. 89

Monday,

No. 88

May 6, 2024

Part II





Department of Health and Human Services





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Food and Drug Administration





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21 CFR Part 809





Medical Devices; Laboratory Developed Tests; Final Rule

  Federal Register / Vol. 89, No. 88 / Monday, May 6, 2024 / Rules and 
Regulations  

[[Page 37286]]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 809

[Docket No. FDA-2023-N-2177]
RIN 0910-AI85


Medical Devices; Laboratory Developed Tests

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration is issuing a final rule to 
amend its regulations to make explicit that in vitro diagnostic 
products (IVDs) are devices under the Federal Food, Drug, and Cosmetic 
Act (FD&C Act) including when the manufacturer of the IVD is a 
laboratory. In conjunction with this amendment, the Food and Drug 
Administration is phasing out its general enforcement discretion 
approach for laboratory developed tests (LDTs) so that IVDs 
manufactured by a laboratory will generally fall under the same 
enforcement approach as other IVDs. This phaseout policy includes 
enforcement discretion policies for specific categories of IVDs 
manufactured by a laboratory, including currently marketed IVDs offered 
as LDTs and LDTs for unmet needs. This phaseout policy is intended to 
better protect the public health by helping to assure the safety and 
effectiveness of IVDs offered as LDTs, while also accounting for other 
important public health considerations such as patient access and 
reliance.

DATES: This rule is effective July 5, 2024.

ADDRESSES: For access to the docket to read background documents or 
comments received, go to https://www.regulations.gov and insert the 
docket number found in brackets in the heading of this final rule into 
the ``Search'' box and follow the prompts, and/or go to the Dockets 
Management Staff, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852, 
240-402-7500.

FOR FURTHER INFORMATION CONTACT: Toby Lowe, Center for Devices and 
Radiological Health, Food and Drug Administration, 10903 New Hampshire 
Ave., Silver Spring, MD 20993, 301-796-6512, [email protected].

SUPPLEMENTARY INFORMATION: 

Table of Contents

I. Executive Summary
    A. Purpose of the Final Rule
    B. Summary of Select Provisions of the Final Rule
    C. Legal Authority
    D. Costs and Benefits
II. Table of Abbreviations/Commonly Used Acronyms in This Document
III. Background
    A. FDA's Current Regulatory Framework
    B. Need for the Rule
    C. Summary of Comments on the Notice of Proposed Rulemaking
    D. General Overview of the Final Amendment to the Definition of 
In Vitro Diagnostic Products
    E. General Overview of the Final Phaseout Policy
IV. Legal Authority
V. Phaseout Policy
    A. Scope
    B. Enforcement Discretion Policies
    C. Stages
VI. Comments on the Notice of Proposed Rulemaking and FDA Responses
    A. General Comments on the Notice of Proposed Rulemaking
    B. Definitions
    C. Need for the Rule
    D. FDA Authority To Regulate LDTs
    E. Other Legal Comments
    F. Phaseout Policy
    G. Impact on Small Businesses
    H. Impact on Pricing
    I. Impact on Access and Innovation
    J. Level Playing Field
    K. Impact to Specific Patient Populations
    L. Specific Types of IVDs
    M. IVD Modifications
    N. FDA Resources
    O. 510(k) Third Party Review Program
    P. Implementation
    Q. Interplay With Oncology Drug Products Used With Certain In 
Vitro Diagnostic Tests Pilot Program
    R. Miscellaneous
VII. Effective Date
VIII. Economic Analysis of Impacts
IX. Analysis of Environmental Impact
X. Paperwork Reduction Act of 1995
XI. Federalism
XII. Consultation and Coordination With Indian Tribal Governments
XIII. References

I. Executive Summary

A. Purpose of the Final Rule

    The Food and Drug Administration (FDA, the Agency, or we) is 
amending its regulations to make explicit that IVDs are devices under 
the FD&C Act including when the manufacturer of the IVD is a 
laboratory. This amendment reflects that the device definition in the 
FD&C Act does not differentiate between entities manufacturing the 
device. In connection with amending the regulation, FDA is phasing out 
its general enforcement discretion approach for LDTs so that IVDs 
manufactured by a laboratory will generally fall under the same 
enforcement approach as other IVDs (i.e., FDA's expectations for 
compliance will generally be the same). This phaseout policy includes 
enforcement discretion policies for specific categories of IVDs 
manufactured by a laboratory, including currently marketed IVDs offered 
as LDTs \1\ and LDTs for unmet needs. For purposes of this document, we 
use ``manufacture'' and related terms as a shorthand for the various 
activities that constitute manufacturing as described in FDA 
regulations (e.g., design, preparation, propagation, assembly, and 
processing).
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    \1\ As discussed in section V.A.1, FDA uses the phrase ``IVDs 
offered as LDTs'' throughout this preamble to refer to IVDs that are 
manufactured and offered as LDTs by laboratories that are certified 
under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) 
and that meet the regulatory requirements under CLIA to perform high 
complexity testing, and used within such laboratories, even if those 
IVDs do not fall within FDA's traditional understanding of an LDT 
because they are not designed, manufactured, and used within a 
single laboratory.
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    In 1976, the Medical Device Amendments of 1976 (the MDA) amended 
the FD&C Act to create a comprehensive system for the regulation of 
devices intended for human use. In implementing the MDA, FDA has 
exercised enforcement discretion such that it generally has not 
enforced applicable requirements with respect to most LDTs. Enforcement 
discretion for LDTs developed as a matter of practice. However, the 
risks associated with LDTs are much greater today than they were at the 
time of enactment of the MDA. As discussed more fully in the notice of 
proposed rulemaking (NPRM) (88 FR 68006, October 3, 2023) and this 
preamble, today's LDTs are, among other things, used more widely, by a 
more diverse population, with an increasing reliance on high-tech 
instrumentation and software, and more frequently for the purpose of 
guiding critical healthcare decisions. In this regard, today's LDTs are 
similar to other IVDs that have not come within FDA's general 
enforcement discretion approach.
    Given these changes, and for the additional reasons discussed in 
the NPRM and this preamble, FDA is phasing out the general enforcement 
discretion approach for LDTs. By phasing out this approach, FDA intends 
to better protect the public health by helping to assure the safety and 
effectiveness of IVDs offered as LDTs, while also accounting for other 
important public health considerations such as patient access and 
reliance.

B. Summary of Select Provisions of the Final Rule

    FDA is amending the definition of ``in vitro diagnostic products'' 
in its regulations to state that IVDs are devices

[[Page 37287]]

under the FD&C Act ``including when the manufacturer of these products 
is a laboratory.''
    In conjunction with this amendment, FDA is phasing out the general 
enforcement discretion approach for LDTs. As discussed further in this 
preamble, however, FDA is adopting targeted enforcement discretion 
policies for several categories of IVDs manufactured by a laboratory in 
certain circumstances. As with any enforcement discretion policy, FDA 
may update any of these enforcement discretion policies as 
circumstances warrant or if the circumstances that inform these 
policies change, consistent with FDA's good guidance practices (21 
U.S.C. 371(h), Sec.  10.115 (21 CFR 10.115)).
    Additional details regarding the phaseout policy are discussed 
further in section V of this preamble.

C. Legal Authority

    FDA is issuing this rule under the Agency's general rulemaking 
authorities and statutory authorities relating to devices. These 
authorities include sections 201(h)(1), 301, 501, 502, 510, 513, 514, 
515, 518, 519, 520, 701, 702, 704, and 801 of the FD&C Act (21 U.S.C. 
321(h)(1), 331, 351, 352, 360, 360c, 360d, 360e, 360h, 360i, 360j, 371, 
372, 374, and 381) and section 351 of the Public Health Service Act 
(PHS Act) (42 U.S.C. 262).

D. Costs and Benefits

    We quantify benefits to patients from averted health losses due to 
problematic IVDs offered as LDTs. We focus mainly on certain broad 
disease categories associated with the majority of misdiagnosis-related 
harms in the United States. Additional benefits include averted non-
health losses from reduced spending on problematic IVDs offered as LDTs 
and unquantified reduction in costs from lawsuits. We quantify costs to 
affected laboratories for complying with statutory and regulatory 
requirements. Additional costs include costs to FDA, which we include 
in our estimates. We estimate that the annualized benefits over 20 
years range from $0.99 billion to $11.1 billion at a 7 percent discount 
rate, with a primary estimate of $3.51 billion, and from $1.24 billion 
to $13.62 billion at a 3 percent discount rate, with a primary estimate 
of $4.34 billion. The annualized costs range from $566 million to $3.56 
billion at a 7 percent discount rate, with a primary estimate of $1.29 
billion, and from $603 million to $3.79 billion at a 3 percent discount 
rate, with a primary estimate of $1.37 billion.

II. Table of Abbreviations/Commonly Used Acronyms in This Document

------------------------------------------------------------------------
     Abbreviation/acronym                    What it means
------------------------------------------------------------------------
3P510k Review Organization...  Third Party Review Organization
                                Accredited Under FDA's Third Party
                                Review Program
510(k).......................  Premarket Notification.
AABB.........................  Association for the Advancement of Blood
                                and Biotherapies.
ACGME........................  Accreditation Council for Graduate
                                Medical Education.
ACLA.........................  American Clinical Laboratory Association.
ADLT.........................  Advanced Diagnostic Laboratory Test.
ACHC.........................  Accreditation Commission for Health Care.
AMC..........................  Academic Medical Center.
AML..........................  Acute Myeloid Leukemia.
AMP..........................  Association for Molecular Pathology.
ANI..........................  Average Nucleotide Identity.
APA..........................  Administrative Procedure Act.
ASHI.........................  American Society for Histocompatibility
                                and Immunogenetics.
ASR..........................  Analyte Specific Reagent.
AST..........................  Antimicrobial Susceptibility Test.
BLA..........................  Biologics License Application.
CAP..........................  College of American Pathologists.
CAPA.........................  Corrective and Preventive Action.
CBRN.........................  Chemical, Biological, Radiological, or
                                Nuclear.
CDER.........................  Center for Drug Evaluation and Research.
CDRH.........................  Center for Devices and Radiological
                                Health.
CDC..........................  Centers for Disease Control and
                                Prevention.
CDx..........................  Companion Diagnostic.
CFR..........................  Code of Federal Regulations.
CGMP.........................  Current Good Manufacturing Practice.
CGT..........................  Cell and Gene Therapy.
CLIA.........................  Clinical Laboratory Improvement
                                Amendments of 1988.
CLIAC........................  Clinical Laboratory Improvement Advisory
                                Committee.
CLSI.........................  Clinical and Laboratory Standards
                                Institute.
CMS..........................  Centers for Medicare & Medicaid Services.
COLA.........................  Commission on Office Laboratory
                                Accreditation.
CRO..........................  Clinical Research Organization.
Cures Act....................  21st Century Cures Act.
DNA..........................  Deoxyribonucleic Acid.
DoD..........................  Department of Defense.
EGFR.........................  Epidermal Growth Factor Receptor.
EMR..........................  Electronic Medical Record.
EO...........................  Executive Order.
EUA..........................  Emergency Use Authorization.
EUCAST.......................  European Committee on Antimicrobial
                                Susceptibility Testing.
FACT.........................  Foundation for the Accreditation of
                                Cellular Therapy.
FCC..........................  Federal Communications Commission.
FDA..........................  Food and Drug Administration.
FDAAA........................  Food and Drug Administration Amendments
                                Act.
FDAMA........................  Food and Drug Administration
                                Modernization Act.
FDA-ARGOS....................  FDA dAtabase for Reference Grade
                                MicrObial Sequences.
FD&C Act.....................  Federal Food, Drug, and Cosmetic Act.

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FRIA.........................  Final Regulatory Impact Analysis.
GAO..........................  Government Accountability Office.
HCFA.........................  Health Care Financing Administration.
HCT/Ps.......................  Human Cells, Tissues, and Cellular and
                                Tissue-Based Products.
HDE..........................  Humanitarian Device Exemption.
HHS..........................  Department of Health & Human Services.
HIV..........................  Human Immunodeficiency Virus.
HLA..........................  Human Leukocyte Antigen.
HUD..........................  Humanitarian Use Device.
ICCS.........................  International Clinical Cytometry Society.
IDE..........................  Investigational Device Exemption.
IND..........................  Investigational New Drug Application.
ISO..........................  International Organization for
                                Standardization.
IVD..........................  In Vitro Diagnostic Product.
IVDR.........................  In Vitro Diagnostic Medical Device
                                Regulation.
LDT..........................  Laboratory Developed Test.
LGBTQIA+.....................  Lesbian, Gay, Bisexual, Transgender,
                                Queer, Intersex, and Asexual.
LoQ..........................  Limit of Quantitation.
MAF..........................  Master File.
MDA..........................  Medical Device Amendments of 1976.
MDAC.........................  Medical Devices Advisory Committee.
MDR..........................  Medical Device Report.
MDUFA........................  Medical Device User Fee Amendments.
MolDx........................  Molecular Diagnostic Services.
NCBI.........................  National Center for Biotechnology
                                Information.
NDA..........................  New Drug Application.
NGS..........................  Next Generation Sequencing.
NIFLA........................  National Institute of Family and Life
                                Advocates.
NIH..........................  National Institutes of Health.
NIPS.........................  Non-Invasive Prenatal Screening.
NLRB.........................  National Labor Relations Board.
NMDP.........................  National Marrow Donor Program.
NOTA.........................  National Organ Transplant Act.
NPRM.........................  Notice of Proposed Rulemaking.
NSQAP........................  Newborn Screening Laboratory Quality
                                Assurance Program.
NYS CLEP.....................  New York State Department of Health's
                                Clinical Laboratory Evaluation Program.
OED..........................  Oxford English Dictionary.
OHT7.........................  Office of Health Technology 7.
OIRA.........................  Office of Information and Regulatory
                                Affairs.
OMB..........................  Office of Management and Budget.
OPTN.........................  Organ Procurement and Transplant Network.
OTC..........................  Over-the-Counter.
PAMA.........................  Protecting Access to Medicare Act of
                                2014.
PCCP.........................  Predetermined Change Control Plan.
PHS Act......................  Public Health Service Act.
PMA..........................  Premarket Approval Application.
PrEP.........................  Pre-Exposure Prophylaxis.
PRIA.........................  Preliminary Regulatory Impact Analysis.
QS...........................  Quality System.
QSR..........................  Quality System Regulation.
RBC..........................  Red Blood Cell.
RNA..........................  Ribonucleic Acid.
RUO..........................  Research Use Only.
SAMHSA.......................  Substance Abuse and Mental Health
                                Services Administration.
SDO..........................  Standards Development Organization.
Secretary....................  Secretary of HHS.
STI..........................  Sexually Transmitted Infection.
STIC.........................  Susceptibility Test Interpretive
                                Criteria.
TMB..........................  Tumor Mutational Burden.
UDI..........................  Unique Device Identification.
UMRA.........................  Unfunded Mandates Reform Act of 1995.
USG..........................  United States Government.
VALID Act....................  Verifying Accurate, Leading-Edge IVCT
                                Development Act of 2023.
VHA..........................  Veterans Health Administration.
------------------------------------------------------------------------

III. Background

    FDA's regulations define IVDs as reagents, instruments, and systems 
intended for use in the diagnosis of disease or other conditions, 
including a determination of the state of health, in order to cure, 
mitigate, treat, or prevent disease or its sequelae, and intended for 
use in the collection, preparation, and examination of specimens taken 
from the human body. IVDs include test systems (also referred to in 
this preamble as ``tests'') that are intended for use in the 
collection, preparation, and examination of samples taken from the 
human body, such as blood or tissue, for the purpose of detecting 
diseases or other conditions, monitoring

[[Page 37289]]

a person's overall health, identifying patients who are likely to 
benefit from specific therapies, or otherwise helping to diagnose, 
cure, mitigate, treat, or prevent disease or its sequelae. Some IVDs 
are manufactured by conventional medical device manufacturers for use 
by other entities such as laboratories, healthcare providers, or, in 
some cases, patients. Such IVDs may include ``test kits,'' containing 
packaged sets of components that are part of or comprise a test system. 
Other IVDs are manufactured by laboratories for use by the same or 
other laboratories. Such IVDs include LDTs. FDA has generally 
considered an LDT to be an IVD that is intended for clinical use and 
that is designed, manufactured, and used within a single laboratory 
that is certified under the Clinical Laboratory Improvement Amendments 
of 1988 (CLIA) and meets the regulatory requirements under CLIA to 
perform high complexity testing.\2\
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    \2\ Such laboratories may include those operating under State 
licensure programs deemed exempt from CLIA. See CMS, ``Exempt States 
Under the Clinical Laboratory Improvement Amendments'' (Ref. 1).
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    However, in implementing the MDA since 1976, FDA has exercised 
enforcement discretion such that it generally has not enforced 
applicable legal requirements with respect to most LDTs. This means 
that, for most LDTs, FDA generally has not enforced requirements 
related to registration and listing, reporting adverse events to FDA, 
current good manufacturing practices (CGMPs), or premarket review of an 
IVD by FDA prior to use of the LDT in patient care, among other 
requirements. The rationale for this approach was that, at the time of 
passage of the MDA, LDTs were mostly manufactured in small volumes by 
laboratories that served their local communities. They were typically 
intended for use in diagnosing rare diseases or for other uses to meet 
the needs of a local patient population, or were generally similar to 
well-characterized, standard IVDs (Refs. 2 and 3). They also tended to 
employ manual techniques (and did not use automation) and were 
performed by laboratory personnel with specialized expertise; to be 
used and interpreted by physicians or pathologists in a single 
institution responsible for the patient (and who were actively involved 
in patient care); and to be manufactured using components legally 
marketed for clinical use, such as general purpose reagents or 
immunohistochemical stains marketed in compliance with FDA 
requirements. Due to these and other factors, FDA exercised enforcement 
discretion such that it generally has not enforced applicable 
requirements for most LDTs.\3\
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    \3\ FDA's general enforcement discretion approach has not 
applied to LDTs in all contexts; for example, it has not applied to, 
among other LDTs, those used for declared emergencies/potential 
emergencies/material threats under section 564 of the FD&C Act (21 
U.S.C. 360bbb-3).
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    However, the LDT landscape has evolved significantly since 1976. 
Today, many LDTs increasingly rely on high-tech or complex 
instrumentation and software to generate results and clinical 
interpretations (Refs. 2 and 3). They are often used in laboratories 
outside of the patient's healthcare setting and are often run in high 
volume for large and diverse populations. Many LDTs are manufactured by 
laboratory corporations that market the IVDs nationwide, as they accept 
specimens from patients across the country and run their LDTs in very 
large volumes in a single laboratory. Today's LDTs are also more 
commonly manufactured with instruments or other components not legally 
marketed for clinical use and are more often used to inform or direct 
critical treatment decisions, to widely screen for common diseases, to 
predict personal risk of developing certain diseases, and to diagnose 
serious medical conditions such as cancer and heart disease.\4\ The 
risks associated with most LDTs today are therefore much greater than 
they were at the time FDA began implementing the MDA, and most LDTs 
today are similar to other IVDs that have not been under FDA's general 
enforcement discretion approach. In addition, FDA is concerned that 
firms are offering IVDs as ``LDTs'' even when they are not LDTs as 
defined on FDA's website, because they are not actually designed, 
manufactured, and used within a single laboratory (see, e.g., Refs. 5 
and 6).
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    \4\ See, e.g., Refs. 2-4. These observations are also informed 
by FDA's own experience, including the review of submissions and 
site visits, and staff with prior experience in the laboratory 
industry manufacturing and performing LDTs.
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    As LDTs increasingly rely on high-tech instrumentation and 
software, the potential for cybersecurity vulnerabilities is growing. 
Many LDTs are connected to Laboratory Information Management Systems 
and other IT infrastructure, making them a potential conduit for those 
looking to access information in such systems. This may include patient 
genetic information, among other things, which could have national 
security implications. Further, it has been demonstrated that hackers 
can modify medical test results (Ref. 7). Through premarket review, FDA 
works with manufacturers to ensure cybersecurity is appropriately 
considered, mitigating the potential for future problems. Through 
medical device reporting (MDR) and correction and removal reporting 
requirements, FDA helps to ensure that any problems are appropriately 
addressed. In fact, FDA has seen cybersecurity problems with certain 
instruments and issued two safety communications where laboratories may 
not have otherwise been aware that the research use only (RUO) versions 
of the instruments used as part of their LDTs had the same 
vulnerabilities (Refs. 8 and 9).
    As a result of these evolutions in the testing landscape, FDA has 
long recognized the need for a change in the Agency's general 
enforcement discretion approach for LDTs. The history of FDA's efforts 
with respect to LDTs is described more fully in the NPRM. Over the past 
few years, FDA has accumulated even more information supporting the 
need for a change, as noted in the NPRM and discussed below. In light 
of these developments, FDA is amending FDA's regulations to make 
explicit that IVDs are devices under the FD&C Act including when the 
manufacturer is a laboratory.\5\ FDA is also issuing a policy (see 
section V) under which FDA is: (1) phasing out its general enforcement 
discretion approach for LDTs so that IVDs manufactured by a laboratory 
will generally fall under the same enforcement approach as other IVDs 
and (2) adopting targeted enforcement discretion policies for specific 
categories of IVDs manufactured by a laboratory. As reflected in FDA's 
Final Regulatory Impact Analysis (FRIA), FDA estimates that the 
benefits of the phaseout policy outweigh the costs (see Ref. 10).
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    \5\ FDA is also amending the statutory citation for the device 
definition included in Sec.  809.3 (21 CFR 809.3) to reflect that it 
is now codified at section 201(h)(1) of the FD&C Act.
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A. FDA's Current Regulatory Framework

    A comprehensive system for the regulation of devices is included in 
the FD&C Act, as amended by the MDA. Section 513 of the FD&C Act (21 
U.S.C. 360c) establishes three categories (classes) of devices 
depending on the regulatory controls needed to provide reasonable 
assurance of their safety and effectiveness. The three categories of 
devices are class I (general controls), class II (special controls), 
and class III (premarket approval).
    Class I devices are those devices for which the general controls of 
the FD&C Act (controls authorized by or under section 501, 502, 510, 
516, 518, 519, or 520 (21 U.S.C. 351, 352, 360, 360f, 360h, 360i, or 
360j) or any combination of

[[Page 37290]]

such sections) are sufficient to provide reasonable assurance of safety 
and effectiveness of the device; or those devices for which 
insufficient information exists to determine that general controls are 
sufficient to provide reasonable assurance of safety and effectiveness 
or to establish special controls to provide such assurance, but because 
the devices are not purported or represented to be for a use in 
supporting or sustaining human life or for a use which is of 
substantial importance in preventing impairment of human health, and do 
not present a potential unreasonable risk of illness or injury, are to 
be regulated by general controls (section 513(a)(1)(A) of the FD&C 
Act).
    General controls include, but are not limited to, provisions that 
relate to establishment registration and device listing; premarket 
notification; prohibitions against adulteration and misbranding (e.g., 
labeling that fails to bear adequate directions for use); recordkeeping 
and reporting, including adverse event reporting and reporting of 
corrections and removals initiated to reduce a risk to health posed by 
the device or to remedy a violation of the FD&C Act caused by the 
device which may present a risk to health; investigational device 
exemption (IDE) requirements; \6\ and CGMP requirements. These controls 
apply to all devices unless an exemption applies.
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    \6\ Under section 520(g) of the FD&C Act and part 812 of FDA's 
regulations (21 CFR part 812), a clinical investigation to determine 
the safety and effectiveness of certain devices must be the subject 
of an approved IDE before such investigation may commence. If an IDE 
has been granted, a failure to comply with a requirement under which 
the device was exempted for investigational use renders the device 
adulterated (see section 501(i) of the FD&C Act).
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    Class II devices are those devices for which general controls by 
themselves are insufficient to provide reasonable assurance of safety 
and effectiveness, but for which there is sufficient information to 
establish special controls to provide such assurance, including the 
promulgation of performance standards, post-market surveillance, 
patient registries, development and dissemination of guidelines, 
recommendations, and other appropriate actions the Agency deems 
necessary to provide such assurance (section 513(a)(1)(B) of the FD&C 
Act).
    Class III devices are those devices for which insufficient 
information exists to determine that general controls and special 
controls would provide a reasonable assurance of safety and 
effectiveness, and are purported or represented for a use in supporting 
or sustaining human life or for a use which is of substantial 
importance in preventing impairment of human health, or present a 
potential unreasonable risk of illness or injury (section 513(a)(1)(C) 
of the FD&C Act).
    Under section 513(d)(1) of the FD&C Act, devices that were 
introduced or delivered for introduction into interstate commerce for 
commercial distribution before the enactment of the MDA on May 28, 1976 
(generally referred to as ``preamendments devices'') are classified 
after FDA: (1) receives a recommendation from a device classification 
panel (an FDA advisory committee); (2) publishes the panel's 
recommendation, along with a proposed regulation classifying the 
device, and provides an opportunity for interested persons to submit 
comments; and (3) publishes a final regulation classifying the device. 
A preamendments device for which a classification regulation has not 
been promulgated is known as an ``unclassified device.'' Until an 
unclassified device type has been formally classified by regulation, 
the marketing of new devices within the device type requires FDA 
premarket review through a premarket notification (510(k)) under 
section 510(k) of the FD&C Act.
    Devices that were not introduced or delivered for introduction into 
interstate commerce for commercial distribution before May 28, 1976 
(generally referred to as ``postamendments devices'') are classified 
automatically by section 513(f) of the FD&C Act into class III without 
any FDA rulemaking process. Those devices remain in class III and 
require approval of a premarket approval application (PMA), unless and 
until: (1) FDA classifies or reclassifies the device into class I or II 
under section 513(f)(2) or (3) of the FD&C Act, or (2) FDA issues an 
order finding the device to be substantially equivalent, in accordance 
with section 513(i) of the FD&C Act, to a predicate device that does 
not require premarket approval. The Agency determines whether new 
devices are substantially equivalent to predicate devices by means of 
premarket notification procedures in section 510(k) of the FD&C Act and 
part 807 of the regulations (21 CFR part 807).
    Failure to comply with applicable requirements of the FD&C Act and 
FDA regulations may render the device adulterated and misbranded under 
sections 501 and 502 of the FD&C Act and may constitute a prohibited 
act under section 301 of the FD&C Act (21 U.S.C. 331). For a further 
discussion of these regulatory measures, and specifically how they help 
to ensure device safety and effectiveness, see section III.B.1 of this 
preamble.
    IVDs, as defined in Sec.  809.3 (21 CFR 809.3), are devices 
intended for human use and are subject to the FD&C Act. They include 
class I, class II, and class III devices, as well as both preamendments 
and postamendments devices. Like other devices, IVDs are subject to 
general controls, and other applicable requirements under the FD&C Act 
and FDA's regulations. IVDs are also subject to specific labeling 
requirements in part 809 of the regulations (21 CFR part 809).
    For additional discussion of how FDA's legal authorities apply to 
LDTs, see the ``Legal Basis for the Amendment'' section (section V.B) 
of the NPRM (88 FR 68006 at 68017) and sections VI.D and VI.E of this 
preamble.

B. Need for the Rule

    This final rule is the culmination of years of study and 
deliberation by FDA and represents a significant step forward for 
public health. By phasing out the general enforcement discretion 
approach for LDTs, FDA is correcting the imbalance in its oversight 
between non-laboratory and laboratory IVD manufacturers--an imbalance 
that harms American patients. As a result of the final phaseout policy, 
the public will benefit from laboratory manufacturer compliance with 
basic FDA requirements that protect and promote public health, such as 
adverse event reporting, establishment registration and device listing, 
labeling standards, investigational use requirements and, as new IVDs 
enter the market or are significantly modified, CGMPs and premarket 
review. Compliance with these time-tested regulatory measures will put 
patients in a better position to understand and have confidence in IVDs 
regardless of where they are manufactured. FDA believes that the 
benefits of this rulemaking will become more and more pronounced over 
time, as new IVDs come on the market and as the circumstances in which 
we exercise enforcement discretion narrow correspondingly (as discussed 
in section V.B of this preamble).
    FDA has considered a wide array of input on this topic. In light of 
that input, we have adapted our thinking and adjusted the phaseout 
policy in a manner that we believe best serves the public health. The 
final phaseout policy, as set forth in section V of this preamble, 
fulfills the core goal of greater oversight of laboratory-manufactured 
IVDs while also accounting for other key public health interests, such 
as helping to maintain access to those beneficial IVDs on which 
patients currently rely and access to certain IVDs for which

[[Page 37291]]

there is little financial incentive for development. This final 
phaseout policy reflects a careful balancing of relevant factors and, 
overall, will substantially promote and protect public health, both now 
and in the future.
1. The Device Regulatory Scheme Advances Public Health, Including as 
Applied to Laboratory Manufacturers
    Since Congress first enacted the FD&C Act, over time and across a 
wide range of product areas, Congress has empowered FDA with a standard 
set of tools to manage the risks (and, as applicable, help assure the 
effectiveness) of regulated products. See 21 U.S.C. 393(b). These 
tools--such as adverse-event reporting, establishment registration and 
product listing, labeling standards, investigational controls, CGMPs, 
and premarket review--routinely appear in FDA statutory schemes because 
they effectively serve the public. See section IV for a more complete 
description of these authorities. As applied to devices, these 
regulatory measures help ensure product safety and effectiveness and 
facilitate greater information production and sharing, among other 
things.\7\ FDA anticipates that compliance with these regulatory 
measures will have equal benefit in the context of laboratory-
manufactured IVDs.\8\
---------------------------------------------------------------------------

    \7\ See, e.g., Ref. 11 (finding, for stents, that the testing 
required under U.S. device premarket review standards improves 
consumer welfare and reflects ``optimal policy in terms of trading 
off testing versus access to innovation''--while also noting that 
post-market surveillance or learning could theoretically yield the 
same benefits as pre-market review at lower cost); Ref. 12 (noting 
that one benefit of ``approval regulation'' is the collection of 
``information useful to `downstream' product users,'' such as 
physicians, who then ``exhibit higher consumption and will more 
readily switch to superior products''); Ref. 13 (``The FDA is a 
critical component to the industries' success because it (1) 
provides appropriate reviews for safety and effectiveness, and (2) 
helps provide consumers with confidence that these technologies are 
safe and effective.'').
    \8\ See, e.g., Ref. 14 (``Negative consequences of poorly 
understood or weakly applied regulatory oversight processes for 
laboratory developed tests have been vividly demonstrated . . . . 
Failure to insist on good clinical and laboratory practices, apply 
rigorous standards for the design, conduct, and analysis of 
biomedical research, and implement safeguards to address conflicts 
of interest poses threats to the integrity of biomedical research 
and exposes patients to potential harms.''); Ref. 15 (``Increasing 
regulatory responsibilities and requirements could encourage 
laboratories seeking to introduce LDTs . . . to prioritize tests 
with the greatest potential to positively affect patient care, which 
could reduce the clutter of available assays with limited 
utility.'').
---------------------------------------------------------------------------

    For example, FDA expects that laboratory compliance with MDR 
requirements will yield significant public health benefits. Today, 
clinical laboratories comply with CLIA, which means that complaints are 
investigated and monitored generally only on a laboratory-by-laboratory 
basis. That approach makes sense in light of CLIA's focus on individual 
laboratory operations. However, FDA is focused on identifying problems 
with an IVD itself--such as design or other manufacturing problems--so 
FDA looks for different types of errors and applies a different 
analysis to the MDRs it receives. Among other things, FDA aggregates 
MDR information across IVD types for tracking and trending, enabling 
the detection of issues that a single laboratory may never see. FDA has 
identified and helped resolve a wide range of IVD issues using this 
type of information (see the response to comment 165 for additional 
information). For example, using MDRs submitted by multiple 
manufacturers, FDA discovered that high dose biotin supplements were 
interfering with certain immunoassays (biotin is commonly used in the 
design of these assays), which caused inaccurate results among those 
tests. FDA's investigation of the issue--an issue that could apply 
equally to laboratory-manufactured tests--led to the redesign of 
multiple tests on the market (see also comment response 122). In order 
to maximize the value of medical device reporting, FDA's Office of 
Health Technology 7 (OHT7): Office of In Vitro Diagnostics, within the 
Office of Product Evaluation and Quality in FDA's Center for Devices 
and Radiological Health (CDRH), employs trained staff dedicated to the 
review of MDRs for each IVD product code. These efforts help ensure 
that FDA catches and addresses potentially problematic IVDs to better 
protect the public.
    Compliance with registration and listing requirements will also 
have substantial public health value. The collection of this 
information provides FDA with the location of device establishments and 
all devices manufactured at those establishments. Knowledge of the 
location where devices are manufactured allows for effective planning, 
coordinating, and scheduling of inspections, ensuring that FDA has 
visibility into the operations and practices at different manufacturing 
facilities. Through inspections, FDA has been able to determine when 
manufacturers have deficient processes, such as failure to investigate 
complaints and adverse events (which can signal larger problems, as 
just described). Although CLIA inspections occur for laboratories, such 
inspections do not have the same focus on design issues, for example, 
such as design changes that fundamentally alter the IVD's safety or 
effectiveness and present novel risks to patients. In addition, 
compliance with listing requirements will give FDA better information 
about the universe of IVDs on the market. With respect to the biotin 
interference issue discussed earlier, for example, FDA's investigation 
led to the redesign of affected tests in FDA's listing database, but 
FDA did not have insight into laboratory developed tests on the market 
that might have the same issue because they were not in the database. 
It is possible that laboratories today are still manufacturing and 
offering tests with inaccurate results due to biotin interference. With 
greater listing information, FDA can better protect the public through 
more comprehensive remediation efforts, among other things. FDA's 
publicly accessible registration and listing database also gives the 
public greater knowledge of IVD manufacturers and the range of IVDs on 
the market, which will benefit patients and providers who seek to 
better understand the different testing options that are available and 
the source and location of those testing options. Right now, as noted 
in the FRIA, there is no reliable inventory of IVDs on the market. More 
comprehensive information will do a great service to the public and 
improve patient care.
    Laboratory compliance with FDA labeling requirements will also 
materially advance public health, because it will provide for the 
availability of a consistent set of information critical to 
understanding the IVD, whether the IVD is manufactured by a laboratory 
or another manufacturer. The labeling requirements in Sec.  809.10 (21 
CFR 809.10) require IVD manufacturers to disclose basic facts about an 
IVD that can inform a doctor or patient's selection decisions, such as 
the intended use, limitations, and performance characteristics of the 
test. Today, ordering physicians do not necessarily have access to this 
standardized set of information for IVDs offered as LDTs, and therefore 
may lack the information needed to understand the use and performance 
of tests for their intended uses, make decisions in the context of an 
individual patient's needs, and pass on relevant information to their 
patients. Laboratory compliance with labeling requirements will mean 
that laboratories both compile and provide access to this type of 
information, which will facilitate knowledge transfer and, 
consequently, more informed healthcare decisions. Labeling also 
provides a frame of

[[Page 37292]]

reference for evaluating a manufacturer's promotional claims, helping 
FDA determine, for example, whether manufacturers may be misleading the 
public about the safety or effectiveness of their IVDs. Based on the 
various lawsuits cited in the NPRM (88 FR 68006 at 68012), FDA is aware 
that such promotion may be taking place and should be addressed.
    FDA is also aware that, today, laboratories are conducting IVD 
clinical investigations without complying with FDA requirements, 
including the requirement to submit an IDE application for FDA review 
before beginning studies involving ``significant risk'' IVDs. When this 
occurs, subjects may be enrolled in studies that lack key human subject 
protections. Among other things, such investigations may lack an 
appropriate evaluation of whether, for example, the informed consent 
documents that are provided to potential subjects contain adequate 
information about the reasonably foreseeable risks or potential 
benefits of participation in the study. Such investigations of 
significant risk IVDs may also lack review by FDA to evaluate whether 
there are sufficient data to justify use of a significant risk IVD in 
the proposed study population. As explained in an FDA memorandum to 
file that was part of the record for this rulemaking, FDA is aware of 
circumstances in which laboratories have failed to conduct appropriate 
analytical validation studies to support the use of tests in clinical 
investigations (Ref. 16). In these instances, in the absence of FDA 
review of these investigations, subjects may have been enrolled in 
studies that exposed them to safety risks with little potential for 
benefit or for generating useful information.
    Laboratory compliance with CGMP requirements will benefit the 
public as well. The Quality System Regulation (QSR) requires 
manufacturers to establish procedures for the consistent, quality 
manufacturing of devices. FDA recently issued comprehensive amendments 
to harmonize the QSR with international quality management system 
requirements (89 FR 7496, February 2, 2024). Under FDA's quality system 
(QS) requirements, design controls are a key area of focus, and an area 
that is distinct from CLIA (see the response to comment 188 for further 
information). Design controls require manufacturers to have procedures 
for generating IVD specifications, making sure their IVDs actually meet 
those specifications, and confirming that those specifications conform 
with user needs and intended use(s). By establishing and following a 
set system of documentation, manufacturers approach device design and 
modifications systemically, ensuring that the original design and any 
changes have been properly evaluated and do not have unintended 
consequences. In 1990, Congress specifically granted FDA authority to 
issue design control requirements after the Agency found that 44 
percent of the quality problems that had led to voluntary recall 
actions between 1983 and 1989 were due to design errors or 
deficiencies, and the Agency promulgated corresponding QS regulations 
in 1996 (61 FR 52602, October 7, 1996). Design controls play such a key 
role because, as FDA explained when it issued those regulations, 
``[t]he intrinsic quality of devices, including their safety and 
effectiveness, is established during the design phase'' (61 FR 52602 at 
52615). Other QS requirements help ensure effective and appropriate 
design, such as acceptance activities, corrective and preventive 
actions, and records requirements. Although FDA recognizes that 
compliance with the QS requirements is associated with relatively 
higher costs for laboratories, and has taken that fact into account in 
crafting the phaseout policy, FDA believes laboratory compliance with 
the requirements generally will advance public health.
    Finally, premarket review is one of FDA's most important tools for 
protecting and promoting public health. Through premarket review, the 
Agency evaluates the scientific information supporting the analytical 
validity, clinical validity, and safety of high- and moderate-risk 
IVDs, which helps ensure the IVD's safety and effectiveness before it 
reaches a patient. In FDA's experience, premarket review serves an 
important gatekeeping function regardless of whether an IVD is 
manufactured by a laboratory or another manufacturer. For example, FDA 
has received submissions for IVDs offered as LDTs showing that 
laboratories do not always properly validate tests or have sound 
clinical data to support a test's intended use (Ref. 16). If marketed 
as originally presented to FDA, many of these tests could have led to 
missed diagnoses or misdiagnoses, improper patient management 
decisions, or missed opportunities for beneficial treatment. Through 
premarket review, FDA works with applicants to obtain adequate data, 
determine whether a device works as intended, and refine labeling to 
reflect the intended use and limitations of an IVD. This process 
motivates the development of robust scientific data on safety and 
effectiveness \9\ and gives patients confidence that an independent, 
expert third party has determined that patients can rely on these IVDs. 
FDA has recognized circumstances in the final phaseout policy in which 
the benefits of laboratory compliance with premarket review 
requirements are outweighed by other public-health considerations. The 
Agency will exercise enforcement discretion in those circumstances, as 
described below. Apart from these circumstances, FDA expects that 
laboratory compliance with premarket review requirements will have a 
significant positive impact on public health.
---------------------------------------------------------------------------

    \9\ See Ref. 17.
---------------------------------------------------------------------------

2. The Oversight Approach Set Forth in This Preamble Will Advance 
Public Health
    Those who object to this rulemaking appear to argue that the IVDs 
manufactured by laboratories are so fundamentally different from, or 
better than, other IVDs that these IVDs should not fall under the 
oversight scheme outlined above. But these commenters are not able to 
point to differences that logically sustain that position. Many 
laboratory-manufactured tests use the same materials and technology, 
are based on the same scientific principles, are intended for the same 
or similar purposes, are developed by those with similar expertise, 
require the same level of training to perform, and are marketed for the 
same patients as tests from other manufacturers. Although some 
activities of these laboratories are also subject to CLIA, CLIA is not 
a substitute for FDA oversight, as detailed throughout this preamble 
and as the Centers for Medicare & Medicaid Services (CMS) has 
explained.
    Furthermore, a review of the evidence does not bear out the 
suggestion that laboratory-manufactured IVDs have higher quality or 
perform better than other IVDs. FDA's memorandum to file describing 
submissions for IVDs offered as LDTs detailed the many defects FDA has 
seen with laboratory validation, among other things, and described the 
submissions as raising ``significant concerns'' in some cases (Ref. 
16). During the COVID-19 emergency, FDA's conversations with laboratory 
manufacturers revealed that many were unfamiliar with what constitutes 
appropriate analytical and clinical validation for an IVD generally 
(see comment response 37 and Ref. 18). FDA's experience is corroborated 
by new information in the record from New York State. New York State 
submitted

[[Page 37293]]

data indicating that more than half of original applications from 
laboratories could not be approved by the New York State Department of 
Health Clinical Laboratory Evaluation Program (NYS CLEP) based on 
deficiencies such as ``design flaws, inadequate validation data, and 
process problems that call into question the reliability of the 
results'' (Ref. 19). And in one of the only true head-to-head 
comparisons between IVDs offered as LDTs and the parallel FDA-
authorized IVD,\10\ the IVDs offered as LDTs were less accurate than 
the FDA-authorized IVD (Ref. 20). Although some commenters suggested 
that a reanalysis of that data supports a different conclusion, even 
under the reanalysis, the laboratory tests had worse performance, with 
only 8 of 19 laboratories correctly reporting all variants (compared to 
7 in the original analysis). For additional information about the 
analysis and reanalysis, see comment responses 34 and 38.\11\
---------------------------------------------------------------------------

    \10\ For purposes of this preamble, ``FDA-authorized'' refers to 
FDA permitting the marketing of a device via the premarket approval, 
510(k), De Novo classification, Biologics License Application (BLA), 
or Humanitarian Device Exemption (HDE) pathway and to devices that 
are exempt from premarket notification. This term does not include 
devices authorized for emergency use under section 564 of the FD&C 
Act.
    \11\ For additional discussion of evidence relevant to IVDs 
offered as LDTs, see section III.B.2 of the NPRM (88 FR 68006 at 
68010-12).
---------------------------------------------------------------------------

    In short, based on the information before us, we do not believe 
that the general enforcement discretion approach for LDTs should 
continue. Today, IVDs offered as LDTs do not have appropriate 
assurances of safety and effectiveness. At least one survey suggests 
that the public agrees.\12\ Therefore, FDA is phasing out the general 
enforcement discretion approach for LDTs, as explained in more detail 
in section V.
---------------------------------------------------------------------------

    \12\ Ref. 21 (``When presented with information on the 
differences between FDA regulation and CMS oversight, most 
participants supported FDA having oversight over all diagnostic 
tests.'').
---------------------------------------------------------------------------

    However, FDA also recognizes the effect that its longstanding 
enforcement discretion approach has had on the market, the role that 
laboratory-manufactured tests play in modern healthcare, and the 
presence of other expert regulatory bodies. Many comments emphasized 
these considerations. FDA agrees with certain comments' concern, for 
example, that expecting compliance with full QS and premarket review 
requirements for all currently marketed IVDs offered as LDTs could lead 
to the loss of access to safe and effective IVDs on which patients 
currently rely, and we are issuing an enforcement discretion policy to 
address that issue (see section V.B.3). FDA also agrees with the 
concern that, for certain LDTs for unmet needs, expecting full 
compliance with FDA requirements could lead to loss of access to tests 
for unmet needs for which laboratories cannot recoup the costs of 
compliance; we are issuing an enforcement discretion policy to address 
that issue in circumstances in which certain risk mitigations apply 
(see section V.B.3). FDA has also incorporated enforcement discretion 
policies recognizing the regulatory role that other Federal and State 
entities play (see sections V.B.1 and 2). In these and other ways, FDA 
has crafted a tailored phaseout policy that balances the important 
public health considerations at issue in this rule.
    We anticipate that the final phaseout policy will provide 
significant benefits to the public. As indicated in the FRIA, the 
anticipated benefits significantly outweigh the anticipated costs. 
Through this Agency action, patients will have greater assurance that 
the IVDs used in their care are safe and effective, a significant step 
forward for public health. In addition, by applying the same general 
oversight approach to laboratories and non-laboratories that 
manufacture IVDs, FDA will reduce regulatory uncertainty, which will 
give stakeholders more stability, clarity, and confidence, and 
facilitate investment in the development of innovative IVDs (Ref. 22). 
FDA oversight will help to support coverage and reimbursement 
determinations for IVDs offered as LDTs, which we anticipate will make 
certain IVDs offered as LDTs for which there is a reasonable assurance 
of safety and effectiveness more affordable for patients. And with 
increased oversight, FDA will be able to help promote adequate 
representation in validation studies, and transparency regarding 
potential differential performance and unknown performance in certain 
patient populations, which will ultimately help advance health equity 
(see comment response 221 for additional information).
    FDA expects the benefits of the phaseout policy to become more and 
more pronounced over time, as new tests come on the market and as the 
circumstances in which we exercise enforcement discretion narrow 
correspondingly. Diagnostic testing is increasingly important; for 
example, as time goes on, more novel treatments will require use of a 
specialized test to identify patients likely to benefit from those 
treatments.\13\ Furthermore, IVDs offered as LDTs are a growing sector 
of the diagnostic testing market (Ref. 4). FDA anticipates that IVDs 
will continue to become more complex and play a greater role in modern 
healthcare (Ref. 3). The U.S. LDT market size is anticipated to grow 6 
percent from 2023 to 2030 due to varying factors including increased 
use in personalized medicine and rising prevalence of chronic diseases. 
(Id.) FDA is therefore taking steps to help ensure that IVDs are safe 
and effective regardless of where they are manufactured, so that both 
now and in the future, patients can have confidence about the tests 
used in their care.
---------------------------------------------------------------------------

    \13\ See, e.g., Ref. 23 (``Demand is increasing in the CDx 
market, due to the paradigm shift to precision medicine.'').
---------------------------------------------------------------------------

C. Summary of Comments on the Notice of Proposed Rulemaking

    In the Federal Register of October 3, 2023, FDA published a rule 
proposing an amendment to its regulations to make explicit that IVDs 
are devices under the FD&C Act including when the manufacturer is a 
laboratory, and proposing a policy under which FDA would phase out its 
general enforcement discretion approach for LDTs. The comment period 
for the NPRM closed on December 4, 2023. FDA received more than 6,500 
comments on the NPRM from a variety of entities including medical 
device associations, members of the medical device and pharmaceutical 
industries, medical and healthcare professional associations, hospitals 
and academic medical centers (AMCs), accreditation organizations, other 
advocacy organizations, government agencies, and individuals.
    Comments supporting FDA's proposal pointed to problems with LDTs, 
concerns about the significant impact of problematic LDTs on patients 
and the treatment decisions of healthcare providers, and the need for 
increased oversight of LDTs by FDA. Some comments also emphasized the 
importance of creating a ``level playing field'' between laboratory and 
non-laboratory manufacturers of IVDs, and described how phasing out the 
general enforcement discretion approach for LDTs would incentivize 
innovation by non-laboratory IVD manufacturers.
    Some comments raised concerns or requested clarification regarding 
the following:

 the evidence related to the safety or effectiveness of IVDs 
offered as LDTs,
 the sufficiency of regulation by CMS and other non-FDA 
entities,
 FDA's legal authority to regulate LDTs,
 the impact of the phaseout policy on access to and the pricing 
of IVDs offered as LDTs,

[[Page 37294]]

 the impact of the phaseout policy on test innovation,
 the impact of the phaseout policy on small laboratories,
 the impact of the phaseout policy on specific patient 
populations, including underrepresented and underserved populations,
 the details of the phaseout policy,
 the types of IVDs offered as LDTs for which FDA intends to 
continue the general enforcement discretion approach and generally not 
enforce some or all applicable requirements, and
 FDA's implementation of the phaseout policy and the resources 
needed for such implementation.

D. General Overview of the Final Amendment to the Definition of In 
Vitro Diagnostic Products

    FDA is amending its regulations to make explicit that IVDs are 
devices under the FD&C Act including when the manufacturer of the IVD 
is a laboratory. This amendment reflects that the device definition in 
the FD&C Act does not differentiate between entities manufacturing the 
device, and provides further clarity, including for stakeholders 
affected by the accompanying changes to FDA's general enforcement 
discretion approach for LDTs.
    FDA is also amending the statutory citation for the device 
definition included in Sec.  809.3 to reflect amendments to section 
201(h) of the FD&C Act as a result of the enactment of the Safeguarding 
Therapeutics Act (Pub. L. 116-304). For many years, the definition of 
``device'' had been codified at section 201(h) of the FD&C Act. Upon 
enactment of the Safeguarding Therapeutics Act, the definition of 
``device'' was redesignated as paragraph (h)(1) and a new definition of 
``counterfeit device'' was codified at paragraph (h)(2).
    FDA considered comments received on the NPRM, as discussed in more 
detail throughout this preamble, and has made no changes to the 
amendment.

E. General Overview of the Final Phaseout Policy

    FDA has had a general enforcement discretion approach for most 
LDTs.\14\ FDA is phasing out this general enforcement discretion 
approach so that IVDs manufactured by a laboratory will generally fall 
under the same enforcement approach as other IVDs. The phaseout is 
intended to help assure the safety and effectiveness of IVDs offered as 
LDTs, while also accounting for other important public health 
considerations such as patient access and reliance.
---------------------------------------------------------------------------

    \14\ As discussed further in section V.A.2, FDA's general 
enforcement discretion approach has not applied to certain 
categories of LDTs. For these categories of LDTs, FDA has generally 
expected applicable requirements to be met, and in the NPRM we 
proposed that this approach be maintained (88 FR 68006 at 68021). 
After considering comments received on this topic we are not 
changing that approach for these categories with the phaseout policy 
described in this preamble.
---------------------------------------------------------------------------

    Following a 4-year phaseout period, FDA will no longer have a 
general enforcement discretion approach for LDTs. The phaseout policy 
includes the following five stages for IVDs offered as LDTs (a term 
discussed further in section V.A.1):
     Stage 1: beginning 1 year after the publication date of 
this final rule, FDA will expect compliance with MDR requirements, 
correction and removal reporting requirements, and QS requirements 
under Sec.  820.198 (21 CFR 820.198) (complaint files);
     Stage 2: beginning 2 years after the publication date of 
this final rule, FDA will expect compliance with requirements not 
covered during other stages of the phaseout policy, including 
registration and listing requirements, labeling requirements, and 
investigational use requirements;
     Stage 3: beginning 3 years after the publication date of 
this final rule, FDA will expect compliance with QS requirements under 
part 820 (21 CFR part 820) (other than requirements under Sec.  820.198 
(complaint files), which are already addressed in stage 1);
     Stage 4: beginning 3\1/2\ years after the publication date 
of this final rule, FDA will expect compliance with premarket review 
requirements for high-risk IVDs offered as LDTs (IVDs that may be 
classified into class III or that are subject to licensure under 
section 351 of the Public Health Service Act), unless a premarket 
submission has been received by the beginning of this stage in which 
case FDA intends to continue to exercise enforcement discretion for the 
pendency of its review; and
     Stage 5: beginning 4 years after the publication date of 
this final rule, FDA will expect compliance with premarket review 
requirements for moderate-risk and low-risk IVDs offered as LDTs (that 
require premarket submissions), unless a premarket submission has been 
received by the beginning of this stage in which case FDA intends to 
continue to exercise enforcement discretion for the pendency of its 
review.
    The phaseout policy includes targeted enforcement discretion 
policies for certain categories of IVDs manufactured by a laboratory, 
as explained in more detail in sections V.B. and V.C. For example, as 
proposed in the NPRM, FDA generally does not intend to enforce 
requirements under the FD&C Act and FDA's regulations for ``1976-Type 
LDTs'' (as described in section V.B.1); Human Leukocyte Antigen (HLA) 
tests that are designed, manufactured, and used within a single 
laboratory certified under CLIA that meets the requirements to perform 
high-complexity histocompatibility testing when used in connection with 
organ, stem cell, and tissue transplantation to perform HLA allele 
typing, for HLA antibody screening and monitoring, or for conducting 
real and ``virtual'' HLA crossmatch tests; and tests intended solely 
for forensic (law enforcement) purposes (88 FR 68006 at 68022).
    In addition, FDA considered comments received on the proposed 
phaseout policy and, based in part on those comments, made various 
changes to the phaseout policy, which include the addition of the 
following enforcement discretion policies:
     FDA intends to exercise enforcement discretion and 
generally not enforce requirements for LDTs manufactured and performed 
within the Veterans Health Administration (VHA) or the Department of 
Defense (DoD);
     FDA intends to exercise enforcement discretion and 
generally not enforce premarket review requirements for LDTs approved 
by NYS CLEP; \15\
---------------------------------------------------------------------------

    \15\ For purposes of this preamble, FDA uses the phrase ``LDTs 
approved by NYS CLEP'' to refer to LDTs that are approved, 
conditionally approved, or within an approved exemption from full 
technical documentation, under NYS CLEP. These three categories of 
LDTs are discussed further below in section V.B.2. Other LDTs, 
including ``LDTs used in Clinical Trials'' and ``Tests Not Subject 
to Evaluation'' which are described on NYS CLEP's website (Ref. 24), 
are not considered ``LDTs approved by NYS CLEP'' and are not within 
the enforcement discretion policy with respect to premarket review 
requirements described in section V.B.2. For additional discussion 
of the NYS CLEP premarket review program, see section V.B.2.
---------------------------------------------------------------------------

     FDA intends to exercise enforcement discretion and 
generally not enforce premarket review requirements and QS requirements 
(except for requirements under part 820, subpart M 
(Records))16 17 for LDTs manufactured and performed by a

[[Page 37295]]

laboratory integrated within a healthcare system to meet an unmet need 
of patients receiving care within the same healthcare system;
---------------------------------------------------------------------------

    \16\ When the final rule to amend part 820 takes effect in 
February 2026, the comparable requirements can be found in 
International Organization for Standardization (ISO) 13485 subclause 
4.2 as modified by part 820.
    \17\ FDA recognizes that part 820, subpart M (Records) includes 
cross-references to Sec. Sec.  820.20, 820.22, 820.40, and 820.50 
(21 CFR 820.20, 820.22, 820.40, and 820.50). For the categories of 
IVDs discussed in section V.B.3 of this preamble, FDA generally 
expects compliance with requirements under subpart M but not 
Sec. Sec.  820.20, 820.22, 820.40, and 820.50, or comparable 
provisions of ISO 13485 in accordance with the amendments to part 
820 once that rule takes effect in February 2026.
---------------------------------------------------------------------------

     FDA intends to exercise enforcement discretion and 
generally not enforce premarket review and QS requirements (except for 
requirements under part 820, subpart M (Records)) for currently 
marketed IVDs offered as LDTs that were first marketed prior to the 
date of issuance of this rule and that are not modified, or that are 
modified in certain limited ways as described in section V.B.3; and
     FDA intends to exercise enforcement discretion and 
generally not enforce premarket review and QS requirements (except for 
requirements under part 820, subpart M (Records)) for non-molecular 
antisera LDTs for rare red blood cell (RBC) antigens where such tests 
are manufactured and performed in blood establishments, including 
transfusion services and immunohematology laboratories and where there 
is no alternative available to meet the patient's need for a compatible 
blood transfusion.
    These enforcement policies do not apply to any IVDs identified in 
section V.A.2 as falling outside the scope of the phaseout policy or as 
discussed in section V.B.

IV. Legal Authority

    FDA is issuing this final rule under the Agency's general 
rulemaking authorities and statutory authorities relating to devices. 
These authorities include sections 201(h)(1), 301, 501, 502, 510, 513, 
514, 515, 518, 519, 520, 701, 702, 704, and 801 of the FD&C Act and 
section 351 of the PHS Act. In particular:
     Under section 201(h)(1) of the FD&C Act, a device is 
defined as ``an instrument, apparatus, implement, machine, contrivance, 
implant, in vitro reagent, or other similar or related article, 
including any component, part, or accessory, which is (A) recognized in 
the official National Formulary, or the United States Pharmacopeia, or 
any supplement to them, (B) intended for use in the diagnosis of 
disease or other conditions, or in the cure, mitigation, treatment, or 
prevention of disease, in man or other animals, or (C) intended to 
affect the structure or any function of the body of man or other 
animals, and which does not achieve its primary intended purposes 
through chemical action within or on the body of man or other animals 
and which is not dependent upon being metabolized for the achievement 
of its primary intended purposes.''
     Section 701(a) of the FD&C Act authorizes FDA to issue 
regulations for the efficient enforcement of the FD&C Act.
    For additional descriptions of some of the authorities referenced 
above, see section III.A of this preamble. For additional discussion of 
how these legal authorities apply to LDTs, see the ``Legal Basis for 
the Amendment'' section (section V.B) of the NPRM (88 FR 68006 at 
68017) and sections VI.D and VI.E of this preamble.

V. Phaseout Policy

    Based on the considerations set forth in the NPRM and this 
preamble, including the public comments discussed in section VI.F 
below, FDA is phasing out the general enforcement discretion approach 
for LDTs in stages, as described in more detail below. FDA's intent is 
that following a 4-year phaseout period, IVDs offered as LDTs generally 
will be expected to meet applicable requirements, with several 
enforcement discretion policies for certain categories of IVDs 
manufactured by a laboratory as discussed further below.
    We note that these policies may not be the only enforcement 
discretion policies applicable to these IVDs, and other enforcement 
discretion policies not addressed in this phaseout policy may apply to 
certain IVDs. As discussed in the NPRM, FDA has adopted and intends to 
continue adopting enforcement discretion policies for certain types of 
IVDs in certain circumstances, as appropriate (88 FR 68006 at 68021). 
For example, FDA issued final guidance documents with enforcement 
discretion policies for certain COVID-19 and mpox tests at the 
beginning of each declared emergency and, concurrent with this final 
rule, is issuing a draft guidance document with an enforcement policy 
for certain IVDs for immediate response to a chemical, biological, 
radiological, or nuclear (CBRN) agent in the absence of a declaration 
under section 564 of the FD&C Act (21 U.S.C. 360bbb-3).
    Although FDA is phasing out its current general enforcement 
discretion approach over a period of years, the phaseout policy does 
not in any way alter the fact that it is illegal to offer IVDs without 
complying with applicable requirements. Regardless of the phaseout 
timeline and enforcement discretion policies for certain IVDs discussed 
below, FDA retains discretion to pursue enforcement action for 
violations of the FD&C Act at any time, and intends to do so when 
appropriate.
    The details of FDA's final phaseout policy, including the scope, 
subsidiary enforcement discretion policies, and stages, are set forth 
below.

A. Scope

1. IVDs Within the Scope of the Phaseout Policy
    While FDA's general enforcement discretion approach has been 
focused on LDTs,\18\ FDA has determined to apply a broader scope for 
the phaseout policy, consistent with FDA's proposal in the NPRM (88 FR 
68006 at 68021).\19\ Specifically, the phaseout policy applies to IVDs 
that are manufactured and offered as LDTs by laboratories that are 
certified under CLIA and that meet the regulatory requirements under 
CLIA to perform high complexity testing, and used within such 
laboratories,\20\ even if those IVDs do not fall within FDA's 
traditional understanding of an LDT because they are not designed, 
manufactured, and used within a single laboratory. Throughout this 
preamble, these IVDs are referred to as ``IVDs offered as LDTs.'' \21\ 
FDA is adopting this scope because it recognizes that not all 
laboratories have understood the limited nature of FDA's general 
enforcement discretion approach and have been offering IVDs based on 
the approach even when those IVDs do not fit what FDA generally 
considers to be an LDT. FDA has determined that this

[[Page 37296]]

approach will help facilitate uniform compliance going forward.
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    \18\ As discussed elsewhere in this preamble, FDA has generally 
considered the term ``laboratory developed test (LDT)'' to mean an 
IVD that is intended for clinical use and that is designed, 
manufactured, and used within a single CLIA-certified laboratory 
that meets the regulatory requirements under CLIA to perform high 
complexity testing.
    \19\ However, certain enforcement discretion policies described 
in sections V.B and V.C apply only to LDTs.
    \20\ Other laboratories would be out of compliance with CLIA 
regulations if they were developing and performing tests that are 
not FDA authorized. Such tests have never fallen within FDA's 
general enforcement discretion approach (see, e.g., Refs. 25-27).
    \21\ We note that ``IVDs offered as LDTs'' does not include IVDs 
manufactured or used outside of a laboratory, including collection 
devices. FDA's statements and actions have shown that the Agency has 
expected compliance where, for example, CLIA is inapplicable (e.g., 
manufacturing outside of a laboratory and collection devices). See, 
e.g., 61 FR 10484 (``in-house developed tests have not been actively 
regulated by the Agency'') (emphasis added); Ref. 23 (describing an 
LDT as an IVD that is ``designed, manufactured, and used within a 
single laboratory'') (emphasis added); United States v. Undetermined 
No. of Unlabeled Cases, 21 F.3d 1026 (10th Cir. 1994) (FDA 
enforcement action against a laboratory that ``purchased specimen 
containers, repackaged them into kits which included instruction 
sheets, and forwarded them along with consent forms to insurers to 
collect specimens''); Ref. 28 (compliance action regarding a blood 
lead testing system manufactured outside of a laboratory but for use 
by a laboratory); Ref. 29 (compliance action involving a laboratory 
and a sample collection kit).
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2. IVDs Outside the Scope of the Phaseout Policy
    Although FDA is adopting a broader scope for the phaseout policy, 
it does not intend to sweep in certain IVDs that were excluded from the 
general enforcement discretion approach, as reflected in compliance 
patterns, multiple public FDA actions and communications, or both. In 
particular, the general enforcement discretion approach has never 
applied to the following tests:
    a. Tests that are intended as blood donor screening or human cells, 
tissues, and cellular and tissue-based products (HCT/P) donor screening 
tests required for infectious disease testing under Sec.  610.40 (21 
CFR 610.40) and Sec.  1271.80(c) (21 CFR 1271.80(c)), respectively, or 
required for determination of blood group and Rh factors under Sec.  
640.5 (21 CFR 640.5). Under the cited regulations, a blood or HCT/P 
establishment must not use a test for the purposes listed here unless 
the test is authorized by FDA for such use. Blood and HCT/P 
establishments must register with FDA and are subject to FDA inspection 
(see parts 207, 607, 807, and 1271 (21 CFR parts 207, 607, 807, and 
1271)). FDA's general enforcement discretion approach for LDTs has 
never applied to these tests because these tests are a critical part of 
the overall process of ensuring the safety of blood and blood 
components and HCT/Ps by preventing infectious disease transmission and 
incompatible blood transfusions which can have life-threatening 
consequences (see, e.g., Refs. 30 and 31). Based on FDA experience, 
establishments have been generally complying with the requirements to 
use authorized tests under Sec. Sec.  1271.80(c), 610.40, and 640.5. 
FDA addresses comments related, in part, to this category of tests in 
sections VI.L.14 and VI.L.15.
    b. Tests intended for emergencies, potential emergencies, or 
material threats declared under section 564 of the FD&C Act. After all 
previous declarations under section 564(b), FDA has generally expected 
LDTs to comply with applicable requirements in the FD&C Act and FDA 
regulations. FDA's general enforcement discretion approach has not 
applied to these tests because of the significant risk posed by the 
disease (as signified by the unusual step of issuing a declaration) and 
because false results can have serious implications for disease 
progression and public health decision-making, in addition to the 
individual patient's care. As it has done in other areas, FDA has 
adopted (and may continue to adopt) specific enforcement discretion 
policies for such tests (see, e.g., Refs. 32 and 33). In addition, 
consistent with the Government Accountability Office (GAO)'s 2022 
recommendation that ``FDA should develop a policy for the use of 
enforcement discretion regarding unauthorized tests in future public 
health emergencies'' (Ref. 34), FDA is issuing a draft guidance 
document, concurrent with this final rule, on factors to consider in 
adopting such enforcement discretion policies. FDA has communicated its 
expectations regarding tests for emergency use in final guidance and 
elsewhere, including ``It has come to our attention'' letters posted on 
FDA's website and other public communications (see, e.g., Refs. 27, 32 
to 37). FDA addresses comments related, in part, to this category of 
tests in section VI.L.10.
    c. Direct-to-consumer tests. FDA's general enforcement discretion 
approach has not applied to tests intended for consumer use (without 
meaningful involvement by a licensed healthcare professional), given 
the greater risks to patients presented by these tests (see, e.g., 
Refs. 28 and 39 to 44). FDA's enforcement discretion approach for LDTs 
was originally premised, in part, on the participation of medical 
professionals to help determine whether a particular test was 
appropriate, counsel patients on the significance and limitations of a 
test, assist in interpreting results, assess how the results fit in the 
overall clinical picture, and consider next steps. When patients order 
tests, receive results, or make decisions (such as a decision to stop 
medication) without this expert intermediary, there is a heightened 
need for FDA oversight. FDA addresses comments related, in part, to 
this category of tests in section VI.L.1.
    For these categories of tests, FDA has generally expected 
applicable requirements to be met, and we are not changing that 
approach with the phaseout policy. FDA intends to continue to enforce 
all applicable requirements for these categories of tests. Neither the 
phaseout policy nor any subsidiary enforcement discretion policies 
described in sections V.B and V.C apply to these tests.
    Finally, as further discussed in the NPRM, tests manufactured and 
offered for use exclusively for public health surveillance are distinct 
from other tests where: (1) they are intended solely for use on 
systematically collected samples for analysis and interpretation of 
health data in connection with disease prevention and control and (2) 
test results are not reported to patients or their healthcare providers 
(88 FR 68006 at 68023). The results of these tests are generally used 
for trending on a population basis or public health outbreaks, where 
the test results are not intended for clinical decision making. FDA 
received several comments on these tests (see section VI.L.6), and for 
the reasons discussed in the NPRM (88 FR 68006 at 68023) and in our 
responses to those comments, we continue to believe that these tests 
should not be affected by the phaseout policy.\22\
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    \22\ Surveillance tests are not used for individual decision-
making. Screening tests are distinct from public health surveillance 
tests and do fall within the phaseout policy.
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B. Enforcement Discretion Policies

    FDA is phasing out the general enforcement discretion approach for 
LDTs so that IVDs manufactured by laboratories will generally fall 
under the same enforcement approach as other IVDs. For certain IVDs, 
however, FDA intends to exercise enforcement discretion and generally 
not enforce all or some applicable requirements, for the reasons 
discussed further below. Specifically, and as described further in 
section V.B.1, FDA intends to exercise enforcement discretion and 
generally not enforce all applicable requirements for 1976-Type LDTs, 
certain HLA tests, tests intended solely for forensic (law enforcement) 
purposes, and LDTs manufactured and performed within DoD or VHA. As 
described further in section V.B.2, FDA also intends to exercise 
enforcement discretion and generally not enforce premarket review 
requirements for LDTs that are approved by NYS CLEP. In addition, and 
as described further in section V.B.3, FDA intends to exercise 
enforcement discretion and generally not enforce premarket review and 
QS requirements (except for requirements under part 820, subpart M 
(Records)) for LDTs manufactured and performed by a laboratory 
integrated within a healthcare system to meet an unmet need of patients 
receiving care within the same healthcare system, currently marketed 
IVDs offered as LDTs, and certain non-molecular antisera LDTs for rare 
RBC antigens.
    As noted above, these policies do not apply to the tests described 
in section V.A.2. Moreover, in an emergent situation (see additional 
discussion of this time period below), these policies do not apply to 
tests that are: (1) intended to detect or diagnose a serious or life-
threatening disease or condition that may be attributed to a newly 
identified, previously unknown, or

[[Page 37297]]

unusual CBRN agent or agents; or a known agent or agents that results 
in a newly identified or unusual clinical presentation of such a 
disease or condition; and (2) needed for immediate response to a 
potential case or cases of such disease or condition for which there is 
no adequate, authorized, and available alternative. FDA is proposing a 
separate enforcement policy for some such tests in a concurrently 
issued draft guidance entitled ``Enforcement Policy for Certain In 
Vitro Diagnostic Devices for Immediate Public Health Response in the 
Absence of a Declaration under Section 564.'' As discussed in that 
draft guidance, that proposed enforcement policy would be for tests 
that are intended to help ensure the government's coordinated and 
effective public health response and so is limited to certain tests and 
certain laboratories, such as those that are U.S. Government (USG) 
laboratories, State or local public health laboratories, or other 
laboratories that have agreements with the USG.\23\ FDA believes that 
the proposed policy in that draft guidance (and not the enforcement 
discretion policies described in section V.B of this preamble) would be 
appropriate for such tests during the limited time period described in 
the draft guidance--specifically, during an emergent situation.\24\ We 
note that prior to an emergent situation and after an emergent 
situation has been resolved, when there is not a critical need for a 
coordinated and immediate public health response and where the 
implications of false results may not have as serious implications for 
public health decision-making, such tests may fall within the 
enforcement discretion policies described in section V.B of this 
preamble.
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    \23\ For tests that meet the description included at the 
beginning of this paragraph but that would not otherwise fall within 
the proposed policy described in the draft guidance because, for 
example, they are manufactured by entities that fall outside the 
scope of the draft guidance, FDA is not proposing an enforcement 
discretion policy in the draft guidance. For such tests, FDA 
generally will expect compliance with applicable FDA requirements in 
line with the phaseout policy during an emergent situation, and 
outside of an emergent situation, these tests could potentially fall 
within an enforcement discretion policy described in section V.B. of 
this preamble.
    \24\ Prior to finalization of that draft guidance, FDA intends 
to act consistent with the relevant policies for LDTs included in 
this final rule and will consider whether to update any policies 
herein as a result of any changes to the proposed enforcement policy 
described in the draft guidance, when finalized.
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    As with any enforcement discretion policy, FDA may update any of 
these policies as circumstances warrant or if the circumstances that 
inform these policies change, consistent with FDA's good guidance 
practices (21 U.S.C. 371(h), Sec.  10.115). Notably, these enforcement 
discretion policies do not confer lawful marketing status on any IVD 
being marketed as described in the policies. These policies do not in 
any way alter the fact that it is illegal to market an IVD that lacks 
required premarket authorization or is otherwise in violation of the 
FD&C Act, the PHS Act, or FDA regulations. These policies set forth 
FDA's general priorities and, consistent with FDA's public health 
mission, FDA intends to take action to enforce applicable requirements 
for IVDs (including IVDs described in these policies) as appropriate, 
taking into account any public health concerns as evaluated on a case-
by-case basis.\25\ For example, if FDA receives reports, or otherwise 
learns of information, that raise safety or effectiveness concerns with 
an IVD that falls within an enforcement discretion policy, FDA 
generally intends to take action with respect to requirements 
applicable to that specific IVD.
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    \25\ See Heckler v. Chaney, 470 U.S. 821, 835 (1985) (providing 
that the FD&C Act's enforcement provisions commit broad discretion 
to the Secretary to decide how and when they should be exercised).
---------------------------------------------------------------------------

1. Enforcement Discretion Policies With Respect to All FDA Requirements
    For several categories of tests, FDA intends to continue the 
general enforcement discretion approach and generally not enforce any 
applicable requirement because tests in these categories are, in our 
experience, unlikely to pose significant risks or are conducted in 
circumstances that themselves will mitigate the risks. One such 
category of tests is referred to in this preamble as ``1976-Type 
LDTs.'' Such tests have the following characteristics common among LDTs 
offered in 1976: (1) use of manual techniques (without automation) 
performed by laboratory personnel with specialized expertise; (2) use 
of components legally marketed for clinical use; and (3) design, 
manufacture, and use within a single CLIA-certified laboratory that 
meets the requirements under CLIA for high complexity testing. The 
characteristics associated with LDTs offered in 1976 resulted in the 
emergence of FDA's general enforcement discretion approach for LDTs, 
and the specific characteristics listed above provide the greatest risk 
mitigation among the characteristics that were commonly associated with 
LDTs offered in 1976 (discussed in section III). Based on changes to 
the LDT landscape since 1976, the risks associated with most modern 
LDTs are generally much greater today than they were in 1976; however, 
for tests that share the characteristics listed above, FDA has 
determined that the risks are sufficiently low such that FDA's general 
enforcement discretion approach for LDTs should continue to apply (see 
section VI.L.3 for a discussion of the comments on this topic and FDA's 
responses to those comments). These tests might include, for example, 
immunohistochemistry tests that involve no automated preparation or 
interpretation, but would not include, for example, lateral flow tests, 
as they do not generally rely on laboratory personnel expertise. This 
enforcement discretion policy does not apply to any IVDs identified in 
section V.A.2 as falling outside the scope of the phaseout policy or as 
discussed in section V.B. FDA intends to consider whether guidance 
containing additional discussion and examples of tests that may fall 
within this category would be helpful, and would issue any such 
guidance in accordance with good guidance practices (see Sec.  10.115).
    Another category of such tests is HLA tests that are designed, 
manufactured, and used within a single laboratory certified under CLIA 
that meets the requirements to perform high-complexity 
histocompatibility testing when used in connection with organ, stem 
cell, and tissue transplantation to perform HLA allele typing, for HLA 
antibody screening and monitoring, or for conducting real and 
``virtual'' HLA crossmatch tests (hereinafter ``HLA tests for 
transplantation''). Physicians must often make prompt decisions about 
transplantation based on medical judgment regarding their patient's 
condition and degree of mismatch between the donor and patient should 
an organ, stem cells, or tissue become available. Because new alleles 
are continuously identified, and the need for assessing degree of 
crossmatch is generally urgent, modifications to HLA tests for 
transplantation are often made rapidly in response to urgent 
situations. Further, these tests are often individualized within each 
medical facility; for example, they include reagents that reflect local 
HLA polymorphisms and patient demographics.
    In addition, oversight under certain Federal programs helps to 
mitigate the risks of harm from inaccurate and unreliable HLA tests for 
transplantation. For example, the National Organ Transplant Act (NOTA) 
of 1984 created the Organ Procurement and Transplant Network (OPTN). 
NOTA, as amended (42 U.S.C. 273 et seq.), and the OPTN

[[Page 37298]]

Final Rule, 42 CFR part 121, establish a comprehensive system for the 
safe and equitable allocation, distribution, and transplantation of 
donated organs. The OPTN Final Rule and OPTN bylaws and policies govern 
operation of all member transplant hospitals, organ procurement 
organizations, and histocompatibility laboratories in the United 
States. The Stem Cell Therapeutic and Research Act of 2005 (Pub. L. 
109-129), as amended, authorizes a national registry (``Be the Match 
Registry'') to support patients in need of bone marrow or umbilical 
cord blood transplants, which is operated under Federal contracts by 
the National Marrow Donor Program[supreg] (NMDP) (Ref. 45). NMDP sets 
forth minimum requirements for organizations working through the NMDP 
to facilitate stem cell transplants (Refs. 46 and 47).
    OPTN has requirements for performance of HLA typing, antibody 
screening, and crossmatching tests, and NMDP requires HLA typing for 
donors and potential recipients for stem cell transplants facilitated 
by the Be the Match Registry, as well as reporting of test results to 
NMDP (Refs. 47 and 48). Both OPTN and NMDP have procedures in place for 
identifying, investigating, and reporting discrepant tests results 
(Refs. 48 and 49).
    In addition to these safeguards designed to identify and resolve 
potentially inaccurate results, each OPTN member histocompatibility 
laboratory must, among other things, meet specified American Society 
for Histocompatibility and Immunogenetics (ASHI) and/or College of 
American Pathologists (CAP) standards as a condition of OPTN membership 
(Ref. 50). NMDP similarly requires histocompatibility laboratories used 
by U.S. transplant centers and donor centers to be accredited by CAP 
and/or ASHI (Refs. 46, 51 and 52). Both ASHI and CAP standards have 
provisions that specifically address OPTN and/or NMDP requirements for 
histocompatibility laboratories that perform tests for those programs. 
Importantly, as discussed below, FDA does not believe that a CAP or 
ASHI accreditation of a laboratory, on its own, is sufficient to 
mitigate risk and provide assurance of the safety and effectiveness for 
all IVDs offered as LDTs by the accredited laboratory. However, we 
consider the fact that OPTN and NMDP require adherence to CAP and/or 
ASHI standards, including provisions specific to OPTN and NMDP 
requirements, to be one factor that helps mitigate risk of inaccurate 
results or unreliable HLA tests for transplantation. After considering 
this factor in combination with the protections provided through the 
programs described above and the urgent circumstances in which HLA 
tests for transplantation may be modified and performed, as well as the 
comments received on our proposed approach to HLA tests for 
transplantation, FDA intends to continue the general enforcement 
discretion approach for these tests. We note that this enforcement 
discretion policy does not apply to HLA tests used for blood 
transfusion, which are highly standardized across institutions, nor 
does it apply to any IVDs identified in section V.A.2 as falling 
outside the scope of the phaseout policy or as discussed in section 
V.B.
    An additional category of such tests is tests intended solely for 
forensic (law enforcement) purposes. FDA has had an enforcement 
discretion approach for such tests for over 20 years and that approach 
applies to such tests regardless of whether they are offered as an LDT. 
See, e.g., 65 FR 18230, April 7, 2000. Tests used in the law 
enforcement setting are subject to protections and requirements 
associated with the judicial process that mitigate risk related to test 
accuracy and sample collection and that generally are not available in 
the home, workplace, insurance, and sports settings. These protections 
include the use of rules of evidence in judicial proceedings and legal 
representation of the accused (i.e., the person being tested) through 
the judicial process during which the accuracy of the test may be 
raised during the adjudication. This enforcement discretion policy does 
not apply to any IVDs identified in section V.A.2 as falling outside 
the scope of the phaseout policy or as discussed in section V.B.
    A final category of such tests is LDTs \26\ manufactured and 
performed within DoD or VHA. This policy applies only to LDTs used for 
patients that are being tested and treated within the DoD or VHA. In 
the NPRM, FDA sought comment on whether it would be appropriate to 
continue the general enforcement discretion approach, such that FDA 
generally would not enforce any applicable device requirements, ``where 
outside programs can be leveraged'' (88 FR 68006 at 68024). FDA 
mentioned programs within VHA as an example, and we received several 
comments stating that FDA should continue the general enforcement 
discretion approach for LDTs manufactured and performed by VHA, 
generally on the grounds that it would avoid ``duplicating regulatory 
oversight regimes'' and promote the efficient use of resources. Two 
comments suggested that FDA should not continue the general enforcement 
discretion approach for LDTs manufactured and performed by VHA because 
VHA's program is not in alignment with FDA regulation (though one of 
these comments supported ``leveraging'' outside programs ``in 
principle''). FDA received one comment, submitted by DoD, which stated 
that FDA should maintain an enforcement discretion approach for LDTs 
``utilized by DoD for our service members.'' Among other things, DoD 
emphasized ``the importance of LDTs to DoD's operational readiness and 
mission success,'' and referenced DoD's internal programs, including 
``the authority, oversight, and responsibilities vested in the 
Assistant Secretary of Defense (Health Affairs).''
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    \26\ Consistent with what FDA has generally considered to be an 
LDT (as discussed elsewhere in this preamble), this enforcement 
discretion policy applies only to tests that are designed, 
manufactured, and used within a single CLIA-certified laboratory 
that meets the requirements under CLIA for high complexity testing.
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    FDA recognizes that DoD and VHA have statutory mandates under 10 
U.S.C. chapter 55 and 38 U.S.C. chapter 73 to provide for the care of 
specific populations in their systems and have existing oversight and 
enforcement groups within their respective systems. Based on 
consultation with DoD and VHA, FDA understands that both departments 
use and will continue to use FDA-authorized IVDs wherever available. 
However, to meet the needs of their patient populations (i.e., military 
personnel, veterans, and their families) and fulfill their mandates, 
DoD and VHA often manufacture unique LDTs, such as tests for diseases 
or chemicals to which their patients may be exposed while serving 
abroad but which do not exist at home. DoD and VHA have developed 
expertise for evaluating these unique tests, and are taking steps in 
consultation with FDA to track all LDTs in their systems and to ensure 
the analytical and clinical validity of their LDTs, the quality 
manufacturing of their LDTs, and the central reporting of adverse 
events.\27\ Additional oversight by FDA would not be an efficient use 
of government resources in these circumstances.
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    \27\ To the extent that VHA and DoD anticipate the need for 
additional resources, FDA understands that such matters will be 
addressed through the management of those departments.
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    This enforcement discretion policy does not apply to any IVDs 
identified in section V.A.2 as falling outside the scope of the 
phaseout policy or as discussed in section V.B.

[[Page 37299]]

2. Enforcement Discretion Policies With Respect to Premarket Review 
Requirements
    FDA also generally intends to exercise enforcement discretion with 
respect to premarket review requirements for LDTs \28\ that are 
approved by NYS CLEP.\29\ For these LDTs, FDA intends to exercise 
enforcement discretion and generally not enforce premarket review 
requirements given certain risk mitigations under NYS CLEP as discussed 
further below. This policy applies only to the approved version of the 
test (FDA is aware that some laboratories may offer different versions 
of an LDT depending on whether a patient specimen comes from NYS or 
from elsewhere). This enforcement discretion policy does not apply to 
any IVDs identified in section V.A.2 as falling outside the scope of 
the phaseout policy or as discussed in section V.B.
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    \28\ Consistent with what FDA has generally considered to be an 
LDT (as discussed elsewhere in this preamble), this enforcement 
discretion policy applies only to tests that are designed, 
manufactured, and used within a single laboratory that is certified 
under CLIA and meets the regulatory requirements under CLIA to 
perform high complexity testing.
    \29\ As noted elsewhere in this preamble, for purposes of this 
preamble FDA uses the phrase ``LDTs approved by NYS CLEP'' to refer 
to LDTs that are approved, conditionally approved, or within an 
approved exemption from full technical documentation, under NYS 
CLEP. These three categories of LDTs are discussed further below in 
this section (section V.B.2). Other LDTs, including ``LDTs used in 
Clinical Trials'' and ``Tests Not Subject to Evaluation'' which are 
described on NYS CLEP's website (Ref. 24), are not considered ``LDTs 
approved by NYS CLEP'' and are not within the enforcement discretion 
policy with respect to premarket review requirements described in 
this section.
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    FDA intends to phase out the general enforcement discretion 
approach with respect to other applicable requirements for these tests 
consistent with the stages described in section V.C below. In brief, 
for these tests, FDA intends at stage 1 to phase out the general 
enforcement discretion approach with respect to MDR requirements, 
correction and removal reporting requirements, and QS requirements 
under Sec.  820.198 (complaint files) 1 year after publication of this 
final rule; at stage 2 to phase out the general enforcement discretion 
approach with respect to requirements not addressed in the other stages 
(these requirements include, e.g., registration and listing 
requirements and labeling requirements) 2 years after publication of 
this final rule; and at stage 3 to phase out the general enforcement 
discretion approach with respect to certain QS requirements (see below 
for further discussion) 3 years after publication of this final rule. 
See section V.C for further information.
    As noted above, in the NPRM, FDA sought comment on whether it would 
be appropriate to continue the general enforcement discretion approach 
with respect to LDTs that are under NYS CLEP or certain other programs 
(88 FR 68006 at 68024), and we received several comments in response 
(see discussion in section VI.F.5 of this preamble). This policy 
reflects consideration of those comments. Should experience with this 
policy indicate that changes are warranted, FDA would consider 
appropriate policy changes through guidance in accordance with good 
guidance practices (see Sec.  10.115).
    FDA believes that NYS CLEP has a program that provides for certain 
mitigations that help reduce the risk of harm from inaccurate and 
unreliable LDTs. Specifically, as discussed further below, NYS CLEP has 
a program under which high risk and moderate risk LDTs generally are 
evaluated for analytical and clinical validity. Based on the available 
information, FDA believes that generally NYS CLEP's review of 
analytical and clinical validity of LDTs helps to mitigate the risk of 
harm from inaccurate and unreliable LDTs and that, rather than 
enforcing premarket review requirements by FDA, it would be more 
efficient and effective to use our resources for other oversight 
activities regarding IVDs offered as LDTs.
    Under NYS CLEP's program, high risk LDTs require full technical 
review and approval prior to testing on specimens from NYS (Ref. 53). 
Moderate risk LDTs require full technical review but may receive 
conditional approval if the laboratory holds a permit in the 
appropriate category (Ref. 53). For classification as a moderate risk 
LDT under NYS CLEP, certain criteria must be met, e.g., the LDT uses 
well-established methodology (as defined by NYS CLEP, this includes, 
among other things, the laboratory having demonstrated competence for 
development of LDTs of the same or similar technology through multiple 
prior high-quality submissions) (Ref. 53). Upon notification of a 
moderate risk classification and conditional approval, the laboratory 
may offer the test (Ref. 53). Once the full technical review has been 
completed, the moderate risk LDT may receive approval (Ref. 53). For 
additional information, see NYS CLEP's Tiered Evaluation of Laboratory 
Developed Tests Policy (Ref. 53).
    In its enforcement discretion policy with respect to premarket 
review requirements, FDA is including not just those moderate risk LDTs 
that receive full approval by NYS CLEP but also those that receive 
conditional approval by that agency. For LDTs receiving conditional 
approval, full technical review is pending and these tests may receive 
approval by NYS CLEP once their review has been completed. FDA does not 
intend to use its resources to enforce premarket review requirements 
for these LDTs that are under review by NYS CLEP and may eventually 
receive approval. However, if an LDT has its conditional approval 
withdrawn by NYS (e.g., because approval is denied after NYS CLEP 
completes the full technical review), the LDT would no longer be under 
this enforcement discretion policy as it would neither have conditional 
approval nor full approval.\30\
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    \30\ Although not relevant to our decision-making with respect 
to our policy regarding LDTs approved by NYS CLEP, it is our 
understanding, based on consultation with NYS CLEP, that withdrawal 
of conditional approval due to approval being denied after NYS CLEP 
completes the full technical review is a rare occurrence.
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    For purposes of full technical review (as mentioned above, this 
applies to high risk and moderate risk LDTs), NYS CLEP requires the 
submission of detailed information as specified in the applicable 
checklist (either the general checklist or test-specific checklist) 
(Ref. 24). For example, under the general checklist, laboratories must 
submit, among other things, a description of the test target, data 
supporting analytical validity, data supporting clinical validity, 
sample test reports, standard operating procedures, and other 
information regarding the subject test (Ref. 54). Additionally, 
laboratories must submit a ``Risk Attestation Form for Laboratory 
Developed Tests'' containing additional information about the test, 
including a summary of intended use (including target population, 
methodology and technology, specimen types, and whether the intend use 
makes claims or direct reference to recognized diseases/conditions), 
whether the laboratory has full approval of other LDTs using the same 
test method that is used for the proposed new test, whether the 
methodology is well-established in the laboratory and generally 
accepted by the field, evidence of clinical validity, and information 
regarding the potential impact of an inaccurate test result (Ref. 55).
    NYS CLEP also has a process for laboratories to request an 
exemption from full technical documentation. As described on NYS CLEP's 
website, ``[o]nce acceptable method validation performance has been 
demonstrated by the NYS approval of a representative sampling of tests 
that utilize a

[[Page 37300]]

methodology that is common across many analytes/targets, the laboratory 
may request an exemption from the requirement to submit full method 
validation documentation for future test/assays that utilize the same 
methodology'' (Ref. 24). An application for an exemption from full 
technical documentation must include: a written request for an 
exemption that identifies ``the previously submitted tests to be used 
as the predicate submissions for the exemption''; ``a standardized 
protocol for method validation to include a description of the 
laboratory's principles and practices for assay development and initial 
validation''; and ``laboratory-specific protocols for on-going 
validation, including quality control procedures and quality assurance 
indicators'' (Ref. 24). If an exemption is approved, then a streamlined 
process applies to new LDTs with the same methodology under the 
exemption. For such new LDTs, certain information must be provided, 
including data on analytical and clinical validity, but this can be 
provided in summary form (see the Add Under Exemption Form available on 
NYS CLEP's website, Ref. 24). The summary of the validation studies 
performed must address how analytical and clinical performance 
characteristics were established (see the Add Under Exemption Form 
available on NYS CLEP's website, Ref. 24). Additionally, for such new 
LDTs, laboratories must submit sample reports for all applicable 
findings (see the Add Under Exemption Form available on NYS CLEP's 
website, Ref. 24), a ``Risk Attestation Form for Laboratory Developed 
Tests'' containing additional information about the test, including 
information regarding the potential impact of an inaccurate test result 
(Ref. 55), and certain other information if applicable (Ref. 24). 
Although specific approval of new LDTs added under an approved 
exemption is not required, it is our understanding that NYS CLEP 
reviews the information submitted for these LDTs. Further, NYS CLEP 
reserves the right to rescind an exemption at any time (Ref. 24). 
Because NYS CLEP reviews the analytical and clinical validity of LDTs 
that are added under an approved exemption and may rescind an exemption 
at any time, FDA is including such LDTs within the enforcement 
discretion policy with respect to LDTs approved by NYS CLEP.
    Based on the available information as discussed above, FDA believes 
that generally NYS CLEP's review of analytical and clinical validity of 
LDTs helps to mitigate the risk of harm from inaccurate and unreliable 
LDTs. First, NYS CLEP reviews much of the same information that FDA 
reviews in assessing analytical and clinical validity (e.g., data 
supporting analytical validity, data supporting clinical validity, 
sample test reports, and standard operating procedures). For example, 
in comments submitted to the docket for this rulemaking, NYS CLEP 
explained, ``Applications must include validation data throughout the 
reportable range, particularly at or near the limit of detection, and 
for intended specimen types, specimen stability range, clinical 
indications, and target populations (pediatric vs adult, symptomatic vs 
asymptomatic, varied ethnicities, etc.).'' Second, NYS CLEP is 
identifying many of the same types of issues that FDA has identified 
with LDTs. In their comments, NYS CLEP provided a detailed description 
of the issues they have identified when reviewing LDT applications. For 
example, NYS CLEP noted that more than half of the LDTs submitted for 
their review cannot be approved based on the original application. For 
such applications, NYS CLEP requests additional information, sometimes 
multiple times, to address a range of issues, including ``design flaws, 
inadequate validation data, and process problems that call into the 
question the reliability of the results.'' These are the same types of 
issues FDA has observed in the review of emergency use authorization 
(EUA) requests from laboratories for molecular tests for COVID-19 (see 
Ref. 18) and in other premarket submissions for LDTs (see Ref. 16). 
Additionally, FDA collaborated with NYS CLEP in the review of the first 
authorized tumor profiling test and found substantial alignment in 
FDA's and NYS CLEP's assessments of the analytical and clinical 
validity of this LDT for tumor profiling. FDA has also accredited NYS 
CLEP as a Third Party Review Organization accredited under FDA's Third 
Party review program (3P510K Review Organization) qualified to conduct 
reviews of 510(k)s for certain IVDs. Accreditation of 3P510K Review 
Organizations is based on many factors, including qualification of 
staff in the scientific disciplines relevant to the review of the 
specific device types that the 3P510K Review Organization intends to 
review (Ref. 56). In the case of IVDs, the 3P510K Review Organization 
must be qualified to assess the analytical and clinical validity of 
tests which NYS CLEP was able to demonstrate.
    Exercising enforcement discretion with respect to the premarket 
review requirements for LDTs approved by NYS CLEP will facilitate more 
efficient use of FDA resources. The resources that FDA would otherwise 
spend on premarket review of such LDTs can instead be focused on 
premarket review of other IVDs offered as LDTs and enforcement of other 
applicable requirements. FDA estimates that 12.1 percent of IVDs 
offered as LDTs would not experience new costs associated with 
submission preparation and review as a result of the enforcement 
discretion policy with respect to LDTs approved by NYS CLEP, as 
discussed in appendix A of the FRIA (Ref. 10).
    As mentioned above, FDA intends to phase out the general 
enforcement discretion approach with respect to other applicable 
requirements for LDTs approved by NYS CLEP, consistent with the stages 
described below in section V.C. Enforcement of other requirements will 
help to protect and promote the public health, e.g., by providing FDA 
and the public with important information about these tests. For 
example, compliance with registration and listing requirements will 
provide FDA and the public with basic information on these LDTs, and 
compliance with MDR requirements will provide FDA and the public with 
adverse event information about these LDTs. Further, under Sec.  
807.26(e) (21 CFR 807.26(e)) (additional device listing information), 
FDA intends to request the labeling for these LDTs, which will provide 
information on test performance and a summary of the supporting 
validation, among other things.\31\ Additionally, compliance with 
labeling requirements, including those in Sec.  809.10(b)(12), will 
help to ensure that healthcare providers and patients have information 
on test performance, among other things, and thus enable more informed 
decision making. The labeling information and adverse event reports 
will help FDA identify LDTs that raise concerns, e.g., concerns 
regarding insufficient validation or inaccurate

[[Page 37301]]

results. Compliance with the QS requirements that FDA intends to 
enforce for these LDTs will help provide for quality manufacturing of 
these tests. As discussed in section V.C, for LDTs, FDA generally will 
expect compliance at the 3-year mark with some, but not all, of the QS 
requirements (specifically, design controls, purchasing controls, 
acceptance activities, corrective and preventive actions (CAPA), and 
records requirements). This includes for LDTs approved by NYS CLEP. 
However, it is our understanding, based on consultation with NYS CLEP, 
that compliance with NYS CLEP's clinical laboratory standards (which 
exceed CLIA requirements in certain respects) and its premarket review 
requirements collectively could generally satisfy these subparts of the 
QSR except as to certain aspects of design control documentation. 
Therefore, although not relevant to our decision-making with respect to 
our policy regarding LDTs approved by NYS CLEP, FDA does not anticipate 
significant additional burden with respect to compliance with these QS 
requirements for laboratories offering LDTs approved by NYS CLEP.
---------------------------------------------------------------------------

    \31\ Devices licensed under section 351 of the PHS Act register 
and list pursuant to part 607 (21 CFR 607.1 and 807.20(e)), which 
does not contain a provision identical to 21 CFR 807.26(e). Most 
licensed IVDs are tests intended for use as blood donor screening 
tests or HCT/P donor screening tests subject to Sec.  610.40 and 
1271.80(c), respectively, or tests for determination of blood group 
and Rh factors subject to Sec.  640.5. As explained in the NPRM (88 
FR 68006 at 68021), FDA's general enforcement discretion approach 
for LDTs has never applied to such tests. Therefore, we anticipate 
that there would be a limited number of IVDs subject to the 
registration and listing requirements in part 607 that would fall 
within this policy or other policies for which FDA intends to 
request laboratories to provide labeling information in connection 
with listing the device. Should FDA receive listing information 
under part 607 for an IVD that is not licensed, we will consider if 
any additional action is appropriate, including with respect to 
information regarding IVD performance.
---------------------------------------------------------------------------

    Finally, as noted elsewhere in this preamble, regardless of this or 
any other enforcement discretion policy, FDA retains discretion to 
pursue enforcement action at any time against violative IVDs when 
appropriate. We intend to carefully monitor tests falling within this 
policy and to take action when appropriate to protect the public 
health.
3. Enforcement Discretion Policies With Respect to Premarket Review and 
Certain QS Requirements
    FDA also intends to exercise enforcement discretion and generally 
not enforce premarket review and most QS requirements for three 
categories of IVDs. These enforcement discretion policies have been 
added to the final phaseout policy after consideration of comments 
received on the NPRM.
    First, for the reasons discussed further below, FDA intends to 
exercise enforcement discretion and generally not enforce premarket 
review requirements and QS requirements (except for requirements under 
part 820, subpart M (Records)) \32\ for LDTs manufactured and performed 
by a laboratory integrated within a healthcare system to meet an unmet 
need of patients receiving care within the same healthcare system. This 
enforcement discretion policy does not apply to any IVDs identified in 
section V.A.2 as falling outside the scope of the phaseout policy or as 
discussed in section V.B.
---------------------------------------------------------------------------

    \32\ As noted in footnote 17, for the categories of IVDs 
discussed in section V.B.3, FDA generally expects compliance with 
requirements under part 820, subpart M (Records) but not Sec. Sec.  
820.20, 820.22, 820.40, and 820.50 (which are cross-referenced in 
subpart M), or comparable provisions of ISO 13485 in accordance with 
the amendments to part 820 once that rule takes effect in February 
2026.
---------------------------------------------------------------------------

    In the NPRM, FDA discussed LDTs for unmet needs, stating that a 
specific enforcement discretion policy for such LDTs was not included 
in the proposed phaseout policy because we anticipated that programs 
currently in place (e.g., the Humanitarian Use Devices (HUD)/HDE 
program and the Breakthrough Devices program) may facilitate the 
development and premarket authorization of IVDs for unmet needs.\33\ 
See 88 FR 68006 at 68026. We received over 100 comments addressing 
whether FDA should adopt a specific enforcement discretion policy for 
LDTs for unmet needs (see section VI.L.5). In particular, we received 
numerous comments that asserted that the perceived burden of premarket 
review and QS requirements would lead laboratories to stop developing 
such LDTs, leaving patients without access to the LDTs they need. For 
this reason, many comments recommended that FDA adopt an enforcement 
discretion policy for LDTs for unmet needs. Two public interest groups 
recommended against adopting a separate policy for LDTs for unmet needs 
for various reasons, including so that LDTs for patients with unmet 
needs would have the same assurances of safety and effectiveness as 
LDTs for other patients. Stakeholders further commented that the 
existing HUD/HDE and Breakthrough Devices programs are insufficient to 
mitigate the perceived burden that laboratories face with respect to 
development of LDTs for unmet needs. Specifically, commenters noted the 
numerical limit of 8,000 tests nationwide per year is too restrictive, 
the requirements for use of tests under HDE (e.g., institutional review 
board approval) dissuade physicians from using them, and the program 
has only been used for 6 IVDs despite existing for over 30 years. We 
also received information in comments indicating that laboratories 
integrated within healthcare systems, including AMCs, often make tests 
to meet the unique needs of their patients, and that patients may be 
referred to those systems because of their ability to meet patient 
needs that cannot be met elsewhere. The comments stated that this is 
often the case for patients with rare diseases for which the market is 
so small that there is no financial incentive for non-laboratory 
manufacturers to meet their needs and for which collecting data to 
validate a test is particularly challenging due to small patient 
populations (for example, rare immunohematology problems, Huntington 
disease, Prader-Willi/Angelman syndrome, and genetic tests for certain 
cancers).
---------------------------------------------------------------------------

    \33\ As described in the NPRM, FDA considered a possible 
premarket-review approach specific to LDTs for unmet needs in the 
``Discussion Paper on Laboratory Developed Tests (LDTs)'' issued by 
the Agency on January 13, 2017 (2017 Discussion Paper) (Ref. 57) (88 
FR 68006 at 68026).
---------------------------------------------------------------------------

    With respect to AMCs in particular, the Agency sought comment in 
the NPRM on whether FDA should have a different enforcement policy for 
tests manufactured by AMC laboratories. See 88 FR 68006 at 68023-24. We 
asked about various aspects of such a policy, including whether any 
continued enforcement discretion policy should take into account 
``whether an FDA cleared or approved test is available for the same 
intended use as the test manufactured by an AMC laboratory,'' and the 
public health rationale for how integration of a laboratory into 
patient care might support a different approach for tests manufactured 
by AMC laboratories. Id. at 68024. We received over 100 comments 
addressing whether FDA should adopt a specific enforcement discretion 
policy for tests offered by AMC laboratories and/or other laboratories 
integrated within healthcare systems (see section VI.F.4 of this 
preamble). Many of the comments we received addressing whether FDA 
should adopt a specific enforcement discretion policy for LDTs for 
unmet needs addressed LDTs for unmet needs manufactured by AMC 
laboratories/other laboratories integrated within healthcare systems. 
These comments were from patients, healthcare providers, AMCs, other 
healthcare systems, and various entities representing such groups.
    The majority of comments recommended that FDA adopt an enforcement 
discretion policy specific to tests manufactured by AMC laboratories 
given risk mitigations provided by the integration of the laboratory 
within the AMC that is providing care to the patient. Many comments 
stated that because other laboratories are similarly integrated within 
healthcare systems, any such enforcement discretion policy should not 
be limited to AMC laboratories. Many of these comments emphasized the 
built-in communication mechanisms between the laboratory and AMC/other 
healthcare system within which the laboratory is integrated. For 
example:
     ``[T]he close connection between the clinical pathologists 
developing the tests and the care providers at AMCs

[[Page 37302]]

further validates the alignment between diagnostic results and clinical 
presentation and helps to provide real-time feedback to the LDT 
developers on test performance and outcomes.''
     ``As hospital-based labs, we are integrated into patient 
care within the healthcare system. Treating clinicians will contact us 
directly when tests don't make sense and we adjust our testing 
strategies if needed. I personally get around 3-10 questions per week 
from clinicians as a laboratory medical director. At AMCs, while we 
implement LDTs we seek information and feedback from our clinical 
colleagues . . . . This direct connection and information flow allows 
for quality control and real-time communication if a test is not 
performing as expected.''
     ``As a CLIA director of a hospital-based lab, I 
occasionally see patients with specimens that were sent to our 
laboratory as well as an off-site, disconnected reference lab for the 
same test at nearly the same time. The results are often not 
consistent. I am able to investigate further by getting a new specimen 
and communicating with the clinician about the patients' signs, 
symptoms, and radiology results. I review our other test results, 
including some of our other LDTs. The reference labs are often not 
aware of the issues because they do not have the same line of 
communication and access to the electronic health record. They continue 
to offer the same test with no knowledge of the problem.''
     ``There is a direct connection or ability to directly 
connect between the laboratory provider/director and the treating 
clinician, and laboratory professionals have access to patient 
electronic medical records, details of which often inform the nuance of 
laboratory testing that is managed locally. This direct connection and 
information flow allows for quality control that cannot be engendered 
by an off-site, disconnected reference lab model for testing and allows 
for issues associated with any particular testing modality to be 
identified; thus it provides quality control at both the patient and 
assay level.''
    Several comments recommended against a separate enforcement 
discretion policy for tests manufactured by AMC laboratories, including 
because they argued that AMC laboratory tests have the same problems as 
other IVDs (which FDA acknowledged in the context of the COVID-19 
pandemic) and having the same enforcement policies for these tests as 
for other tests will level the playing field and promote the 
development of new and improved tests.
    As an initial matter, we understand that laboratories that develop 
LDTs for unmet needs, often laboratories integrated within a healthcare 
system, may be more likely to stop developing many of these LDTs for 
unmet needs if the proposed phaseout policy were finalized. The cost of 
compliance with premarket review and QS requirements may be deemed too 
high given the limited market for many of these LDTs for unmet needs, 
and so laboratories may not have financial incentives to develop these 
types of LDTs in particular (for example, FDA's primary estimates 
anticipate the cost per premarket submission to range from 
approximately $250,000 to $4.5 million depending on the type of 
submission required, in addition to costs associated with QS 
requirements, annual reporting requirements (for PMAs) and applicable 
user fees, as described in sections II.F.3, II.F.4 and II.H of the FRIA 
(Ref. 10)). In their comments, various laboratories noted challenges 
and limitations associated with the HDE pathway that would dissuade 
them from seeking HDE approval for their LDTs. Specifically, commenters 
noted the numerical limit of 8,000 tests nationwide per year is too 
restrictive in that it applies to the cumulative testing volume of all 
patients who would be tested with a diagnostic device annually, and the 
requirements for use of tests under HDE (e.g., administration of the 
test in a facility having oversight by an institutional review board, 
monitoring whether the national testing volume exceeds 8,000 patients 
per year, and limitations on profit, etc.) dissuade laboratories from 
developing such tests and submitting them for HDE approval. Although we 
think that the HDE pathway could help to facilitate the manufacture and 
premarket authorization of certain LDTs for unmet needs, based on these 
comments, we are concerned that many laboratories would stop 
manufacturing LDTs for unmet needs altogether, instead of seeking HDE 
approval for the LDTs, in light of the perceived financial costs of 
premarket review and QS requirements. Moreover, although we think that 
the Breakthrough Devices program would help to facilitate the premarket 
review process for LDTs for unmet needs, again based on the comments, 
we are concerned many laboratories would stop manufacturing LDTs for 
unmet needs altogether if they are expected to comply with premarket 
review and QS requirements.
    As such, and upon further consideration, FDA has determined that a 
targeted enforcement discretion policy is appropriate to help avoid 
patients being deprived of critically needed LDTs where certain risk 
mitigations exist. Specifically, FDA intends to exercise enforcement 
discretion and generally not enforce premarket review and QS 
requirements (except for requirements under part 820, subpart M 
(Records)) for LDTs manufactured and performed by a laboratory 
integrated within a healthcare system to meet an unmet need of patients 
receiving care within the same healthcare system. FDA intends to phase 
out the general enforcement discretion approach for these LDTs with 
respect to all other applicable requirements consistent with the stages 
described in section V.C. Should experience with this policy indicate 
that changes are warranted, FDA would consider appropriate policy 
changes through guidance in accordance with good guidance practices 
(see Sec.  10.115).
    This policy is limited to LDTs for patients who are receiving care 
within the healthcare system within which the laboratory offering the 
LDT is integrated. FDA does not consider this to include patients that 
are being treated at an affiliated hospital with different corporate 
ownership than the laboratory. Where the laboratory and the treating 
physicians are in the same corporate entity, there is shared 
responsibility and potential liability for patient outcomes, which 
helps mitigate risk. Moreover, the policy is limited to LDTs that are 
ordered by a healthcare practitioner on the staff or with credentials 
and privileges at a facility owned and operated by the same healthcare 
system employing the laboratory director and performing the LDT. In 
these circumstances, FDA believes that the risk mitigations present 
help to address some of the concerns raised regarding problematic IVDs 
offered as LDTs discussed in the NPRM and this preamble.
    For LDTs manufactured and performed by laboratories integrated 
within healthcare systems, FDA generally has greater confidence that 
ordering physicians will communicate any questions about LDTs or 
concerns regarding the safety and effectiveness of the LDT (e.g., when 
the patient's symptoms point to another diagnosis; when subsequent test 
results contradict the original test result) to a laboratory given the 
built-in communication mechanisms present. Moreover, FDA generally has 
greater confidence that laboratories will communicate any limitations 
of the LDT or other relevant information to the ordering physician 
given these mechanisms. We think this is particularly likely to happen 
in the context of LDTs for unmet needs, which

[[Page 37303]]

are likely to be a focus of attention and communication between 
laboratorians and providers given the uncommon nature of the issues 
presented.
    Communication from ordering physicians to laboratories may help 
laboratories to identify any problems with their LDT and make necessary 
adjustments, improvements, and other changes to the LDT. Although we 
acknowledge that any identification and subsequent modification of the 
LDT would happen postmarket, and thus would not prevent potentially 
problematic LDTs from ever being used, subsequent modification would 
benefit future patients and providers who are relying on the LDT. In 
addition, communication from laboratories to ordering physicians may 
help to underscore to the ordering physicians any limitations with the 
LDT and provide other relevant information to ordering physicians, for 
example that is specific to the unique needs of their patient, which in 
turn should help inform appropriate use and interpretation of the 
LDT.\34\
---------------------------------------------------------------------------

    \34\ See Ref. 58 (``more aggressive laboratory involvement in 
[the interpretation and reporting] step may be necessary to ensure a 
more nearly perfect hit rate on proper interpretation and action 
after reporting of laboratory results''); see also Ref. 59. Shaw and 
Miller compared hospital laboratories and hospital-independent 
reference laboratories, and highlighted the following advantages, 
among others, of the former over the latter: (1) tracking problems 
(hospital laboratories ``[c]an easily work with medical and nursing 
services to coordinate patient care efforts'' whereas hospital-
independent reference laboratories ``[c]an only track internal 
problems effectively'') and (2) physician consultation (this is 
``[r]eadily available'' for hospital laboratories whereas it is 
``[n]ot as readily available'' for hospital-independent reference 
laboratories).
---------------------------------------------------------------------------

    We believe that generally these features associated with 
integration of a laboratory within the healthcare system, along with 
enforcement of other applicable regulatory requirements as described in 
the phaseout policy (see section V.C), help to mitigate the risk of 
harm from inaccurate and unreliable LDTs. While we recognize that these 
features do not mitigate all risk and there may still be some 
uncertainty about the performance of LDTs that fall within this policy, 
we believe that these features support an enforcement discretion policy 
for premarket review and most QS requirements in the specific context 
of LDTs for unmet needs.
    This policy is limited to LDTs for unmet needs. FDA considers an 
LDT to be for an unmet need where there is no available FDA-authorized 
IVD that meets the patient's needs. This may be because: (1) there is 
no FDA-authorized IVD for the disease or condition (for example, 
because it is for a rare disease or condition); (2) there is an FDA-
authorized IVD for the disease or condition but it is not indicated for 
use on the patient, or a unique attribute needs to be added to the LDT 
to meet the patient's needs; or (3) there is an FDA-authorized IVD but 
it is not available to the patient. Examples of LDTs for unmet needs 
are:
     An LDT that is intended for cytogenetic analysis of 
certain genes and chromosomes associated with rare diseases or 
conditions, certain metals testing, viral load monitoring for some 
transplant-associated viruses, or diagnosis of certain mosquito- and 
tick-borne-diseases, where there is no FDA-authorized IVD for the 
disease/condition (rare disease or condition);
     An LDT to accommodate an alternative specimen type that is 
infrequently tested when the specimen type required for the FDA-
authorized IVD is not and cannot be made available (variation from the 
indications for use of an FDA-authorized IVD);
     An LDT for use on pediatric patients when FDA-authorized 
IVDs are indicated for use on adults only (variation from the 
indications for use of an FDA-authorized IVD);
     An LDT that generates results in a significantly shorter 
period (e.g., hours versus days) than an FDA-authorized IVD with the 
same indication where, due to the circumstances of the patient, the 
shorter time period to get results is critical for the clinical 
decision being made (unique attribute needed to be added to an FDA-
authorized IVD);
     An LDT for the same indication as an FDA-authorized IVD 
that is offered only in another healthcare system that is not 
accessible to the patient and the developing laboratory will not make 
the IVD available outside its system (FDA-authorized IVD is not 
available); and
     An LDT for an emerging pathogen for which there is no FDA-
authorized IVD and for which FDA has not identified an emergent 
situation (no FDA-authorized IVD).
    In contrast, FDA does not consider an LDT to be for an unmet need 
when there is an available FDA-authorized IVD that would sufficiently 
meet the needs of the patient. For example, potential improvements in 
performance or lower cost in comparison to an FDA-authorized IVD that 
meets the patient's needs does not fall within this policy.
    FDA intends this policy to be targeted. It is not intended to serve 
as an alternative ``pathway'' to market for LDTs for unmet needs. FDA 
intends to provide additional guidance on this enforcement discretion 
policy, which would be issued in accordance with good guidance 
practices (see Sec.  10.115).
    We note that if there is no longer an unmet need for an LDT 
because, for example, FDA authorizes an IVD that meets the needs of the 
patient, then the LDT would no longer fall within this enforcement 
discretion policy. This will encourage manufacturers, including the 
manufacturers of LDTs falling within this policy, to seek premarket 
authorization, without delaying patient access to the LDT. It also will 
provide patients and providers with greater confidence that once an IVD 
has been authorized by FDA, all similar devices, regardless of who 
makes them, should have appropriate assurance of safety and 
effectiveness because all such devices should comply with premarket 
review and QS requirements. Moreover, such a limitation helps to ensure 
that the enforcement discretion policy will ultimately target only 
those LDTs where there is insufficient financial incentive to seek 
authorization for the LDTs (in such cases, there is unlikely to ever be 
an available FDA-authorized IVD).
    Notably, this unmet needs LDT policy applies only to LDTs that are 
validated. We acknowledge that validation may vary depending on many 
factors, including the accessibility of specimens and the number of 
affected patients. FDA intends to consider whether issuing additional 
guidance regarding validation of tests, including those for rare 
diseases that takes into consideration the challenges in obtaining a 
robust number of samples for validation, would be helpful.
    In developing this policy, FDA took into consideration various 
factors that mitigate the risk that LDTs offered as described in this 
policy may not have appropriate assurance of safety and effectiveness. 
As an initial matter, the phaseout of the general enforcement 
discretion approach for all other applicable requirements will provide 
greater assurances regarding these LDTs than the Agency, healthcare 
providers, and patients currently have. Compliance with registration 
and listing requirements, for example, will provide FDA and the public 
with insight into what LDTs for unmet needs are being offered by 
laboratories integrated within healthcare systems. Moreover, compliance 
with labeling requirements, including those in Sec.  809.10(b)(12), 
will help to ensure that healthcare providers and patients have 
information on the performance of the LDT and thus will help to enable 
more informed decision making. In addition, FDA generally intends to 
request that laboratories that offer LDTs as described in this policy 
submit labeling information to FDA in

[[Page 37304]]

connection with the listing of the device as provided in Sec.  
807.26(e) (this regulation is discussed above). This labeling will 
facilitate FDA surveillance for potentially poor performing LDTs that 
should otherwise be addressed.
    Finally, as noted elsewhere in this preamble, regardless of this or 
any other enforcement discretion policy, FDA retains discretion to 
pursue enforcement action at any time against violative IVDs when 
appropriate. We intend to carefully monitor LDTs falling within this 
policy and intend to take action regarding such LDTs as appropriate 
taking into account any public health concerns as evaluated on a case-
by-case basis.
    We considered various alternative policies proposed in comments 
regarding LDTs for unmet needs and LDTs manufactured by AMC 
laboratories or laboratories integrated within other healthcare 
systems, but we believe this policy best serves FDA's public health 
mission by helping to assure the safety and effectiveness of LDTs while 
also accounting for patient access. For example, an enforcement 
discretion policy whereby FDA generally does not enforce premarket 
review and most QS requirements for any LDT manufactured by AMC 
laboratories and laboratories integrated within other healthcare 
systems would appear to be overly broad, including because it would 
encompass LDTs for which there are FDA-authorized alternatives that we 
know have appropriate assurances of safety and effectiveness. 
Similarly, an enforcement discretion policy whereby FDA generally does 
not enforce premarket review and most QS requirements for all LDTs for 
unmet needs would also appear to be overly broad, as there are not the 
same risk mitigations present for all such LDTs that would help address 
and avoid the use of problematic LDTs. We also considered several 
narrower enforcement discretion policies, such as an enforcement 
discretion policy where a premarket submission would be expected after 
an LDT is offered for use and where the LDT is offered until FDA makes 
a final decision on the LDT (see, e.g., the 2017 Discussion Paper (Ref. 
57)) or a longer phaseout policy for QS requirements. We do not think 
such policies would make sense here because many laboratories would 
likely be dissuaded from developing LDTs in this space if compliance 
with premarket review and QS requirements is routinely expected at any 
point in time due to the lack of financial incentives and perceived 
costs associated with premarket review and QS requirements.
    Second, FDA intends to exercise enforcement discretion and 
generally not enforce premarket review and QS requirements (except for 
requirements under part 820, subpart M (Records)) \35\ for currently 
marketed IVDs offered as LDTs that were first marketed prior to the 
date of issuance of this rule (hereinafter, ``currently marketed IVDs 
offered as LDTs''). FDA intends for this policy to apply to currently 
marketed IVDs offered as LDTs as long as they are not modified 
following the issuance of this final rule, or are modified but only in 
certain limited ways that are described below. This enforcement 
discretion policy does not apply to any IVDs identified in section 
V.A.2 as falling outside the scope of the phaseout policy or as 
discussed in section V.B.
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    \35\ As noted in footnote 17, for the categories of IVDs 
discussed in section V.B.3, FDA generally expects compliance with 
requirements under part 820, subpart M (Records) but not Sec. Sec.  
820.20, 820.22, 820.40, and 820.50 (which are cross-referenced in 
subpart M), or comparable provisions of ISO 13485 in accordance with 
the amendments to part 820 once that rule takes effect in February 
2026.
---------------------------------------------------------------------------

    As part of this policy, FDA intends to request submission of the 
labeling for currently marketed IVDs offered as LDTs under Sec.  
807.26(e) and to use this information, along with information obtained 
through laboratory compliance with other relevant requirements (such as 
adverse event reporting), to identify and address those currently 
marketed IVDs offered as LDTs that specifically raise concerns. We 
recognize that patients, the healthcare community, and the laboratory 
industry have likely made decisions in reliance on access to, or the 
continued manufacturing of, many currently marketed IVDs offered as 
LDTs, and that loss of beneficial currently marketed IVDs offered as 
LDTs could cause harm and undermine those reliance interests. We 
believe this policy appropriately balances the various competing 
interests at issue to best serve public health because it helps 
facilitate continued access to those IVDs offered as LDTs that are 
beneficial while incorporating targeted use of available tools to 
identify and act against currently marketed IVDs offered as LDTs that 
are problematic. As IVDs evolve, compliance with premarket review and 
QS requirements will be phased in according to the natural lifecycle of 
test development and use.
    FDA is adopting this policy after a review of the comments, which 
leads us to conclude that an expectation of compliance with premarket 
review and QS requirements for currently marketed IVDs offered as LDTs 
may be more harmful than helpful to the public because, for example, it 
will prompt many laboratories to stop offering tests even if they are 
safe and effective. One commenter stated that ``[i]f the rule is 
implemented, it is likely that we would consider no longer offer [sic] 
[IVDs offered as LDTs] due to the administrative and financial burdens 
of the regulations.'' Another commenter stated that ``the most 
prominent reason [the proposed rule should not move forward] is that 
patient care will suffer as most small laboratories will be forced to 
close because of increased cost and need to reduce their test menu.'' 
These comments corresponded to data in FDA's Preliminary Regulatory 
Impact Analysis (PRIA) suggesting a potentially high burden on 
laboratories associated with compliance for currently marketed IVDs 
offered as LDTs--a burden that could potentially cause some 
laboratories (particularly small laboratories) to close (Ref. 60). As 
reflected in section II.F of the FRIA (Ref. 10), a significant fraction 
of the estimated overall costs of compliance with applicable 
requirements under the FD&C Act and FDA's regulations is attributable 
to premarket review (where applicable) and QS requirements. 
Specifically, out of the total estimated discounted costs to industry 
of $1.17 billion, the average estimated costs of compliance with stages 
1 and 2 of the phaseout policy (as described in section V.C below) are 
approximately $9,522 per test ($74,783 per laboratory) and the average 
estimated costs of compliance with premarket review and QS requirements 
are approximately $3.02 million per test ($1.26 million per 
laboratory).
    In the NPRM and this preamble, FDA explained that relevant evidence 
points to a high degree of variability in the performance of IVDs 
offered as LDTs today, but FDA does not take the view that all 
laboratory-manufactured IVDs are problematic (see, e.g., 88 FR 68006 at 
68010-68012 and responses to comments 28, 32-33). We believe that an 
appreciable proportion of IVDs currently offered as LDTs likely help 
patients and are important to patient care (see section II.E.1 of the 
FRIA (Ref. 10)), and as noted above, we understand that patients, the 
healthcare community, and the laboratory industry have likely made 
decisions in reliance on access to, or the continued manufacturing of, 
such IVDs. The loss of such IVDs could cause harm and undermine those 
reliance interests.
    FDA is aware, for instance, that certain patients may have embarked 
on a course of treatment in reliance on regular testing to help monitor 
their treatment or condition, and the loss of that testing could pose 
serious risks and

[[Page 37305]]

complications for that patient. For example, consistent access to tests 
that are already being used to measure plazomicin to aid in the 
management of patients with complicated urinary tract infection 
receiving plazomicin therapy and tests to measure levels of 
immunosuppressants--such as cyclosporine, tacrolimus, everolimus, and 
sirolimus--in transplant patients are important for treating physicians 
to make well-informed treatment decisions for those patients. In the 
context of patients receiving tests that are not well-standardized to 
monitor their diseases or conditions, consistent access to the same 
test at the same laboratory over time is also important for treating 
physicians to make accurate diagnostic and treatment decisions. 
Examples of such tests include thyroid hormone tests that are used to 
monitor thyroid disease, adrenal function tests that are used to 
monitor adrenal disorders, and flow-cytometry-based minimal residual 
disease tests that are used to monitor patients with cancer that have 
undergone treatment to determine if they are at risk for relapse.
    FDA also recognizes that healthcare professionals may have made 
significant financial investments in reliance on access to certain 
tests (e.g., contracts for certain tests that they need for long-term 
patient monitoring, where such monitoring must continue with the same 
test because test results are compared over time and results from a 
different test are not interchangeable), and that the loss of access 
could harm their practice and, ultimately, the patients they serve. In 
addition, laboratories may have made financial investments and other 
decisions based on a past assumption about the presence of the general 
enforcement discretion approach.
    In light of these reliance considerations and, in particular, the 
risk that laboratories may stop offering safe and effective tests on 
which patients and the healthcare community currently rely, we do not 
think it is appropriate to expect compliance with premarket review and 
most QS requirements for all currently marketed IVDs offered as LDTs. 
Instead, we have determined it is in the best interest of the public 
health to expect compliance with premarket review and QS requirements 
in a more targeted fashion--i.e., for those currently marketed IVDs 
offered as LDTs that specifically raise concerns. As new IVDs come on 
the market following issuance of this rule, they will be expected to 
comply with premarket review and QS requirements--in accordance with 
the phaseout policy--gradually phasing in those requirements for the 
overall market. In the meantime, compliance with other applicable 
requirements will help enable FDA to identify and address safety and 
effectiveness problems that may arise.
    In deciding on this policy, FDA considered alternatives to address 
the concerns identified above, including the risk of market exit, such 
as: (1) extending the phaseout timeline to give more time for currently 
marketed IVDs offered as LDTs to come into compliance with premarket 
review and QS requirements and (2) expecting compliance with premarket 
review and QS requirements only for high-risk currently marketed IVDs 
offered as LDTs. However, based on FDA's economic projections, neither 
of these alternatives resolves the concern about market exit resulting 
in loss of access to beneficial IVDs on which patients and others 
currently rely because neither substantially changes the economic 
burden on laboratories. For example, under Alternative 3 in section 
II.J of the PRIA, FDA evaluated the reduction in burden of an extended 
phaseout policy, and based on the calculations there, we doubt that the 
reduction would be sufficient to prevent the outcomes described above 
(see Ref. 60). In addition, the PRIA shows that the greatest costs in 
the phaseout policy are those associated with high-risk IVDs, so a 
policy that involves compliance for currently marketed high-risk IVDs 
offered as LDTs also would not resolve the concern about market exit. 
Given this information, and given the information we received in 
comments, FDA has concluded that the best course is to adopt the policy 
for currently marketed IVDs offered as LDTs outlined above. (This 
policy is keyed to the date of this final rule, rather than the 
proposed rule, because patients and the healthcare community may have 
begun relying on IVDs during the period between publication of the 
proposed and final rule.)
    Based on FDA's understanding of the current IVD industry, we expect 
IVDs offered as LDTs to continue to advance to meet new patient needs, 
accommodate new technologies, and incorporate the latest scientific 
findings. Under this policy for currently marketed IVDs offered as 
LDTs, when such IVDs are modified in certain significant ways that 
would, under FDA requirements, generally prompt the need for premarket 
review relative to the original currently marketed IVD, FDA expects 
laboratories to comply with premarket review and QS requirements for 
that modified IVD. This policy is intended to preserve access to 
beneficial IVDs on which patients and the healthcare community 
currently rely, including versions of that IVD with minor changes. 
However, we expect compliance with premarket review and QS requirements 
once the IVD is changed in certain, more significant ways that could 
affect its basic safety and effectiveness profile. In particular, under 
this policy, FDA generally expects compliance with premarket review and 
QS requirements for currently marketed IVDs offered as LDTs when a 
laboratory's modifications (individually or in aggregate):
     change the indications for use of the IVD;
     alter the operating principle of the IVD (e.g., changes in 
critical reaction components);
     include significantly different technology in the IVD 
(e.g., addition of artificial intelligence or machine learning to the 
test algorithm, a change from targeted sequencing to whole genome 
sequencing, a change from immunoassay to mass spectrometry, or a change 
from manual to automated procedures); or
     adversely change the performance or safety specifications 
of the IVD.\36\
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    \36\ Under FDA regulations, the listed modifications to an IVD 
would generally require a new submission, such as a new 510(k), PMA, 
BLA, or De Novo, or certain types of PMA or BLA supplements. See, 
e.g., 21 CFR 601.2, 601.12, 807.81(a)(3), 814.39, and 860.200; see 
also ``Deciding When to Submit a 510(k) for a Change to an Existing 
Device'' (Ref. 61).
---------------------------------------------------------------------------

    FDA believes this approach appropriately limits the scope of this 
policy and reduces the risk for patients.
    As noted above, FDA also intends to take targeted steps to address 
currently marketed IVDs offered as LDTs that are problematic. In 
particular, we intend to use available tools to identify and act 
against currently marketed IVDs offered as LDTs that specifically raise 
concerns, such as IVDs that are potentially inaccurate or poorly 
validated. In this way, FDA can work to assure the safety and 
effectiveness of currently marketed IVDs offered as LDTs without 
creating the risk of widespread market exit. FDA has a range of tools 
to assist in this effort.
    First, FDA intends to request that laboratories offering currently 
marketed IVDs offered as LDTs submit labeling to FDA as provided in 
Sec.  807.26(e). Labeling includes IVD performance information and a 
summary of supporting validation, as applicable. This information will 
help FDA more closely monitor currently marketed IVDs offered as LDTs 
and identify those that may lack analytical validity, clinical 
validity, or safety. As part of its review of labeling, FDA also 
intends to

[[Page 37306]]

look closely at claims of superior performance and whether those claims 
are adequately substantiated.\37\ Such claims are of particular public 
health concern because, in FDA's experience, they have led to 
escalating claims from competitors that can ultimately mislead the 
public. FDA generally intends to take action where the labeling of a 
currently marketed IVD offered as an LDT is false or misleading, and/or 
the IVD offered as an LDT lacks the appropriate assurance of safety and 
effectiveness for its intended uses as a result of any such claims that 
are not adequately substantiated.
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    \37\ See, e.g., FDA, Final Guidance for Industry: Medical 
Product Communications That Are Consistent With the FDA-Required 
Labeling--Questions and Answers at 18 (June 2018) (``[P]romotional 
material is misleading'' when ``it makes a claim of superior 
effectiveness for Drug A versus Drug B based on a study that was not 
designed to establish superiority of Drug A to Drug B.''). See Ref. 
62.
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    Second, FDA intends to enforce records requirements in part 820, 
subpart M, for manufacturing activities related to a currently marketed 
IVD offered as an LDT that occur after the date of issuance of this 
final rule. Compliance with these requirements will facilitate FDA's 
review of these IVDs during inspections, enabling FDA to understand the 
validation bases and processes underlying these IVDs, and will support 
appropriate adverse event reporting (MDRs).
    Third, under the policy, FDA expects laboratories to comply with 
applicable requirements other than premarket review and most QS 
requirements, including MDR requirements, corrections and removals 
reporting requirements, registration and listing requirements, and 
labeling requirements. Compliance with these requirements will provide 
FDA with additional important information regarding currently marketed 
IVDs offered as LDTs, such as information enabling FDA to track 
adverse-event trends.
    Finally, based on our experience with other devices, we anticipate 
that laboratory manufacturers will alert us to potential problems with 
their competitors' IVDs once IVD performance information is 
transparent, which will help direct FDA's attention to problematic 
tests.
    FDA emphasizes that these tools are not a substitute for premarket 
review or full QS compliance. FDA continues to believe that premarket 
review and full QS compliance are important tools to help assure the 
safety and effectiveness of IVDs going forward. However, there are 
sufficient countervailing reasons to take a more targeted approach for 
currently marketed IVDs offered as LDTs, including the risk of market 
exit and the potentially significant reliance on currently marketed 
IVDs offered as LDTs. Thus, FDA has determined that the enforcement 
discretion policy outlined above best serves public health.
    The third category of tests for which FDA intends to exercise 
enforcement discretion and generally not enforce premarket review and 
QS requirements (except for requirements under part 820, subpart M 
(Records)) \38\ is non-molecular antisera LDTs \39\ for rare RBC 
antigens when such tests are manufactured and performed by blood 
establishments, including transfusion services and immunohematology 
laboratories \40\ and when there is no alternative IVD available to 
meet the patient's need for a compatible blood transfusion. This policy 
does not apply to molecular tests used for genotyping RBC antigens. 
This policy also does not apply to any IVDs identified in section V.A.2 
as falling outside the scope of the phaseout policy or as discussed in 
section V.B.
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    \38\ As noted in footnote 17, for the categories of IVDs 
discussed in section V.B.3, FDA generally expects compliance with 
requirements under part 820, subpart M (Records) but not Sec. Sec.  
820.20, 820.22, 820.40, and 820.50 (which are cross-referenced in 
subpart M), or comparable provisions of ISO 13485 in accordance with 
the amendments to part 820 once that rule takes effect in February 
2026.
    \39\ Consistent with what FDA has generally considered to be an 
LDT (as discussed elsewhere in this preamble), this enforcement 
discretion policy applies only to tests that are designed, 
manufactured, and used within a single CLIA-certified laboratory 
that meets the requirements under CLIA for high complexity testing.
    \40\ In our experience, establishments that perform 
compatibility tests for blood transfusion include establishments, 
such as reference laboratories, that are not integrated within a 
healthcare system. Therefore, the non-molecular antisera LDTs at 
issue may not fall within the policy described above for LDTs 
manufactured and performed by a laboratory integrated within a 
healthcare system to meet an unmet need of patients receiving care 
within the same healthcare system.
---------------------------------------------------------------------------

    Some individuals develop antibodies to certain antigens that they 
lack on their own RBCs following exposure to foreign RBC antigens 
through blood transfusion or pregnancy. These may be clinically 
significant, causing a hemolytic transfusion reaction if the patient 
receives a transfusion of RBCs that have the corresponding antigen(s). 
As of July 2023, there are currently 45 recognized blood group systems 
containing 360 RBC antigens (Ref. 63). FDA understands that there are 
occasions where licensed antisera IVDs are not available for rare RBC 
antigens but testing for such rare antigens is necessary to help ensure 
that patients receive a compatible blood transfusion \41\ and avoid 
potentially life-threatening reactions. Although FDA has also approved 
molecular tests for use in genotyping RBC antigens, there may not be an 
available, approved molecular test to use as an alternative for all 
rare antigens.
---------------------------------------------------------------------------

    \41\ Such tests are not subject to the requirements in Sec.  
640.5. As noted elsewhere in this document, FDA's general 
enforcement discretion approach for LDTs has not applied to tests 
for determination of blood group and Rh factors that are subject to 
Sec.  640.5.
---------------------------------------------------------------------------

    FDA is adopting this policy after consideration of comments that 
requested that FDA continue to exercise enforcement discretion with 
respect to antisera LDTs for rare RBC antigens and/or molecular tests 
for genotyping rare RBC antigens. This included comments pointing to 
FDA's existing 2018 final guidance (Ref. 64), which, among other 
things, recognized that blood establishments sometimes use unlicensed 
antisera tests or unapproved molecular tests for RBC antigen typing in 
circumstances where a licensed reagent for a rare antigen is not 
available.
    The non-molecular antisera LDTs within the scope of this policy 
share certain characteristics with ``1976-Type LDTs,'' as they use 
manual techniques performed by laboratory personnel with specialized 
expertise. For such LDTs, in instances where there is no available 
alternative to ensure that a patient receives a compatible transfusion, 
FDA has determined it is in the best interest of public health to adopt 
this enforcement discretion policy. However, this policy does not apply 
to molecular tests for genotyping RBC antigens. Compared to serologic 
tests, molecular RBC typing is a relatively new and complex technique 
for detection of RBC antigens. Some limitations of molecular RBC typing 
tests include that the genotype does not always correlate with the 
phenotype due to samples with rare null phenotypes, and the assay may 
not be designed to detect all rare or new variants of an antigen. As 
such, FDA has greater concern regarding risk of error with molecular 
tests for genotyping RBC antigens that do not comply with applicable 
FDA requirements.
    For LDTs offered as described in this policy, FDA expects the LDT 
to be validated. As discussed previously, we acknowledge that such 
expectations may vary depending on many factors, including the 
accessibility of specimens and the number of affected patients.
    In addition, this enforcement policy applies only to premarket 
review and QS requirements (except for

[[Page 37307]]

requirements under part 820, subpart M (Records)). FDA expects 
compliance with records requirements in part 820, subpart M, for non-
molecular antisera LDTs that fall within this policy. Compliance with 
these requirements will facilitate FDA's review of these LDTs during 
inspections and will support appropriate adverse event reporting. The 
phaseout of the general enforcement discretion approach for other 
applicable requirements will provide greater assurances regarding tests 
that fall within this policy than the Agency, healthcare providers, and 
patients currently have.
    Finally, as noted elsewhere in this preamble, regardless of this or 
any other enforcement discretion policy, FDA retains discretion to 
pursue enforcement action at any time against violative IVDs. We intend 
to carefully monitor LDTs falling within this policy and intend to take 
action regarding such LDTs as appropriate, taking into account any 
public health concerns as evaluated on a case-by-case basis.

C. Stages

    As previously discussed, FDA has determined to gradually phase out 
its current general enforcement discretion approach for LDTs so that 
IVDs manufactured by a laboratory will generally fall under the same 
enforcement approach as other IVDs. In particular, FDA has structured 
the phaseout policy to contain five key stages:
     Stage 1: beginning 1 year after the publication date of 
this final rule, FDA will expect compliance with MDR requirements, 
correction and removal reporting requirements, and QS requirements 
under Sec.  820.198 (complaint files).
     Stage 2: beginning 2 years after the publication date of 
this final rule, FDA will expect compliance with requirements not 
covered during other stages of the phaseout policy, including 
registration and listing requirements, labeling requirements, and 
investigational use requirements.
     Stage 3: beginning 3 years after the publication date of 
this final rule, FDA will expect compliance with QS requirements under 
part 820 (other than requirements under Sec.  820.198 (complaint 
files), which are already addressed in stage 1).
     Stage 4: beginning 3\1/2\ years after the publication date 
of this final rule, FDA will expect compliance with premarket review 
requirements for high-risk IVDs offered as LDTs, unless a premarket 
submission has been received by the beginning of this stage in which 
case FDA intends to continue to exercise enforcement discretion for the 
pendency of its review.
     Stage 5: beginning 4 years after the publication date of 
this final rule, FDA will expect compliance with premarket review 
requirements for moderate-risk and low-risk IVDs offered as LDTs (that 
require premarket submissions), unless a premarket submission has been 
received by the beginning of this stage in which case FDA intends to 
continue to exercise enforcement discretion for the pendency of its 
review.
    These stages, along with certain narrower enforcement discretion 
policies specific to certain stages, are discussed in further detail 
below.
    We note that FDA generally does not intend to enforce requirements 
to include certain information (e.g., registration numbers, premarket 
submission numbers) in reports or other submissions to the Agency until 
the information is addressed in a later stage of the phaseout policy.
    We received several comments on the structure, sequencing, and 
timing of the proposed phaseout policy described in the NPRM (see 
section VI.F.6 of this preamble). Some indicated that the proposed 
timing for all phases was appropriate while others recommended it be 
shortened or lengthened. Some also proposed different approaches for 
organizing or implementing the phaseout.
    FDA carefully considered these comments, and also considered the 
impact of other policies included in the final phaseout policy on the 
considerations noted in these comments. For the reasons discussed below 
and in section VI.F.6, FDA has determined that it should retain the 
general structure, sequencing, and timelines proposed in the NPRM (88 
FR 68006 at 68021) for the phaseout policy in this final rule.
    FDA encourages laboratory manufacturers to begin early and work 
toward compliance with requirements sooner than the end of the 
timeframes specified for each stage of the phaseout policy, as 
described below. FDA also intends to consider providing more targeted 
guidance and/or making additional resources available on specific 
topics, such as compliance with applicable labeling requirements, over 
the course of the phaseout period, as discussed in section VI.P.
1. Stage 1: Beginning 1 Year After the Publication Date of This Final 
Rule, FDA Will Expect Compliance With MDR Requirements, Correction and 
Removal Reporting Requirements, and QS Requirements Under Sec.  820.198 
(Complaint Files)
    As detailed elsewhere in this preamble, FDA is concerned that some 
IVDs offered as LDTs may be posing risks to patients; therefore, FDA 
seeks to obtain information about potentially harmful IVDs offered as 
LDTs as soon as feasible. In light of that objective, and after 
reviewing the comments, FDA continues to believe that 1 year is an 
appropriate time for laboratory manufacturers to come into compliance 
with MDR and correction and removal reporting requirements. Among other 
things, this timeline is reasonable in light of the estimates in the 
FRIA, and under CLIA, laboratories should already have some processes 
in place for detecting problems with their IVDs. In addition, the new 
enforcement discretion policies set forth in section V.B (particularly 
the policy for currently marketed IVDs offered as LDTs) may help 
laboratories with limited resources focus on compliance with 
requirements at stage 1. Therefore, FDA is retaining the 1-year period 
for the phaseout of the general enforcement discretion approach with 
respect to MDR and correction and removal reporting requirements, in 
order to prioritize the phaseout of the general enforcement discretion 
approach for requirements that would help FDA identify and monitor 
significant issues with IVDs offered as LDTs.
    Enforcement of the MDR requirements under 21 U.S.C. 360i(a) through 
(c) and part 803 (21 CFR part 803), in particular, will enable FDA to 
systematically monitor significant adverse events to identify 
problematic IVDs offered as LDTs, such as those with poor performance 
or other safety issues. FDA has made a determination that gathering 
this information early in the phaseout period is important for IVDs 
that do not have the safeguards associated with compliance with other 
FDA requirements, such as manufacturing under QS requirements or 
confirmation of appropriate safety and effectiveness through premarket 
review.
    For similar reasons, FDA is prioritizing the collection of 
information about when a manufacturer has initiated a correction or 
removal of its IVD to reduce a risk to health or to remedy a violation 
of the FD&C Act that may present a risk to health. Under 21 U.S.C. 
360i(g) and part 806 (21 CFR part 806), manufacturers are required to 
report

[[Page 37308]]

such corrections or removals to FDA, and FDA intends to phase out the 
general enforcement discretion approach for these requirements at the 
same time it does so for MDR requirements.
    In addition, FDA has determined that it should include compliance 
with one additional regulatory provision at stage 1 of the phaseout 
policy. In particular, while FDA generally expects compliance with most 
QS requirements beginning in stage 3 of the phaseout policy (as 
described below), FDA intends to phase out the general enforcement 
discretion approach with respect to the QS requirements under Sec.  
820.198 (complaint files) \42\ in stage 1 of the phaseout policy, given 
the connection between the complaint investigation and complaint file 
requirements under Sec.  820.198 and the MDR reporting regulations. 
Under Sec.  820.198, manufacturers are required to document complaints, 
investigate them, and determine if they require reporting under MDR 
requirements. Absent compliance with these requirements under Sec.  
820.198, manufacturers would not be able to comply with applicable MDR 
requirements (see Sec.  803.18(e)), and FDA believes that developing 
procedures for compliance with Sec.  820.198 can be accomplished on the 
same timeline as compliance with MDR requirements.
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    \42\ 21 CFR 820.198 generally requires that a manufacturer 
maintain complaint files and establish and maintain procedures for 
receiving, reviewing, and evaluating complaints, including requiring 
that certain complaints which are required to be reported to FDA 
under part 803 be promptly reviewed, evaluated, and investigated. 
When the final rule to amend part 820 takes effect in February 2026, 
the comparable requirements can be found in International 
Organization for Standardization (ISO) 13485 subclause 8.2.2 as 
modified by part 820. Under these provisions, manufacturers will 
generally be required to document procedures for timely complaint 
handling, including minimum requirements and responsibilities for 
receiving and recording information, evaluating whether the 
information constitutes a complaint, investigating complaints, 
determining the need to report information to appropriate regulatory 
authorities, handling of complaint-related product, and determining 
the need to initiate corrective action. Additionally, new Sec.  
820.35 will require, among other things, that manufacturers maintain 
records of such review and report to FDA complaints that are 
required under part 803.
---------------------------------------------------------------------------

2. Stage 2: Beginning 2 Years After the Publication Date of This Final 
Rule, FDA Will Expect Compliance With Requirements Not Covered During 
Other Stages of the Phaseout Policy, Including Registration and Listing 
Requirements, Labeling Requirements, and Investigational Use 
Requirements
    After considering the comments, FDA has determined to phase out the 
general enforcement discretion approach for requirements not covered 
during other stages of the phaseout policy (i.e., requirements other 
than MDR, correction and removal reporting, QS, and premarket review 
requirements) 2 years after publication of this final rule. These other 
requirements include registration and listing requirements under 21 
U.S.C. 360 and parts 607 and 807 (excluding subpart E); labeling 
requirements under 21 U.S.C. 352 and parts 801 and 809, subpart B (21 
CFR parts 801 and 809, subpart B); and investigational use requirements 
under 21 U.S.C. 360j(g) and part 812 (21 CFR part 812).\43\ We have 
included compliance with investigational use requirements at this 
stage, in recognition that there has been some confusion about our 
enforcement approach in this area. Our understanding is that 
laboratories often are not complying with investigational use 
requirements currently, even though FDA has generally expected 
compliance with these requirements.\44\ We are therefore including 
these requirements in the phaseout policy.
---------------------------------------------------------------------------

    \43\ An IVD that is also a biological product and subject to 
licensure under section 351 of the PHS Act may be studied under an 
IND and subject to the investigational use requirements in section 
351(a)(3) of the PHS Act and 21 CFR part 312, instead of the IDE 
requirements in part 812 (see, e.g., 21 CFR 312.2(a) and Ref. 65). 
IVDs studied under an IND are generally those intended for use as 
blood donor screening or HCT/P donor screening tests to which FDA's 
general enforcement discretion approach for LDTs has not applied 
(see section V.A.2). Therefore, we anticipate that there would be a 
limited number of IVDs offered as LDTs, if any, subject to 
investigational use requirements under 21 CFR part 312 for which the 
phase out of enforcement discretion would be relevant. However, to 
the extent such IVDs offered as LDTs exist, we intend to phase out 
enforcement discretion with respect to those investigational use 
requirements at stage 2, consistent with our policy regarding other 
investigational use requirements.
    \44\ For example, FDA stated in the ``Framework for Regulatory 
Oversight of Laboratory Developed Tests (LDTs)'' draft guidance that 
``FDA intends to continue to enforce investigational device 
requirements under 21 CFR part 812 for all clinical investigations 
of LDTs that are conducted under clinical protocols that require 
institutional review board approval'' (Ref. 38).
---------------------------------------------------------------------------

    As described in the NPRM (88 FR 68006 at 68025), FDA anticipates 
that it will best serve the public health to phase out the general 
enforcement discretion approach for these requirements at the 2-year 
mark, and FDA did not receive information changing its view with 
respect to that timeline. Under this timeline, FDA will obtain 
registration and listing information before the enforcement discretion 
phaseout for premarket review requirements, which may give the Agency a 
better understanding of the universe of IVDs offered as LDTs to 
facilitate premarket review of those IVDs. Relatively few commenters 
raised concerns about this timeline, and FDA's estimates of the 
resources required for compliance with the requirements covered by 
stage 2 suggest 2 years is adequate time (see FRIA section II.F.2). 
Furthermore, the new enforcement discretion policies set forth in 
section V.B may free up time and resources for laboratories to focus on 
compliance with requirements at stage 2. FDA has determined that this 
timeline appropriately balances the importance of compliance with 
registration and listing, labeling, and investigational use 
requirements, among others, relatively quickly--in order to address 
IVDs offered as LDTs that are problematic, among other things--with the 
recognition that laboratories generally have not complied with FDA 
requirements and may need time to order their affairs and build out 
FDA-compliant systems.
    FDA notes that the labeling requirements under part 801 include 
unique device identification (UDI) requirements, as applicable (see 
part 801, subpart B).
3. Stage 3: Beginning 3 Years After the Publication Date of This Final 
Rule, FDA Will Expect Compliance With QS Requirements
    At the 3-year mark, FDA generally will expect compliance with the 
CGMP requirements of the QS requirements under 21 U.S.C. 360j(f) and 
part 820. (FDA notes that we expect compliance with requirements under 
Sec.  820.198 (complaint files) during stage 1 of the phaseout policy.) 
We recognize that the costs of compliance with QS requirements are 
comparatively high among the range of costs quantified in the FRIA (and 
as suggested in certain comments), but FDA continues to believe that 
the 3-year timeline is appropriate given, in particular, the new 
enforcement discretion policies in section V.B.3, which we anticipate 
will significantly reduce laboratories' work at this stage (see section 
II.F.3 of the FRIA). FDA has determined that this timeline is 
consistent with our goal of improving the quality of IVDs manufactured 
by laboratories as soon as feasible while also taking into account the 
resources and time required to set up quality systems.
    FDA also notes that we expect laboratories to retain manufacturing 
records they may already have or may create for certain IVDs prior to 
stage 3 of the phaseout policy. In particular, for any IVDs for which 
FDA generally intends to exercise enforcement discretion for all QS 
requirements other

[[Page 37309]]

than requirements under part 820, subpart M (Records), FDA expects 
laboratories to retain existing records and records created prior to 
the start of stage 3 that are relevant to validation and the other 
topics covered under part 820, subpart M (Records)). This documentation 
will help FDA understand the manufacturing for IVDs offered as LDTs 
that are marketed prior to stage 3, including helping FDA identify IVDs 
that are potentially problematic.
    FDA issued its final rule amending the QSR on February 2, 2024, 
which will take effect on February 2, 2026, meaning that the amended QS 
requirements will be in effect before the beginning of stage 3. When a 
laboratory undertakes to comply with QS requirements, FDA will expect 
compliance with the QS requirements that are in effect at that time 
whether that be at the start of stage 3 or earlier (if the laboratory 
complies with QS requirements prior to the start of stage 3).\45\ For 
further information on the QS requirements established pursuant to the 
amendments to the QSR, please refer to 89 FR 7496.
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    \45\ As noted elsewhere in this phaseout policy, FDA intends to 
phase out the general enforcement discretion approach with respect 
to requirements under Sec.  820.198 (complaint files) during stage 1 
of the phaseout policy. However, upon the start of stage 1, and 
prior to the effective date of the amended QSR, FDA intends to 
exercise enforcement discretion and generally not enforce 
requirements under Sec.  820.198 for laboratories that are in 
compliance with Subclause 8.2.2 of ISO 13485. Following the 
effective date of the amended QSR (February 2, 2026), laboratories 
must comply with the QS requirements that are in effect at that 
time.
---------------------------------------------------------------------------

    In addition, specifically for LDTs,\46\ FDA is adopting the 
enforcement discretion policy proposed in the NPRM under which FDA 
generally will expect compliance at the 3-year mark with some, but not 
all, of the QS requirements (88 FR 68006 at 68025). FDA continues to 
believe this policy is helpful and appropriate. Although FDA and CMS 
regulation are different and complementary, compliance with CLIA 
requirements provides some quality assurances that may be relevant to 
laboratories' manufacturing practices. In particular, laboratories may 
in practice be able to apply concepts set forth under CLIA requirements 
for laboratory operations to certain manufacturing activities regulated 
by FDA. For FDA to effectively take into account the CLIA requirements, 
this policy will apply only for LDTs (i.e., when all manufacturing 
activities occur within a single laboratory and the IVD is not 
transferred outside that laboratory). However, this policy is limited 
in scope because CLIA regulations do not provide relevant assurances 
for certain QS requirements. These requirements include design controls 
under Sec.  820.30; purchasing controls (including supplier controls) 
under Sec.  820.50; acceptance activities (receiving, in-process, and 
finished device acceptance) under Sec. Sec.  820.80 and 820.86; CAPA 
under Sec.  820.100; and records requirements under part 820, subpart 
M.47 48 Because CLIA does not provide assurances relevant to 
these requirements, FDA has determined to phase out the general 
enforcement discretion approach for these specific requirements 3 years 
after publication of this final rule (except for requirements under 
Sec.  820.198 (complaint files), for which FDA intends to phase out the 
general enforcement discretion approach during stage 1 of the phaseout 
policy).
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    \46\ As explained elsewhere in this preamble, FDA has generally 
considered the term ``laboratory developed test (LDT)'' to mean an 
IVD that is intended for clinical use and that is designed, 
manufactured, and used within a single CLIA-certified laboratory 
that meets the regulatory requirements under CLIA to perform high 
complexity testing.
    \47\ For LDTs, FDA generally expects compliance with 
requirements under part 820, subpart M (Records) but not Sec. Sec.  
820.20, 820.22, and 820.40 (which are cross-referenced in subpart 
M), or comparable provisions of ISO 13485 in accordance with the 
amendments to part 820 once that rule takes effect in February 2026.
    \48\ Upon the effective date of the amendments to the QSR, the 
requirements relating to design controls, purchasing controls, 
acceptance activities, CAPA, and records requirements will be set 
forth in the following ISO 13485 clauses as modified by the codified 
for part 820: Clause 4. Quality Management System, Subclause 4.2.5; 
Clause 6. Resource Management; Clause 7. Product Realization, 
Subclause 7.1, Subclause 7.3, Subclause 7.4, and Subclause 7.4.3; 
and Clause 8. Measurement, Analysis, & Improvement, Subclause 
8.2.2., Subclause 8.2.5, Subclause 8.2.6, and Subclause 8.3.
---------------------------------------------------------------------------

    Finally, FDA notes that under section 515(d)(2) of the FD&C Act, 
the Agency may not approve a PMA if the applicant fails to demonstrate 
conformity with the QS requirements. Therefore, compliance with the QS 
requirements is needed to support approval of a PMA. As provided in 
section 520(f)(2) of the FD&C Act, any person subject to the QS 
requirements may petition for an exemption or variance from any QS 
requirement (see also Sec.  820.1).
4. Stage 4: Beginning 3\1/2\ Years After the Publication Date of This 
Final Rule, FDA Will Expect Compliance With Premarket Review 
Requirements for High-Risk IVDs Offered as LDTs, Unless a Premarket 
Submission Has Been Received by the Beginning of This Stage in Which 
Case FDA Intends To Continue To Exercise Enforcement Discretion for the 
Pendency of Its Review
    FDA has determined that the phaseout for the general enforcement 
discretion approach with respect to premarket review requirements for 
high-risk IVDs offered as LDTs should occur 3\1/2\ years from 
publication of this final rule, consistent with the timeline proposed 
in the NPRM (88 FR 68006 at 68026). The premarket review requirements 
for PMAs are set forth in 21 U.S.C. 360e and part 814 (21 CFR part 
814). The information in the record has not changed our view that 3\1/
2\ years will provide sufficient notice and opportunity for 
laboratories manufacturing IVDs to plan for and prepare PMAs.\49\ 
Although we received comments indicating that it would be difficult for 
laboratories to comply within this 3.5-year timeline, the new 
enforcement discretion policies included in this final phaseout policy 
should help address those concerns. For example, the policy for 
currently marketed IVDs offered as LDTs and the policy for certain 
unmet needs LDTs mean FDA generally does not expect compliance with 
premarket review requirements for a substantial subset of IVDs. 
Overall, in light of these policies, FDA has determined that a 3.5-year 
period is a reasonable amount of time to expect laboratories to come up 
to speed on PMA requirements, gather the information required for PMAs, 
and complete their PMA submissions (see section II.F.4 of the FRIA).
---------------------------------------------------------------------------

    \49\ Under the phaseout policy, laboratories that intend to 
submit an HDE application or a BLA should do so within the same 3\1/
2\-year timeframe for submission of PMAs. As in the case of PMAs, 
under the phaseout policy, FDA generally does not intend to enforce 
against IVDs after a complete HDE application or BLA has been 
submitted (within the 3\1/2\-year timeframe) until FDA completes its 
review of the application. Premarket review requirements specific to 
HDE applications are set forth in 21 U.S.C. 360j(m) and part 814, 
subpart H. Licensure requirements are set forth in 42 U.S.C. 262 and 
21 CFR part 601.
---------------------------------------------------------------------------

    This timeline is also intended to align the phaseout for the 
general enforcement discretion approach for premarket review 
requirements for high-risk IVDs offered as LDTs with the start of 
fiscal year 2028, which coincides with the beginning of a new user fee 
cycle. This alignment will provide an opportunity for industry 
participation in

[[Page 37310]]

negotiations regarding the next user fee cycle with the knowledge that 
laboratory manufacturers will be expected to comply with premarket 
review requirements. (Although a trade association representing 
laboratories previously has participated in Medical Device User Fee 
Amendments (MDUFA) negotiations, the prior negotiations have not 
incorporated similar expectations regarding laboratory compliance with 
premarket requirements.) Thus, we have determined that this amount of 
time is appropriate to foster stability and consistency in the 
marketplace for the current MDUFA cycle, and FDA will take into account 
the need for adequate FDA resources to implement the phaseout policy in 
a manner that does not compromise the capacity to achieve MDUFA V 
performance expectations. FDA anticipates that during this 3\1/2\-year 
period, laboratories will work with FDA to determine whether PMAs 
should be submitted for their IVDs.
    Under this phaseout policy, FDA generally does not intend to 
enforce against IVDs offered as LDTs for lacking premarket approval 
after a complete PMA has been submitted until FDA completes its review 
of the application, provided that the PMA has been submitted within the 
3\1/2\-year timeframe. Given that such IVDs may already be on the 
market and available to patients, FDA generally does not intend to 
interrupt access at the point when a submission is made. IVDs for which 
a PMA is submitted after the 3\1/2\-year timeframe would not fall 
within this enforcement discretion policy; FDA approval is expected 
prior to such IVDs being offered.
    Based on a review of the comments, FDA is also adopting a policy 
under which it generally does not intend to enforce premarket review 
requirements for certain laboratory changes to another manufacturer's 
lawfully marketed test. In particular, this policy applies when a 
laboratory certified under CLIA and meeting the regulatory requirements 
under CLIA to perform high complexity testing modifies another 
manufacturer's 510(k) cleared or De Novo authorized test, following 
design controls and other quality system requirements for which FDA 
expects compliance as described in section V.C.3, in a manner that 
could not significantly affect the safety or effectiveness of the test 
and does not constitute a major change or modification in intended use, 
and where the modified test is performed only in the laboratory making 
the modification. FDA is adopting this policy to promote more efficient 
and effective use of Agency resources and because it understands 
laboratories may make such changes to, for example, integrate a test 
into its operations, accommodate local conditions (e.g., storage 
conditions), or address supply shortages. Under the policy, FDA would 
expect premarket submissions from laboratories modifying a third 
party's 510(k) cleared or De Novo authorized test for the same types of 
changes for which FDA would expect a premarket submission from the 
original manufacturer making changes to its own IVD. Taking into 
account the risks associated with relatively minor changes to 510(k) 
cleared or De Novo authorized tests when they occur in a single 
laboratory (i.e., without broad distribution), at this time, we believe 
the resources needed to review these types of changes generally can be 
better spent on other Agency priorities and activities. For a 
description of changes that could significantly affect the safety or 
effectiveness of the test or constitute a major change or modification 
in intended use under this policy, see FDA's regulations at Sec.  
807.81(a)(3) and further discussion in the final guidance ``Deciding 
When to Submit a 510(k) for a Change to an Existing Device'' (Ref. 61). 
If the modification (individually or in the aggregate) could 
significantly affect the safety or effectiveness of the test or does 
constitute a major change or modification in intended use and the 
modified test does not fall within an enforcement discretion policy 
discussed in section V.B above, FDA expects laboratories to submit the 
applicable premarket submission. If the laboratory modification is so 
significant that the IVD is no longer substantially equivalent to the 
original IVD and requires a PMA, FDA expects the PMA to be submitted 
either by stage 4 or before the modified test is marketed, whichever 
comes later.
    We are not applying this enforcement discretion policy to 
modifications to another manufacturer's PMA-approved or BLA-licensed 
test because such tests are high-risk, and changes to such tests pose 
corresponding increased risks. We note that relatively few IVDs are 
considered high risk today, and, further, FDA has announced its intent 
to initiate the reclassification process for most IVDs that are 
currently class III into class II (Ref. 66). FDA aims to complete this 
reclassification process before stage 4 of the phaseout policy. We 
therefore anticipate that there will be even fewer class III (high-
risk) IVDs going forward. As such, these tests present resource 
considerations that are different from those discussed above.
5. Stage 5: Beginning 4 Years After the Publication Date of This Final 
Rule, FDA Will Expect Compliance With Premarket Review Requirements for 
Moderate-Risk and Low-Risk IVDs Offered as LDTs (That Require Premarket 
Submissions), Unless a Premarket Submission Has Been Received by the 
Beginning of This Stage in Which Case FDA Intends To Continue To 
Exercise Enforcement Discretion for the Pendency of Its Review
    FDA has determined to phase out the general enforcement discretion 
approach with respect to premarket review requirements for moderate-
risk IVDs offered as LDTs (IVDs that may be eligible for classification 
into class II) and low-risk IVDs offered as LDTs (IVDs that may be 
eligible for classification into class I) that require a premarket 
submission 4 years from publication of this final rule. These premarket 
submissions include 510(k) submissions, the requirements for which are 
set forth at 21 U.S.C. 360(k), 360c(i), and part 807, subpart E. These 
submissions also include De Novo requests, which laboratories may 
submit for IVDs offered as LDTs for which there is no legally marketed 
device upon which to base a determination of substantial equivalence, 
and for which the laboratory seeks classification into class I or class 
II. These requirements are set forth at 21 U.S.C. 360c(f)(2) and 21 CFR 
part 860, subpart D.
    FDA is retaining the same 4-year timeline that was proposed in the 
NPRM for stage 5 for reasons similar to those for stage 4 (see 88 FR 
68006 at 68027). Specifically, when taking into account the enforcement 
discretion policies in section V.B, we believe the original timeline 
for compliance with 510(k) and De Novo requirements is feasible, 
particularly given that these submissions are generally less resource-
intensive than PMAs (for additional information see section II.F.4 of 
the FRIA (Ref. 10)). As noted in the NPRM, the 6-month interval between 
stages 4 and 5 will enable FDA to prioritize the review of applications 
for high-risk IVDs offered as LDTs (subject to premarket approval 
requirements), so that we can focus first on IVDs for which the 
consequences of a false result are generally most significant (88 FR 
68006 at 68027). In addition, this timeline aligns with the user fee 
cycle, as previously discussed.
    FDA generally does not intend to enforce against IVDs offered as 
LDTs for lacking premarket authorization after a complete 510(k) or De 
Novo request has been submitted until FDA completes its

[[Page 37311]]

review of the submission, provided that the 510(k) or De Novo request 
has been submitted within the 4-year timeframe. Given that such IVDs 
may already be on the market and available to patients, FDA generally 
does not intend to interrupt access at the point when a submission is 
made. IVDs for which a 510(k) or De Novo request is submitted after the 
4-year timeframe would not fall within this enforcement discretion 
policy; FDA clearance or authorization is expected prior to such IVDs 
being offered.
    FDA is also adopting the policy regarding laboratory modifications 
to another manufacturer's lawfully marketed test that is discussed 
under stage 4. As explained in that discussion, under this policy, FDA 
generally does not intend to enforce premarket review requirements when 
a laboratory certified under CLIA and meeting the regulatory 
requirements under CLIA to perform high complexity testing modifies 
another manufacturer's 510(k) cleared or De Novo authorized test, 
following design controls and other quality system requirements for 
which FDA expects compliance as described in section V.C.3, in a manner 
that could not significantly affect the safety or effectiveness of the 
test and does not constitute a major change or modification in intended 
use, and where the modified test is performed only in the laboratory 
making the modification. If the modification (individually or in the 
aggregate) could significantly affect the safety or effectiveness of 
the test or does constitute a major change or modification in intended 
use and the modified test does not fall within an enforcement 
discretion policy discussed in section V.B above, FDA expects 
laboratories to submit the applicable premarket submission. If the 
applicable premarket submission is a 510(k) or De Novo request, FDA 
expects the 510(k) or De Novo request to be submitted either by stage 5 
or before the modified test is marketed, whichever comes later.
    FDA also anticipates that laboratories may seek to utilize FDA's 
Third Party review program. FDA currently operates a Third Party review 
program for medical devices, and multiple organizations are accredited 
to conduct reviews of 510(k) submissions for certain IVDs (see Ref. 
67). We anticipate interest in the Third Party review program among IVD 
manufacturers, as well as potential new 3P510k Review Organizations. In 
particular, FDA is aware of certain CLIA accreditation organizations 
that have expressed interest in potentially becoming Third Party 
reviewers under FDA's program, and to the extent laboratories are 
already familiar with these organizations, laboratories may be more 
inclined to use the Third Party review program. In addition, under the 
MDUFA V agreement, FDA is currently working to enhance the Third Party 
review program, which may make it more attractive to manufacturers 
including laboratories.

VI. Comments on the Notice of Proposed Rulemaking and FDA Responses

    We received more than 6,500 comment letters on the NPRM by the 
close of the comment period, each containing one or more comments on 
one or more issues. We received comments from medical device 
associations, members of the medical device and pharmaceutical 
industries, medical and healthcare professional associations, hospitals 
and AMCs, accreditation organizations, other advocacy organizations, 
government agencies, and individuals. We describe and respond to the 
comments in this section of the document. We have numbered each comment 
to help distinguish between different comments. We have grouped similar 
comments together under the same number so that FDA's responses can be 
addressed by topic, and, in some cases, we have separated different 
issues discussed in the same comment and designated them as distinct 
comments for purposes of our responses. The number assigned to each 
comment or comment topic is purely for organizational purposes and does 
not signify the comment's value or importance or the order in which 
comments were received or considered.

A. General Comments on the Notice of Proposed Rulemaking

    (Comment 1) FDA received comments in support of and in opposition 
to the NPRM. Comments supporting the proposal generally discussed the 
importance of FDA oversight of IVDs offered as LDTs to protect the 
public health and ensure that patients and healthcare providers are 
able to trust and rely on test results which impact important 
healthcare decisions. Some comments expressed concern regarding the use 
of IVDs offered as LDTs that are not clinically validated, and 
regarding scientifically dubious claims made about such IVDs, 
especially in areas like cancer prognosis and genetic screening. 
Several comments noted that without independent oversight the work to 
ensure LDT effectiveness and consistency is left to those with a 
financial interest in the continued use of those LDTs. Comments 
expressing general opposition cited various reasons for their 
opposition, including that the proposal is too broad in scope, is too 
difficult for laboratories to follow, would require laboratories to 
``follow processes that are unfit for the purpose of assessing the 
quality of laboratory tests,'' is not necessary, and reflects 
regulatory overreach.
    (Response 1) FDA agrees that phasing out the general enforcement 
discretion approach for LDTs is important to protect the public health, 
as discussed further in section III.B. Current evidence points to 
problems associated with IVDs offered as LDTs such that there is a 
fundamental uncertainty about whether IVDs offered as LDTs provide 
accurate and reliable results. These issues highlight the need for 
increased oversight to help ensure the safety and effectiveness of IVDs 
offered as LDTs.
    FDA disagrees with the comments stating that FDA's proposal is 
overly broad. As described throughout this preamble and in the NPRM, 
the evidence supports increased oversight of IVDs offered as LDTs. The 
final phaseout policy fulfills the goal of greater oversight of such 
IVDs while also accounting for other key public health interests. For 
example, upon further consideration, including of the comments received 
regarding particular aspects of the phaseout policy, FDA is adopting 
several new targeted enforcement discretion policies, as detailed in 
section V.B.
    FDA also disagrees with comments stating that FDA's proposal is 
difficult to follow. We believe the scope and five stages of the 
proposed and final phaseout policy, discussed further in section V, are 
clear and, as noted throughout this preamble, we intend to issue 
additional guidance as appropriate and offer other resources to the 
public, which will assist stakeholders during implementation of the 
phaseout.
    In addition, we disagree with the statement that the proposal would 
require laboratories to follow processes that are ``unfit for the 
purpose of assessing the quality'' of IVDs offered as LDTs. As further 
discussed in sections VI.C.2 and VI.C.3 of this preamble, FDA has the 
experience and the scientific and regulatory expertise to oversee IVDs, 
including LDTs. Moreover, the requirements and processes for devices in 
the FD&C Act and FDA regulations apply to all IVDs, including LDTs, and 
the requirements/processes set forth in part 809 are specifically 
tailored to IVDs, including LDTs. We also disagree that the proposal 
(or final rule) reflects ``regulatory overreach'' for the reasons 
discussed in section VI.D.

[[Page 37312]]

B. Definitions

    (Comment 2) Several comments stated that the rule should explicitly 
define in Sec.  809.3 terms such as ``LDTs,'' ``IVDs,'' and 
``enforcement discretion'' for clarity. Other comments suggested that 
FDA identify the differences between IVDs and LDTs, with one comment 
suggesting that FDA refer to LDTs as CLIA-LDTs because laboratories 
must be CLIA-certified. Another comment requested that FDA define the 
terms ``diagnostic'' and ``impact clinical outcomes'' as used in the 
proposed rule. One comment requested clarity on whether digital 
scanning of pathology slides is within the scope of the LDT definition 
included in the NPRM.
    (Response 2) The term ``in vitro diagnostic products'' (IVDs) is 
defined in Sec.  809.3(a). Through this rulemaking, FDA is amending the 
definition of ``in vitro diagnostic products'' in its regulations to 
state that IVDs are devices under the FD&C Act ``including when the 
manufacturer of these products is a laboratory.'' Therefore, as amended 
by this rule, IVDs are defined in Sec.  809.3(a) as those reagents, 
instruments, and systems intended for use in the diagnosis of disease 
or other conditions, including a determination of the state of health, 
in order to cure, mitigate, treat, or prevent disease or its sequelae. 
Such products are intended for use in the collection, preparation, and 
examination of specimens taken from the human body. These products are 
devices as defined in section 201(h)(1) of the FD&C Act, and may also 
be biological products subject to section 351 of the PHS Act, including 
when the manufacturer of these products is a laboratory.
    FDA disagrees that the terms ``LDTs'' and ``enforcement 
discretion'' should be defined in Sec.  809.3. Neither term is used in 
part 809, so adding definitions to part 809 would have no effect, and 
would likely be confusing. To the extent the commenter believed the use 
of those terms in the NPRM was not sufficiently clear, FDA also 
disagrees, as it has clearly explained those terms in both the proposed 
and final rules (see, e.g., 88 FR 68006 at 68008 (stating that ``FDA 
has generally exercised enforcement discretion such that it generally 
has not enforced applicable requirements with respect to most LDTs''); 
88 FR 68006 at 68009 (stating that ``FDA has generally considered an 
LDT to be an IVD that is intended for clinical use and that is 
designed, manufactured, and used within a single laboratory that is 
certified under [CLIA] and meets the regulatory requirements under CLIA 
to perform high complexity testing'')).
    With regards to the definition of ``diagnostic,'' FDA interprets 
this comment as a request to further define the term in the definition 
of an IVD. We see no reason, and the comment does not include any 
rationale, why this term should be defined. Moreover, we note that the 
term applies across many devices and so defining it in part 809, which 
is limited in scope to IVDs, would likely cause confusion. With regard 
to the comment requesting clarification of the phrase ``impact clinical 
outcomes,'' FDA did not use the phrase ``impact clinical outcomes'' in 
the NPRM and, as a result, does not understand this request.
    Finally, regarding the comment requesting clarity on whether 
digital scanning of pathology slides is within the scope of the LDT 
definition, FDA would need to know more about the product to assess 
whether it falls within what FDA has generally considered to be an 
LDT--i.e., an IVD that is intended for clinical use and that is 
designed, manufactured, and used within a single laboratory that is 
certified under CLIA and meets the regulatory requirements under CLIA 
to perform high complexity testing. FDA notes that whole slide imaging 
systems are class II devices with special controls and are subject to 
510(k) notification requirements (21 CFR 864.3700). For additional 
information about specific classifications for devices, we recommend 
consulting 21 CFR parts 862 through 892.
    (Comment 3) A comment requested FDA clarify how it regulates common 
laboratory equipment (such as general-purpose computer monitors or 
printers, microscopes, centrifuges, and incubators), and expressed 
concern that increased FDA oversight of LDTs would impact FDA's 
regulation of such equipment.
    (Response 3) FDA regulates common laboratory equipment that meets 
the FD&C Act's definition of a device. Section 201(h)(1) of the FD&C 
Act defines a device, in relevant part, as ``An instrument, apparatus, 
implement, machine, contrivance, implant, in vitro reagent, or other 
similar or related article, including a component part, or accessory 
which is: . . . . (B) intended for use \50\ in the diagnosis of disease 
or other conditions, or in the cure, mitigation, treatment, or 
prevention of disease, in man or other animals, . . . . The term 
`device' does not include software functions excluded pursuant to 
section 520(o) [of the FD&C Act].'' Whether a product falls within the 
device definition involves a fact-specific inquiry, including an 
inquiry into the product's intended use. In general, general-purpose 
computer monitors or printers that are not intended for a medical use 
would not fall within the device definition, whereas general purpose 
laboratory equipment labeled or promoted for specific medical uses 
intended to prepare or examine specimens from the human body would fall 
within the device definition.
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    \50\ ``Intended use'' as used in this provision is determined by 
the objective intent of the persons legally responsible for the 
labeling of an article (or their representatives) (see Sec.  801.4). 
The intent may be shown by such persons' expressions, the design or 
composition of the article, or by the circumstances surrounding the 
distribution of the article (Id.).
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    FDA has classified such general purpose laboratory equipment into 
class I and has exempted these devices from premarket notification 
under section 510(k) of the FD&C Act (21 CFR 862.2050). FDA has also 
classified certain microscopes and accessories and microbiological 
incubators into class I and has exempted them from premarket 
notification under section 510(k) of the FD&C Act (21 CFR 864.3600 and 
866.2540). For additional information about specific classifications 
for devices, we recommend consulting 21 CFR parts 862 through 892. This 
rule does not change FDA's authority to regulate such equipment and FDA 
does not anticipate a significant impact from the phaseout policy on 
such equipment, which is generally not designed, manufactured, and used 
within a single CLIA-certified laboratory.

C. Need for the Rule

1. FDA's Description of the Current State of the LDT Market
    (Comment 4) FDA received several comments on the current state of 
the LDT market. Some asserted that the potential risk to patients of 
false results from LDTs remains unchanged from 1976.
    (Response 4) FDA disagrees with comments which claim that the risk 
to patients is unchanged from 1976. As discussed in the NPRM and this 
preamble, today LDTs are commonly used to diagnose infectious diseases, 
screen for various diseases and conditions, and identify the best 
treatment for patients with cancer, among other uses. The consequences 
of false results in these contexts can include spread of disease, 
missed diagnoses, misdiagnoses, use of ineffective treatments with 
toxic side effects, and lack of use of life-saving treatments. LDTs are 
relied upon for high stakes medical decisions. Further, genetic 
sequencing technology has advanced such that a person's

[[Page 37313]]

deoxyribonucleic acid (DNA) can be quickly sequenced and different 
variations identified in a single analysis; the clinical significance 
of many of these variations is unknown. FDA is aware of IVDs offered as 
LDTs, particularly genetic IVDs offered as LDTs, that are offered for 
uses that lack sufficient scientific support. The availability of new 
technologies and increasing reliance on them for clinical decision-
making has increased the risk of IVDs offered as LDTs.
    (Comment 5) Some comments claimed FDA overestimated the number of 
IVDs offered as LDTs on the market while others claimed FDA 
underestimated the number of IVDs offered as LDTs on the market. Some 
comments said the breadth of reach of LDTs is small whereas another 
comment pointed out that LDTs are used for routine clinical tests in 
addition to ``advanced diagnostics.'' One comment claimed that FDA's 
estimate of the number of IVDs offered as LDTs was more than ``10 times 
what researchers found in a peer-reviewed study published in the 
American Journal of Clinical Pathology of actual clinical test orders 
at University of Utah Health: 3.9%'' (see Ref. 68).
    (Response 5) FDA acknowledges that it does not know exactly how 
many IVDs are currently offered as LDTs, precisely what those IVDs are 
used for, or the exact breadth of the reach of those IVDs. FDA will 
receive information regarding IVDs offered as LDTs and their intended 
uses through registration and listing in stage 2 of the phaseout 
policy. FDA disagrees with the assertion that the cited publication 
suggests that FDA's estimates may be 10 times higher than what has been 
reported in scientific literature. According to the publication cited 
in the comment, the percentage of test orders fulfilled with IVDs 
offered as LDTs at a single health system was 3.9 percent (which seems 
to have been the basis of the commenter's ``10 times higher'' claim) 
but the percentage of distinct tests that were IVDs offered as LDTs 
within this health system was 45 percent (880/1,954). While it is 
helpful to understand that 3.9 percent of test orders were fulfilled 
with IVDs offered as LDTs, this does not support the assertion that 
FDA's estimate of the percentage of distinct IVDs offered as LDTs is 
``10 times higher'' than that reported by the publication. In section 
II.D of the PRIA, FDA estimated that LDTs account for about 50 percent 
of total IVDs that are used in some laboratories (see Ref. 60), which 
is very similar to the 45 percent reported in the publication. 
Additional information regarding these estimates is provided in 
response to comment 3 in the FRIA (see Ref. 10).
    (Comment 6) One comment questioned FDA's statement that test 
results are often used by treating clinicians to inform their 
professional judgments and that the incidence of false positive and 
false negative test results inherent in any form of testing can present 
treatment challenges. This comment asserted that treating clinicians 
are well aware of the inherent limitations of testing, regardless of 
whether the test is an LDT or not, and that such clinicians base their 
treatment on holistic considerations of treatment factors. Thus, an 
erroneous test result from an LDT does not necessarily mean an 
erroneous treatment decision. A similar comment from a physician stated 
that FDA oversight will not increase the safety of LDTs and any risks 
associated with inaccurate test results are better left to physicians 
to assess.
    (Response 6) FDA disagrees with these comments. Despite the 
suggestion to the contrary, not all clinicians are ``well aware'' of 
limitations of tests, including tests that are not FDA-authorized. 
Rather, FDA routinely consults with experts and has encountered many 
who do not understand the limitations of tests and do not consider that 
a test result provided by a test may be incorrect. For example, a 
cardiologist at an FDA public workshop on troponin testing stated, 
``[d]octors trust numbers and if they are wrong we don't care we trust 
them anyway'' (Ref. 69). Similarly, an article authored by a physician 
and published in the Washington Post explained that his ``research has 
found that many physicians misunderstand test results'' and noted that 
``your doctor may have a blind spot, an unconscious tendency to have 
too much trust in a test'' (Ref. 70). While we agree that erroneous 
test results do not always lead to direct harm/erroneous treatment 
decisions, they often do, and FDA is addressing these risks in the 
phaseout policy.
2. CLIA Oversight
    (Comment 7) FDA received comments stating that CLIA and CLIA 
regulations do not provide sufficient regulation of manufacturer 
laboratories and their tests. One comment noted that this is because 
laboratories are not equipped with appropriate ``QMS systems,'' 
development teams, manufacturing, and production processes. Some 
comments stated that CLIA lacks requirements related to design controls 
and other important QS requirements. Comments also asserted that CMS 
does not review a laboratory's methodology for assessing analytical 
validity, does not assess clinical validity, and inspects only every 2 
years under CLIA. A comment stated that CLIA and the related laboratory 
accreditation by CMS do not necessarily preclude additional oversight 
by FDA, especially for direct-to-consumer and ``commercialized'' 
products.
    (Response 7) FDA agrees that CLIA and CLIA regulations are not a 
substitute for FDA's oversight of IVDs offered as LDTs under the FD&C 
Act. As discussed in the NPRM, laboratories that offer IVDs as LDTs are 
subject to both the FD&C Act and CLIA (88 FR 68006 at 68013-14). CMS 
determines whether a laboratory meets CLIA requirements, which is a 
specific role distinct from FDA's statutory responsibilities. FDA's 
device authorities under the FD&C Act are intended to help ensure that 
devices, including IVDs offered as LDTs, have appropriate assurance of 
safety and effectiveness.
    FDA acknowledges that CLIA establishes requirements for laboratory 
operations and personnel and the issuance of clinical laboratory 
certifications. However, those requirements do not provide sufficient 
assurance of safety and effectiveness for the tests themselves. For 
example, in administering CLIA, CMS does not regulate critical aspects 
of laboratory test development; does not evaluate the performance of a 
test before it is offered to patients and healthcare providers; does 
not assess clinical validity (i.e., the accuracy with which a test 
identifies, measures, or predicts the presence or absence of a clinical 
condition or predisposition in a patient); does not regulate certain 
manufacturing activities, such as design controls and acceptance 
activities; does not provide human subject protections for individuals 
who participate in clinical trials; and does not require adverse event 
reporting. FDA also agrees that inspections under CLIA do not provide 
sufficient assurances of safety and effectiveness for IVDs offered as 
LDTs, as discussed further in response to comment 8.
    CMS has consistently agreed that its role in administering the CLIA 
Program, which regulates the operations of clinical laboratories 
performing testing, is distinct from FDA's role in enforcing the FD&C 
Act to ensure that tests have appropriate assurance of safety and 
effectiveness. In order to ensure the accuracy and reliability of 
patient test results, the CLIA regulations provide oversight covering 
the operation and administration of the laboratory, to

[[Page 37314]]

include the appropriate qualification of its personnel. For example, 
the CLIA regulations include requirements pertaining to proficiency 
testing, laboratory personnel qualifications, test ordering and 
reporting, quality control, and the development and use of laboratory 
processes and procedures. FDA and CMS have long stood together in 
mutual support of FDA oversight of the analytical and clinical validity 
of LDTs, and CMS agrees with FDA that the CLIA program is separate in 
scope and purpose from FDA oversight (Ref. 71). Each regulatory scheme 
serves a different function, and as CMS notes, ``CMS and FDA's 
regulatory schemes are different in focus, scope, and purpose, but they 
are intended to be complementary'' (Ref. 26). In 2015, Dr. Patrick 
Conway, then the Deputy Administrator for Innovation and Quality & 
Chief Medical Officer of CMS, stated that ``CMS does not have 
scientific staff capable of reviewing complex medical and scientific 
literature in determining clinical validity. This expertise resides 
within the FDA, which assess the clinical validity in the context of 
premarket reviews and other activities aligned with their regulatory 
efforts under the Food, Drug and Cosmetic Act.'' Statement of Dr. 
Patrick Conway, Deputy Administrator for Innovation and Quality & Chief 
Medical Officer, CMS, Committee Hearing (October 29, 2015), at 25. This 
was not a new position for CMS; nearly 30 years earlier, the then-
Administrator of the Health Care Financing Administration (HCFA, CMS's 
predecessor agency) stated that FDA, under the FD&C Act, had a role to 
play in the regulation of laboratory testing: ``On the quality issue, 
first, the Health Care Financing Administration has oversight authority 
and will use that to do a better job under our new regulations. The 
role of the Centers for Disease Control is to provide expert advice to 
us on how we regulate laboratories. The role of the FDA is in oversight 
of the devices and other technical aspects of lab testing.'' Statement 
of Dr. William L. Roper, Administrator, HCFA, Committee Hearing on H.R. 
4325 (July 6, 1988), at 77.
    (Comment 8) FDA received several comments stating that CLIA 
provides sufficient regulation of IVDs offered as LDTs. Some comments 
stated that regulation under CLIA is sufficient because obtaining a 
CLIA certificate requires a laboratory to demonstrate that the 
personnel in the laboratory have the training, experience, and level of 
proficiency required to perform the types of tests offered by the 
laboratory. Other comments stated that regulation under CLIA is 
sufficient because CLIA-certified laboratories are subject to 
inspections to confirm that the testing complies with CLIA regulations, 
including ensuring that there is adequate validation of the tests, 
supervision by the laboratory director, and quality procedures. Many 
comments contended that laboratories certified by CLIA follow a robust 
and rigorous set of requirements regarding validation, verification, 
and monitoring of IVDs offered as LDTs. In particular, some comments 
asserted that CLIA provides a regulatory mechanism designed to ensure 
accurate test results. Other comments stated that FDA has not 
demonstrated that FDA's premarket review process is more effective than 
CLIA in ensuring the accuracy of tests.
    (Response 8) FDA acknowledges that CLIA and CLIA regulations 
establish requirements for laboratory operations and laboratory 
personnel, and specific requirements that must be met to obtain a 
clinical laboratory certification (see, e.g., 42 CFR part 493 subparts 
C, K, and M). CLIA-certified laboratories also are subject to 
inspection under 42 CFR part 493 subpart Q to verify that laboratories 
are conducting testing in compliance with the CLIA regulation. 
Inspections do not, however, verify that the tests themselves comply 
with the requirements of the FD&C Act that are designed to ensure that 
tests have appropriate assurance of safety and effectiveness for their 
intended purpose. Likewise, while FDA agrees that CLIA-certified 
laboratories are required to meet certain verification, validation, and 
monitoring requirements, FDA disagrees that those requirements provide 
sufficient assurance of safety and effectiveness for the tests 
themselves. As more fully set forth in response to comment 7, CMS does 
not regulate critical aspects of laboratory test development; does not 
evaluate the performance of a test before it is offered to patients and 
healthcare providers; does not assess clinical validity; does not 
regulate certain manufacturing activities; does not provide human 
subject protections for individuals who participate in test clinical 
trials; and does not require adverse event reporting.
    FDA disagrees with comments indicating that FDA's premarket review 
process ``is not more effective'' than CLIA regulation. FDA's premarket 
review process serves a role that CLIA regulation does not. During 
review of a marketing submission for an IVD, FDA reviewers closely 
examine data relevant to safety and effectiveness and draw on their 
expertise and experience to understand both the product and the science 
supporting the product. FDA reviewers evaluate whether a test 
accurately and reliably detects or quantifies its intended target and 
whether results from the test accurately and reliably identify, 
measure, or predict the presence or absence of the intended clinical 
condition or predisposition. For example, for a test that is intended 
to detect genetic variants to predict the risk of a person developing a 
particular disease, FDA reviewers would evaluate whether the test can 
accurately and reliably detect the intended genetic variants in the 
intended use specimen type (e.g., blood, saliva), and they would also 
evaluate evidence demonstrating whether the genetic variant is 
associated with the risk of developing that particular disease. As 
another example, for a test intended to quantify the levels of a 
protein to aid in the diagnosis of a particular disease, FDA would 
evaluate whether the device can accurately and reliably quantify the 
levels of the protein in the intended specimen type and also whether 
the levels of protein quantified by the test can be used to diagnose 
the disease. FDA also reviews IVD labeling to ensure there are adequate 
instructions for use, which includes directions for performing the test 
and interpreting the results, warnings, limitations, a summary of test 
performance (for example, accuracy), and how the results are reported. 
See our response to comment 10 for additional discussion of FDA's 
expertise.
    (Comment 9) FDA received comments stating that regulation under 
CLIA is sufficient because CLIA-certified laboratories perform 
proficiency testing to ensure that assays are performing properly. One 
comment suggested that FDA authorization is a one-time event with no 
ongoing monitoring of product performance, whereas proficiency testing 
is an ongoing requirement through which laboratories periodically 
confirm their capabilities to perform tests. In contrast, FDA received 
a comment which suggested that proficiency testing is not sufficient, 
as a laboratory may fail proficiency testing several times before 
receiving a notice to cease testing.
    (Response 9) FDA disagrees that proficiency testing provides 
sufficient regulation of IVDs offered as LDTs. Under CLIA, enrollment 
in a Department of Health & Human Services (HHS)-approved proficiency 
testing program is a requirement for only a portion of tests that a 
laboratory offers, and proficiency testing programs do not

[[Page 37315]]

address all IVDs offered as LDTs (see 87 FR 41194). Under the CLIA 
regulations, proficiency testing is required for only the limited 
number of analytes found in 42 CFR part 493 subpart I (Proficiency 
Testing Programs for Nonwaived Testing), which are referred to as 
``regulated'' analytes by CMS. From the list of LDTs approved by NYS 
CLEP, FDA has seen that many IVDs offered as LDTs are tests for 
analytes other than the regulated analytes listed in 42 CFR part 493 
subpart I. Additionally, the list of regulated analytes does not 
include any genetic markers, and FDA is aware from the NYS CLEP 
approval database as well as discussions with stakeholder that many 
IVDs offered as LDTs are genetic tests. There are also many other 
analytes for which there are no programs that offer proficiency 
testing. When a laboratory performs tests, including IVDs offered as 
LDTs, for analytes that are not regulated under CLIA or where there is 
no proficiency testing program available, the laboratory is required 
only to verify the accuracy of the test at least twice annually, which 
may be done by splitting a patient sample with a laboratory that offers 
the same test and comparing results. The number of samples tested and 
the acceptability of the results is determined by the laboratory 
director. Comparing results from a small number of samples, possibly 
even a single sample, without prospective metrics for success is not 
equivalent to a prospective determination of safety and effectiveness 
prior to initiating testing on patient samples. FDA also appreciates 
the concern raised in the comment which stated that laboratories may 
potentially continue testing after failing proficiency testing. For 
these reasons, proficiency testing alone does not provide sufficient 
assurance of safety and effectiveness for an IVD offered as an LDT for 
its intended use.
    FDA also disagrees with the suggestion that FDA regulation involves 
no ongoing monitoring of product performance. Under FDA regulations, 
test manufacturers are generally subject to a variety of ongoing 
requirements, including labeling requirements, registration and 
listing, quality system requirements, adverse event reporting, and 
periodic inspections that confirm compliance with design controls and 
other QS requirements.
    (Comment 10) A number of comments suggested that FDA is not the 
appropriate entity to oversee LDTs, and that any changes to the manner 
in which tests are regulated should be implemented through amendments 
to CLIA, or through modifications to the CLIA regulation, which many 
comments described as ``modernizing'' that regulation. Comments 
asserted that FDA does not have the required expertise, and one comment 
stated that CMS/CLIA and certain CLIA accreditation organizations are 
best able to verify the accuracy of laboratory testing. This comment 
stated that requiring all ``laboratory testing'' to be certified under 
CLIA would be better than enforcing laboratory compliance with medical 
device regulations. Other comments stated that complaints about test 
quality should be evaluated by CMS rather than FDA, to avoid creating 
what the comments described as duplicative regulation. Some comments 
noted that laboratories are unfamiliar with the premarket requirements 
and other requirements of the FD&C Act. Some comments argued that FDA 
is slow to clear or approve tests, and asserted that for that reason, 
FDA should not oversee IVDs offered as LDTs. On the other hand, some 
comments asserted that FDA has a role to play in assuring that tests 
produce reliable results for patients and providers, and some comments 
pointed to FDA's demonstrated expertise in review of analytical and 
clinical validity of IVDs.
    (Response 10) FDA does not agree that concerns regarding the safety 
and effectiveness of LDTs should be addressed by amending CLIA or 
modifying the CLIA regulation. CMS determines whether a laboratory and 
its personnel meet CLIA requirements, whereas FDA, among other things, 
reviews and evaluates the tests themselves, including IVDs offered as 
LDTs, to ensure that they have appropriate assurance of safety and 
effectiveness under the FD&C Act. CMS and FDA agree: CMS does not have 
the resources and expertise to assure that tests work for their 
intended clinical purpose; FDA does (Ref. 71). Congress specifically 
charged FDA with such oversight, as discussed further in response to 
comments in section VI.D.2. In particular, FDA has the scientific and 
regulatory expertise to review data and information on individual IVDs 
offered as LDTs and determine their safety and effectiveness. FDA 
employs hundreds of scientists with expertise in review of safety and 
effectiveness, including those who have worked in clinical laboratories 
and developed LDTs. FDA is comprised of physicians, statisticians, 
engineers, biologists, chemists, geneticists, and others, who evaluate 
the science behind medical products before they are marketed and 
utilized. Understanding the complex technical information in 
applications, such as clinical trial data, bench testing results, and 
product design characteristics--and putting that information in context 
to assess whether a product has appropriate assurance of safety and 
effectiveness for its intended use--is within FDA's unique expertise. 
This type of expertise is no less important for IVDs offered as LDTs, 
the safety and effectiveness of which may significantly impact not only 
individual health but also the public health, as described elsewhere in 
this preamble.
    Moreover, establishing a duplicative system for the oversight of 
IVDs would create bureaucracy and inconsistencies (Ref. 71). As 
described in the NPRM, such an approach would cause a problematic split 
in oversight, with the same types of IVDs being reviewed by different 
Agencies depending on where the IVD was made (88 FR 68006 at 68014). 
For example, a cancer diagnostic test developed by a conventional 
manufacturer would be reviewed by FDA while a similar cancer diagnostic 
test (using the same sample type and testing for the same analytes) 
developed by a laboratory would be reviewed by another Agency. Further, 
with that divided oversight, an IVD developed by a conventional 
manufacturer could even be reviewed and cleared by FDA and subsequently 
reviewed by another Agency if a laboratory made certain modifications 
to it. However, if those same modifications were made by the original 
manufacturer, they would be reviewed by FDA. This could lead to 
confusion and inconsistency.
    In response to the comment that stated that CLIA should require 
certification of all ``laboratory testing,'' FDA acknowledges that CLIA 
establishes requirements for laboratory operations and their personnel 
and issues clinical laboratory certifications. However, FDA disagrees 
that those requirements provide sufficient assurance of safety and 
effectiveness for the tests themselves. CLIA does not assess clinical 
validity or certain manufacturing activities.
    We further note that to the extent laboratories may be unfamiliar 
with the premarket requirements of the FD&C Act, current familiarity 
with applicable requirements is not determinative of the need for such 
requirements to be enforced. FDA has made several resources available 
to stakeholders to increase familiarity with applicable requirements, 
including final guidance documents and information on FDA's website 
(see, e.g., Ref. 72), and will provide additional materials and 
outreach to laboratories during the phaseout period. In addition, with 
respect to the speed of FDA's premarket

[[Page 37316]]

review, FDA notes that its premarket review timelines are negotiated 
with industry in connection with MDUFA reauthorization. For information 
regarding FDA's recent performance with respect to MDUFA decision 
goals, see Ref. 73. FDA generally meets the timeframes for MDUFA 
decisions negotiated with industry, including for IVD submissions. 
However, FDA's response to the unprecedented COVID-19 public health 
emergency significantly impacted the Agency's ability to meet its MDUFA 
IV performance goals, resulting in some missed decision goals.
    (Comment 11) Comments stated that CLIA has its own mechanism for 
making improvements to its regulations, through the Clinical Laboratory 
Improvement Advisory Committee (CLIAC), which includes members from the 
Centers for Disease Control and Prevention (CDC) and FDA. Comments 
noted that CLIAC has provided advice and guidance to HHS on revisions 
and improvements to the CLIA standards. Comments suggested that 
modernizing CLIA is a pathway which is supported by a significant 
number of ``major organizations.'' A comment stated that effectuating 
changes through CLIA would be a streamlined and cost-effective 
approach, for both the government and laboratories, and the least 
disruptive and burdensome approach to addressing clinical and 
analytical validity, transparency, and other concerns.
    (Response 11) FDA disagrees with these comments. CLIAC's advice is 
one of many sources available to the Secretary of HHS (Secretary) and 
is only a recommendation (Ref. 74). As set forth in response to 
comments 7 and 10, neither CMS nor FDA consider changing CLIA or the 
CLIA regulations to be appropriate to address the issues discussed in 
this preamble; to the contrary, it would lead to costly and inefficient 
bifurcation of the regulation of IVDs offered as LDTs. FDA appreciates 
that stakeholders seek a streamlined, cost-effective approach that is 
the least disruptive to their laboratories. FDA shares those goals, 
which are addressed throughout this preamble, and particularly in the 
phaseout policy described in section V.
    (Comment 12) FDA has received comments stating that FDA oversight 
of IVDs offered as LDTs would be duplicative of, or conflict with, 
CLIA. In particular, comments stated that QS requirements and 
validation requirements would be duplicative or conflict. A comment 
stated that FDA oversight of LDTs is not in line with Executive Order 
(E.O.) 13563, which asks executive branch agencies to harmonize 
regulatory requirements. In addition, some comments stated that 
increased oversight would be cumbersome, and therefore would not follow 
FDA's least burdensome principles.
    (Response 12) FDA disagrees with these comments. As set forth 
elsewhere in this preamble, CMS and FDA enforce two different 
regulatory schemes, separate in scope and purpose from each other. CMS 
agrees the two are complementary, not duplicative, as discussed in 
response to comment 7. The portion of CLIA that addresses quality 
systems relates to laboratory operations, laboratory personnel, and 
requirements for laboratory procedures relevant to testing. FDA's QS 
requirements are focused on design control and validation and other 
requirements intended to ensure that the IVD has appropriate assurance 
of safety and effectiveness for its intended use. FDA also notes that 
this rule comports with E.O. 13563 because this rule promotes 
coordination and harmonization by taking into account the assurances 
that CLIA provides (see section V.C).
    As described in section V.C regarding FDA's intention to phase out 
the general enforcement discretion approach with respect to QS 
requirements during stage 3 of the phaseout policy (other than 
requirements under Sec.  820.198 (complaint files), which are addressed 
in stage 1), FDA intends to take into account CLIA requirements as 
appropriate. As to validation, CLIA regulations do not address clinical 
validation of tests, and analytical validation under CLIA is different 
from that under the FD&C Act. FDA's review of analytical validity 
(i.e., the ability of the test to accurately and reliably measure or 
detect the analyte(s) it is intended to measure or detect) is done 
prior to marketing, and FDA assesses the analytical validity of the IVD 
offered as an LDT in greater depth and scope. FDA also assesses 
clinical validity, which is the accuracy and reliability with which the 
test identifies, measures, or predicts the presence or absence of a 
clinical condition or predisposition in a patient, in reviewing the 
safety and effectiveness of the test. As noted, unlike the FDA 
regulatory scheme, CMS' CLIA program does not address the clinical 
validity of any test.
    We also note that FDA collaborates closely with CMS. The two 
Agencies have entered into a memorandum of understanding that 
facilitates information sharing, and FDA, CMS, and CDC participate in 
monthly ``Tri-Agency'' meetings to discuss topics related to CLIA 
oversight. Tri-Agency meetings often include sharing of non-CLIA 
information that is pertinent to the CLIA program, such as issues 
related to specific tests, safety communications, recalls, or warning 
letters. FDA and CMS also share information between meetings as needed, 
particularly when there are signals that may warrant investigation by 
either Agency.
    FDA also disagrees that increased FDA oversight of IVDs offered as 
LDTs would not follow FDA's least burdensome principles. As explained 
in a final guidance document issued by FDA on February 5, 2019, 
entitled ``The Least Burdensome Provisions: Concept and Principles,'' 
FDA ``defines least burdensome to be the minimum amount of information 
necessary to adequately address a relevant regulatory question or issue 
through the most efficient manner at the right time (e.g., need to know 
versus nice to know). Our least burdensome definition and principles do 
not change the applicable statutory and regulatory standards, such as 
the device authorization standards, nor the applicable requirements, 
including premarket submission content requirements and the requirement 
for valid scientific evidence'' (Ref. 75). In developing the phaseout 
policy, FDA has considered least burdensome principles consistent with 
this definition. As described extensively in the NPRM and this 
preamble, oversight of LDTs is necessary to adequately address safety 
and effectiveness concerns regarding LDTs. The phaseout policy is 
designed to achieve this objective in the most efficient manner and at 
the right time, by phasing out the general enforcement discretion 
approach with respect to applicable statutory and regulatory 
requirements in a gradual manner and including various targeted 
enforcement discretion policies, as further described in section V. 
With respect to the comment that invoked E.O. 13563, we note that 
section 7(d) of the E.O. states that it ``is not intended to, and does 
not, create any right or benefit, substantive or procedural, 
enforceable at law or in equity. . . .''
    (Comment 13) FDA received comments which stated that FDA oversight 
is not necessary, as CLIA has its own enforcement mechanism. Some 
comments stated that CMS can, and has, used its enforcement capability 
from CLIA to sanction both laboratories and individual laboratory 
directors. Some comments stated that FDA oversight is unnecessary, 
because laboratory medical directors have medical, legal, and ethical 
responsibility for their laboratories, which includes personally

[[Page 37317]]

approving all new technical procedures and approving all test 
validations. One comment stated, however, that when an LDT does not 
meet specifications or ``quality standards,'' a laboratory director can 
continue to release results after making ``a deviation/exception 
report.''
    (Response 13) FDA agrees that CLIA has certain enforcement 
capabilities, and that CMS has exercised those enforcement tools to 
take certain actions against laboratories that do not comply with CLIA 
regulations. FDA also agrees that medical and laboratory directors have 
responsibilities for their laboratories, and that some of those 
responsibilities include approving certain procedures and activities. 
However, FDA disagrees that relying on CMS enforcement tools, personal 
responsibilities, or the activities of the laboratory director alone 
are sufficient to protect the public health if a test does not have 
appropriate assurance of safety and effectiveness. As one comment 
noted, under CLIA, laboratory directors may continue to release test 
results that do not meet their own specifications. The CLIA regulations 
focus on laboratory operations whereas the FD&C Act focuses on the 
design and manufacturing of the test. While this rule does not change 
the responsibilities of a laboratory director, FDA oversight ensures 
compliance with quality requirements set forth in the FD&C Act.
    In contrast to CMS, FDA generally is authorized to review the 
safety and effectiveness of individual IVDs, including an IVD offered 
as an LDT, prior to marketing, to impose special controls or post-
approval conditions for certain tests as risk mitigations, to receive 
reports of device malfunctions and adverse events, and to require 
reports of corrections and removals of a device, as well as to take 
specific steps when a device presents a risk to the public health such 
as advisory, administrative, or enforcement actions, including issuance 
of warning letters, injunction, seizure, mandatory recall, and 
assessment of civil monetary penalties.
    (Comment 14) A comment suggested that instead of implementing FDA's 
proposal, FDA should work with CMS to establish a national registry of 
LDTs to register all existing and new LDTs. The comment suggested that 
FDA include in that registry test type classification, clinical utility 
claims, and validated performance with confidence intervals or other 
relevant statistics. The comment further suggested that FDA coordinate 
with CMS, CAP, clinical laboratory professional organizations, AMCs, 
and ``commercial'' laboratories to establish a system for LDT review 
and regulation.
    (Response 14) FDA enforcement of existing registration and listing 
requirements is appropriate for IVDs offered as LDTs. FDA already has a 
process and database for establishment registration and device listing, 
and there is no need to establish a new ``registry'' for LDTs. FDA also 
has labeling requirements for IVDs in part 809 that include, among 
other things, required information on performance characteristics. 
Given the existing statutory and regulatory framework, there is no need 
to establish a new system for LDT review and regulation as suggested by 
the comment. As set forth in section V.C, FDA is phasing out the 
general enforcement discretion approach with respect to registration 
and listing requirements (21 U.S.C. 360, part 607 (for IVDs subject to 
licensure), and part 807 (excluding subpart E)) 2 years after the 
phaseout policy is published. Under this timeline, FDA will be able to 
utilize registration and listing information to obtain an initial 
understanding of the universe of IVDs offered as LDTs to facilitate 
premarket review of those IVDs. As set forth in section V.C, FDA also 
is phasing out the general enforcement discretion approach with respect 
to labeling requirements 2 years after the phaseout policy is 
published.
    (Comment 15) Some comments claimed that the fact that FDA has 
identified some problematic tests demonstrates that CLIA is providing 
sufficient oversight. Comments requested that FDA explain why CLIA 
regulation is insufficient for the majority of laboratories that follow 
CLIA guidelines. See also comment 16.
    (Response 15) FDA agrees that CLIA serves an important role: CMS 
regulates laboratories that perform testing on individuals in the 
United States by regulating laboratory testing and personnel under 
CLIA. As discussed elsewhere in this preamble, CLIA is separate in 
scope and purpose from the FD&C Act and FDA regulations. CLIA 
regulations help to determine whether laboratories are conducting 
testing in a manner consistent with CLIA, but CLIA does not ensure that 
the test itself has appropriate assurance of safety and effectiveness 
for its intended use.
    As more fully set forth in section III.B and in response to 
comments in section VI.C.4, FDA is aware of numerous examples of 
potentially inaccurate, unsafe, ineffective, or poor quality IVDs 
offered as LDTs that caused or may have caused patient harm. FDA would 
not expect the types of problems observed among these IVDs offered as 
LDTs to be identified under CLIA, and as described elsewhere in this 
preamble, the evidence of these problems cuts across test types and 
laboratories and is from a variety of sources, including published 
studies in the scientific literature, allegations of problematic tests 
reported to FDA, FDA's own experience in reviewing IVDs offered as 
LDTs, news articles, and class-action lawsuits.
    (Comment 16) Several comments asserted that FDA's experience with 
Theranos is evidence that FDA oversight will not address problematic 
tests, particularly those that are fraudulent. They pointed out that 
FDA cleared a 510(k) from Theranos and that the company's fraudulent 
behaviors were addressed by CMS through the CLIA program.
    (Response 16) This comment does not reflect a complete accounting 
of events. First, FDA cleared one test from Theranos early in our 
experience with the company. Per standard practice, FDA reviewed the 
data provided and based our decision on it. We subsequently identified 
significant device performance concerns based on the data submitted in 
submissions for other tests of Theranos, including questions about 
inaccurate results that may put patients at risk. We did not clear 
those devices. Less than 2 months after the clearance of the one test, 
we sent investigators to all Theranos sites, where we identified 
concerns with IVDs offered as LDTs and an unapproved collection device 
(Ref. 76). Recognizing the immediate risk to patients, we took a 
strategic compliance approach. Specifically, FDA took quick action that 
directly led to the firm ceasing distribution of its unapproved 
collection device. We also alerted CMS to potential CLIA concerns, and 
CMS promptly confirmed CLIA violations in a follow-up inspection. Thus, 
FDA was integral to the government's handling of Theranos, and FDA 
disagrees with the comment's assertions that FDA did not address 
problematic IVDs offered as LDTs by Theranos.
    (Comment 17) Some comments suggested that CLIA could be 
``modernized'' to incorporate oversight of clinical validity and 
address concerns raised by FDA.
    (Response 17) These comments are outside the scope of this 
rulemaking. This rulemaking is focused on FDA's oversight of devices 
under the current statutory authorities set forth in the FD&C Act, and 
in consideration of CMS's current authorities under CLIA.
    In any event, FDA disagrees that concerns with IVDs offered as LDTs 
should be addressed through expansion

[[Page 37318]]

of CLIA. First, the authority and expertise to oversee the safety and 
effectiveness of tests already lies with FDA, and not with CMS; 
expanding CMS oversight would require legislation and would establish a 
duplicative regulatory program. Second, neither FDA nor CMS supports 
such an approach. It would establish a dual system for the oversight of 
tests and create more government bureaucracy, duplication of effort, 
and potential inconsistencies. For example, a test made by a non-
laboratory manufacturer (and any modifications to that test made by the 
laboratory manufacturer) would be regulated by FDA, but if the test is 
modified by a laboratory, CMS would regulate it. The same/similar tests 
made by a laboratory and non-laboratory manufacturer would be reviewed 
by two different agencies under different frameworks. This approach 
does not make sense.
3. Other Controls
    (Comment 18) FDA received comments claiming that FDA should not 
enforce the requirements of the FD&C Act for IVDs offered as LDTs, as 
it is more appropriate for accrediting entities, including the 
Commission on Office Laboratory Accreditation (COLA), CAP, the 
Accreditation Commission for Health Care (ACHC), the Association for 
the Advancement of Blood and Biotherapies (AABB), the Joint Commission, 
and ASHI to oversee IVDs offered as LDTs. Some comments suggested that 
FDA should exercise enforcement discretion with respect to IVDs offered 
as LDTs at certain facilities with relevant accreditations, such as 
accreditation by ASHI or the Foundation for the Accreditation of 
Cellular Therapy (FACT), because such accreditations provide the 
necessary assurances relevant to the type and volume of work performed 
by these accredited facilities.
    (Response 18) FDA disagrees that CLIA accreditation organizations 
such as COLA, CAP, or ACHC provide sufficient oversight of IVDs offered 
as LDTs. As discussed in response to comment 7, CLIA accreditation 
entities, including COLA, CAP, and ACHC, determine whether a laboratory 
meets CLIA requirements. Moreover, various accreditation entities, 
including AABB, the Joint Commission, ASHI, and FACT, may also 
determine whether a laboratory meets these organizations' voluntary 
accreditation standards. Unlike these organizations, which assess 
laboratories/laboratory operations under CLIA and their own 
accreditation standards, FDA (and FDA's device authorities under the 
FD&C Act) focus on whether devices, including IVDs offered as LDTs, 
have appropriate assurances of safety and effectiveness.
    In particular, COLA evaluates and, if appropriate, certifies that 
certain laboratories that conduct tests in certain specialties 
(chemistry, hematology, microbiology, immunology, and immunohematology/
transfusion services) meet CLIA requirements and any applicable COLA 
accreditation standards (Ref. 77). CAP conducts inspections to 
determine compliance with CLIA and applicable CAP accreditation 
standards (Ref. 78). Although CAP and COLA have their own accreditation 
standards, these additional standards address the manner in which the 
laboratory performs tests, and do not assess the clinical validity of 
the test itself. COLA and CAP do not perform premarket review of 
individual IVDs offered as LDTs for overall safety and effectiveness 
for the devices' intended uses. More generally, third-party 
accreditation entities have their own standards for accreditation of 
facilities that may not assess the clinical validity of the tests that 
the facility performs. Thus, an accreditation of a facility by one of 
these third parties does not, on its own, provide sufficient assurance 
of safety and effectiveness for the IVDs offered as LDTs by the 
accredited facility for their intended uses.
    We note that pursuing CAP, COLA, ACHC, AABB, Joint Commission, 
ASHI, or FACT (or other) accreditation is a voluntary process. CAP, 
COLA, and other accreditation organizations' standards are not 
regulatory or statutory requirements.
    Finally, we note that for reasons more fully set forth in response 
to comment 7, FDA is the appropriate entity to provide the necessary 
oversight of IVDs offered as LDTs to better assure their safety and 
effectiveness.
    (Comment 19) FDA received comments stating that many laboratories 
follow guidelines provided by the Association for Molecular Pathology 
(AMP), the International Clinical Cytometry Society (ICCS), and the 
Clinical and Laboratory Standards Institute (CLSI), and voluntary 
standards issued by ISO. Some comments suggested that laboratories that 
follow such standards are already highly regulated. Other comments 
stated that following such guidelines and/or standards provides a level 
of assurance that the laboratories' assays are ``safe and reliable.'' 
Comments recommended that FDA permit AMP, ICCS, CLSI, and other 
entities to continue to offer such guidelines. Another comment stated 
that the ``solution for . . . incompetent tests should be . . . 
standardization and not regulation.''
    (Response 19) FDA acknowledges that many entities, including the 
entities that the comments listed, offer guidelines, standards, and 
other resources to laboratories. However, the guidelines and standards 
that the comments describe are, in most instances, voluntary and non-
binding.\51\ FDA disagrees that a laboratory that chooses to follow 
such guidelines or standards is ``highly regulated'' as a result of 
these voluntary actions. FDA further disagrees that following such 
voluntary guidelines or standards provides assurances of safety or 
reliability (or effectiveness), as the guidelines and standards do not 
address IVD safety and effectiveness (see, e.g., Refs. 79 to 81). 
Notably, nothing in this rule will prevent AMP, ICCS, CLSI, or other 
entities from continuing to provide voluntary guidelines or standards 
to laboratories.
---------------------------------------------------------------------------

    \51\ FDA may incorporate a voluntary consensus standard by 
reference. See 5 U.S.C. 552(a) and 1 CFR part 51. Where FDA has 
incorporated a voluntary consensus standard by reference, that 
standard is treated as if it were published in the Federal Register 
and CFR, and this material has the full force and effect of law.
---------------------------------------------------------------------------

    (Comment 20) Comments asserted that the Federal program entitled 
Molecular Diagnostic Services (MolDx) already provides significant 
regulatory oversight and overlaps with FDA's proposal. Comments also 
stated that MolDx addresses technical requirements for assays by 
assessing a test's analytical and clinical validity, and for this 
reason, the comments suggested that increased FDA oversight is not 
needed.
    (Response 20) FDA regulation and the MolDx program differ in 
several key respects. MolDx is a limited program, which evaluates 
whether tests are reasonable and necessary with a focus on the Medicare 
population (Ref. 82). In contrast, FDA's authority extends to IVDs for 
all people and includes various compliance and enforcement authorities 
(that MolDx lacks), which enable FDA to take action when an IVD 
presents a risk to health (e.g., through recalls). The MolDx program 
does not mitigate the need for increased FDA oversight of IVDs offered 
as LDTs.
    (Comment 21) FDA received a comment stating that CDC's Newborn 
Screening Laboratory Quality Assurance Program (NSQAP) administers 
proficiency testing and validates new screening tests, ensuring the 
accuracy of results generated by laboratories. The comment suggested 
that because of this program, increased FDA oversight is not needed.
    (Response 21) FDA disagrees that NSQAP is a substitute for FDA 
oversight

[[Page 37319]]

of IVDs offered as LDTs. The NSQAP program provides quality assurance 
services to newborn screening laboratories by providing reference 
materials, providing proficiency testing regarding laboratory 
operations, providing quality control reports, and offering training 
and consults (Ref. 83). NSQAP evaluates the proficiency of laboratory 
personnel and procedures, not the safety and effectiveness of IVDs 
offered as LDTs. See our response to comment 9 for additional 
discussion regarding proficiency testing.
    (Comment 22) Comments stated that New Jersey and Washington 
certification programs ensure that laboratories conduct LDT validations 
and proficiencies at high quality standards. The comments stated that 
laboratories that adhere to New Jersey's certification requirements and 
other certification programs provide patients with a high level of 
care. The comments suggested that such certification programs obviate 
the need for increased FDA oversight.
    (Response 22) FDA acknowledges that several States have 
certification programs. New Jersey and Washington State certification 
programs certify laboratories within those states if they meet the 
State certification requirements. FDA disagrees, however, that 
compliance with these State certification requirements provides 
sufficient risk mitigations for IVDs offered as LDTs. For example, 
there is no indication that these State programs evaluate both the 
analytical and clinical validity of LDTs (see Refs. 84 and 85). 
According to the website of the cited program in Washington State, the 
program covers licensure, biennial surveys, and proficiency testing 
(Ref. 84). In the comment submitted to the docket regarding New 
Jersey's program, no specific information or citation was provided 
regarding the program. Nor did FDA receive a comment to the docket from 
the New Jersey program. Based on information available to FDA regarding 
New Jersey's program, we believe this program is focused on laboratory 
operations, and not the evaluation of the IVDs themselves (see Ref. 
85).
    (Comment 23) Some comments stated that when electronic medical 
records (EMRs), inter-specialty cooperation, and educational and 
safety-reporting systems are integrated within a healthcare system, the 
risk to patients from IVDs manufactured by the laboratory within that 
system is minimized and there is no need for additional FDA oversight.
    (Response 23) FDA disagrees that these elements alone are a 
substitute for FDA oversight of IVDs offered as LDTs. FDA acknowledges 
that these elements may play a role in patient care, but FDA oversight 
of IVDs offered as LDTs serves a vital role in assuring the appropriate 
safety and effectiveness of the IVDs. Critical aspects of FDA's 
oversight, including premarket review, QS, registration and listing, 
centralized adverse event reporting, labeling, and other requirements, 
are not addressed by the elements described in these comments.
    We note that FDA does believe that integration of a laboratory 
within a healthcare system provides some risk mitigations, as discussed 
further in section V.B.3. FDA has taken those risk mitigations into 
consideration in adopting an enforcement discretion policy for 
premarket review and most QS requirements for LDTs manufactured and 
performed by a laboratory integrated within a healthcare system to meet 
an unmet need of patients receiving care within the same healthcare 
system.
    (Comment 24) One comment stated that concerns about manufacturing 
controls and other device-specific concerns regarding IVDs offered as 
LDTs are managed by ``lot-to-lot'' validation and a laboratory's 
quality control.
    (Response 24) FDA disagrees with this comment. While premarket and 
post-market validation activities are an essential element of quality 
management, there are other critical aspects of a quality management 
system, and a laboratory's quality control does not address other 
critical aspects of FDA oversight.
    (Comment 25) FDA received comments which noted that laboratories 
consult with clinicians, diagnosticians, tumor boards, and case 
conferences, and which suggested that this consultation provides 
clinical validation and ensures that tests are interpreted 
appropriately.
    (Response 25) FDA disagrees that consultation provides clinical 
validation, or that consultation alone is a substitute for FDA 
oversight of IVDs offered as LDTs. Although FDA agrees that 
consultation between laboratories and clinicians, diagnosticians, and 
others as described in this comment may help to mitigate risks from 
IVDs offered as LDTs in certain circumstances and particularly in the 
context of LDTs for unmet needs (see further discussion in section 
V.B.3), such consultation does not obviate the need for FDA oversight 
such as would justify continuing the general enforcement discretion 
approach for all FDA requirements for all LDTs, as suggested by the 
comments.
    (Comment 26) FDA received a comment stating that ``financial 
restrictions to laboratory testing'' represent another layer of 
oversight beyond CMS and FDA regulation, and serve to maintain the 
quality of laboratory testing. The comment did not define ``financial 
restrictions,'' but referenced payment codes and payor coverage 
decisions. The comment suggested that because of this additional layer 
of oversight, increased FDA oversight is not needed.
    (Response 26) FDA disagrees that ``financial restrictions'' related 
to coverage and reimbursement considerations provide sufficient 
assurances of safety and effectiveness for IVDs offered as LDTs. In the 
analysis that CMS conducts to determine Medicare coverage, it may 
consider various factors, including coverage indications, coverage 
limitations, and the clinical circumstances that demonstrate medical 
necessity, but those factors are not equivalent to, or a substitute 
for, the assurances of safety and effectiveness provided by FDA 
oversight. In general, CMS considers claims after marketing evaluations 
regarding whether expenses incurred are reasonable and necessary for 
the diagnosis and treatment of illness or injury or improve the 
functioning of a malformed body member, and whether the claim for 
payment contains the necessary information for CMS to process the claim 
(see section 1862(a)(1)(A) and section 1833(e) of Title XVIII of the 
Social Security Act).
    (Comment 27) One comment indicated that ``review by peer 
organizations'' would be superior to FDA review due to subspecialty 
expertise and cost ``to the taxpayer.''
    (Response 27) FDA disagrees that review by peer organizations would 
be superior to FDA review of IVDs offered as LDTs due to subspecialty 
expertise. First, FDA has the appropriate expertise to review the 
safety and effectiveness of IVDs, as discussed in response to comments 
7 and 10. Where additional expertise may be beneficial, FDA can seek 
input from advisory committees in accordance with the Federal Advisory 
Committee Act. Second, peer review may introduce bias and variability 
of oversight, particularly if unblinded. For example, where two peers 
review each others' work, they may potentially be inclined to overlook 
issues and expect the same in return.
    Use of peer reviewers is also not necessary to address costs to 
taxpayers or FDA. FDA receives funding from Congressional non-user fee 
appropriations (``budget authority'') and user fees to support 
operation of the

[[Page 37320]]

medical device program, including premarket review. FDA also intends to 
enhance the Third Party review program, which will reduce costs to the 
Agency while providing for assistance with 510(k) reviews by entities 
that are independent of the manufacturer.
4. Evidence of the Need for Greater FDA Oversight
    (Comment 28) FDA received comments stating that there is no problem 
with LDTs. One comment from a laboratory director voiced confidence in 
LDT results and stated that any areas for improvement seldom have to do 
with ``faulty results or improper care related to testing.'' Other 
comments stated that the errors in laboratory testing often stem from 
operational issues and human error rather than the design or nature of 
LDTs, and opined that FDA oversight would not address these issues. 
Several asserted that laboratories are diligent in their validation of 
LDTs, that there is no evidence of problems with LDTs, and that LDTs 
are as safe as FDA-authorized tests. One comment cited a 2014 
publication concluding that the quality of clinical DNA testing for 
rare diseases in the United States was excellent (Ref. 86). Another 
comment pointed to a 2022 opinion article in the Wall Street Journal 
claiming ``a review of all reported cases in state and federal courts 
reveals no reported suits filed against a laboratory for an LDT 
result'' (Ref. 87).
    FDA also received comments indicating problems with LDTs. One 
comment described the commenter's experience witnessing ``unsafe 
practices similar to those described in FDA's proposed rule'' while 
working in a profitable laboratory. This commenter left that laboratory 
to work at ``labs that care for the health of individuals.'' Another 
comment described the commenter's experience with marketing of RUO 
products for clinical diagnostic testing. One company reported that 
laboratories offer inferior LDTs that compete with the company's FDA-
approved test, and that proficiency testing programs allow inferior 
tests to pass. In these cases, patients receiving an inferior test may 
not get the most up to date treatment they should have. An AMC 
laboratory director indicated the laboratory often sees inconsistent 
results for the same patient tested in the AMC laboratory and at 
reference laboratories. Several other comments, including comments 
submitted by healthcare providers, laboratorians, patients, and public 
interest organizations, provided specific examples of problematic IVDs 
offered as LDTs, including IVDs offered as LDTs that, according to the 
comments, lacked clinical validity, provided false results, provided 
inconsistent results, or were promoted with false or misleading claims. 
A comment submitted by NYS CLEP described several examples of LDTs that 
NYS CLEP did not approve based on the original application due to 
issues such as design flaws and inadequate validation data, including 
an LDT with an ``error [that] would have endangered patient safety.'' 
Another comment submitted in support of FDA's proposal stated that 
``[t]he current state of laboratory developed testing in the US is 
quite honestly, astonishingly bad. . . . as a CAP inspector, I have 
seen firsthand the absolutely shoddy laboratory developed tests in 
place at many laboratories.''
    (Response 28) The information discussed in the NPRM, and additional 
information provided in various comments submitted to the Agency, 
demonstrates that performance problems exist with certain IVDs offered 
as LDTs (see 88 FR 68006 at 68010-12). FDA disagrees with comments 
claiming that there is no problem with LDTs or that deficiencies in 
laboratory testing are mostly caused by operational or human error. As 
described in the NPRM (88 FR 68006 at 68010-12), in memoranda included 
in the docket for this rulemaking (Refs. 16 and 18), and in other 
comments submitted to the docket such as those described above, we are 
aware of problems with IVDs offered as LDTs, many of which stem from 
issues with the IVD itself, such as design issues. We have become aware 
of these problems even though the general enforcement discretion 
approach has applied to requirements for postmarket reporting, such as 
MDR requirements.
    We acknowledge that the 2014 publication cited in the comment 
refers to a ``high level of confidence that most U.S. laboratories 
offering rare disease testing are providing consistent and reliable 
clinical interpretations''; however, this is based on a survey 
conducted from 2010 through 2012 for a proficiency testing program to 
assess the performance of laboratories running Sanger sequencing IVDs 
for rare and ultra-rare disorders. Laboratory proficiency testing 
results for Sanger sequencing IVDs for rare and ultra-rare diseases 
from over a decade ago do not support the assertion that the quality of 
clinical DNA testing in the United States is excellent today, let alone 
that there are no concerns with IVDs offered as LDTs generally. First, 
proficiency testing data are not appropriate as standalone or 
comparative results to support test validation and performance. Please 
see our response to comment 34 for a more detailed assessment of the 
limitations of proficiency testing data. Second, laboratory performance 
for Sanger sequencing IVDs for rare and ultra-rare disorders, which are 
a limited subset of genetic IVDs, do not represent the landscape of 
clinical genetic tests used today where most tests use next generation 
sequencing (NGS) and other technologies. As noted in the NPRM, FDA's 
concerns with IVDs offered as LDTs have grown in recent years (88 FR 
68006 at 68010). Moreover, we disagree with the statement that no suits 
have been filed against a laboratory for a false result associated with 
an IVD offered as an LDT; the NPRM cited evidence to the contrary (see 
88 FR 68006 at 68012 (stating that ``consumers, shareholders, and 
investors are filing lawsuits against laboratory manufacturers for 
false and misleading statements about test efficacy,'' and citing to 
Complaint, Davis v. Natera, Inc., No. 3:22-cv-00985 (N.D. Cal. 2022); 
Biesterfeld v. Ariosa Diagnostics, Inc., No. 1:21-CV-03085, 2022 WL 
972281 (N.D. Ill. 2022); and other lawsuits)). FDA shares the concern 
of comments that described problems observed with IVDs offered as LDTs.
    (Comment 29) FDA received comments stating that the proposed rule 
is not necessary for FDA ``to take action against bad actors'' or 
``ill-intended individuals and laboratories'' that abuse the system, 
because FDA could choose to enforce in ``egregious cases of patient 
harm or attempts to exploit regulatory loopholes.''
    (Response 29) FDA agrees that the Agency may choose to enforce 
against violations of the FD&C Act or PHS Act at any time, including 
(but not limited to) in response to egregious cases of patient harm, 
attempts to exploit loopholes, or other conduct involving ``bad 
actors'' or ``ill-intended individuals and laboratories.'' The general 
enforcement discretion approach does not bind the Agency or prevent FDA 
from taking enforcement action. However, as described in section III.B 
of this preamble, FDA is choosing to adjust its approach to enforcement 
discretion moving forward to address the fundamental uncertainty about 
whether IVDs offered as LDTs provide accurate and reliable results. The 
phaseout policy clarifies FDA's expectations regarding laboratories' 
compliance with applicable requirements and will bring more stability 
to the overall testing market. By phasing out the general enforcement 
discretion approach for LDTs, FDA may gain a more comprehensive 
understanding of the universe of IVDs

[[Page 37321]]

offered as LDTs (through enforcement of registration and listing 
requirements), monitor safety signals and more readily identify 
problematic IVDs (through enforcement of MDR requirements and 
corrections and removals reporting requirements), better assure that 
patients and providers have access to the information they need and 
that IVDs are not promoted with false or misleading claims (through 
enforcement of labeling requirements), and better assure analytical 
validity, clinical validity, and safety (through enforcement of QS, 
premarket review, and other applicable requirements). Ultimately, as 
noted elsewhere in this preamble, by applying the same general 
oversight approach to both laboratory and non-laboratory manufacturers 
of IVDs, FDA may better assure the safety and effectiveness of IVDs 
offered as LDTs, incentivize innovation by nonlaboratory manufacturers, 
and help ensure that innovation from laboratory manufacturers yields 
IVDs for which there is a reasonable assurance of safety and 
effectiveness (Refs. 15, 22, 88 to 90).
    (Comment 30) FDA received comments suggesting certain steps FDA 
should take prior to phasing out the overall general enforcement 
discretion approach. Different comments provided different suggestions, 
but several suggested that FDA first gather more information about IVDs 
offered as LDTs through, for example, a survey, use of CMS's ``data 
from every licensed laboratory on the test type and annual volume,'' 
use of data available from CAP, or a U.S. GAO study. One comment 
suggested FDA enforce registration and listing and adverse event 
reporting requirements in order to gather information prior to 
determining whether to phase out the general enforcement discretion 
approach for premarket review requirements. Another comment stated that 
FDA needed to develop a better understanding of how ``in-office'' tests 
in particular are operationalized in clinical practice and undertake a 
more ``inclusive and deliberative process'' that accounts for ``diverse 
stakeholders,'' but did not specify how.
    (Response 30) FDA acknowledges that we do not know exactly how many 
laboratories manufacture IVDs offered as LDTs nor precisely how many 
such IVDs they make. Based on direct interactions with CMS and CAP, FDA 
understands that neither organization collects this information for all 
IVDs offered as LDTs. However, FDA's FRIA provides estimates of how 
many laboratories currently offer IVDs as LDTs and how many IVDs 
offered as LDTs are on the market (Ref. 10). The basis for these 
estimates is described in section II.D.1 and appendix A of the FRIA. 
FDA does not agree that it should wait until it has more precise 
information about how many laboratories offer IVDs as LDTs and how may 
IVDs offered as LDTs are on the market before finalizing this rule, 
because more precise numbers would not affect the fundamental public 
health concerns that have motivated this rulemaking. FDA also notes 
that the longer it waits, the higher the numbers will become and the 
greater the risk posed to patients. Nor does FDA believe it should 
gather more information about potential problems with IVDs offered as 
LDTs prior to phasing out the overall general enforcement discretion 
approach; as discussed further in response to comments 32 and 160, 
while FDA is uncertain of the impact to the existing market, FDA 
already possesses enough information to conclude that there is no 
longer a sound basis to generally treat LDTs differently from other 
IVDs, and that the general enforcement discretion approach for LDTs 
does not best serve the public health.
    With respect to the suggestion that FDA initially focus solely on 
registration and listing and adverse event reporting requirements, 
please see the response to comment 160 in section VI.F.6 of this 
preamble.
    With respect to the comment about a more inclusive and deliberative 
process, FDA notes that, through this rulemaking, it has solicited and 
received many comments from diverse stakeholders that provided 
information on how in-office and other tests are operationalized in 
clinical practice, and we have carefully considered those comments. 
Furthermore, FDA has engaged with the public on this topic on multiple 
occasions over the last 30 years, including through draft guidances and 
public meetings. This rulemaking reflects FDA's best judgment based on 
a significant amount of input over many years, and we intend to 
continue to engage with the public on this topic. See our response to 
comment 296 for additional discussion regarding stakeholder engagement.
    We also note that FDA does not control the U.S. GAO, and cannot 
compel a U.S. GAO study.
    (Comment 31) Comments called on CMS, the National Institutes of 
Health (NIH), and HHS to review FDA's proposal.
    (Response 31) Per standard practice, all relevant components of 
HHS, including CMS, NIH, and HHS leadership, reviewed and cleared FDA's 
proposed rule and this final rule.
    (Comment 32) FDA received comments calling on FDA to produce more 
evidence of a problem. Some noted that FDA's existing evidence is 
largely anecdotal and called for ``evidence of multiple, conclusive, 
high-quality studies that show . . . that errors in laboratory testing 
are a pervasive and particularly dangerous problem.'' Other comments 
asked FDA to provide evidence of a problem with LDTs in specific areas, 
such as clinical toxicology. Some stated that the examples provided are 
not reflective of the landscape of LDTs, particularly at AMCs.
    (Response 32) FDA does not agree with these comments. FDA has 
considered a wide range of evidence, including evidence described in 
the NPRM (88 FR 68006 at 68010-12) and information submitted in 
comments, and has determined that this evidence is adequate to conclude 
that there is a concerning level of variability in the performance of 
IVDs offered as LDTs.
    As discussed in the NPRM, information about IVDs offered as LDTs in 
the scientific literature, as well as news articles and anecdotal 
reports submitted to the Agency, among other sources, has exposed 
evidence of problems associated with some of these tests (88 FR 68006 
at 68010-12; Refs. 20 and 91 to 97). Regarding the scientific 
literature, the NPRM described multiple publications that document high 
variability in performance among IVDs offered as LDTs, including the 
potential for inaccurate or incomplete results (see comment responses 
38, 39, and 41 for additional information) (88 FR 68006 at 68010-12). 
In addition, in support of this rulemaking, FDA prepared and submitted 
a memorandum to the docket regarding ``Examples of In Vitro Diagnostic 
Products (IVDs) Offered as Laboratory Developed Tests (LDTs) that Raise 
Public Health Concerns,'' which contained additional details from non-
public sources (and some public MDRs) regarding examples of IVDs 
offered as LDTs with reported or known issues that were referenced in 
the NPRM (Ref. 16). FDA also submitted a second memorandum to the 
docket entitled ``Summary of 2020 Assessment of the First 125 EUA 
Requests from Laboratories for Molecular Diagnostic Tests for SARS-CoV-
2'' (Ref. 18). Comments submitted to the docket provided additional 
evidence that further exposed problems associated with IVDs offered as 
LDTs (see discussion in response to comment 28). FDA also notes that 
the evidence of problematic IVDs offered as LDTs has

[[Page 37322]]

been growing, a trend that increases FDA's concerns.\52\
---------------------------------------------------------------------------

    \52\ For example, consider the years in which concerns with the 
IVDs offered as LDTs that raise public health concerns described in 
FDA's memorandum in the docket (Ref. 16) were first identified. Four 
concerns were identified between 2008 and 2011, 10 concerns between 
2012 and 2015, 15 concerns between 2016 and 2019, and 23 concerns 
between 2020 and 2023.
---------------------------------------------------------------------------

    To the extent that comments raised questions about the quality of 
the evidence cited in the NPRM, FDA has addressed those questions in 
our responses to other comments in this section, including comments 36, 
37, 38, and 43.
    FDA does not take the position that all IVDs offered as LDTs are 
problematic, but the collective evidence, including anecdotal evidence, 
regarding certain IVDs offered as LDTs is of significant concern, 
especially given there is no consistent reporting of adverse events. 
Because this evidence covers a wide variety of tests across a range of 
laboratories, including AMCs, FDA considers it fairly representative of 
the landscape of IVDs offered as LDTs, contrary to one comment's claim. 
FDA also disagrees that it must have evidence specific to every type of 
test, such as clinical toxicology tests, in order to justify this 
rulemaking, and we disagree that ``multiple, conclusive, high-quality 
studies'' are needed here. See FCC [Federal Communications Commission] 
v. Prometheus Radio Project, __ U.S. __, 141 S. Ct. 1150, 1160, 209 
L.Ed.2d 287 (2021) (``[T]he [Administrative Procedure Act (APA)] 
imposes no general obligation on agencies to conduct or commission 
their own empirical or statistical studies.''). Instead, FDA has ``made 
a reasonable predictive judgment based on the evidence it ha[s].'' Id. 
Specifically, based on careful consideration of the information in the 
record, FDA has determined that the final phaseout policy appropriately 
balances the relevant considerations and will advance public health.
    (Comment 33) FDA received comments regarding the risks and benefits 
of FDA's proposal, with some comments indicating that FDA has not 
adequately considered the benefits of IVDs offered LDTs. One comment 
stated that the data provided by FDA ``appears to overstate the risks 
associated with LDTs, while understating the benefits.''
    (Response 33) FDA disagrees that the data provided in the NPRM 
overstates the risks associated with IVDs offered as LDTs. FDA has 
considered evidence from a variety of sources that, taken together, 
demonstrates fundamental uncertainty about whether such IVDs provide 
accurate and reliable results. FDA acknowledges the benefits that IVDs 
offered as LDTs offer when those IVDs do provide accurate and reliable 
results, and has taken these and other public health considerations 
into account in developing the phaseout policy. The fact that accurate 
and reliable IVDs offered as LDTs have benefits does not mean that the 
current status quo--in which problematic IVDs offered as LDTs are 
marketed with limited FDA oversight--should continue indefinitely.
    (Comment 34) FDA received comments indicating FDA failed to include 
all available data relevant to the need for rulemaking. For example, 
one comment stated FDA is ``ignoring broad evidence of the high quality 
of genetic LDTs.'' Comments asserted that there was omission of 
multiple publications claiming comparable or better performance of IVDs 
offered as LDTs compared to ``FDA IVDs.'' Comments pointed to the 
following publications:

     Benayed, R., Offin, M., Mullaney, K., Sukhadia, P., et 
al. (2019). ``High Yield of RNA [Ribonucleic acid] Sequencing for 
Targetable Kinase Fusions in Lung Adenocarcinomas with no Mitogenic 
Driver Alteration Detected by DNA Sequencing and Low Tumor Mutation 
Burden.'' Clinical Cancer Research, 25(15), 4712-4722. (Ref. 98).
     Keegan, A., Bridge, J.A., Lindeman, N.I., Long, T.A., 
et al. (2020). ``Proficiency Testing of Standardized Samples Shows 
High Interlaboratory Agreement for Clinical Next-Generation 
Sequencing-Based Hematologic Malignancy Assays with Survey Material-
Specific Differences in Variant Frequencies.'' Archives of Pathology 
& Laboratory Medicine, 144(8), 959-966. (Ref. 99).
     Kim, A.S., Bartley, A.N., Bridge, J.A., Kamel-Reid, S., 
et al. (2018). ``Comparison of Laboratory-Developed Tests and FDA-
Approved Assays for BRAF, EGFR, and KRAS Testing.'' JAMA Oncology, 
4(6), 838-841. (Ref. 100).
     Merker, J.D., Devereaux, K., Iafrate, A.J., Kamel-Reid, 
S., et al. (2019). ``Proficiency Testing of Standardized Samples 
Shows Very High Interlaboratory Agreement for Clinical Next-
Generation Sequencing-Based Oncology Assays.'' Archives of Pathology 
& Laboratory Medicine, 143(4), 463-471. (Ref. 101).
     Moncur, J.T., Bartley, A.N., Bridge, J.A., Kamel-Reid, 
S., et al. (2019). ``Performance Comparison of Different Analytic 
Methods in Proficiency Testing for Mutations in the BRAF, EGFR, and 
KRAS Genes: A Study of the College of American Pathologists 
Molecular Oncology Committee.'' Archives of Pathology & Laboratory 
Medicine, 143(10), 1203-1211. (Ref. 102).
     Zehir, A., Nardi, V., Konnick, E.Q., Lockwood, C.M., et 
al. ``SPOT/Dx Pilot Reanalysis and College of American Pathologists 
Proficiency Testing for KRAS and NRAS Demonstrate Excellent 
Laboratory Performance.'' Archives of Pathology & Laboratory 
Medicine. (Ref. 103).
     Zhang, B.M., Keegan, A., Li, P., Lindeman, N.I., et al. 
(2021). ``An Overview of Characteristics of Clinical Next-Generation 
Sequencing-Based Testing for Hematologic Malignancies.'' Archives of 
Pathology & Laboratory Medicine, 145(9), 1110-1116. (Ref. 104).

    One comment further asserted that ``publications have demonstrated 
major deficiencies in FDA-approved tests that would result in patient 
mismanagement had LDTs not been available to address those 
deficiencies,'' citing to the above-listed publication from Benayed et 
al. There were two other publications referenced by a comment that were 
mis-cited or not identifiable from the information provided.
    (Response 34) FDA does not agree that the publications cited by 
these comments vitiate the need for greater oversight of IVDs offered 
as LDTs. FDA does not take the position that all IVDs offered as LDTs 
are problematic. Instead, as described in section V.B.3, FDA believes 
that beneficial IVDs offered as LDTs are likely on the market. But the 
fact that some IVDs offered as LDTs that are on the market may be 
beneficial does not mean that the current status quo--in which 
problematic IVDs offered as LDTs are marketed with limited FDA 
oversight--should continue indefinitely. Thus, even if the seven 
articles cited above showed that certain IVDs offered as LDTs have 
performance comparable to or better than that of certain FDA-authorized 
tests--which FDA does not believe to be the case, as discussed below--
that would only support the accuracy and reliability of the cited 
tests. It would not negate evidence of problematic IVDs offered as LDTs 
or uncertainty as to whether IVDs offered as LDTs provide accurate and 
reliable results, as discussed in the NPRM and elsewhere in this 
preamble.
    Moreover, we disagree that the referenced publications demonstrate 
comparable or better performance of IVDs offered as LDTs compared to 
FDA-authorized IVDs, for the reasons described below.
    a. Six of the 7 publications report results from proficiency 
testing, which are not appropriate as standalone or comparative results 
to support test validation and performance. Performing well during 
proficiency testing does not mean that a test is analytically and 
clinically valid. Kim et al., Moncur et al., Keegan et al., Merker et 
al., and Zehir et al. (Refs. 99 to 103) use data from the CAP 
proficiency testing programs for NGS, which are only a subset of IVDs 
overall, to contend that IVDs offered as LDTs are accurate and have 
comparable performance to FDA-

[[Page 37323]]

authorized tests. However, proficiency testing data, as standalone or 
comparative results, do not support test validation and performance 
expectations. Proficiency testing programs evaluate the performance of 
laboratories running tests that should have already been validated. 
Proficiency testing is performed to ensure that certain 
characteristics, e.g., detection of a specific analyte, can be achieved 
at a similar level in relation to results obtained by a group of 
referee laboratories or ``peers.'' Proficiency testing samples ensure 
results are detected within an acceptable range within a pre-determined 
limit, independent of an individual test's performance specifications. 
Proficiency testing program data is an aggregate assessment of 
laboratory performance rather than an evaluation of results on a test-
by-test basis, the latter of which is more aligned with the clinical 
reality that patient care is generally determined by a single test 
performed in a single laboratory. One cannot assess the performance of 
an individual test from aggregate data across multiple tests. Looking 
at data in aggregate can mask poor performance of an individual test. 
Proficiency testing programs are not adequately representative of the 
routine conditions of clinical use, do not consider a test's intended 
use, and do not represent the challenges encountered in routine 
testing. For example, proficiency testing does not cover the entire 
test procedure. Specimens in proficiency testing are generally highly 
contrived and do not closely mimic patient specimens. Proficiency 
testing is generally insufficiently challenging (e.g., less complex 
variant types and variant allele fractions for genetic tests). Although 
laboratories are expected to adhere to their typical testing protocols, 
proficiency testing exercises are highly controlled and come with 
specific instructions, so laboratories are aware that they are 
participating in a proficiency testing exercise, which may influence 
how the test is performed and results obtained. Proficiency testing 
does not ensure that a test has been analytically and clinically 
validated based on its intended use.
    b. Even if the results of proficiency testing were appropriate to 
evaluate the performance of IVDs offered as LDTs compared to FDA-
authorized tests, these studies only evaluated NGS-based IVDs, which 
are only a subset of IVDs. In addition, 2 publications purported to 
compare the performance of IVDs offered as LDTs to FDA-authorized tests 
but because of flawed methodology did not do so; 1 publication reported 
results that suggest performance issues with IVDs offered as LDTs; and 
1 publication did not evaluate the performance of IVDs offered as LDTs 
compared to FDA-authorized tests. Two publications (Kim et al. and 
Moncur et al.) (Refs. 100 and 102) purporting to compare IVDs offered 
as LDTs with FDA-authorized tests were actually mainly comparing IVDs 
offered as LDTs with other IVDs offered as LDTs and not comparing IVDs 
offered as LDTs with FDA-authorized tests. These publications provided 
limited information about the relative performance of FDA-authorized 
tests and IVDs offered as LDTs because the majority of tests referred 
to as ``FDA-approved companion diagnostics'' had been modified in ways 
outside of their FDA authorizations, rendering them IVDs offered as 
LDTs. In addition, the authors considered any test from a manufacturer 
with any FDA-approved companion diagnostic (CDx) to be ``FDA-
approved,'' even though some of these tests may not in fact have been 
FDA-authorized.
    Zehir et al. (Ref. 103) used CAP proficiency testing methods and 
data to reanalyze a comparison of the performance of an FDA-approved 
CDx with IVDs offered as LDTs intended for the same use using the same 
set of samples that was reported in another publication (Pfeifer et al) 
(Ref. 20). Despite the authors' claims that the study demonstrated 
excellent laboratory performance, individual laboratories had a 
significant number of errors. Only eight laboratories correctly 
reported all variants in Zehir et al.'s reanalysis, and four 
laboratories had greater than five errors. The laboratory performing 
the FDA-approved CDx correctly reported all variants in both dry and 
wet samples. Therefore, while FDA does not consider it appropriate to 
use proficiency testing data to demonstrate or compare test performance 
(as earlier explained), this study does not in any way undermine FDA's 
position regarding the need for increased oversight. Please see our 
response to comment 38 for a more detailed assessment of this study.
    Zhang et al. provided an overview of certain NGS-based test 
characteristics for hematologic malignancies with no discussion of test 
validation or performance and, therefore, does not conclude or even 
assert equivalence between IVDs offered as LDTs and FDA-authorized IVDs 
(Ref. 104). This may be an erroneous citation given the lack of 
relevant content to support the comment's assertion.
    c. Of the 7 publications cited above, only one (Benayed et al.) did 
not report on proficiency testing results. This publication did not 
demonstrate comparable or better performance of IVDs offered as LDTs 
compared to FDA-authorized tests, nor did it identify ``major 
deficiencies'' in FDA-authorized tests as the comments assert. FDA 
disagrees that the publication from Benayed et al. supports the 
assertion that ``publications have demonstrated major deficiencies in 
FDA-approved tests that would result in patient mismanagement had LDTs 
not been available to address those deficiencies.'' (Ref. 98). After 
careful review, FDA has determined that the study did not identify a 
``major deficiency'' with an FDA-approved test and does not demonstrate 
that the unauthorized IVD offered as an LDT in question was necessary 
in order to avoid patient mismanagement. Moreover, even if the study 
had demonstrated that the unauthorized IVD offered as an LDT was 
necessary to avoid patient mismanagement in certain instances, that 
fact would not mean that FDA oversight is unnecessary for IVDs offered 
as LDTs in general.
    The Benayed study evaluated the use of the FDA-authorized MSK-
IMPACT DNA sequencing test and use of the unauthorized MSK-FUSION RNA 
sequencing IVD offered as an LDT in patients with lung cancer. The MSK-
FUSION was designed to detect fusions and rearrangements (complex 
variants) while the MSK-IMPACT is authorized for detection of single 
nucleotide variants, insertions and deletions (indels), MET exon 14 
skipping, and microsatellite instability but not complex variants. The 
authors concluded that the IVD offered as an LDT identified complex 
variants that were not detected by the FDA-authorized test (and which 
the FDA-authorized test was not intended to detect). However, a test's 
inability to identify variants that it is not intended to detect is not 
inherently a ``major deficiency'' for that test. We note that FDA 
oversight of IVD labeling helps ensure that the instructions for use 
are clear, including clearly describing the intended use, which for 
genetic tests includes describing the variants detected by the test.
    The authors of the Benayed study reported that 10 patients received 
targeted therapy based on identification of complex variants by the 
MSK-FUSION test and claimed that 80 percent of those patients had 
clinical benefit. FDA disagrees with the authors' conclusions that 80 
percent of patients experienced clinical benefit. First, the authors 
considered the denominator to include only those patients who went

[[Page 37324]]

on to receive targeted therapy (n=10) rather than all patients 
identified by the MSK-FUSION test as having complex variants (n=33). 
Second, the authors considered clinical benefit to include stable 
disease, which FDA does not consider to be an appropriate endpoint for 
therapeutic efficacy when treating cancer. Adjusting for these 
considerations, only 6 percent of patients identified by the MSK-FUSION 
test as having complex variants (2 out of 33) experienced clinical 
benefit, and both of these patients could have been identified for 
therapy with FDA-authorized tests. Only 2 of the 10 patients who 
received therapy based on the MSK-FUSION test would not have otherwise 
been identified, and neither of those patients necessarily benefited 
from the therapy. Following treatment, one had progression of disease 
and the other had stable disease (i.e., disease with no substantial 
change). Thus, it cannot be concluded that patients would have been 
mismanaged had the IVD offered as an LDT not been available.
    (Comment 35) FDA received a comment that increased FDA oversight 
will not result in quantitative agreement between assays, and that any 
implication that it will result in such agreement ``is not supported by 
an empirical evaluation of approved, marketed tests.''
    (Response 35) FDA has not implied that increased FDA oversight 
would ensure quantitative agreement for all tests. FDA's discussion 
regarding variability between tests in the NPRM referred primarily to 
variability in tests' clinical interpretation (e.g., positive or 
negative for the clinical condition being diagnosed by the test) based 
on differing results (88 FR 68006 at 68011). For example, when two 
different tests are both intended to determine whether a patient with 
cancer is eligible for a specific treatment and one result is 
``negative'' while the other is ``positive,'' there is variability 
between those tests that represents a clinically significant problem.
    For tests that provide a numerical value, there is reasonable 
quantitative agreement for FDA-authorized tests that are standardized 
(for example tests that are traceable to a reference material) or 
harmonized. However, not all tests are standardized or harmonized, nor 
do all tests provide a numerical result (for example, qualitative 
genetic tests).
    (Comment 36) FDA received comments regarding FDA's use of a New 
York Times article on non-invasive prenatal screening (NIPS) as 
evidence of a problem (Ref. 96). Specifically, comments stated that the 
article conflated screening with diagnostic testing. They asserted that 
the article mischaracterized false positive results as test failures 
and that the ``problem'' with this category of tests is with ``the lack 
of understanding of its purpose and limitations by the providers and 
patients who were interviewed by the reporters.''
    (Response 36) FDA agrees that NIPS tests, which may tell people the 
risk of their fetus having certain genetic abnormalities, are different 
from diagnostic tests used to more definitively confirm or rule out a 
suspected genetic abnormality. FDA agrees with comments that NIPS tests 
should not be used to confirm or rule out a suspected abnormality. 
After publication of the New York Times article, FDA issued a safety 
communication to explain the limitations of NIPS tests and provide 
information to educate both patients and healthcare providers to help 
reduce the inappropriate use of NIPS tests (Ref. 97). Increased 
oversight of NIPS tests, including an expectation of compliance with 
labeling requirements, can help ensure such tests are appropriately 
labeled with transparent information regarding performance, clear 
instructions, and appropriate limitations.
    (Comment 37) FDA received several comments regarding experience 
with IVDs offered as LDTs during the COVID-19 pandemic. Some suggested 
that FDA's policies slowed availability of tests early in the pandemic 
and slowed down development of over-the-counter (OTC) home tests. Some 
pointed to long review times for EUA requests as indicative that FDA 
does not have the bandwidth to handle review of IVDs offered as LDTs. 
Others suggested that it is unfair to point to problems with COVID-19 
laboratory-made tests as evidence of a broader problem with IVDs 
offered as LDTs given that COVID-19 laboratory-made tests were 
developed under unusual circumstances, including ``overnight demands to 
dramatically expand testing capacity, continuous reagent shortages, 
[and] global supply chain disruptions.'' Another comment, from an AMC, 
reported on the AMC's own experience and that of colleagues at other 
AMCs, stating that ``in no case that I know of was anyone submitting 
data that was remotely representative of what we would generally 
consider sufficient for an assay.'' The comment explained that their 
strategy involved submitting ``minimal verification data so that we 
could get feedback on the initial submission . . . about how to 
proceed.''
    (Response 37) As an initial matter, we disagree that FDA's policies 
unnecessarily slowed availability of COVID-19 laboratory-based or home 
tests that had appropriate assurances of safety and effectiveness. As 
discussed in section V.A.2, FDA has not applied the general enforcement 
discretion approach to LDTs used for declared emergencies because of 
the significant risk posed by the disease (as signified by the unusual 
step of issuing a declaration under section 564 of the FD&C Act) and 
because false results can have serious implications for disease 
progression and public health decision-making, as well as for the 
individual patient's care. For these reasons, FDA generally expected 
EUA authorization for COVID-19 LDTs.
    Notably, FDA took steps to expedite submission and review of EUA 
requests for COVID-19 IVDs to help ensure that patients and providers 
had access to authorized IVDs. FDA made a template available in January 
of 2020 to help manufacturers prepare and submit EUA requests for 
COVID-19 IVDs, and engaged with 100 manufacturers by the end of 
February 2020 to discuss EUA requests and the EUA process. Early in the 
pandemic, FDA authorized IVDs, including several IVDs offered as LDTs, 
within a day of receiving complete datasets. Moreover, FDA issued 
enforcement discretion policies to help address access concerns as 
appropriate. FDA acknowledges that review times grew as a backlog of 
EUA requests grew, but we note that many test manufacturers offered 
their tests as described in these enforcement discretion policies while 
FDA review of their EUA requests was pending.
    FDA also acknowledges that the entire healthcare community, 
including test manufacturers, operated under unusual circumstances that 
do not reflect the environment in which tests are typically developed. 
However, while the pandemic was an unusual circumstance, our 
conversations with laboratory manufacturers during that time revealed 
that many were unfamiliar with what constitutes appropriate analytical 
and clinical validation for an IVD generally. FDA's validation 
expectations for tests seeking EUAs were also lower than expectations 
for traditional marketing authorization, and many allegedly 
``complete'' validation packages in EUA requests submitted to FDA were 
still insufficient. FDA appreciates that many laboratories were new to 
interactions with FDA and not familiar with FDA's expectations for 
validation, but we note that many of these laboratories were 
nonetheless offering their unvalidated IVDs as LDTs for COVID-19, and 
in

[[Page 37325]]

many cases for other diseases or conditions, to the public.
    Moreover, the issues identified with COVID-19 IVDs offered as LDTs 
were similar to those that FDA has identified with IVDs manufactured by 
non-laboratory manufacturers. FDA's identification of these issues for 
IVDs offered as LDTs, by laboratories certified under CLIA, highlights 
the importance of FDA phasing out the general enforcement discretion 
approach for LDTs. Once the phaseout described in this preamble is 
complete, laboratory manufacturers will gain experience with FDA's 
general expectations for validation, providing greater assurances of 
safety and effectiveness for tests and making the country better 
prepared for future outbreaks. Further, FDA intends to publish guidance 
on validation of tests used after a determination and declaration under 
section 564 of the FD&C Act.
    Finally, FDA disagrees that EUA review times for COVID-19 IVDs 
indicate that FDA does not have the capacity to handle review of IVDs 
offered as LDTs, as explained in response to comment 275.
    (Comment 38) Several comments suggested that a study cited by FDA 
as evidence of variable performance among IVDs offered as LDTs was 
flawed (Pfeifer et al. (Ref. 20)). One comment suggested that FDA 
incorrectly described the findings of the study. Comments also 
referenced a recent publication that purported to be a reanalysis of 
the same data but was by different authors (Zehir et al. (Ref. 104)). 
Comments claimed that the reanalysis showed ``excellent'' LDT 
performance and that the original analysis was biased. Others 
questioned the use of the FDA-approved comparator in the original 
study. One comment suggested that FDA failed to disclose the reanalysis 
publication.
    (Response 38) As an initial matter, FDA disagrees that the Zehir et 
al. study has any bearing on FDA's reliance on the Pfeifer et al. 
publication to support the need for this rulemaking. CAP proficiency 
testing programs' performance data are not appropriate comparative 
results to those reported in Pfeifer et al. due to various limitations 
with proficiency testing programs, including that the programs are not 
sufficiently challenging and adequately representative of the routine 
conditions of clinical test use. For example, proficiency testing does 
not cover the entire test procedure, proficiency testing specimens that 
are highly contrived do not closely mimic patient specimens, 
proficiency testing samples include less challenging variant types and 
variant allele fractions, and laboratories are aware of participation 
in highly controlled proficiency testing exercises, which may influence 
how the test is performed and results obtained. Furthermore, aggregate 
data reported by Zehir et al. (Ref. 103) and referenced by the comments 
may mask individual poor performing laboratories. Please see our 
response to comment 34 for additional details regarding FDA's concerns 
with the use of proficiency testing data to evaluate the performance of 
IVDs. The SPOT/Dx pilot study reported in Pfeifer et al. was intended 
to evaluate laboratories individually, using samples that mimic as 
closely as possible patient samples, and compares the accuracy of LDTs 
with an FDA-approved CDx in a specific clinical scenario, to model an 
actual patient encounter (Ref. 20). Thus, it is one of the only truly 
reliable head-to-head comparisons between IVDs offered as LDTs and a 
parallel FDA-authorized IVD.
    We also disagree with the assertion that SPOT/Dx was confounded by 
comparing the performance of IVDs offered as LDTs with that of the FDA-
approved CDx because the CDx was performed as intended, and the SPOT/Dx 
pilot was intended to assess the performance of IVDs offered as LDTs in 
detecting the same variants as the FDA-approved CDx. In both the SPOT/
Dx pilot study and the Zehir et al. reanalysis, testing using the CDx 
led to accurate reporting of all variants for both wet and dry samples 
while testing involving IVDs offered as LDTs did not accurately report 
all variants. SPOT/Dx demonstrated that using the same set of samples, 
intended to mimic formalin-fixed paraffin embedded samples, certain 
IVDs offered as LDTs would not identify the same patient population as 
the approved CDx. FDA notes that the SPOT/Dx working group that 
developed the pilot comprised many stakeholders, including NGS 
laboratories, professional oncology organizations, payors, regulatory 
agencies, patient advocacy groups, and others. CAP specifically 
coordinated the Scientific and Technical Working Group and provided 
professional, logistical, and operational expertise in support of the 
pilot.
    FDA disagrees with the comments' assertion that FDA incorrectly 
described the findings of the SPOT/Dx pilot study (Ref. 20). The 
description of this study in the NPRM stated that ``the same samples 
were sent to 19 laboratories for testing using their own manufactured 
test, and only 7 of those laboratories correctly reported all results. 
For almost half of the tests studied, analytical accuracy was 
significantly lower than that of the parallel test approved by FDA'' 
(88 FR 68006 at 68011). This aligns with the findings reported by the 
study authors that, of the 19 laboratories that analyzed both the wet 
and dry samples, ``7 (37 percent) of 19 laboratories correctly reported 
all variants, 3 (16 percent) of 19 had fewer than five errors, and 9 
(47 percent) of 19 had five or more errors.'' The authors also reported 
that the Praxis Extended Ras Panel correctly reported all variants for 
both wet and dry samples. As discussed in the NPRM (88 FR 68006 at 
68010 and 68011), this study documents high variability in performance 
among IVDs offered as LDTs, which is reflected in the study authors' 
key point that ``the accuracy of detection of genetic variants differed 
among the laboratory-developed tests (LDTs) performed by different 
laboratories,'' as well as the authors' conclusion that ``variable 
accuracy in detection of genetic variants among some LDTs may identify 
different patient populations for targeted therapy'' (Ref. 20).
    FDA disagrees that the findings from the referenced reanalysis 
(Ref. 103) show ``excellent'' LDT performance. Despite Zehir et al.'s 
claims that the reanalysis demonstrated excellent laboratory 
performance, individual laboratories still had a significant number of 
errors, with only eight laboratories correctly reporting all variants 
in the reanalysis (compared to seven in SPOT/Dx) and four laboratories 
still had greater than five errors.
    Finally, FDA did not fail to disclose the published reanalysis, as 
it was not published prior to the posting of FDA's NPRM for public 
inspection by the Office of the Federal Register on September 29, 2023. 
It has since been published and, in addition to the discussion in our 
comment responses, is included as a reference to the rule.
    (Comment 39) One comment claimed that the Friends of Cancer 
Research Tumor Mutational Burden (TMB) study cited by FDA as evidence 
of variability among laboratories' tests actually showed similar 
variability as that seen in two FDA-approved tests.
    (Response 39) FDA acknowledges there can be variability among FDA-
approved tests and that the referenced TMB study included two FDA-
authorized tests, one tumor mutation profiling test that includes 
detection of TMB, and one CDx test for detection of TMB for identifying 
patients for treatment with pembrolizumab. FDA further acknowledges 
that the results from the laboratories performing those tests were 
included among the authors' conclusions regarding variability across 
tests. The authors of the study did not

[[Page 37326]]

conduct an analysis to compare variability of IVDs offered as LDTs to 
those that are FDA-authorized nor comment on differences in variability 
between the two. While FDA accurately described the results of this 
study as finding ``substantial variability among tumor mutational 
burden (TMB) tests manufactured by laboratories and used to identify 
patients with cancer most likely to benefit from immunotherapy'' in the 
NPRM (88 FR 68006 at 68011), FDA does not mean for this to imply that 
the results of this study indicate greater variability in the studied 
IVDs offered as LDTs compared to the studied FDA-authorized tests. As 
such, FDA is clarifying here that the study does not support the 
proposition that TMB tests manufactured by laboratories have worse 
performance than FDA authorized TMB tests. However, other evidence in 
the NPRM supports this proposition as applied to tests more generally 
(see Refs. 20, 91 to 96, 105 to 110).
    (Comment 40) One comment claimed that the publication on epidermal 
growth factor receptor (EGFR) testing for non-small cell lung cancer 
that was referenced in the PRIA is biased in multiple ways: the authors 
had a vested interest in the outcome, the work was funded by a company 
with a vested interest in the outcome, the IVD offered as an LDT was in 
Europe and therefore not required to comply with CLIA, and the trial 
did not assess the same material extracted from residual tissue 
specimens with the laboratory-made and FDA-approved test.
    (Response 40) FDA acknowledges that, as is clear from the study 
publication, the work reported in this publication: (1) was authored 
and funded by a company who may be a competitor with the relevant 
laboratory manufacturers and (2) utilized IVDs offered as LDTs in 
Europe, which may not be representative of IVDs offered as LDTs in the 
United States. This study was not included in the NPRM but was included 
in the PRIA. FDA no longer cites this publication in the FRIA.
    (Comment 41) One comment addressed FDA's citation of Manrai et al., 
2016 (Ref. 95), arguing that this publication did not show that IVDs 
offered as LDTs exacerbate health disparities. The comment claimed that 
FDA did not properly describe the findings of the publication, stating 
that ``the message of the paper was the lack of testing in both control 
and diseased populations for underrepresented minorities is what led to 
poorer outcomes.'' The comment also asserted that an FDA-approved assay 
would have similar limitations to those described for IVDs offered as 
LDTs.
    (Response 41) FDA cited this publication for the proposition that 
IVDs offered as LDTs may exacerbate health disparities. FDA did not 
contend that the publication showed that IVDs offered as LDTs do in 
fact exacerbate health disparities. FDA also separately cited this 
publication because it describes problems with IVDs offered as LDTs, 
regardless of any impact on health disparities (see 88 FR 68006 at 
68011 (stating that the publication ``reported false positive results 
from genetic IVDs offered as LDTs for hypertrophic cardiomyopathy in 
multiple patients of African American descent.'')).
    FDA believes it is appropriate to cite this publication to support 
that IVDs offered as LDTs may exacerbate health disparities for the 
following reasons. First, the study identified multiple persons of 
African or unspecified ancestry who had received false positive test 
results from IVDs offered as LDTs related to the historical dearth of 
data that include persons of diverse racial and ethnic backgrounds, 
which prevented accurate variant interpretation at the time of results 
reporting; higher rates of these types of false results in 
underrepresented populations may exacerbate health disparities. Second, 
the paper reports on disparities that may result from errors unrelated 
to access to care, particularly genetic variant misclassification (a 
type of inaccurate test result). The authors specifically state that 
their findings ``show how health disparities may arise from genomic 
misdiagnosis'' (i.e., a type of inaccurate result) and describe the 
negative consequences of the ``provision of false genetic information'' 
not just to a patient but to their relatives as well. The authors also 
report that their ``findings suggest that false positive reports are an 
important and perhaps underappreciated component'' of certain tested 
persons. Despite the comment's assertion that the message of this paper 
was that the lack of testing in underrepresented minorities is what led 
to poorer health outcomes, that message was not explicitly stated in 
the publication. Rather, the authors call for diverse genomic data in 
their conclusion: ``the misclassification of benign variants as 
pathogenic that we found in our study shows the need for sequencing the 
genomes of diverse populations, both in asymptomatic controls and the 
tested patient population.''
    FDA acknowledges that lack of data on the genomes of diverse 
populations makes demonstrating accurate genetic variant classification 
in diverse populations challenging. While FDA-authorized tests may face 
challenges due to the paucity of data from genetically diverse 
populations, FDA-authorized tests generally have greater transparency 
regarding the population(s) in which they were validated, information 
pertaining to device safety and effectiveness for specific demographic 
characteristics if performance differs within the target population, 
and population-specific limitations, if applicable. In addition, during 
FDA premarket review, FDA may ask that sponsors provide data for 
different intended use populations as well as diversity action plans to 
improve the generation of evidence regarding device performance in 
diverse populations. As such, in general, there is greater confidence 
in the accuracy and reliability of FDA authorized genetic tests, and 
FDA oversight of IVDs offered as LDTs may help to advance health 
equity, as discussed in the NPRM and in our responses to comments in 
section VI.K of this preamble.
    (Comment 42) FDA received a comment from a sponsor that submitted a 
510(k) for an IVD offered as an LDT that was discussed in FDA's 
memorandum to file regarding ``Examples of In Vitro Diagnostic Products 
(IVDs) Offered as Laboratory Developed Tests (LDTs) that Raise Public 
Health Concerns,'' which was included in the docket for this rulemaking 
(Ref. 16). The comment expressed concerns regarding the inclusion of 
this particular submission in the memorandum, contending that FDA's 
review of the submission was inappropriate and that the validation data 
submitted for this IVD offered as an LDT was sufficient. In particular, 
the comment stated that ``leading journals'' had published studies 
demonstrating the utility of the sponsor's techniques; that the sponsor 
withdrew its submission because FDA refused to use a certain ``fit-for-
purpose'' assessment of the data; that the sponsor had demonstrated the 
detection limits and precision of the IVD; that quality controls 
embedded in the IVD provided for the identification of any interfering 
substances; that FDA inappropriately focused on certain details while 
dismissing other important information; that the review process was 
overly time-consuming and expensive; and that the IVD has become 
standard of care.
    (Response 42) FDA disagrees with this comment. In relevant part, 
the memorandum to file stated that ``[i]n 2021, FDA received a 510(k) 
submission from [redacted] for their [redacted] test for monitoring 
changes in burden of

[[Page 37327]]

disease in pediatric and adult patients with [acute myeloid leukemia 
(AML)] during and after treatment. The submission did not contain 
adequate analytical and clinical validation studies to show the test 
worked as intended. For example, the sponsor did not provide any data 
from interference, detection limit, and reagent stability studies; did 
not submit data from precision studies to demonstrate the test is 
reliable in intended use specimens; only used one specimen to evaluate 
sample stability rather than the recommendation of at least ten; and 
included samples in the clinical study that were not the sample type 
intended for use with the test. The sponsor withdrew the submission 
after FDA raised concerns with the inadequate validation data. Without 
sufficient information to demonstrate adequate validation, a test's 
performance is unknown, which may put patients at risk of harm due to 
inaccurate results. In general, inaccurate results from tests to 
monitor disease burden during and after treatment for AML could lead to 
suboptimal clinical management of patients with AML. The risk of false 
negative results (i.e., a patient assumed to have a more favorable 
prognosis based on the false negative result) could potentially result 
in a reduction in the level of care such as less medication use, 
subsequent confirmatory testing, and other possible treatment 
decisions. False positive results (i.e., a patient who is disease free 
presumed to have a hematologic malignancy based on the positive test 
result) could result in additional unnecessary testing'' (Ref. 16).
    With respect to the comment's statement that ``leading journals'' 
published studies demonstrating the utility of the sponsor's 
techniques, FDA notes that during review of the 510(k) submission, the 
sponsor referenced three publications that it claimed supported the 
clinical validation of the IVD. The first publication described a 
feasibility study and was not a validation study. The second 
publication described a clinical validation study that used a different 
version of the device than the subject device under review (i.e., the 
device evaluated had a different operating principle than the device 
under review). The sponsor did not provide information adequate to 
support leveraging clinical performance data from a version of the 
device that differed in significant ways from the subject device. In 
addition, there was a difference in the limit of quantitation (LoQ) 
reported in the publication and the LoQ estimated by precision and 
linearity data submitted by the sponsor, which raised significant 
uncertainty in the clinical validation data. The third publication was 
a clinical study that utilized the device to aid in the diagnosis of a 
different disease and was thus for a different intended use. Therefore, 
the data could not be leveraged to support the device's safety and 
effectiveness for the AML claim being sought.
    FDA also disagrees with the comment's statement that FDA refused to 
use a ``fit-for-purpose'' assessment of the data. FDA's review was 
risk-based and intended to be consistent with least burdensome 
principles. The expectations for safety and effectiveness for this test 
were based on the intended use of the device and in the context of 
special controls required for devices of this type, thereby ensuring 
the device performance was validated in a fashion encompassed by the 
fit-for-purpose concept. Throughout the review, FDA considered and 
proposed multiple alternatives as least-burdensome approaches.
    The comment further contended that the sponsor had demonstrated the 
detection limit of the assay and had submitted precision studies to 
demonstrate test reliability. However, during FDA's review of the 
submission, the Agency did not agree that the detection limit of the 
assay could be demonstrated solely in the manner suggested by the 
sponsor as the output assessed by the sponsor in the studies conducted 
was different from the output of the device. In addition, although the 
sponsor had submitted multiple precision studies, the sponsor failed to 
provide information on how the studies were conducted and how the data 
were analyzed (e.g., study protocols), such that FDA could not 
determine whether the reported precision would be adequate to support a 
determination that the test was as safe and effective as the predicate 
device. In addition, when the sponsor provided a reanalysis of the 
precision data, there were unexplained deviations in results 
calculations, raising concerns with the reliability of the data 
submitted.
    With respect to the comment's assertion that quality controls 
embedded in the IVD provided for the identification of any interfering 
substances, the sponsor made this assertion during FDA's review of the 
submission as well, in an effort to justify why studies to assess the 
impact of potentially interfering substances on test performance were 
inapplicable. However, the sponsor did not provide critical explanatory 
information or documentation, or any validation data to demonstrate the 
capability of the laboratory's continuous process controls to identify 
failures in instrument, reagent, or specimen integrity. FDA also 
disagrees that the Agency focused too heavily on certain aspects of the 
submission, such as cell counting, and dismissed the importance of 
other aspects, such as fluorescence intensity. FDA discussed 
fluorescence intensity with the sponsor on several occasions. The 
comment's assertion that FDA never asked about the results from three 
clinical trials is likewise not accurate; during review of the 
submission, FDA made multiple requests to the sponsor for additional 
information on the studies submitted, and identified various concerns 
with the studies. Ultimately, throughout the review, FDA considered the 
available data and least burdensome approaches for providing the data 
necessary to demonstrate that the device was as safe and effective as 
the predicate device, considering the intended use and special controls 
for this device type, but the sponsor's assertions did not obviate the 
need for adequate clinical validation. During the review process, the 
sponsor acknowledged its ability to perform validation studies 
requested by FDA, but stated that it declined to do so.
    The comment also suggested that FDA's review took too long and was 
too expensive, stating that the review process took 9 years and cost 
more than $1,000,000. FDA acknowledges that the Agency worked with the 
sponsor over 9 years, but notes that much of this interaction was in 
the context of 6 voluntary Pre-Submissions submitted by the sponsor, 
beginning approximately 9 years before the 510(k) was submitted.
    With respect to the comment's statement that the subject assay has 
become the standard of care, FDA was not able to determine whether in 
fact this test is now used as part of the standard of care. Regardless, 
a test being used as part of the standard of care is not sufficient to 
provide appropriate assurances regarding safety and effectiveness. Use 
in clinical practice does not necessarily establish that a device is 
appropriately safe and effective.
    (Comment 43) One comment stated that FDA's memorandum regarding 
examples of IVDs offered as LDTs that raise public health concerns did 
not provide enough details to determine whether the stated problems 
were related to assay design or procedural issues, and noted that 
procedural issues are under the regulatory authority of CLIA. The 
comment also asserted that FDA's statement in the memorandum

[[Page 37328]]

that FDA did not confirm the veracity of the reports suggests that FDA 
did not deem the public health risks severe enough to warrant 
investigation by the Agency at the time of submission.
    (Response 43) FDA disagrees that the Agency did not deem the public 
health risks severe enough to warrant investigation by the Agency. The 
referenced statement regarding the Agency not confirming the veracity 
of information was specific to complaints, MDRs, and allegations, where 
FDA relies on information submitted by the entity filing the report. As 
described in that memorandum, any follow up by the Agency on the 
complaints, MDRs, and allegations is not included in the memorandum. As 
a general matter, FDA does not comment on such investigations.
    FDA acknowledges that the details included in the memorandum 
regarding the MDRs and allegations cited therein do not indicate 
whether the problems were related to assay design or other aspects not 
covered by CLIA, due to the nature of MDRs where the information 
available to the Agency is the information submitted in the report and 
does not typically include detailed information on test design or 
validation of the test. The memorandum describes what was reported in 
the MDR or allegation. However, all of the examples from submissions 
FDA reviewed had issues related to analytical validation that would 
negatively impact the test's intended clinical use, or inadequate 
clinical validation that CLIA does not address. For these examples, FDA 
had sufficient data and information that pointed to issues CLIA would 
not address. Furthermore, FDA was able to confirm that the laboratories 
that developed 22 of the 26 IVDs offered as LDTs reviewed in these 
submissions were CLIA-certified laboratories. For the others that FDA 
was not able to confirm, those laboratories should have been CLIA 
certified since they were performing the tests on samples from United 
States subjects. Taken together, FDA identification of these issues 
demonstrates potential problems with the tests despite CLIA regulation.

D. FDA Authority To Regulate LDTs

1. General Comments Regarding FDA's Authority
    (Comment 44) Various comments stated that FDA has statutory 
authority over LDTs. Other comments asserted (without specific 
analysis) that FDA lacks authority to finalize the proposed rule.
    (Response 44) For the reasons set forth in the NPRM and this 
preamble, FDA agrees with the commenters who stated that FDA has this 
authority. FDA has long stated that LDTs, like other IVDs, are 
``devices'' subject to applicable requirements in the FD&C Act (see 62 
FR 62243 at 62249 (November 21, 1997), 65 FR 18230 at 18231 (April 7, 
2000), Ref. 27, Ref. 32-33, Ref. 35, Ref. 39, Ref. 57, Ref. 97, Ref. 
111-121). FDA responds to more specific jurisdictional arguments in the 
paragraphs that follow.
    (Comment 45) Some comments suggested that FDA's failure to publicly 
announce its authority over LDTs closer to enactment of the FD&C Act or 
MDA raises questions about whether the Agency has authority over LDTs. 
Several comments noted that FDA did not communicate its authority over 
LDTs until 1992, 16 years after enactment of the MDA. Two comments 
suggested that FDA's position that it gained authority over IVDs, 
including LDTs, ``when key legislation was passed'' but exercised 
enforcement discretion constitutes ``revisionist history'' or an ``ex 
post facto'' narrative.
    (Response 45) FDA disagrees with these comments. First, the 
Agency's jurisdiction depends on the scope of authority granted to it 
under the statute, and that jurisdiction existed (as explained in the 
NPRM and elsewhere in this preamble) regardless of when FDA publicly 
discussed it. See Bostock v. Clayton Cty., 140 S. Ct. 1731, 1737 (2020) 
(``extratextual considerations'' do not trump ``the express terms of a 
statute'').
    Second, the comments appear to take the position that FDA may not 
assert its statutory authority unless it issued a public statement 
announcing that authority within some timeframe after which Congress 
granted it. FDA is aware of no such obligation. On the contrary, the 
U.S. Supreme Court has held that agencies are not required to 
prospectively announce their interpretations to the public before 
applying that interpretation in an individual case. SEC v. Chenery 
Corp., 332 U.S. 194 (1947). Moreover, because FDA generally did not 
enforce device requirements with respect to LDTs when the MDA was 
passed (as a matter of practice and based on relevant public-health 
considerations), it would not necessarily have made sense for FDA to 
expend resources to issue a public statement about its authority. FDA 
did not put itself to that task until public-health considerations 
justified it in 1992. (Ref. 111). Thus, as these comments appear to 
concede, FDA squarely announced its understanding that LDTs are devices 
over 30 years ago, nearly double the 16-year period cited in these 
comments.
    Third, to the extent that comments are suggesting that laboratories 
would not have understood their potential status as manufacturers 
around the time the MDA was passed, FDA disagrees. FDA signaled this 
interpretation in various contemporaneous materials. In 1973, before 
enactment of the MDA, FDA issued a final rule announcing regulatory 
requirements for IVD products, including systems, which contained no 
carveout or exception for laboratories (38 FR 7096, March 15, 1973). 
Following the MDA, FDA amended the rule to clarify that IVDs are 
devices, consistent with Congress's intent. 45 FR 7474, 7484 (February 
1, 1980) (revising the definition to state that IVD products are 
``devices'' rather than ``drugs or devices'' under the FD&C Act). 
Again, FDA did not create any carveout or exception for LDTs. These 
facts put laboratories on notice that FDA interpreted the device 
requirements to apply to test systems regardless of who manufactured 
them. In addition, 3 years earlier, in 1977, FDA issued regulations 
regarding device registration and listing and exempted only those 
clinical laboratories ``whose primary responsibility to the ultimate 
consumer is to dispense or provide a service through the use of a 
previously manufactured device'' (see Sec.  807.65(i) (21 CFR 
807.65(i)); 42 FR 42520 at 42528, August 23, 1977)). This exemption 
conveyed that: (1) FDA considered clinical laboratories to manufacture 
devices (otherwise this exemption would not have been necessary) and 
(2) some laboratories are not exempt from registration and listing 
(i.e., those who fall outside the ``use of a previously manufactured 
device'' limitation). In addition, in the context of a different 
exemption, the preamble to that rule emphasized that ``exemption from 
registration does not relieve such persons from their obligation to 
comply with other provisions of the act or regulations'' (42 FR 42520 
at 42521). Thus, laboratories were on notice that FDA considered them 
device manufacturers subject to applicable provisions of the FD&C Act 
and regulations.
    (Comment 46) Several comments suggested that FDA's enforcement 
discretion approach for LDTs raises questions about FDA's authority in 
this area. One comment stated that the commenter ``believes that any 
authority to regulate LDTs has been waived through the agency's actions 
since 1988 if they even existed when the Medical Device Amendments 
passed in 1976.'' Another comment noted, in arguing that

[[Page 37329]]

FDA lacks authority, that the Agency has a ``history of inconsistent 
positions on LDTs'' and ``has never exercised [its] claimed authority 
in a comprehensive manner in the 85 years it had authority over 
devices.'' Other comments stated that FDA's ``position on [its] 
authority has vacillated in significant ways, even recently.''
    (Response 46) FDA disagrees that its enforcement discretion 
approach suggests that FDA lacks or ``waived'' authority over LDTs. As 
an initial matter, FDA is not aware of any legal support for the 
proposition that an agency can waive statutory authority granted to it 
by Congress through the exercise of enforcement discretion. Indeed, the 
Supreme Court has expressly distinguished an agency's exercise of 
enforcement discretion--what FDA has done in the case of LDTs--from the 
refusal to initiate enforcement proceedings based on the agency's 
conclusion ``that it lacks jurisdiction''--a conclusion FDA has never 
reached in this context. Heckler v. Chaney, 470 U.S. 821, 833 n.4 
(1985).
    In addition, although FDA recognizes that it has initiated a number 
of efforts to address LDTs, as explained in section III.D.2 of the 
NPRM, these policy efforts do not cast doubt on FDA's authority or its 
understanding of its authority (88 FR 68006 at 68016). On the contrary, 
FDA's initiation of different policy approaches over the course of many 
years confirms that it uniformly believed it had authority and certain 
discretion with respect to LDTs. Furthermore, as explained in response 
to comment 45, FDA interpreted laboratories to be manufacturers, and 
IVD products, including systems, to be devices, even before the 
initiation of these policy efforts. And since 1992, FDA has 
consistently and publicly announced that IVDs manufactured by 
laboratories are devices under the FD&C Act (see section III.D.1 of the 
NPRM, ``FDA's Longstanding Recognition That IVDs Manufactured by 
Laboratories Are Devices,'' 88 FR 68006 at 68015-16). Thus, contrary to 
commenters' suggestion, FDA has not had ``inconsistent positions'' but 
rather has consistently maintained a single position: it has authority 
over LDTs.
    (Comment 47) One comment argued that ``it has long been the 
mainstream view of legal experts that the FDA lacks authority to 
regulate LDTs in the absence of legislation to grant them such 
authority,'' referencing a white paper coauthored by Paul Clement and 
Laurence Tribe as well as a June 2020 memorandum by the then-General 
Counsel of HHS. Another comment also quoted the HHS then-General 
Counsel's June 2020 memorandum for the proposition that ``the Agency's 
jurisdiction to regulate these devices is not uniform and not as 
plenary as it is for a traditional device.''
    (Response 47) FDA disagrees with the assertion that legal experts 
generally think FDA lacks authority over LDTs. In FDA's experience, 
many legal scholars who have occasion to discuss LDTs describe them as 
tests treated differently as a matter of Agency discretion, rather than 
because FDA lacks authority.\53\ Although the first comment relies on a 
document authored by Paul Clement and Lawrence Tribe as support for the 
proposition regarding the ``mainstream view of legal experts,'' these 
authors did not write that document in their capacity as independent 
legal experts, but as counsel to the American Clinical Laboratory 
Association (ACLA). Therefore, that document reflects the view of one 
interested party. To the extent that particular commenters incorporated 
arguments from that document, we address the substance of those 
arguments in our responses to the specific comments in question. In any 
event, FDA's analysis is based upon the substantive merits of the 
issues, not upon surveying how many ``legal experts'' have advocated 
for or against a given view.
---------------------------------------------------------------------------

    \53\ See, e.g., Refs. 122-124.
---------------------------------------------------------------------------

    In addition, the June 2020 memorandum identified in the comments 
did not (contrary to one comment's suggestion) take the position that 
FDA lacks authority to regulate LDTs in the absence of legislation. 
Instead, the memorandum indicated that FDA has discretion to treat LDTs 
as devices but that there is legal risk in taking that position absent 
notice-and-comment rulemaking (for further detail on the June 2020 
memorandum's position, see, for example, Ref. 125 at 2, n. 5). As noted 
by the second comment, the memorandum did suggest that FDA's authority 
over LDTs was constrained by certain statutory limitations; the 
memorandum focused in particular on the following statutory language: 
``introduction or delivery for introduction into interstate commerce,'' 
``commercial distribution,'' ``held for sale,'' and ``person.'' HHS no 
longer agrees with that memorandum, which has since been superseded, 
for the reasons set forth in sections VI.D.3, VI.D.4, and VI.E (comment 
response 105) of this preamble. More generally, we note that even if 
FDA's authorities were limited in the ways proposed in the June 2020 
memorandum, that would not implicate the question of whether LDTs are 
devices and thus FDA's authority to regulate LDTs under other relevant 
provisions of the statute and regulations. Not all provisions apply 
equally to all regulated products. For example, some statutory 
provisions apply depending on the specific activities of a manufacturer 
(see response to comment 54). Similarly, some statutory provisions 
impose requirements with respect to a device on certain actors but not 
others--for example, some provisions apply only to manufacturers and 
importers but not to distributors (e.g., 21 U.S.C. 360i(a)(1)) and 
others apply to all three (e.g., 21 U.S.C. 360h(a))--but the device is 
nonetheless within FDA's jurisdiction. FDA has jurisdiction to regulate 
devices including LDTs, even if some subset of substantive statutory 
provisions do not apply to LDTs.
    (Comment 48) One comment stated that ``[f]alse advertising by some 
rogue companies overstating the benefits of their tests is the purview 
of the [Federal Trade Commission (FTC)], not the FDA.''
    (Response 48) Although the comment appears to argue that IVDs 
manufactured by laboratories are not devices (and instead fall solely 
within an FTC-regulated category), laboratory-made IVDs are devices, as 
explained elsewhere in this preamble and the NPRM. Because these IVDs 
are devices, advertising for them does not fall within the sole purview 
of the FTC. Such IVDs are subject, for example, to the provisions in 
the FD&C Act that deem a device misbranded if its labeling (or 
advertising, in the case of a restricted device) is ``false or 
misleading in any particular.'' 21 U.S.C. 352(a)(1) and (q). FDA 
recognizes that the FTC also has authority regarding the advertising of 
devices. E.g., 15 U.S.C. 52(a)(1) (prohibiting the dissemination of 
``any false advertisement . . . for the purpose of inducing, or which 
is likely to induce, directly or indirectly, . . . the purchase . . . 
of . . . devices''). Because the two Agencies share authority, they 
have long worked together to effectively coordinate and use their 
authorities in complementary ways, particularly mindful of each 
Agency's substantive expertise, such as FDA's scientific expertise. 
Thus, the FTC is not the sole regulator of device advertisements.
    (Comment 49) Two comments drew an analogy between the preparation 
of a laboratory test and the preparation of a restaurant meal. One 
comment stated that while FDA regulates the ingredients of a restaurant 
meal, such as pasta, it does not regulate the preparation of a 
restaurant meal, and the same should be true for laboratory tests. 
Another comment stated that restaurant recipes

[[Page 37330]]

are like laboratory testing procedures and should be regulated in the 
same manner.
    (Response 49) Food and devices present different public health 
considerations and are subject to different requirements under the FD&C 
Act, including differing premarket review requirements, so FDA 
oversight of restaurants should not be understood to determine FDA's 
authority over, or approach to, laboratory tests. Furthermore, these 
comments appear to take as their premise that restaurants are exempt 
from the FD&C Act, but that is not the case. FDA has jurisdiction over 
``food,'' a term defined broadly at 21 U.S.C. 321(f), and restaurants 
are subject, for example, to the prohibition on doing an act with 
respect to a food if such act is done while the food is held for sale 
after shipment in interstate commerce and results in it being 
adulterated or misbranded (21 U.S.C. 331(k)).
    (Comment 50) One comment argued that if the Supreme Court overturns 
or narrows the Chevron doctrine through its decision in Loper Bright 
Enterprises v. Raimondo, that would ``further undermine FDA's authority 
to regulate LDTs and further place in question the validity of a final 
LDT rule.''
    (Response 50) Because the FD&C Act confers clear authority on FDA 
to regulate IVD products, without any exception for products made by 
laboratories, the Chevron doctrine is not necessary to resolve any 
question of FDA's authority over LDTs. FDA's reasoning for this 
position, taking into account the traditional tools of statutory 
construction, is set forth in the following responses to comments 51-
54.
2. Application of the Device Definition to LDTs
    A number of comments argued that LDTs are not devices within the 
meaning of 21 U.S.C. 321(h)(1) because they are intangible services 
rather than tangible or material objects. Comments raised arguments 
related to the plain language, canons of construction, legislative 
history, and other provisions of the FD&C Act to support this position.
    (Comment 51) Several comments took the position that because the 
device definition does not contain the terms ``in vitro diagnostic 
product'' (as defined in Sec.  809.3), ``system,'' ``assay,'' ``test,'' 
or ``laboratory developed test,'' it does not encompass these articles. 
Some stated that these terms are broader than the terms that do appear 
in the definition, including ``in vitro reagent,'' ``instrument,'' and 
``similar or related article,'' and concluded that they therefore fall 
outside the definition. One comment stated that because Congress 
presumably was aware that diagnostic tests are ``key elements of 
medical diagnoses'' when it enacted the MDA, if Congress had intended 
to cover such tests, it would have done so expressly. Several comments 
stated that Congress's decision not to include the term ``system'' in 
the device definition in 1976, following issuance of the IVD 
regulations in 1973, undermines the Agency's reliance on that concept. 
One commenter also noted that the concept of an LDT was not discussed 
in congressional hearings prior to the passage of the MDA, suggesting 
that Congress did not intend for LDTs to be included.
    (Response 51) FDA disagrees with the position that the device 
definition does not include IVD systems because it does not contain the 
terms ``system,'' ``assay,'' ``test,'' or ``laboratory developed 
test.'' As explained in the NPRM, IVD systems fell within the device 
definition (which included the terms ``apparatus'' and ``contrivance'') 
even before passage of the MDA (88 FR 68006 at 68017). In FDA's 1973 
rulemaking, which occurred 3 years before the MDA's enactment, the 
Agency publicly announced its view that IVD systems fell within the 
device and drug definitions and thus within its authority. If Congress 
had disagreed with FDA's interpretation, it had the opportunity to 
clarify that in the MDA, but it did not do so. Instead, it retained the 
same terms from the device definition in the 1938 Act, without any 
exemption for ``systems,'' ``assays,'' ``tests,'' or ``laboratory 
developed tests.'' This sequence of events indicates that despite 
numerous opportunities to do so, over decades' worth of subsequent 
legislation concerning devices, Congress did not disagree with FDA's 
interpretation that IVD systems fall within its authority.
    In fact, Congress clarified in the MDA that IVD systems are devices 
and not drugs. To do so, it added the terms ``in vitro reagent'' and 
``other similar or related articles'' to the device definition. See S. 
Rep. No. 93-670 at 16 (January 29, 1974) (explaining, with respect to 
nearly identical language, that ``[t]he Committee recognizes that there 
is confusion at the present time about whether certain articles are to 
be treated as devices or drugs under the Food, Drug and Cosmetic Act. 
Therefore, the Committee reported bill has carefully defined `device' 
so as to specifically include implants, in vitro diagnostic products, 
and other similar or related articles.''). The purpose of adding the 
term ``in vitro reagent'' was not to narrow FDA's authority over IVD 
products (again, Congress had much clearer ways to accomplish that); 
instead, the goal was to clarify that all in vitro diagnostic products 
were devices rather than drugs. Id. (explaining that the term 
``device'' includes ``in vitro diagnostic products'') (emphasis added). 
Other evidence in the legislative history confirms that Congress 
intended for FDA to regulate IVD systems as devices, as explained in 
response to comment 53. More recently, in the Protecting Access to 
Medicare Act of 2014 (PAMA) (passed in 2014), Congress enacted 
provisions that support an interpretation that LDTs are subject to FDA 
regulation. 42 U.S.C. 1395m-1(d)(5) & (d)(5)(B).
    FDA also disagrees with the comment that suggested that Congress 
would have discussed LDTs in congressional hearings if it had intended 
for LDTs to be included in the definition. The topics covered in 
congressional hearings do not trump the plain text of the device 
definition, which encompasses LDTs. See Bostock v. Clayton Cty., 140 S. 
Ct. 1731 at 1754 (``Judges are not free to overlook plain statutory 
commands on the strength of nothing more than suppositions about 
intentions or guesswork about expectations.''). Also, it would not be 
reasonable to expect that Congress would have discussed every 
conceivable device during congressional hearings.
    (Comment 52) Many comments stated that tests made by laboratories, 
or some subset of such tests termed ``LDTs,'' are not devices under the 
FD&C Act because the device definition is limited by its plain language 
to physical objects or material things, and tests made by laboratories 
are intangible methods, services, procedures, or processes. One comment 
stated that a device within the definition has ``mass and volume'' and 
``can be touched and held.'' Another comment relied on a canon of 
construction that words grouped together in a list should be given 
related meaning, and stated that because, according to the comment, the 
terms ``instrument,'' ``implement,'' ``machine,'' ``implant,'' and ``in 
vitro reagent'' refer to tangible objects, the terms ``apparatus'' and 
``contrivance'' should also be understood to be tangible objects. The 
same comment noted that an ``article'' is defined as a ``particular 
material thing'' in the Oxford English Dictionary (OED). Several 
comments stated that courts have construed the term ``article'' to mean 
a material thing.
    (Response 52) The FD&C Act defines a device, in relevant part, as 
``an instrument, apparatus, implement, machine, contrivance, implant, 
in vitro

[[Page 37331]]

reagent, or other similar or related article, including any component, 
part, or accessory, which is . . . intended for use in the diagnosis of 
disease or other conditions, or in the cure, mitigation, treatment, or 
prevention of disease.'' 21 U.S.C. 321(h)(1)). FDA does not agree that 
this definition is limited by its plain language to physical objects or 
material things, but even if it were, a test system is a physical 
object and a material thing.
    As an initial matter, FDA does not read the definition of device to 
encompass only physical objects. The definition includes terms such as 
``contrivance,'' whose plain meaning goes beyond objects that can be 
``touched and held.'' Contrivance, Merriam-Webster.com (last accessed 
January 5, 2024) (defining ``contrivance'' as ``a thing contrived'' and 
``an artificial arrangement or development,'' among other things). 
(Ref. 126). (See also Ref. 127 (defining ``contrivance'' as ``an 
arrangement or thing in which the foregoing action or faculty is 
embodied; something contrived for, or employed in contriving to effect 
a purpose.'') Although commenters advocate for a narrow interpretation 
of the device definition, the Supreme Court has specifically considered 
and rejected a narrow reading of the FD&C Act, instead embracing broad 
constructions of the FD&C Act based on the Court's understanding of its 
text, congressional intent, and remedial purpose. See United States v. 
Bacto-Unidisk, 394 U.S. 784, 798 (1969) (``Congress fully intended that 
the [FD&C] Act's coverage be as broad as its literal language 
indicates.'').\54\ Software is an example of an article that cannot be 
``touched and held'' but falls within the device definition. FDA has 
long interpreted software to be a device, see, e.g., 52 FR 36104, 
September 25, 1987, and Congress reinforced that interpretation in the 
21st Century Cures Act (Cures Act) (Pub. L. 114-255). The Cures Act, 
enacted in 2016, amended the FD&C Act to exclude certain software 
functions from the statutory ``device'' definition unless certain 
criteria are met. See 21 U.S.C. 360j(o). Congress would have had no 
need to make this amendment to the FD&C Act if the device definition 
did not already cover software, which is a thing that cannot be 
``touched and held.'' This underscores that a plain reading of the 
device definition may include things that cannot be ``touched and 
held.''
---------------------------------------------------------------------------

    \54\ See also United States v. Dotterweich, 320 U.S. 277, 280 
(1943) (``The purposes of [the FD&C Act] thus touch phases of the 
lives and health of people which, in the circumstances of modern 
industrialism, are largely beyond self-protection. Regard for these 
purposes should infuse construction of the legislation if it is to 
be treated as a working instrument of government and not merely as a 
collection of English words.''); United States v. 25 Cases, 942 F.2d 
1179, 1182 (7th Cir. 1991) (quoting 79 Cong. Rec. at 4841 (1935)) 
(``the language [of the bill] is broad enough to cover any device of 
which the Food and Drug Bureau . . . . . . chooses to take 
jurisdiction''); United States v. Diapulse Corp. of America, 457 
F.2d 25, 27-28 (2d Cir. 1972) (``[t]he reach of the Act is broad''); 
Clinical Reference Lab. v. Sullivan, 791 F. Supp. 1499, 1508-09 (D. 
Kan. 1992), rev'd in part on other grounds sub nom U.S. v. 
Undetermined No. of Unlabeled Cases, 21 F.3d 1026 (10th Cir. 1994) 
(``congressional reports . . . . . . indicate approval of the 
Supreme Court's method in Bacto-Unidisk of broadly defining terms 
within the [FD&C Act]'').
---------------------------------------------------------------------------

    Regardless, a test system manufactured by a laboratory is a 
physical product and a material thing. As explained in the NPRM, a test 
system is a set of components--such as reagents, instruments, and other 
articles--that function together to produce a test result (88 FR 68006 
at 68017). No comment disputed that these individual components are 
physical or tangible, and there is no reason to think that uniting 
those physical objects in a system takes away from their physical or 
material nature. The instrument clause of the device definition clearly 
encompasses collections of this sort because it includes the term 
``apparatus,'' which Merriam-Webster defines as ``a set of materials or 
equipment designed for a particular use'' (Ref. 128. See also Ref. 129-
130). The fact that there is human involvement to fulfill the intended 
use of the system does not exclude it from the definition of a device. 
Such involvement is neither unique to LDTs nor unusual for devices more 
generally, as the examples offered in comment response 66 illustrate.
    In short, the statute makes clear that test systems, including 
those manufactured by laboratories, are devices. To argue otherwise not 
only would be inconsistent with the FD&C Act's plain text, but also 
would be at odds with the way FDA has understood and regulated IVDs 
(and other devices) for at least half a century. See 38 FR 7096 at 
7098, see 62 FR 62243 at 62249 (November 21, 1997), 65 FR 18230 at 
18231 (April 7, 2000), Ref. 27, Ref. 32-33, Ref. 35, Ref. 39, Ref. 57, 
Ref. 97, Refs. 111 to 121. Indeed, under the commenters' construction 
of the FD&C Act, FDA would not be able to regulate any test systems at 
all, such as a COVID-19 test for at-home use: the Agency could oversee 
the safety and effectiveness of the individual test components in the 
context of their individual intended uses, but it could not evaluate 
the safety and efficacy of the COVID-19 test system as a whole, 
including the accuracy and reliability of the test results yielded when 
those individual components are used together. Such a construction 
defies the basic theory and premise of FDA's existing IVD program, 
which is to ensure that tests work. Nothing in the text or history of 
the FD&C Act justifies the commenters' proposed interpretation of the 
definition. On the contrary, the device definition specifically 
includes ``any component, part, or accessory,'' showing that the mere 
fact that an article, such as a COVID-19 test system, has individual 
components does not defeat the possibility that the article is a 
``device.'' The legislative history also supports that Congress 
intended for FDA to regulate such systems, as discussed in response to 
comment 53. And Congress, which has been aware of FDA's interpretation 
for over 50 years (see 38 FR 7096), has never expressed disagreement 
with it. See, e.g., United States v. Tuente Livestock, 888 F. Supp. 
1416, 1423 (S.D. Ohio 1995) (upholding FDA interpretation of statutory 
term ``food'' based, among other things, on the fact that ``Congress 
has been aware of the FDA's understanding and practice concerning live 
animals for almost twenty-five years, yet has in no way acted to limit 
the agency's jurisdiction'').
    Furthermore, at least two Federal statutes contemplate that tests 
manufactured by laboratories can be subject to FDA regulation. First, 
CLIA refers to ``laboratory examinations and procedures'' that have 
been ``approved by the Food and Drug Administration for home use'' as 
among the types of tests a laboratory with a CLIA certificate of waiver 
can perform. 42 U.S.C. 263a(d)(3). Second, in PAMA, Congress expressly 
recognized that ``a clinical diagnostic laboratory test . . . offered 
and furnished only by a single laboratory and not sold for use by a 
laboratory other than the original developing laboratory (or a 
successor owner),'' a description that may include an LDT, can be 
``cleared or approved by the Food and Drug Administration.'' 42 U.S.C. 
1395m-1(d)(5) and (d)(5)(B). These provisions refute the comments' 
suggestion that tests developed by laboratories never fall within the 
definition of a device.
    Various comments focused specifically on the term ``article'' in 
the device definition, citing narrow descriptions of the term 
``article'' in a dictionary or in case law to support a narrow 
understanding of the term ``device.'' For example, one comment 
indicated that the term ``article'' is limited to a ``particular 
material thing'' based on a definition in the OED,

[[Page 37332]]

arguing that the definition of ``device'' cannot include intangible 
objects. FDA disagrees that this OED definition narrows the meaning of 
``article'' in the FD&C Act's device definition. As an initial matter, 
other dictionary definitions of the term ``article'' are not so 
limited. See, e.g., Merriam-Webster.com (Merriam Webster Collegiate 
Dictionary), article (``a member of a class of things'') (Ref. 131). 
More important, the text of the FD&C Act indicates that ``article'' is 
not so limited. As explained above, Congress has made clear that as 
used in the device definition, the term article includes software, an 
intangible thing. It has also made clear that the device definition 
encompasses clinical diagnostic laboratory tests, as just discussed.
    With respect to comments' citations to cases interpreting the term 
``article,'' FDA notes that none of these cases interpret language in 
the FD&C Act. Because these cases involve different legal schemes, 
contexts, and history, they are of limited relevance. Regardless, FDA 
has reviewed the cases and has concluded that they do not counsel in 
favor of a different understanding of the device definition as applied 
to LDTs.
    Comments cited three cases: ClearCorrect Operating, LLC v. ITC, 810 
F.3d 1283 (Fed. Cir. 2015), petition for rehearing en banc denied, 819 
F.3d 1334 (Fed. Cir. 2016); Wilton Meadows Ltd. P'ship v. Coratolo, 14 
A.3d 982 (Conn. 2011); and Fortin v. Marshall, 608 F.2d 525 (1st Cir. 
1979). In ClearCorrect, the Federal Circuit determined that the term 
``articles'' in the Tariff Act does not include digital data, relying 
on certain dictionary definitions contemporaneous with passage of the 
1922 Tariff Act, among other things. This case is particularly 
inapposite because, as discussed previously, the FD&C Act specifically 
lists (to name one example) a ``contrivance,'' as within the device 
definition (unlike the Tariff Act, which does not further define the 
term ``articles''), and Congress has endorsed the view that the device 
definition in the FD&C Act (both as drafted in 1976 and currently) 
includes software functions. Regardless, an IVD system falls within the 
ClearCorrect court's understanding of an article because it is 
comprised of material things, as discussed earlier in this comment 
response. In Fortin and Wilton Meadows, courts interpreted the term 
``article'' to exclude services (air transportation services in the 
former case and nursing home services in the latter). However, FDA's 
position is not that laboratory services are articles but that in vitro 
diagnostic products used in laboratories (such as test systems) are 
articles. Courts have agreed that medical services and articles used in 
medical services are distinguishable for purposes of FDA regulation. 
See, e.g., United States v. Regenerative Sciences, 741 F.3d 1314, 1319 
(D.C. Cir. 2014). And the Wilton Meadows court itself acknowledged this 
distinction, 14 A.3d at 987 (holding that the term ``article'' does not 
include nursing home services but ``could reasonably be construed to 
include food, medicine or many other items that are associated with 
nursing home care,'' although upon review of relevant ``extratextual 
sources,'' it did not).
    (Comment 53) Several comments asserted that the legislative history 
of the MDA bolsters the interpretation that the definition of 
``device'' under 21 U.S.C. 321(h)(1) means physical objects. For 
example, these comments pointed to use of the terms ``products,'' 
``machines'' and ``articles'' in congressional reports to argue that 
Congress only intended for physical objects to be devices.
    (Response 53) At the outset, FDA notes that even if it were true 
that the legislative history suggested a narrow understanding of the 
device definition, that history would not trump the definition's plain 
text, which encompasses LDTs, as explained in comment response 52. See 
Bostock v. Clayton Cty., 140 S. Ct. 1731 at 1737 (``When the express 
terms of a statute give us one answer and extratextual considerations 
suggest another, it's no contest. Only the written word is the law.''). 
Moreover, FDA does not agree that the legislative history suggests a 
narrow understanding of the device definition. Comments point to 
passing references to terms such as ``products,'' ``machines'' and 
``articles'' in the legislative history, but these terms, such as the 
term ``article,'' do not necessarily refer solely to tangible objects, 
as discussed in the previous comment response. Likewise, ``product'' 
commonly refers to things that are either tangible or intangible, 
insurance and software being examples of the latter. Regarding 
software, the FD&C Act uses the term ``product'' to specifically refer 
to ``software'' in section 520(o)(2). This is consistent with 
dictionary definitions of ``product.'' See, e.g., Merriam-Webster.com 
(Merriam Webster Collegiate Dictionary), product (``(1): something 
produced'' ``(2): something (such as a service) that is marketed or 
sold as a commodity'') (Ref. 132). The legislative history's passing 
references to ``machines'' also could not have been intended to limit 
the scope of the device definition to tangible objects. The instrument 
clause of that definition, section 201(h)(1) of the FD&C Act, is not 
limited to machines. Rather, it refers to ``an instrument, apparatus, 
implement, machine, contrivance, implant, in vitro reagent, or other 
similar or related article, including any component, part, or 
accessory.'' In accordance with this definition, FDA regulates as 
devices a wide variety of products--such as surgical instruments, 
surgical masks, and blood collection containers--that are not 
``machines.'' In addition, the legislative history does not indicate 
that Congress intended for these references to limit the scope of FDA's 
authority; in fact, the legislative history also includes terms that 
cut in the opposite direction, such as a reference to a ``diagnostic 
service,'' as discussed later in this comment response.
    Regardless, as explained in response to comment 52, LDTs are 
physical objects. Generally, they are systems consisting of a 
combination of physical objects. FDA has not identified evidence in the 
legislative history to suggest that when IVD components are combined as 
intended, the resulting in vitro diagnostic product falls outside FDA's 
jurisdiction; rather, the legislative history states the opposite. For 
example, a House report issued months before enactment of the MDA noted 
a district court's skepticism of FDA authority over a ``pregnancy 
detection kit'' and then emphasized the need for ``more comprehensive 
authority,'' suggesting that the Committee agreed that this type of kit 
(or combination of components) should fall within FDA's authority. H.R. 
Rep. 94-853 at 9 (February 29, 1976). A Senate report signaled 
Congress's intent that FDA regulate a test system (described as a 
``diagnostic service'' in the report) under which an ``operator'' used 
various physical components--a ``Blood Specimen Carrier,'' a ``wand,'' 
``metal plates,'' and a machine known as the ``Radioscope''--to 
determine the ``identity, kind, location, and significance of any 
disease present.'' S. Rep. 94-33 at 4-5 (March 11, 1975). The Committee 
described the system in detail, including how the individual components 
were used, and explained that practitioners ``received, for a fee, a 
diagnosis blank filled in with the diseases which the patient was 
supposed to have.'' Id. It noted with concern that the ``service was 
incapable of distinguishing the blood of animals or birds from that of 
man, or that of the living from the dead.'' Id. at 5. The Committee's 
emphasis on faulty results makes clear that it was focused on the harms 
from the test system, not from

[[Page 37333]]

any one individual component. (Although one commenter argued that the 
relevant ``device'' in this passage of the Senate Report was the 
Radioscope, that interpretation fails to account for the Committee's 
overall focus on the results, which were attributable to the 
combination of components.) The discussions in these reports reflect 
the degree of focus on IVDs at the time and show that, contrary to some 
commenters' suggestions, the MDA was enacted precisely with test 
systems in mind. The Committees' support for FDA authority over IVD 
systems is particularly notable given that FDA had, by regulation, 
announced that a ``system'' was a type of IVD only a few years before 
passage of the MDA. See 38 FR 7096. If Congress has disagreed with 
FDA's position, it presumably would have said so.
    In sum, FDA does not agree that the legislative history casts doubt 
on its authority over LDTs; instead, it supports it. See Clinical 
Reference Lab. v. Sullivan, 791 F. Supp. 1499, 1508-09 (D. Kan. 1992) 
(``congressional reports [associated with the MDA] . . . indicate 
approval of the Supreme Court's method in Bacto-Unidisk of broadly 
defining terms within the [FD&C Act]'').
    (Comment 54) Some comments stated that various provisions of the 
FD&C Act do not apply in the context of LDTs, which they contended 
supports their interpretation that LDTs do not fall within the device 
definition. These comments cited: (1) provisions referencing interstate 
commerce or movement in interstate commerce, commercial distribution, 
and ``held for sale,'' (2) requirements to repair, replace, or refund 
the purchase price of a device under 21 U.S.C. 360h(b); (3) provisions 
related to packaging; (4) packing, storage, and installation 
requirements at 21 U.S.C. 351(h), 360b, and 360j(f)(1); (5) import and 
export provisions at 21 U.S.C. 381; and (6) labeling requirements, such 
as those at 21 U.S.C. 352(a), (f). These comments concluded that FDA 
authority over LDTs is incompatible with the statute as a whole. 
Several comments also suggested that FDA regulations undermine the 
Agency's position, including the reference to ``in-process devices, 
finished devices and returned devices'' at Sec.  820.3(r) and the UDI 
requirements at part 801.
    (Response 54) As an initial matter, FDA disagrees with the premise 
of these comments that if some particular provisions in the FD&C Act do 
not apply to a system which meets the statutory definition of 
``device,'' that means FDA lacks authority over that system. That 
premise is incompatible with the FD&C Act itself, which contains 
detailed provisions laying out the scope of the Agency's authority, the 
Agency's obligations, private party obligations, and private party 
exemptions. Congress included, for example, express statutory 
exclusions from certain requirements for certain healthcare personnel 
(such as ``practitioners licensed by law to prescribe or administer 
drugs or devices and who manufacture . . . drugs or devices solely for 
use in the course of their professional practice'' under 21 U.S.C. 
360(g)(2)). It would be incongruous to conclude that it also intended, 
without saying so, to exclude a whole type of healthcare product or 
institution (namely, a laboratory). Instead, courts ``assume that 
Congress meant what it said, and said what it meant.'' See Aqualliance 
v. U.S. Bureau of Reclamation, 856 F.3d 101, 105 (D.C. Cir. 2017). The 
comments' interpretive approach also is inconsistent with how the 
Supreme Court has counseled interpretation of the FD&C Act. See United 
States v. Bacto-Unidisk, 394 U.S. 784, 798 (1969) (``[R]emedial 
legislation such as the Food, Drug, and Cosmetic Act is to be given a 
liberal construction consistent with the Act's overriding purpose to 
protect the public health.''). And it runs counter to Congress's 
understanding of the MDA as expressed in the legislative history. See 
H.R. Rep. 94-853 at 13 (``Because the Committee recognizes . . . that, 
in general, authority under the [FD&C Act] to regulate food, drugs, 
cosmetics, and devices is too often vague thus lending itself to 
interpretive regulation having the force of law, the Committee has 
attempted to design device authority such that the law and the intent 
of the Congress is clear.'').
    Moreover, in the case of LDTs, the alleged ``inapplicability'' of 
many of the provisions identified by comments arises from a 
laboratory's own choice not to engage in certain activities that would 
be governed by such provisions, not from some fundamental 
incompatibility between the FD&C Act and LDTs. For example, even if a 
given laboratory chooses not to package or ship an IVD, that is not a 
reason to conclude that it, or the devices it makes, are excluded from 
the scope of the statute altogether. It simply means the laboratory is 
not engaged in conduct--such as packaging--that triggers a particular 
statutory requirement--such as the requirement that packaged devices 
bear certain information in their label under 21 U.S.C. 352(b).
    Under commenters' logic, any manufacturer could narrow the scope of 
her or his operations, such that only some provisions of the FD&C Act 
applied, and then assert that none of its activities are ``what 
Congress had in mind when it drafted the statute'' (i.e., that none of 
its activities are within FDA's jurisdiction). FDA disagrees with this 
logic. That would run counter to the statute's text and would cause 
negative public-health outcomes. If an entity is engaged in activities 
subject to the FD&C Act, even if those activities are limited in scope, 
the entity is subject to the FD&C Act--though obviously the nature of 
those activities will determine which provisions of the statute apply. 
A manufacturer's choice to engage in only a limited number of 
activities to which the FD&C Act is applicable should not mean that the 
FD&C Act does not apply at all.
    FDA also has the following responses regarding specific provisions 
identified by commenters as inapplicable:
     For responses to comments regarding FD&C Act provisions 
that reference interstate commerce, commercial distribution, and ``held 
for sale,'' see sections VI.D.3 and VI.D.4 of this preamble.
     To the extent that commenters argued that the repair, 
replacement, and refund provisions in 21 U.S.C. 360h(b) do not apply to 
LDTs because they cannot be repaired, replaced, or refunded, FDA 
disagrees. A faulty IVD system could be repaired, for example, by 
repairing a faulty component, such as an instrument. The system could 
also be replaced with another IVD system, such as one from a 
conventional IVD manufacturer. Or the purchase price of the system 
could be refunded to the same extent and in the same manner as for most 
other devices that are used in medical practice.
     With respect to packaging, although it is true that 
laboratories making LDTs generally do not package those LDTs, the FD&C 
Act does not assume that regulated articles are packaged. On the 
contrary, the FD&C Act expressly contemplates that some drugs and 
devices will not be packaged, as it imposes certain label requirements 
only ``[i]f [the device is] in a package form.'' 21 U.S.C. 352(b)) 
(emphasis added).
     The provisions in 21 U.S.C. 351(h) and 360j(f)(1) do not 
contemplate that all devices will be packed, stored, and/or installed. 
Rather, these statutory provisions empower FDA to establish 
requirements governing these activities, to the extent they occur, and 
also require entities to comply with FDA requirements when applicable. 
See 21 U.S.C. 360j(f)(1) (authorizing the Secretary to ``prescribe 
regulations requiring that the methods used in, and the facilities and 
controls used for, the

[[Page 37334]]

manufacture, pre-production design validation . . ., packing, storage, 
and installation of a device conform to current good manufacturing 
practice''); 21 U.S.C. 351(h) (device adulterated if ``the methods used 
in, or the facilities or controls used for, its manufacture, packing, 
storage, or installation are not in conformity with applicable 
requirements''). It is not the case that all these activities must 
occur in order for an article to be a device. For example, a cotton 
swab or a tongue depressor intended for a use specified in the device 
definition is not ``installed'' but is indisputably a device. Neither 
the FD&C Act nor FDA regulations assume that all these activities will 
occur with respect to every device. See, e.g., 21 U.S.C. 360e(c)(1)(C) 
(requiring premarket approval applications to contain ``a full 
description of the methods used in, and the facilities or controls used 
for, the manufacture, processing, and, when relevant, packing and 
installation of, such device'') (emphasis added); Sec.  820.1(a)(1) 
(``If a manufacturer engages in only some operations subject to the 
requirements in this part, and not in others, that manufacturer need 
only comply with those requirements applicable to the operations in 
which it is engaged.''). Therefore, FDA disagrees that the potential 
inapplicability of these statutory provisions to some laboratories 
signals a broader mismatch between the FD&C Act and LDTs. Finally, 
although a comment referenced 21 U.S.C. 360b in connection with 
packing, storage, and installation, that provision relates to new 
animal drugs and not to devices.
     Import and export are not necessary for an article to be a 
device. FDA regards arguments concerning the import and export 
provisions at 21 U.S.C. 381 to be similar to arguments about physical 
shipment of an article in interstate commerce. Please see section 
VI.D.3 of this preamble for a detailed response to those arguments.
     Labeling requirements, such as those at 21 U.S.C. 352(a) 
and (f), do apply to LDTs. Although laboratories generally choose not 
to package LDTs or place them in a container, LDTs are accompanied by 
``written, printed, or graphic matter'' that falls within the 
definition of labeling at 21 U.S.C. 321(m). Therefore, the labeling 
requirements at 21 U.S.C. 352(a) and (f) apply to LDTs.
     The comments citing FDA regulations appear to argue that 
despite FDA's publicly stated view that LDTs are devices, certain 
regulations governing device packages or returned devices may not apply 
to LDTs, which calls into question FDA's view of its authority. FDA 
disagrees with that reasoning. FDA has stated its interpretation that 
LDTs are devices on many occasions in clear terms and that 
interpretation is not undermined if some regulations do not apply to 
LDTs. See 62 FR 62243 at 62249 (November 21, 1997), 65 FR 18230 at 
18231 (April 7, 2000), Refs. 27, 32 and 33, 35, 39, 57, 97, 111 to 
121). In any event, the regulations the comments point to are not 
necessarily inapplicable to LDTs. First, the terms ``in-process 
devices'' and ``finished devices'' in the definition of ``product'' at 
Sec.  820.3(r) apply to LDTs. An LDT can be ``in-process,'' for 
example, when system components are in process, such as when a 
laboratory manufacturer is sourcing and qualifying critical reagents 
such as primers and probes or antibodies for their test system. In 
addition, FDA recognizes that the UDI requirements at part 801 
generally apply to ``labels'' and ``device packages,'' and that 
laboratories generally do not package their IVDs, such as test systems. 
However, this is not necessarily the case for all laboratories' IVDs 
and does not mean that laboratories are incapable of compliance with 
UDI requirements. For the reasons previously stated, FDA does not agree 
that these UDI requirements have any broader meaning with respect to 
FDA's authority over LDTs.
3. Interstate Commerce and ``Held for Sale''
    (Comment 55) Several comments asserted that FDA lacks authority to 
regulate LDTs under the FD&C Act because many of FDA's authorities to 
regulate devices, such as the premarket notification provision in 
section 510(k) of the FD&C Act (21 U.S.C. 360(k)), require introduction 
or delivery for introduction into interstate commerce and, according to 
the comments, LDTs do not meet this element. One comment argued that in 
addition to section 510(k), the FD&C Act's premarket approval and De 
Novo classification provisions are limited to devices that are or will 
be introduced or delivered for introduction into interstate commerce, 
citing sections 513(c)(2)(C)(ii), 513(f)(1), 515(b)(1), and 515(i)(1) 
of the FD&C Act.
    (Response 55) We disagree that introduction or delivery for 
introduction into interstate commerce is required for FDA jurisdiction 
of devices, including LDTs, under the FD&C Act. The FD&C Act's 
definition of a ``device'' subject to FDA's jurisdiction does not 
include an interstate commerce element. Whether a particular provision 
of the FD&C Act requires a connection to interstate commerce goes to 
the reach of that specific provision, not of the device definition or 
of the Act as a whole. If an FD&C Act provision does not contain an 
interstate commerce element, ``interstate commerce'' imposes no limit 
on FDA's powers beyond the constitutional minimum.
    Section 510(k) of the FD&C Act illustrates this point. That 
provision states that a person who is required to register and 
``proposes to begin the introduction or delivery for introduction into 
interstate commerce'' of a device ``shall'' submit a premarket 
notification. The inclusion of an interstate commerce element in 
section 510(k) of the FD&C Act means that the requirements of that 
section do not apply where that element is not satisfied. It does not 
mean that FDA lacks jurisdiction to enforce other device provisions of 
the FD&C Act that do not include such an element.\55\
---------------------------------------------------------------------------

    \55\ Additionally, as discussed in the NPRM, section 510(k) of 
the FD&C Act does not preclude regulated entities from submitting 
premarket notifications even if the device is not introduced into 
interstate commerce (88 FR 68006 at 68020). Therefore, laboratories 
may utilize the less burdensome 510(k) process to market their LDT 
even assuming the device is not introduced or delivered for 
introduction into interstate commerce. Regardless, the inclusion of 
an interstate commerce element in section 510(k) in no way affects 
FDA's overall authority to regulate IVDs manufactured by 
laboratories.
---------------------------------------------------------------------------

    Contrary to the assertion in comments that ``many'' of the FD&C 
Act's device requirements require introduction or delivery for 
introduction into interstate commerce, relatively few of the device 
provisions in the FD&C Act and FDA regulations include a specific 
interstate commerce element, and most of the device-related prohibited 
acts do not. See, e.g., 21 U.S.C. 331(e) (prohibiting the failure to 
establish or maintain any record, or make any report, required under 
the device adverse-event reporting requirements without reference to 
interstate commerce); 21 U.S.C. 331(p) (prohibiting the failure to 
register a device establishment without reference to interstate 
commerce); 21 U.S.C. 331(q)(1) (prohibiting the failure to comply with 
device investigational use requirements without reference to interstate 
commerce); 21 U.S.C. 331(f)(3) (prohibiting the doing of any act which 
causes a device to be a counterfeit device, or the sale or dispensing, 
or holding for sale or dispensing, of a counterfeit device without 
reference to interstate commerce). For further discussion, see the NPRM 
(88 FR 68006 at 68019-20). Additionally, the FD&C Act gives FDA 
authority to take action, without satisfying any particular interstate 
commerce element, when there is a violation of device requirements. For 
example, FDA has the

[[Page 37335]]

authority to seize any ``adulterated or misbranded device'' without 
reference to an interstate commerce element (21 U.S.C. 334(a)(2)). 
Thus, FDA does not somehow lose jurisdiction if a particular device has 
not been introduced or delivered for introduction into interstate 
commerce.
    Further, Congress clearly intended that FDA have jurisdiction over 
devices that violate the FD&C Act even if they are not introduced or 
delivered for introduction into interstate commerce. For example, as 
discussed in the NPRM, Congress intentionally revised the 
aforementioned seizure provision of the FD&C Act, section 304, to 
ensure that FDA could take action against devices without satisfying 
any particular interstate commerce element. For further discussion, see 
the NPRM (88 FR 68006 at 68020). Additionally, one of the key 
prohibited acts on which FDA relies, section 301(k) of the FD&C Act (21 
U.S.C. 331(k)), contains an interstate commerce element, but it does 
not require a complete violative device to have itself been introduced 
or delivered for introduction into interstate commerce. That provision 
prohibits ``the doing of any . . . act with respect to, a . . . device 
. . . if such act is done while such article is held for sale (whether 
or not the first sale) after shipment in interstate commerce and 
results in such article being adulterated or misbranded.'' Courts have 
held that even if a product is wholly manufactured and sold intrastate, 
the interstate commerce element in this provision is satisfied if a 
component used in manufacturing the product has traveled in interstate 
commerce. (See, e.g., United States v. Regenerative Scis., LLC, 741 
F.3d 1314, 1320-21 (D.C. Cir. 2014) (upholding FDA enforcement action 
under section 301(k) of the FD&C Act because a drug component had 
traveled in interstate commerce); Baker v. United States, 932 F.2d 813, 
814-15 (9th Cir. 1991); United States v. Dianovin Pharm., Inc., 475 
F.2d 100, 102-103 (1st Cir. 1973)). At least some components of test 
systems, such as reagents and instruments, are usually shipped in 
interstate commerce even if the system itself is designed, 
manufactured, and used within the laboratory. And section 709 of the 
FD&C Act (21 U.S.C. 379a) establishes a presumption that any required 
connection with interstate commerce exists for enforcement actions, 
meaning that the burden is on regulated parties to demonstrate, for 
example, that no component of a system traveled across State lines. 
(``In any action to enforce the requirements of this Act respecting a 
device . . . the connection with interstate commerce . . . shall be 
presumed to exist.''). Thus, under the FD&C Act, FDA has authority over 
devices even assuming they are not introduced or delivered in completed 
form for introduction into interstate commerce.
    FDA also disagrees with the comment's apparent presumption that, if 
a device is not subject to 510(k) requirements (because that 
provision's interstate commerce element is not satisfied), then it must 
not be subject to any of the FD&C Act's other requirements for 
marketing a device. As explained in the rest of this response, the 
relevant statutory text contains no such limitation.
    Section 513(f)(1) of the FD&C Act applies to devices intended for 
human use that were ``not introduced or delivered for introduction into 
interstate commerce for commercial distribution before [May 28, 
1976].'' (emphasis added). Under sections 513(f)(1) and 515(a), such 
devices fall into class III by operation of law, and must have an 
approved PMA, unless either: (1) they are exempt as investigational 
devices under section 520(g) of the FD&C Act (21 U.S.C. 360j(g)) or (2) 
they satisfy one of the criteria established in section 513(f)(1)(A)-
(C) (21 U.S.C. 360c(f)(1)(A)-(C)).\56\
---------------------------------------------------------------------------

    \56\ Those criteria are substantial equivalence under section 
513(i), reclassification under section 513(f)(3), and De Novo 
authorization under section 513(f)(2) of the FD&C Act.
---------------------------------------------------------------------------

    References in sections 513(c)(2)(C)(ii), 515(b)(1), and 515(i)(1) 
of the FD&C Act to devices that were ``introduced or delivered for 
introduction into interstate commerce for commercial distribution 
before [May 28, 1976]'' do not impose a general interstate commerce 
limitation on the FD&C Act's PMA requirements or the De Novo 
provisions. Rather, these sections use that language to identify the 
preamendments devices that are subject to specific processes under the 
FD&C Act.
    The FD&C Act's De Novo and reclassification provisions (sections 
513(f)(2) and (f)(3) of the FD&C Act, respectively) are also not 
limited to devices that are or will be introduced or delivered for 
introduction into interstate commerce. The De Novo provisions provide 
an alternative process for classifying new devices into class I or II 
where there is no legally marketed device upon which to base a 
substantial equivalence determination (section 513(f)(2) of the FD&C 
Act). Indeed, as mentioned above, De Novo is available as a non-PMA 
marketing pathway for certain devices that were ``not introduced or 
delivered for introduction into interstate commerce for commercial 
distribution before [May 28, 1976].'' (emphasis added). Manufacturers 
may also utilize the reclassification process in section 513(f)(3) of 
the FD&C Act, which likewise applies to devices ``not introduced or 
delivered for introduction into interstate commerce for commercial 
distribution before [May 28, 1976]'' (emphasis added) (see sections 
513(f)(1) and (3)).
    In sum, a device that is not subject to the premarket notification 
requirements under section 510(k) of the FD&C Act because it does not 
satisfy that provision's interstate commerce element is not thereby 
exempted from other requirements under the FD&C Act that do not include 
such an element.
    (Comment 56) A comment asserted that FDA's interpretation of 
interstate commerce deviates from the plain language definition of the 
term and that FDA's concept of interstate commerce in section IV.B.3.a. 
of the NPRM (88 FR 68006 at 68019 and 68020) is so expansive as to 
negate the entirety of the meaning of the word interstate. Further, the 
comment asserted that if Congress did not intend to restrict FDA's 
authority to interstate commerce, it would not have used the term in 
legislation.
    (Response 56) FDA did not provide a specific interpretation of the 
term ``interstate commerce'' in the NPRM but rather, we explained that 
interstate commerce is not a prerequisite to FDA device jurisdiction 
(beyond the constitutional minimum). To the extent the comment is 
asserting that interstate commerce is a prerequisite to FDA device 
jurisdiction, FDA disagrees. As explained in the NPRM and in response 
to comment 55, in the FD&C Act there are a limited number of provisions 
applicable to devices that include a specific interstate commerce 
element (88 FR 68006 at 68019-20). Where a provision applicable to 
devices includes an interstate commerce element, the particular 
interstate commerce element must be met in order for FDA to exercise 
authority under that provision. However, there are many provisions 
applicable to devices that do not include an interstate commerce 
element. Where a provision applicable to devices does not include an 
interstate commerce element, the provision applies without satisfying 
any particular interstate commerce element. ``[Where] Congress includes 
particular language in one section of a statute but omits it in another 
section of the same Act, it is generally presumed that Congress acts 
intentionally and purposely in the disparate inclusion or exclusion.'' 
See,

[[Page 37336]]

e.g., Russello v. United States, 464 U.S. 16, 23 (1983) (quoting United 
States v. Wong Kim Bo, 472 F.2d 720, 722 (CA5 1972)). Additionally, as 
discussed in the NPRM and in response to comment 55, Congress 
intentionally revised section 304 of the FD&C Act (seizure provisions) 
to ensure that FDA could take action against devices without satisfying 
any particular interstate commerce element (88 FR 68006 at 68020; H.R. 
Rep. No. 94-853 (1976), at 15). Thus, the statutory text of the FD&C 
Act, caselaw construing that text (such as United States v. Walsh, 331 
U.S. 432, 434-36 (1947), discussed in the NPRM (88 FR 68006 at 68020)), 
and the legislative history of the MDA clearly support that interstate 
commerce is not a prerequisite to FDA jurisdiction over devices under 
the FD&C Act (beyond the constitutional minimum).
    (Comment 57) One comment asserted that the NPRM was dismissive of 
concerns that Congress, by granting FDA the statutory authorities 
relied on here, may have exceeded its authority under the Interstate 
Commerce Clause of the U.S. Constitution, adding that some current 
justices of the U.S. Supreme Court might not agree that Congress may 
constitutionally authorize FDA to regulate purely intrastate 
operations.
    (Response 57) The legal position FDA described in the NPRM and 
reflected in the final rule is fully consistent with current Interstate 
Commerce Clause jurisprudence, including numerous cases decided over 
decades by the U.S. Supreme Court. See, e.g., Gonzales v. Raich, 545 
U.S. 1, 17-18 (2005).
    As an initial matter, many laboratories that at first glance might 
appear to be operating exclusively within a single state are in fact 
operating interstate. Their online advertising may attract patients, 
the human samples they test may have been collected, the components 
they purchase to assemble their LDTs may have been shipped, and the 
test reports they generate may go to ordering physicians, from out-of-
state. So not all laboratory manufacturers have operations that are 
purely intrastate.
    But, even if a laboratory's operations are purely intrastate, 
Congress can still regulate the laboratory's activities under the 
Interstate Commerce Clause. The Supreme Court's ``case law firmly 
establishes Congress' power to regulate purely local activities that 
are part of an economic `class of activities' that have a substantial 
effect on interstate commerce.'' Gonzales v. Raich, 545 U.S. at 17. 
Congress ``may regulate these intrastate activities based on their 
aggregate effect on interstate commerce.'' Taylor v. United States, 579 
U.S. 301, 303 (2016). When a laboratory offers a test for purchase and 
use by healthcare providers and patients for diagnosis or treatment, it 
is engaged in economic activity. And that economic activity, in the 
aggregate, has a substantial effect on interstate commerce. As 
explained in the FRIA, FDA's primary estimated market revenue for IVDs 
offered as LDTs for 2023 is, in 2022 dollars, approximately $20 
billion. IVDs offered as LDTs divert patients and providers from using 
IVDs not offered as LDTs, whose market FDA estimates at 65 percent of 
all IVDs (Ref. 10). And the test results obtained from IVDs offered as 
LDTs will lead patients and providers to choose to undergo or forgo a 
variety of health treatment decisions, with clear effects in both 
directions on the markets for the relevant treatments.
    (Comment 58) A comment argued that LDTs are not ``held for sale'' 
under section 301(k) of the FD&C Act because there is no transfer of 
title or possession of an LDT to the ordering physician, and that this 
view comports with case law, which extends FDA's jurisdiction to 
regulate drugs and devices after release by the original manufacturer, 
but only insofar as such regulated products are being delivered or 
transferred to another ultimate consumer. The comment also argued that 
United States v. Regenerative Scis., LLC, 741 F.3d 1314 (D.C. Cir. 
2014), is inapplicable to LDTs because that case involved a drug-cell 
mixture administered to a patient for treatment, and LDTs are not 
transferred to anyone but performed by the manufacturer. The comment 
further argued that ``held for sale'' does not include use of a device 
to facilitate the work of a healthcare professional where that device 
is not transferred to the patient, citing Shahinian v. Kimberly-Clark 
Corp., No. 14-CV-8390, 2017 WL 11595343 (C.D. Cal. March 7, 2017). 
Additionally, the comment argued that in cases cited by FDA in its 
response to a citizen petition from ACLA and in a memorandum by the 
then-General Counsel to HHS, the regulated drug or device product was 
delivered or transferred from one party (typically a doctor) to an 
ultimate consumer (typically a patient), and that this does not occur 
with LDTs.
    (Response 58) FDA disagrees with the comment. Section 301 of the 
FD&C Act identifies prohibited acts that are intended to provide 
protection against adulterated and misbranded devices all the way to 
the consumer or patient. For example, section 301(a) addresses acts 
early in the distribution chain, by prohibiting ``[t]he introduction or 
delivery for introduction into interstate commerce'' of an adulterated 
or misbranded device (21 U.S.C. 331(a)). Separately, section 301(k) of 
the FD&C Act addresses circumstances later in the distribution process, 
in which the defendant does an act that results in the adulteration or 
misbranding of a device that is held for sale. Specifically, this 
section prohibits ``the doing of any . . . act with respect to, a . . . 
device . . . if such act is done while such article is held for sale 
(whether or not the first sale) after shipment in interstate commerce 
and results in such article being adulterated or misbranded'' (21 
U.S.C. 331(k)). Courts have adopted a broad interpretation of the 
phrase ``held for sale'' in section 301(k) of the FD&C Act. This 
interpretation is based on the 1948 Supreme Court decision, United 
States v. Sullivan, 332 U.S. 689, in which the Court explained: 
sections 301(a)-(c) of the FD&C Act ``alone would not supply protection 
all the way to the consumer. The words of paragraph (k) `while such 
article is held for sale after shipment in interstate commerce' 
apparently were designed to fill this gap and to extend the Act's 
coverage to every article that had gone through interstate commerce 
until it finally reached the ultimate consumer.'' Id. at 696-97.
    LDTs are ``held for sale'' under section 301(k) of the FD&C Act. 
Among other things, laboratories generally sell their LDTs. Similar to 
other prescription products, a physician orders a test (which may or 
may not be an LDT) and the patient (or another party such as the 
patient's insurer) pays for it. With LDTs, patients and their 
healthcare providers are the ultimate consumers. LDTs are used on 
patients, specifically their specimens (as is the nature of in vitro 
diagnostic products), and the LDT output--the test results--are 
provided to healthcare professionals and/or patients for use in 
diagnosing or treating patients.
    Consistent with section 301(k) of the FD&C Act's purpose, courts 
have held that devices used in the diagnosis or treatment of patients 
may properly be considered ``held for sale'' within the meaning of the 
FD&C Act, even where the device itself is not delivered or transferred 
to a patient. See, e.g., United States v. Diapulse Corp. of Am., 514 
F.2d 1097, 1098 (2d Cir. 1975) (the Diapulse machine, which was held by 
practitioners and ``used in the treatment of patients, may properly be 
considered `held for sale' within the meaning of the [FD&C Act], 21 
U.S.C. 331(k).'' (citations omitted)); United States v. Articles of 
Device (Acuflex; Pro-Med), 426 F. Supp. 366, 368 n.3 (W.D. Pa. 1977) 
(``Therefore, by their use in diagnosis [the electric acupuncture 
devices] were

[[Page 37337]]

held for sale after interstate shipment.''); United States v. Device 
Labeled ``Cameron Spitler Amblyo-Syntonizer,'' etc., 261 F. Supp. 243, 
246 (D. Neb. 1966) (``The court is also of the opinion that the devices 
were misbranded while being held for sale. Although the claimant never 
sold the devices in the commercial sense, the device was used in the 
claimant's treatment of patients.''). This interpretation of section 
301(k) of the FD&C Act by the courts is consistent with the FD&C Act's 
intent to supply protection ``all the way to the consumer.'' The view 
asserted by the comment is not only inconsistent with the case law, but 
also would leave a serious gap in protecting patients under the FD&C 
Act. For example, under the comment's view, devices such as x-ray 
systems, MRI systems, excimer lasers, and proton therapy beams could 
never fall within section 301(k) of the FD&C Act because these devices 
are not delivered or transferred to a patient, even though they are 
used on patients. Whether a device is physically transferred/delivered 
to a patient or used on a patient without physical transfer/delivery, 
the public health interest in safe and effective devices is the same.
    Although some of the cases discussing section 301(k) of the FD&C 
Act involved a product that was delivered or transferred to a patient, 
that does not mean that these cases stand for the proposition that 
delivery or transfer to a patient must occur in order for section 
301(k) to apply. For example, in United States v. Regenerative Scis., 
LLC, 741 F.3d 1314 (D.C. Cir. 2014), cited in one of the comments, the 
D.C. Circuit did not state that an article is held for sale only if 
there is physical delivery or transfer to a patient. Indeed, it did not 
address the ``held for sale'' requirement at all. On appeal the issue 
concerning section 301(k) of the FD&C Act was whether the defendant's 
entire Mixture product had to be shipped in interstate commerce in 
order to fall within section 301(k), which applies ``after shipment in 
interstate commerce.'' Id. at 1320. The court held ``that, by virtue of 
its use of doxycycline, [a component shipped in interstate commerce,] 
the Mixture is within the scope of drugs--and, by extension, biological 
products, see 42 U.S.C. 262(j)--regulated by [21 U.S.C.] Sec.  
331(k).'' Id. at 1321. Contrary to the comment's assertion, the D.C. 
Circuit's holding applies to LDTs because, among other things, LDTs are 
generally manufactured with components that are shipped in interstate 
commerce. Additionally, the district court's opinion in the same case 
did address the ``held for sale'' requirement, and endorsed FDA's 
interpretation. The district court stated: ``Defendants create the cell 
product, the `drug' in this case, and use it to treat their patients. 
Such conduct satisfies the `held for sale' requirement of the 
statute.'' United States v. Regenerative Scis., LLC, 878 F. Supp. 2d 
248, 258. Both courts determined that the defendants who manufactured 
the Mixture fell within the scope of section 301(k) of the FD&C Act, 
because the Mixture was made with doxycycline that had been shipped in 
interstate commerce and the defendants used the Mixture to treat 
patients. Similarly, laboratories that manufacture LDTs with any 
component that has been shipped in interstate commerce and use their 
LDTs in the diagnosis or treatment of patients fall within the scope of 
section 301(k). 21 U.S.C. 331(k).
    Additionally, the comment misconstrues Shahinian v. Kimberly-Clark 
Corp., No. 14-CV-8390, 2017 WL 11595343 (C.D. Cal. March 7, 2017). 
Although not explicitly stated, it appears that the court considered 
the surgical gowns not to be ``held for sale'' by the surgery center 
because the surgery center purchased the surgical gowns for its own 
personal consumption.
    In contrast, laboratories are not manufacturing LDTs solely for 
their own personal consumption. Rather, laboratories manufacture LDTs 
for healthcare providers and patients. Consistent with the case law 
discussed above, LDTs are generally held for sale under section 301(k) 
because LDTs are generally sold and used on patients, specifically 
their specimens (as is the nature of in vitro diagnostic products), and 
the LDT output--the test results--are provided to healthcare 
professionals and/or patients for use in diagnosing or treating 
patients.
    (Comment 59) A comment argued that even if LDTs were ``held for 
sale,'' section 301(k) of the FD&C Act only applies while LDTs are held 
for sale ``after shipment'' in interstate commerce, and LDTs are never 
shipped in interstate commerce, but rather performed only within the 
laboratory in which they are developed.
    (Response 59) FDA disagrees with the comment. The comment's 
assertion--that section 301(k) of the FD&C Act only applies while LDTs 
are held for sale after the LDT is shipped in interstate commerce--is 
contrary to the case law. For example, as discussed in response to 
comment 58, the appellants in United States v. Regenerative Scis., LLC, 
741 F.3d 1314, raised this issue, arguing that section 301(k) did not 
apply because the entire Mixture product was not shipped in interstate 
commerce. Id. at 1320. The court disagreed, holding ``that, by virtue 
of its use of doxycycline''--a component shipped in interstate 
commerce--``the Mixture is within the scope of drugs--and, by 
extension, biological products, see 42 U.S.C. 262(j)--regulated by [21 
U.S.C.] Sec.  331(k).'' Id. at 1321. The court noted that other 
circuits had come to the same conclusion, citing Baker v. United 
States, 932 F.2d 813, 814 (9th Cir. 1991) (holding that section 301(k) 
of the FD&C Act's `` `shipment in interstate commerce' requirement is 
satisfied even when only an ingredient is transported interstate.''); 
and United States v. Dianovin Pharmaceuticals, Inc., 475 F.2d 100, 103 
(1st Cir. 1973) (holding that the company's ``use of components shipped 
in interstate commerce to make vitamin K for injection brought their 
activities within [21 U.S.C.] Sec.  331(k).''). Thus, even if the LDT 
itself is not shipped in interstate commerce, LDTs generally are 
manufactured with components (e.g., reagents and instruments) that are 
shipped in interstate commerce, and as discussed in response to comment 
58, generally LDTs are held for sale under section 301(k) of the FD&C 
Act.
4. Commercial Distribution
    (Comment 60) Some comments asserted that FDA lacks authority to 
regulate LDTs under the FD&C Act because certain device provisions 
under the FD&C Act, such as the premarket notification provision in 
section 510(k) of the FD&C Act, require ``commercial distribution'' and 
that LDTs do not meet this element. For example, several comments 
argued that LDTs are not in commercial distribution because there is no 
transfer of title with an LDT, and the test is not distributed to the 
clinician or the patient. A comment further argued that ``commerce'' 
refers to ``the exchange or buying and selling of commodities 
especially on a large scale and involving transportation from place to 
place'' and that ``distribution'' requires a ``delivery'' or 
``conveyance'' of a good from a main source. Additionally, the comment 
alleged that the preamble to part 807 took pains to emphasize that 
commercial distribution is satisfied only where the product at issue is 
transferred to an unaffiliated third party, claiming that this is the 
reason why Sec.  807.3(b)(1) specifically exempts the ``[i]nternal or 
interplant transfer of a device between establishments within the same 
parent, subsidiary, and/or affiliate company,'' and that this is also 
the reason why the preamble to the analyte specific reagent (ASR) rule 
expressly distinguished between ``ASR's that move in

[[Page 37338]]

commerce'' and ``tests developed in-house by clinical laboratories or 
ASR's created in-house and used exclusively by that laboratory for 
testing services.'' (62 FR 62243 at 62249, November 21, 1997). 
Additionally, a comment argued that in Compliance Policy Guide (CPG) 
Sec.  300.600 (Commercial Distribution with Regard to Premarket 
Notification (Section 510(k))) (1978, reissued 1987) (Ref. 133), FDA 
interpreted commercial distribution to require actual or anticipated 
delivery of the device to purchasers or consignees and that in United 
States v. An Article of Device Consisting of 1,217 Cardboard Boxes, 607 
F. Supp. 990, 993-95 (W.D. Mich. 1985), a court upheld this 
interpretation.
    (Response 60) FDA disagrees with these comments. As discussed in 
the NPRM, LDTs generally are in commercial distribution (88 FR 68006 at 
68020-21). Under our longstanding interpretation, ``commercial 
distribution'' does not require the physical transfer of an object, nor 
does it require transfer of title. Instead, the legislative history of 
the MDA, FDA's near contemporaneous regulation, and at least one 
judicial decision reflect that the phrase ``commercial distribution'' 
means ``on the market.'' See H.R. Rep. No. 94-853 at 36 (Feb. 29, 1976) 
(`` `Commercial distribution' is the functional equivalent of the 
popular phrase `on the market.' ''); 41 FR 37458 at 37459, September 3, 
1976 (in the preamble to proposed part 807, FDA equated ``commercial 
distribution'' with the phrase ``on the market''); and United States v. 
An Article of Device Consisting of 1,217 Cardboard Boxes, 607 F. Supp. 
990, 994-95 (upholding as reasonable FDA's interpretation of 
``commercial distribution'' to mean, ``in its popular sense, `on the 
market' ''). For further discussion, see the NPRM (88 FR 68006 at 
68020). Because LDTs generally are ``on the market,'' they are for 
commercial distribution. For example, like manufacturers of other IVDs 
do, laboratories often promote their LDTs on their websites and hold or 
offer them for sale.
    Additionally, the dictionary definitions of ``commercial,'' 
``distribute'' and ``distribution'' are not limited to physical 
transfer of an object. The dictionary defines ``commercial'' to mean 
``of or relating to commerce,'' providing examples of ``commercial 
regulations'' and ``commercial services,'' thus making it clear that 
the term ``commercial'' is not limited to ``the exchange or buying and 
selling of commodities especially on a large scale and involving 
transportation from place to place'' as suggested in the comment (Ref. 
134). Regardless, the manufacture of LDTs generally involves 
components, such as reagents and instruments, that are purchased by and 
transported to the laboratory, and thus, involves commerce even under 
the more limited definition described in the comment. Moreover, the 
dictionary definitions of ``distribute'' and ``distribution'' include 
``supply for sale'' and ``the marketing or merchandising of 
commodities'' (Refs. 135 and 136).\57\ Thus, the plain meanings of 
``commercial,'' ``distribute,'' and ``distribution'' are not limited to 
physical transfer of an object, and are consistent with FDA's 
longstanding interpretation of ``commercial distribution.''
---------------------------------------------------------------------------

    \57\ The definition of ``commodity'' includes ``an economic 
good'' and ``something useful or valued'' (Ref. 137).
---------------------------------------------------------------------------

    FDA's interpretation of ``commercial distribution'' is also 
consistent with the FD&C Act's overriding purpose to ``protect the 
public health by ensuring that . . . there is reasonable assurance of 
the safety and effectiveness of devices intended for human use.'' 
Section 1003(b)(2)(C) of the FD&C Act (21 U.S.C. 393(b)(2)(C)). 
Moreover, FDA's interpretation of ``commercial distribution'' is 
consistent with section 301(k) of the FD&C Act which is intended to 
supply protection all the way to the consumer. As discussed in our 
responses to comments in section VI.D.3, the case law on section 301(k) 
of the FD&C Act supports FDA's jurisdiction over medical products that 
never leave a physician's office, and that are used in the diagnosis or 
treatment of patients even where the product itself is not delivered or 
transferred to a patient. See, e.g., United States v. Diapulse Corp. of 
Am., 514 F.2d 1097, 1098 (the Diapulse machine, which was held by 
practitioners and ``used in the treatment of patients, may properly be 
considered `held for sale' within the meaning of the [FD&C Act], 21 
U.S.C. 331(k).'' (citations omitted)); United States v. Articles of 
Device (Acuflex; Pro-Med), 426 F. Supp. 366, 368 n.3 (``Therefore, by 
their use in diagnosis [the electric acupuncture devices] were held for 
sale after interstate shipment.''); United States v. Device Labeled 
``Cameron Spitler Amblyo-Syntonizer,'' etc., 261 F. Supp. 243, 246 
(``The court is also of the opinion that the devices were misbranded 
while being held for sale. Although the claimant never sold the devices 
in the commercial sense, the device was used in the claimant's 
treatment of patients.'').
    However, even assuming LDTs were not in commercial distribution, 
this would not preclude FDA jurisdiction over these devices. As an 
initial matter, even assuming that certain provisions in the FD&C Act 
do not apply to a particular device, that does not mean FDA lacks 
authority to regulate the device under the FD&C Act. As discussed in 
the NPRM, ``commercial distribution'' appears in certain device 
provisions of the FD&C Act, including section 510(k), but as with 
``interstate commerce,'' the presence of this term in certain device 
provisions does not bear on the Agency's overall jurisdiction (88 FR 
68006 at 68019-21). For example, ``commercial distribution'' is not 
needed to trigger or enforce the PMA requirements. Specifically, 
section 515(a)(2) of the FD&C Act requires, without reference to 
commercial distribution, an approved PMA for any device that is class 
III under section 513(f) of the FD&C Act (which applies to all 
postamendments devices) unless it is exempt under section 520(g) of the 
FD&C Act, and section 501(f)(1)(B) of the FD&C Act deems adulterated, 
without reference to commercial distribution, any device that is 
classified into class III under section 513(f) of the FD&C Act and is 
required to have an approved PMA under section 515(a) of the FD&C Act, 
unless it is exempt under section 520(g) of the FD&C Act. Simply put, 
any requirement of commercial distribution is conspicuously absent from 
the statutory provisions that require an approved PMA for a 
postamendments class III device and that render the device adulterated 
in its absence. Further, FDA may initiate seizure of an adulterated 
device regardless of whether the device is in commercial distribution 
(21 U.S.C. 334(a)(2)(D) (stating that any adulterated device ``shall be 
liable to be proceeded against at any time on libel of information and 
condemned in any district court of the United States . . . within the 
jurisdiction of which they are found,'' without reference to 
``commercial distribution'')).
    The fact that Congress chose to include commercial distribution as 
an element only in certain device provisions but omitted it in others 
further supports that Congress did not intend for commercial 
distribution to be a prerequisite for device jurisdiction under the 
FD&C Act. ``[Where] Congress includes particular language in one 
section of a statute but omits it in another section of the same Act, 
it is generally presumed that Congress acts intentionally and purposely 
in the disparate inclusion or exclusion.'' See, e.g., Russello v. 
United States, 464 U.S. 16, 23 (quoting United States v. Wong Kim Bo, 
472 F.2d 720, 722). When

[[Page 37339]]

Congress enacted the MDA, it could have made commercial distribution an 
overarching element for device jurisdiction, but instead Congress chose 
to include this element only in a limited number of device provisions.
    Regarding the regulatory exclusion from commercial distribution in 
Sec.  807.3(b)(1) for ``[i]nternal or interplant transfer of a device 
between establishments within the same parent, subsidiary, and/or 
affiliate company,'' the preambles to the regulation support that this 
was intended to exclude such transfers as such devices were not on the 
market at that point. In the preamble to proposed part 807, FDA 
explicitly equated ``commercial distribution'' with ``on the market.'' 
41 FR 37458 at 37459 (``The Amendments contain special provisions 
relating to the classification of devices not in commercial 
distribution (i.e., not actually on the market) prior to May 28, 
1976''). Further, commenters understood ``commercial distribution'' to 
mean ``on the market.'' See 42 FR 42520 (with regard to the internal/
interplant transfer exclusion in the ``commercial distribution'' 
definition, commenters recommended that transfers between a foreign 
subsidiary and domestic parent also be excluded as ``premarket 
notification in such a situation would not serve any useful purpose 
since the device will not go `on the market' at that point.''). Thus, 
the exclusion in Sec.  807.3(b)(1) is consistent with FDA's 
longstanding interpretation of ``commercial distribution.''
    Regarding the CPG on commercial distribution and United States v. 
An Article of Device Consisting of 1,217 Cardboard Boxes, 607 F. Supp. 
990, neither the CPG nor the court in this case limited ``commercial 
distribution'' to delivery. The CPG is clearly directed to devices that 
were not delivered. Specifically, the CPG identifies certain factors 
that FDA considers in determining whether a device is in commercial 
distribution before May 28, 1976, ``even though no units of the device 
had been delivered to purchasers or consignees.'' (Ref. 133). The 
factor in the CPG that the manufacturer had, before May 28, 1976, 
accepted or been prepared to accept at least one purchase order 
``generally with delivery to occur immediately or at a promised future 
date'' indicates that delivery is typical but not necessary. Id. 
(emphasis added). Regardless, given that the CPG clearly covers devices 
that were not delivered, it reflects FDA's view that delivery is not 
required for commercial distribution. Additionally, in United States v. 
An Article of Device Consisting of 1,217 Cardboard Boxes, 607 F. Supp. 
990, 993-95, the court upheld FDA's interpretation of commercial 
distribution, stating ``This explanation, together with the agency's 
compliance policy guide . . . is a reasonable interpretation of the 
phrase `commercial distribution'.'' The court was referring to the 
explanation in FDA's letter to the firm that, among other things, 
``indicated that the agency views `commercial distribution' to mean, in 
its popular sense, `on the market', pursuant to H.R. 94-853, 94th Cong. 
2d Sess. 36 (1976).'' Id. at 994.
    Regarding the preamble to the ASR rule, FDA's limitation of the 
scope of the ASR rule to ``the classification and regulation of ASR's 
that move in commerce, not tests developed in-house by clinical 
laboratories,'' was a statement that those products were outside the 
scope of the rule and not a statement that there was no commercial 
distribution or that they were outside of FDA's jurisdiction or 
authority to regulate. 62 FR 62243 at 62249 (``The focus of this rule 
is the classification and regulation of ASR's that move in commerce, 
not tests developed in-house by clinical laboratories. . . .''). In 
fact, FDA made clear in the preamble to the ASR rule that ``FDA 
believes that clinical laboratories that develop [in-house] tests are 
acting as manufacturers of medical devices and are subject to FDA 
jurisdiction under the act.'' Id.
    (Comment 61) A comment argued that neither the FD&C Act nor FDA's 
own interpretation of the statute supports an interpretation that a 
device not subject to section 510(k) may be independently subject to 
the PMA requirements in section 515 or the De Novo provisions in 
section 513(f)(2) of the FD&C Act. The comment argued that this is 
because submission of a PMA under section 515 or a De Novo request 
under section 513(f)(2) satisfies the requirement to submit a 510(k) 
premarket notification, which generally applies to all devices unless 
subject to a specific exemption. As support, the comment points to 
Sec.  807.81, which states that a premarket notification is not 
required for a device for which a PMA, or for which a reclassification 
petition under section 513(f)(2) of the FD&C Act, is pending before 
FDA. The comment also refers to the preamble to proposed part 807 in 
which the Agency stated that ``[a] premarket notification under Sec.  
807.81 is not required for a device for which a premarket application 
under section 515 of the act, or for which a petition to reclassify 
from class III to class I or II under section 513(f)(2) of the act, is 
pending before FDA. For such devices, the other submissions will serve 
the purpose of a notification under section 510(k) of the act.'' 41 FR 
37458 at 37460. Additionally, the comment refers to the preamble to the 
final rule setting out part 807 in which FDA explained ``[i]f a 
premarket approval application has been submitted, a premarket 
notification submission would not be required since FDA would already 
be advised of the intent to market.'' 42 FR 42520 at 42523. Another 
comment also argued that it ``defies logic that Congress would create a 
system to regulate LDTs where foundational provisions would not 
apply.'' The comment also alleged that the principal pathway to market 
for devices would be unavailable to LDTs, and claimed that the tens of 
thousands of LDTs that FDA estimated to be eligible for the 510(k) 
pathway in the PRIA would be subject to the lengthier, more expensive 
PMA and De Novo pathways.
    (Response 61) The comment suggests that the fact that there are 
exemptions from the 510(k) requirements in the FD&C Act and in FDA 
regulations supports the conclusion that a device must be subject to 
the 510(k) requirements in order to be subject to the PMA requirements. 
FDA disagrees. Exemptions from the 510(k) requirements in the FD&C Act 
and FDA regulations are provided for various reasons, e.g., because a 
510(k) submission is not necessary to provide for reasonable assurance 
of safety and effectiveness as reflected in section 510(m) of the FD&C 
Act or because a 510(k) submission is not necessary where another 
submission informs the Agency of the intent to market the device as 
reflected in Sec.  807.81(b)(1) and the accompanying preambles. The 
fact that these exemptions from 510(k) requirements exist do not 
signify that a device must be intended for ``introduction or delivery 
for introduction into interstate commerce for commercial distribution'' 
under section 510(k) of the FD&C Act in order for FDA to have 
jurisdiction over the device or for the PMA requirements to apply. This 
is supported by the device framework in the FD&C Act where all 
postamendments devices are class III by operation of law and subject to 
the PMA requirements, without satisfying any particular interstate 
commerce or commercial distribution element, unless one of the criteria 
under section 513(f)(1) of the FD&C Act is met or the device is exempt 
under section 520(g) of the FD&C Act (section 513(f)(1) of the FD&C 
Act). This is also supported by the numerous other provisions 
applicable to devices that do not require these elements, including the 
seizure

[[Page 37340]]

provision in section 304(a)(2) which was amended through the MDA. The 
legislative history of the MDA reinforces that under section 304(a)(2) 
of the FD&C Act, FDA has the authority to seize adulterated and 
misbranded devices without satisfying any particular interstate 
commerce element (see H.R. Rep. 94-853 at 15 (Congress made clear that 
it was amending this seizure provision to ``permit seizure of devices 
without reference to interstate commerce'' because ``whether or not a 
medical device actually crosses state lines has nothing to do with the 
principal intent of this proposal: to assure the safety and 
effectiveness of medical devices.'')).
    Further, the 510(k) and PMA requirements are separate and distinct 
as reflected by the different charges under the FD&C Act. Specifically, 
the failure to provide a premarket notification as required under 
section 510(k) of the FD&C Act misbrands the device (section 502(o) of 
the FD&C Act), and the failure to obtain approval of a PMA as required 
under section 515 of the FD&C Act adulterates the device (section 
501(f)(1) of the FD&C Act). Indeed, FDA routinely cites both charges in 
warning letters issued to manufacturers that appear to be marketing a 
device that FDA did not review (see https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/compliance-actions-and-activities/warning-letters). Thus, the FD&C Act supports that a 
device may be subject to the PMA requirements regardless of whether the 
device is subject to the 510(k) requirements and the fact that there 
are exemptions from 510(k) requirements do not lead to a contrary 
conclusion.
    We note that the De Novo provisions in section 513(f)(2) of the 
FD&C Act exist simply to provide another pathway to classify a 
postamendments device (which is class III by operation of law under 
section 513(f)(1) of the FD&C Act) into class I or II. A manufacturer 
is not required to follow the De Novo pathway but may instead submit a 
reclassification petition under section 513(f)(3) of the FD&C Act.
    Regarding the comment claiming that it ``defies logic that Congress 
would create a system to regulate LDTs where foundational provisions 
would not apply,'' we assume the comment is referring to the 510(k) 
requirements as this comment was made in the context of referring to 
other premarket pathways. We addressed this above and in other 
responses in this preamble.
    Regarding the comment alleging that the principal pathway to market 
for devices would be unavailable to LDTs, we assume the comment is 
referring to the 510(k) pathway. As we explained in the NPRM (88 FR 
68006 at 68020), section 510(k) of the FD&C Act does not preclude 
regulated entities from submitting premarket notifications even 
assuming their devices are not introduced or delivered for introduction 
into interstate commerce for commercial distribution. Thus, such 
regulated entities may still obtain a substantial equivalence 
determination through the submission of a 510(k) as a substantial 
equivalence determination is one way for a device that is otherwise 
class III by operation of law to be classified into class I or II 
(section 513(f)(1) of the FD&C Act).
    Regarding the comment claiming that the tens of thousands of LDTs 
that FDA estimated to be eligible for the 510(k) pathway in the PRIA 
would be subject to the lengthier, more expensive PMA and De Novo 
pathways, as discussed in the paragraph above, LDTs may be eligible for 
the 510(k) pathway. Further, given that a substantial equivalence 
determination through a 510(k) submission is less burdensome than a PMA 
or De Novo submission, such regulated entities have an incentive to 
follow this less burdensome path to market (see 88 FR 68006 at 68020). 
Thus, the 510(k) pathway should play the same role in device 
reclassification regardless (88 FR 68006 at 68020).
    (Comment 62) One comment argued that the presence of ``commercial 
distribution'' in the 510(k) and certain other specific device 
provisions of the FD&C Act bears on FDA's overall jurisdiction because 
statutes must be read as a whole, citing Territory of Guam v. United 
States, 141 S. Ct. 1608, 1613 (2021), and that a statute's language has 
meaning only in context, citing Graham Cnty. Soil & Water Conservation 
Dist. v. United States ex rel. Wilson, 545 U.S. 409, 415 (2005). The 
comment further stated that consequently, the words of a statute must 
be read in their context and with a view to their place in the overall 
statutory scheme, citing Sturgeon v. Frost, 577 U.S. 424, 438 (2016).
    (Response 62) As explained in more detail in response to comment 
60, FDA disagrees that the inclusion of commercial distribution as an 
element in certain device provisions in the FD&C Act bears on FDA's 
overall jurisdiction of devices or on the applicability of those 
provisions in the FD&C Act in which Congress did not include commercial 
distribution as an element. However, even assuming ``commercial 
distribution'' were necessary for a device to be within FDA's 
jurisdiction under the FD&C Act, this would not affect FDA's 
jurisdiction over LDTs because LDTs are generally in commercial 
distribution, and therefore, LDTs generally would meet such an element. 
See NPRM (88 FR 68006 at 68021) and response to comment 60.
    (Comment 63) A comment asserted that there is not much support for 
``commercial distribution'' meaning ``on the market.'' Specifically, 
the comment argued that the cited legislative history is a statement in 
one committee report, and that an isolated statement in a committee 
report does not represent an authoritative interpretation of a 
congressional enactment, citing NLRB v. Health Care & Retirement Corp. 
of Am., 511 U.S. 571, 582 (1994). The comment also argued that the case 
cited in the NPRM, United States v. An Article of Device Consisting of 
1,217 Cardboard Boxes, 607 F. Supp. 990, deferred to an FDA letter 
citing the committee report in the course of improperly deciding a 
genuine issue of material fact on summary judgment. Another comment 
argued that the aforementioned case arose from a traditional device 
manufacturer's introduction without premarket notification of a 
prosthetic ligament device, and that the parties' only dispute turned 
on whether the defendant's product was the same or different from a 
pre-1976 version of the product. The comment further alleged that the 
government itself ``argue[d] that the FDA's definition of `commercial 
distribution' has only minor relevance to this action . . . since the 
device in question did not exist prior to enactment of the [MDA],'' and 
the district court fully agreed. Another comment argued that the case 
cited in the NPRM, United States v. An Article of Device Consisting of 
1,217 Cardboard Boxes, 607 F. Supp. 990, 994-95, fails to support that 
no transfer, movement, transportation, or exchange of title between 
unaffiliated parties is required to trigger statutory provisions 
requiring commercial distribution.
    (Response 63) FDA disagrees with the comments. As discussed in 
response to comment 60, the plain meanings of ``commercial,'' 
``distribute,'' and ``distribution'' support FDA's interpretation that 
``commercial distribution'' in the relevant provisions of the FD&C Act 
means ``on the market.'' This interpretation has been endorsed by at 
least one judicial decision, as explained in more detail below, and is 
reinforced by a House Report issued 3 months before the MDA that 
contained an unusually clear statement on the intended meaning of 
commercial distribution. H.R. Rep. No. 94-853 at 36 (`` `Commercial 
distribution' is the

[[Page 37341]]

functional equivalent of the popular phrase `on the market.' ''). See 
also Garcia v. United States, 469 U.S. 70, 76 (1984) (the Court has 
``repeatedly stated that the authoritative source for finding the 
Legislature's intent lies in the Committee Reports on the bill, which 
`[represent] the considered and collective understanding of those 
Congressmen involved in drafting and studying proposed legislation.' 
'') (citation omitted).
    FDA's interpretation of ``commercial distribution'' is also 
consistent with the FD&C Act's overriding purpose to ``protect the 
public health by ensuring that . . . there is reasonable assurance of 
the safety and effectiveness of devices intended for human use.'' 
Section 1003(b)(2)(C) of the FD&C Act. Moreover, as discussed in 
response to comment 60, FDA's interpretation is consistent with section 
301(k) of the FD&C Act which is intended to supply protection all the 
way to the consumer, and under which courts have upheld FDA's 
jurisdiction over medical products that never leave a physician's 
office, and that are used in the diagnosis or treatment of patients 
even where the product itself is not delivered or transferred to a 
patient. See, e.g., United States v. Diapulse Corp. of Am., 514 F.2d 
1097, 1098 (the Diapulse machine, which was held by practitioners and 
``used in the treatment of patients, may properly be considered `held 
for sale' within the meaning of the [FD&C Act], 21 U.S.C. 331(k).'' 
(citations omitted)); United States v. Articles of Device (Acuflex; 
Pro-Med), 426 F. Supp. 366, 368 n.3 (``Therefore, by their use in 
diagnosis [the electric acupuncture devices] were held for sale after 
interstate shipment.''); United States v. Device Labeled ``Cameron 
Spitler Amblyo-Syntonizer,'' etc., 261 F. Supp. 243, 246 (``The court 
is also of the opinion that the devices were misbranded while being 
held for sale. Although the claimant never sold the devices in the 
commercial sense, the device was used in the claimant's treatment of 
patients.'').
    The case cited by the comment to support the assertion that a 
committee report does not represent an authoritative interpretation of 
a congressional enactment is inapposite. In that case, which involved 
the interpretation of a phrase in the definition of ``supervisor'' in 
the National Labor Relations Act, the Court found the legislative 
history to be unpersuasive where the interpretation asserted by the 
National Labor Relations Board (NLRB) was inconsistent with the plain 
meaning of the phrase and court precedent. NLRB v. Health Care & Ret. 
Corp. of Am., 511 U.S. 571, 578-79 (1994). Additionally, the Court 
noted that the legislative history relied on by the Board was not 
contemporaneous as it related to the 1974 amendments to the National 
Labor Relations Act that amended other sections of the statute but not 
the provision at issue which was enacted in 1947. Id. at 581-82. Thus, 
the Court stated: ``the isolated statement in the 1974 Committee Report 
does not represent an authoritative interpretation of the phrase `in 
the interest of the employer,' which was enacted by Congress in 1947.'' 
Id. at 582. In contrast, FDA's interpretation of commercial 
distribution is consistent with the plain meaning of the terms. 
Moreover, the legislative history that provides additional support for 
the Agency's interpretation is contemporaneous to the enactment of the 
relevant statutory language.
    Additionally, FDA maintains that United States v. An Article of 
Device Consisting of 1,217 Cardboard Boxes, 607 F. Supp. 990 supports 
the Agency's reasonable interpretation of ``commercial distribution.'' 
In this case, which involved summary judgment motions filed by both the 
government and claimant, one of the charges was that the device was 
misbranded under section 502(o) of the FD&C Act because the claimant 
did not submit a 510(k) for the device. Id. at 992-97. The court stated 
that ``[w]hether the device was in commercial distribution before May 
28, 1976, was a factual issue'' because it pertained to whether an 
exemption from the 510(k) requirements would apply. Id. at 993-94. This 
factual issue was ``hotly debated'' by the parties and given that 
``commercial distribution'' was a key element of the exemption, the 
court considered the Agency's interpretation of the term and the 
relevant CPG in deciding the issue. Id. at 994-95. Ultimately, the 
court agreed with the government that the seized device was not in 
commercial distribution prior to May 28, 1976, because it was not the 
same as the device that was manufactured prior to May 28, 1976. Id. at 
995 (``I find myself in agreement with the Government that the device 
which it has seized is not the same device manufactured by Meadox prior 
to enactment of the amendments.''). The court did not address the 
argument that the definition of ``commercial distribution'' has only 
minor relevance but regardless, the meaning of ``commercial 
distribution'' was still relevant given that ``commercial 
distribution'' was an element of the exemption; therefore, it was 
appropriate for the court to consider the meaning of the term and to 
uphold FDA's interpretation.
    Although An Article of Device Consisting of 1,217 Cardboard Boxes 
was not specifically about transfer, movement, transportation, or 
exchange of title between unaffiliated parties, FDA referenced this 
case to support its longstanding interpretation of ``commercial 
distribution'' to mean ``on the market.'' It is clear in this case that 
the court upheld this interpretation.
    (Comment 64) One comment argued that clinical laboratories cannot 
be considered manufacturers within the scope of the FD&C Act or key 
regulatory requirements because ``distribution'' of a device in 
interstate commerce is a threshold requirement for the applicability of 
many of the key regulatory requirements applicable to device 
manufacturers, including the requirements for medical device reporting, 
correction and removal reporting, and registration and listing, citing 
as an example, the definition of ``manufacturer'' in part 806 which 
includes ``distribution'' or ``commercial distribution.''
    (Response 64) FDA disagrees with the comment. Although the 
definition of ``manufacturer'' in various regulations includes 
``distribution,'' ``distribution'' is not a required element of the 
definition. For example, Sec.  806.2(h) defines ``manufacturer'' to 
mean ``any person who manufactures, prepares, propagates, compounds, 
assembles, or processes a device by chemical, physical, biological, or 
other procedures. The term includes any person who: (1) [r]epackages or 
otherwise changes the container, wrapper, or labeling of a device in 
furtherance of the distribution of the device from the original place 
of manufacture to the person who makes final delivery or sale to the 
ultimate user or consumer; (2) [i]nitiates specifications for devices 
that are manufactured by a second party for subsequent distribution by 
the person initiating the specifications; or (3) [m]anufactures 
components or accessories which are devices that are ready to be used 
and are intended to be commercially distributed and are intended to be 
used as is, or are processed by a licensed practitioner or other 
qualified person to meet the needs of a particular patient'' (emphasis 
added). Although the definition lists three specific types of persons, 
the term ``includes'' indicates that the list is not intended to be 
exhaustive or limit the first part of the definition. The term 
``includes'' means, among other things, ``to take in or comprise as a 
part of a whole or group.'' (Ref. 138). Thus, the

[[Page 37342]]

specific list is intended to be part of the whole or group described in 
the prior sentence of the ``manufacturer'' definition, i.e., ``any 
person who manufactures, prepares, propagates, compounds, assembles, or 
processes a device by chemical, physical, biological, or other 
procedures.'' In other words, any person who engages in any of these 
activities is a manufacturer under part 806 and subject to the 
requirements therein.
    (Comment 65) A comment claimed that the use of ``distributed'' in 
section VI.B.3 (``distributed outside that laboratory'') of the NPRM, 
which describes certain settings where limited QS requirements may be 
implemented, is inconsistent and illogical, and asserted that the 
Agency uses expansive definitions only when it supports its own claims 
for increased regulatory authority.
    (Response 65) FDA disagrees with the comment. Words can have 
different meanings depending on their context. For example, the 
dictionary provides multiple definitions of ``distribute'' and 
``distribution.'' (Refs. 135 and 136). As explained in response to 
comment 60, ``distribute'' and ``distribution'' in the context of the 
term ``commercial distribution'' include ``supply for sale'' and ``the 
marketing or merchandising of commodities,'' consistent with FDA's 
interpretation of ``commercial distribution'' to mean ``on the 
market.'' However, in other contexts, ``distribute'' and 
``distribution'' can have different meanings. In section VI.B.3 of the 
NPRM (88 FR 68006 at 68025), FDA was using ``distributed'' consistent 
with the meaning ``to give out or deliver. . . .'' (Ref. 139). FDA 
believes it was obvious the Agency was not using the term consistent 
with commercial distribution as FDA was not saying that the IVD could 
not be on the market. However, to avoid potential confusion about this 
subset of IVDs for which FDA intends to enforce only certain QS 
requirements, FDA has decided to use ``transferred'' instead of 
``distributed'' in section V.C of this preamble.
5. Asserted Distinctions From Devices
    A number of comments argued that laboratory activities, tests, or 
both have unique characteristics that distinguish them from devices and 
device manufacturers. Many comments argued that these characteristics 
mean that LDTs are ``services'' or ``processes'' not subject to FDA 
jurisdiction.
    (Comment 66) A number of comments argued that laboratory tests 
should not be understood to be devices because there is a strong human 
professional component to the performance of these tests. One comment 
stated, for example, that ``[t]he quality of [an LDT] procedure depends 
not only on the tangible components of a cancer genomics assay such as 
the reagents, and platforms and software but quite heavily on the 
qualifications, expertise, and experience of the operator both at the 
level of test performance and interpretation.'' Several comments stated 
that ``LDTs are comprised of not only medical products, but also 
analytic processes.'' Many comments emphasized the expertise and 
training of laboratory professionals who perform tests, including that 
they may be ``doctoral-level'' and ``board-certified,'' and may have 
``specialty training to implement and run assays, interpret results, 
and ensure that clinicians understand them.'' One comment distinguished 
between laboratory tests that, in the commenter's view, are subject to 
FDA's jurisdiction--tests in which the device ``does all the work''--
and those that are not, such as tests that involve a ``complex 
interplay between highly trained personnel, at multiple steps 
throughout the process.'' One comment suggested that LDT system 
components do not make up a system at all, stating that an LDT ``is a 
protocol or process by which a laboratory uses various tools--some of 
which are individually regulated as devices--to derive a test result 
for a patient,'' similar to ``a surgery'' that is ``performed by a 
physician using various tools (scalpels, sutures, etc.).'' The comment 
stated that LDTs ``do not become devices because they use devices.''
    (Response 66) FDA does not agree that the involvement of qualified 
personnel in the administration of laboratory tests eliminates FDA's 
jurisdiction over IVDs, including LDTs.
    The comments argue that test systems manufactured by laboratories 
are distinct from ``devices'' because professional users play a 
significant role in the achievement of the systems' intended uses, but 
that fact is not unusual or unexpected for devices. Devices are often 
complex and difficult to use; many contain a range of features, parts, 
and accessories, and functions that necessitate extensive user 
instructions to enable healthcare professionals to administer the 
device safely and effectively. Some devices are so difficult to use 
that FDA requires manufacturers to provide end-user training for them. 
See, e.g., 21 CFR 870.5700(b)(5); 876.4340(b)(9); 884.4050(b)(5); 
892.5725(b)(2). For this reason, human factors testing can be a core 
element of device design and important area of review during device 
premarket review. See, e.g., Ref. 140.
    The devices that require sophisticated user involvement regularly 
consist of disparate components that must be organized, manipulated, 
and evaluated by healthcare professionals, just like the complex 
laboratory test systems described in the comments. Sometimes, 
healthcare professionals must use the disparate components to build the 
device in accordance with the manufacturer's instructions for use. For 
example, FDA regulates a type of device known as a ``thoracolumbosacral 
pedicle screw system'' consisting of ``multiple components,'' such as 
screws, plates, rods, and connectors, that ``allow the surgeon to build 
an implant system to fit the patient's anatomical and physiological 
requirements.'' 21 CFR 888.3070(a); see also 21 CFR 870.1350(a) 
(identifying as a device a ``catheter balloon repair kit,'' which 
includes the materials, such as glue and balloons, necessary to repair 
or replace a catheter balloon). These systems are still ``devices'' 
even though significant healthcare practitioner involvement is required 
to effectuate their intended use.
    FDA regulation of such devices is important--even in the context of 
use by highly trained and expert users--because, among other things, 
FDA regulation helps assure the safe and effective design of the 
device, which is separate from the safe and effective use of a device. 
For example, if a stent has a serious design defect, a cardiologist 
implanting the stent cannot necessarily assure the safety and 
effectiveness of the procedure no matter how great her stent 
implantation expertise. Similarly, if a laboratory test system lacks 
clinical validity (for example, it identifies a gene that has no 
clinical meaning), the test will not provide meaningful diagnostic 
information no matter how great the expertise or experience of the 
professionals performing the test.
    Taken to its logical conclusion, commenters' argument would mean 
that few or no test systems intended for laboratory use (even those 
made by non-laboratories) would be devices, because most such systems 
consist of different components that must be organized and managed by 
expert personnel performing the test, in accordance with a 
manufacturer's instructions for use. No comments appeared to embrace 
the conclusion that even these sorts of systems are not devices, which 
would run counter to 50 years of established IVD regulation and 
enforcement. It would also mean that none of the device types described 
earlier in this comment response are actually ``devices,'' contrary to 
decades of FDA regulation of those articles.

[[Page 37343]]

    FDA also emphasizes that the fact that these systems are devices 
does not mean that the use of the devices--i.e., the performance of a 
test--in accordance with a manufacturer's instructions for use is a 
``device.'' Those two things are distinct. See, e.g., United States v. 
Regenerative Scis., LLC, 741 F.3d 1314, 1319 (distinguishing FDA 
regulation of a defendant's ``Mixture'' product from ``the procedures 
used to administer the Mixture'') (citation omitted).
    FDA recognizes that extensive training and clinical knowledge can 
be required to perform laboratory tests, and does not seek in any way 
to diminish that expertise required for, or the important public-health 
contributions associated with, laboratorians performing testing. The 
fact that an entire statute was enacted to govern laboratory operations 
and laboratory personnel--CLIA--is evidence of the degree of 
complexity, technical skill, and experience required to perform many 
laboratory tests. But FDA believes that expertise in performing tests 
is not the same thing as expertise in designing and developing tests. 
For example, the set of skills required to develop a test that 
accurately detects COVID-19 is not the same as the set of skills 
required to correctly perform a test that accurately detects COVID-19. 
FDA's responsibility under the FD&C Act is to help ensure that such 
tests are designed in a way that, when they are performed as the 
manufacturer intends, they can produce accurate and reliable results, 
and that responsibility exists whether or not the test is designed by a 
laboratory.
    (Comment 67) Various comments argued that design and development by 
laboratories should be viewed as distinct from design and development 
by other IVD manufacturers because laboratories provide medical care or 
employ medical experts. For example, one comment argued that LDTs are 
neither ``products'' nor ``manufactured'' because they may be developed 
in medical care settings. Another comment stated that LDTs ``do not fit 
into the category of medical devices'' because ``[t]he development and 
usage of LDTs are heavily reliant on the expertise of professional 
laboratory personnel.''
    (Response 67) As an initial matter, FDA does not agree that IVDs 
offered as LDTs are necessarily designed and manufactured under 
circumstances that are distinct from other IVDs. As explained in the 
NPRM, FDA's understanding is that many test systems offered as LDTs are 
designed at Fortune 500 and other large companies by a ``development 
team,'' similar to how systems from conventional IVD manufacturers are 
designed (88 FR 68006 at 68018) (see also Ref. 141). And in FDA's 
experience, the individuals on these development teams (as well as 
individuals developing laboratory test systems at smaller laboratories) 
generally have the same training and expertise as those employed by a 
conventional manufacturer. Usually, this training is scientific or 
technical in nature rather than medical in nature. Therefore, FDA 
disagrees that the background and training of the individuals who 
develop LDTs is necessarily a distinguishing feature of these devices.
    In any event, whether an article meets the definition of a 
``device'' in the FD&C Act does not turn on who manufactures the 
article or where it is manufactured. Thus, even assuming that LDTs were 
always designed by healthcare professionals in medical care settings, 
those facts would not affect whether the LDT is a device under the 
plain language of the statutory definition. Other provisions in the 
FD&C Act confirm this fact because they exempt healthcare professionals 
who manufacture devices solely for use in the course of their 
professional practice from certain requirements. See, e.g., 21 U.S.C. 
360(g)(2). These exemptions would be superfluous if licensed healthcare 
professionals operating in medical care settings could not 
``manufacture'' ``devices'' in the first place. For additional 
discussion of these exemptions, see our response to comment 77.
    (Comment 68) Various comments took the position that LDTs are 
services and not devices because they are tailored to patients. For 
example, comments stated that LDTs ``are informed by the clinical needs 
of the individuals we treat,'' address patients' ``unique needs,'' and 
``can be adjusted to the specific needs of the patient.''
    (Response 68) FDA does not agree that the fact that LDTs can be 
customized to patients is a reason to conclude that they are not 
devices. The FD&C Act does not require mass production, marketing, or 
use in order for an article to be a ``device.'' On the contrary, the 
FD&C Act contains special provisions for ``custom devices,'' thus 
recognizing that an article can be tailored to patients and still be a 
device. See 21 U.S.C. 360j(b) (exempting devices that have been 
designed and manufactured to suit the unique needs of a physician or 
patient from certain requirements). The legislative history for these 
provisions reinforces that they were intended to cover the 
circumstances in which devices are ``ordered from manufacturers by 
members of the health professions to conform to their own special needs 
or to those of their patients'' as well as when ``health professionals 
themselves develop or alter devices to serve such needs.'' H.R. Rep. 
94-853 at 44. Thus, the provisions were designed for exactly the types 
of circumstances asserted to exist with certain LDTs. Furthermore, 
Congress limited the applicability of the exemptions to premarket 
approval and performance standards, meaning that custom devices are not 
entirely exempt from the FD&C Act. Id. (explaining that ``[custom] 
devices are not exempt from otherwise applicable provisions . . . such 
as provisions with respect to investigational use, banning, 
restriction, adulteration or misbranding''). Reading the definition of 
``device'' to exclude customized devices would render these provisions 
superfluous.
    (Comment 69) One comment stated that LDTs are distinct from other 
IVDs because they ``are not produced or marketed for use outside of the 
originating laboratory.'' The comment stated that ``[t]he lack of 
marketing and sales to other laboratories further differentiates LDTs 
from IVDs--a distinction that is crucial to understanding why LDTs do 
not fit into the category of medical devices.''
    (Response 69) FDA recognizes that LDTs are designed, manufactured, 
and used within a single laboratory (without being sold for use outside 
that laboratory), but that fact does not mean these IVDs are not 
devices. The statute defines a ``device,'' in relevant part, as ``an 
instrument, apparatus, implement, machine, contrivance, implant, in 
vitro reagent, or other similar or related article, including any 
component, part, or accessory, which is . . . intended for use in the 
diagnosis of disease or other conditions, or in the cure, mitigation, 
treatment, or prevention of disease.'' 21 U.S.C. 321(h)(1). The 
definition does not exclude an article produced, sold, and used in a 
single location, and reading in such a limitation would undermine 
Congress's purpose in the MDA to assure the safety and effectiveness of 
devices (see response to comment 53).
    (Comment 70) One comment suggested that LDTs are not devices 
because they have purposes that are distinct from other IVDs. The 
comment stated that the ``primary role of LDTs is to detect and/or 
quantify substances within the human body, aiding in disease detection, 
health condition assessment, monitoring of drug treatments and other 
testing processes'' and that ``over 83 percent of LDTs offered by NILA 
[National Independent Laboratory Association] and AAB [American 
Association of Bioanalysts]-

[[Page 37344]]

member laboratories serve these purposes.''
    (Response 70) FDA disagrees that LDTs have purposes that are 
distinct from other IVDs. The detection and/or quantification of 
substances within the human body to aid in ``disease detection, health 
condition assessment, monitoring of drug treatments and other testing 
processes'' is consistent with the intended uses of non-LDT IVDs, and 
articles intended for such uses generally fall within the device 
definition because they are intended for use in ``the diagnosis of 
disease or other conditions'' and/or ``the cure, mitigation, treatment, 
or prevention of disease.'' Many FDA-authorized IVDs are indicated for 
use in conjunction with clinical assessments and not as the sole basis 
for clinical decisions, and IVDs offered as LDTs are not unique in that 
respect (see our response to comment 196 for examples of IVDs that fit 
this description). Therefore, even assuming the comment's factual 
assertions are correct that these are the primary intended uses of 
LDTs, these uses are not distinct from the intended uses of other IVDs, 
and they do not distinguish LDTs from devices.
    (Comment 71) Several comments argued that test development 
activities occurring in a laboratory are distinct from conventional IVD 
manufacturing. One comment asserted, for example, that the laboratory 
validation is distinct because ``[v]alidation of each clinical test 
requires specific equipment and personnel that is unique to the lab and 
test being performed.'' Another comment stated that ``LDTs are 
developed specifically for use by the laboratory that created them, or 
laboratories under the same ownership/control,'' which promotes ``great 
consistency in performance'' and more limited ``potential for user 
error'' compared with manufacturing by non-laboratories. A separate 
comment argued that ``Quality Management applied to procedures have to 
be inherently different from those applied to products and need to 
consider the entire laboratory and not just individual procedures.'' 
The same comment stated that LDT development is unique because ``the 
primary output of a test development process is a standard operating 
procedure document, which is essentially a set of instructions to 
appropriately qualified individuals.''
    (Response 71) With respect to comments' factual assertions about 
laboratory test development, FDA does not necessarily agree,\58\ but 
even assuming those assertions are correct, FDA disagrees that they 
would mean that laboratory test development is distinct from device 
manufacturing. As explained in the NPRM and elsewhere in this preamble, 
IVDs manufactured by laboratories are devices. Under FDA regulations, 
any ``person who designs, manufactures, fabricates, assembles, or 
processes a finished device'' is a manufacturer (Sec.  820.3(o)). Thus, 
laboratories that design, manufacture, fabricate, assemble, or process 
IVDs are manufacturers subject to FDA requirements.
---------------------------------------------------------------------------

    \58\ In particular, FDA disagrees that the need for specific 
equipment and personnel for validation is unique to laboratory 
manufacturers. Validation of each clinical test, regardless of 
whether that test is manufactured by a laboratory or a non-
laboratory manufacturer, may require equipment and personnel to 
perform the validation that is specific or unique to the type of 
test being performed. FDA also disagrees that developing a test for 
use in a single laboratory or laboratories under common ownership/
control necessarily promotes ``great consistency in performance'' or 
more limited ``potential for user error.'' Elsewhere in this 
preamble, FDA has described examples of problematic tests that were 
designed or used in a single laboratory. In addition, standard 
operating procedures for LDTs must include instructions that specify 
the components for use (this may include specifically naming 
components that are procured or specifications for components that 
may be otherwise procured). This is no different from IVD kit 
instructions that list components that are necessary but not 
provided.
---------------------------------------------------------------------------

    Furthermore, laboratory IVD development is fully amenable to 
regulation under FDA's CGMP requirements for devices (the QSR) even if 
that development occurs in a single laboratory. These requirements are 
flexible and recognize that manufacturing circumstances may vary. For 
example, the QSR requires design validation that ``ensure[s] that 
devices conform to defined user needs and intended uses'' and 
``include[s] testing of production units under actual or simulated use 
conditions'' for most devices (Sec.  820.30(g)). This requirement does 
not prescribe a single, rigid approach to validation; instead, under 
the QSR, a manufacturer's design validation obligations vary based on 
specific user needs and actual or simulated use conditions. In 
addition, the FD&C Act and FDA regulations provide for the issuance of 
``exemption[s]'' and ``variance[s]'' from the QSR to account for unique 
circumstances in manufacturing. 21 U.S.C. 360j(f)(2)(A); Sec.  
820.1(e).
    With respect to one comment's statement that laboratories primarily 
produce ``standard operating procedure document[s]''--and to the extent 
that the comment was suggesting that such documents are incongruous 
with FDA manufacturing requirements--FDA disagrees. First, we disagree 
that laboratories only produce standard operating procedure documents; 
laboratories produce test systems, which are the devices that generate 
results and implicate patient health and safety. For example, when a 
laboratory develops a test for measurement of hormone levels using mass 
spectrometry, they must source or manufacture calibrators and qualify a 
mass spectrometry instrument in order to perform that test. These 
calibrators and instrument, along with other components, comprise a 
test system. Second, the QSR specifically requires the development of 
documents, including procedures, laying out the design of a test (Sec.  
820.30(d) (requiring device design output to be documented, reviewed, 
and approved before release)). Thus, this type of work is directly 
contemplated under the QSR. We note that even if laboratories were only 
engaged in design activity, they would still be manufacturers under the 
QSR (Sec.  820.3(o) (``manufacturer'' includes those ``perform[ing] the 
function[ ] of . . . specification development'')).
    (Comment 72) One comment stated that an individual laboratory 
should not be considered a manufacturer because the instruments, 
software, and many reagents used in IVD testing are not manufactured by 
the laboratory. In addition, the comment stated that ``the term 
manufacture doesn't necessarily apply to the process individual 
laboratories use to assemble reagents for use in running an IVD test'' 
because they ``are not sold to other entities, do not leave the 
laboratory, take no part in interstate commerce, and may be 
individually labeled for their many uses within the laboratory 
environment.''
    (Response 72) If a laboratory manufactures a test system, it is a 
manufacturer, even if it does not manufacture the components of that 
system (such as instruments, software, and reagents). In addition, FDA 
notes that entities who ``assemble[ ]'' devices constitute 
manufacturers (Sec.  820.3(o)). Laboratories do this by sourcing 
individual components and combining them to assemble a single test 
system with a specific intended use. For example, a laboratory that 
develops a PCR-based, targeted genetic test for Factor V Leiden 
thrombophilia must source or manufacture primers and probes and 
validate a PCR instrument to assemble their test. These primers, probes 
and instrument together, along with other components, comprise a test 
system with a specific intended use that is independent of each 
individual component's intended use. Under the FD&C Act and FDA 
regulations, manufacturing is not limited to devices that are sold to 
other entities, leave a laboratory, take part in interstate

[[Page 37345]]

commerce, or are labeled for different uses. See generally 21 U.S.C. 
360j(f); part 820. FDA addresses interstate-commerce arguments in more 
detail in section VI.D.3 of this preamble.
    (Comment 73) One comment argued that FDA regulations recognize that 
laboratories are performing services, and not manufacturing devices, 
based on the language in Sec.  807.65(i) that exempts clinical 
laboratories from registration and listing under certain circumstances.
    (Response 73) This comment misunderstands the legal framework 
behind the exemption at Sec.  807.65(i). Contrary to the comment's 
suggestion, Sec.  807.65(i) is premised on the position that 
laboratories are device manufacturers. If they were not device 
manufacturers, there would have been no need to exempt them from the 
registration and listing requirements because those requirements only 
apply to those who own or operate establishments engaged in the 
``manufacture, preparation, propagation, compounding, or processing'' 
of a device. See 21 U.S.C. 360(b)(2), (c), (i), and (j). In other 
words, FDA issued Sec.  807.65(i) because it understood laboratories to 
be engaged in the ``manufacture, preparation, propagation, compounding, 
or processing'' of a device and concluded laboratories engaged in 
limited activities falling within that description should be exempt 
from the registration and listing requirements. Specifically, FDA 
decided that laboratories ``whose primary responsibility to the 
ultimate consumer is to dispense or provide a service through the use 
of a previously manufactured device'' should not have to register and 
list.
    As noted in response to comment 45, this exemption means not only 
that FDA considers clinical laboratories to manufacture devices, as 
just explained, but also that only certain laboratories should be 
exempt from registration (i.e., those ``whose primary responsibility to 
the ultimate consumer is to dispense or provide a service through the 
use of a previously manufactured device''). Laboratories who go beyond 
that do not fall within the exemption. Furthermore, even for those 
laboratories who fall within Sec.  807.65(i), the exemption does not 
confer broad immunity on laboratories or suggest they are not 
manufacturing devices. In the preamble to the registration and listing 
rule, for example, FDA emphasized (in the context of a different 
exemption) that ``exemption from registration does not relieve such 
persons from their obligation to comply with other provisions of the 
act or regulations'' (42 FR 42521, August 23, 1977). Although FDA 
acknowledges that the exemption implicates listing and the 510(k) 
premarket notification requirements because those requirements are tied 
to registration, it does not implicate the premarket approval or 
investigational use requirements, for example.
    Thus, Sec.  807.65(i) confirms, rather than undermines, the 
position that laboratories are manufacturers and that they are subject 
to a variety of requirements under the FD&C Act.
6. Practice of Medicine
    (Comment 74) Several comments asserted that FDA cannot regulate the 
``practice of medicine,'' which (in the commenters' view) includes all 
laboratory testing activities, but did not cite a specific source of 
authority for either the general assertion about FDA authority or the 
specific assertion about laboratory testing activities. To support the 
position that laboratory development falls within the ``practice of 
medicine,'' comments emphasized: (1) the training, board 
certifications, technological expertise, and medical judgment required 
for these activities, (2) that medical specialties associated with 
laboratory testing are sometimes defined to include the ``develop[ment 
of] new testing methods,'' (3) that the focus of laboratorians is on 
patient care, and (4) the involvement of a treating physician in 
ordering a test and receiving results. Some comments explained why, in 
the commenters' opinion, this type of ``practice of medicine'' 
limitation on FDA's authority is justified, including the fact that 
laboratories consider many factors in developing an LDT, such as 
clinical need, accuracy, and cost-effectiveness to the patient, and 
ensure ``quality'' in a more comprehensive sense than does FDA.
    (Response 74) FDA does not agree that an atextual ``practice of 
medicine'' limitation precludes FDA regulation of all laboratory 
testing activities. The statute does not contain such a limitation, and 
FDA ``assume[s] that Congress meant what it said, and said what it 
meant.'' See Aqualliance v. U.S. Bureau of Reclamation, 856 F.3d 101 at 
105. Instead, Congress enacted a narrower provision, entitled 
``Practice of Medicine,'' that spells out in clear terms what conduct 
within the practice of medicine falls outside FDA's statutory 
authority. That provision states, in relevant part: ``Nothing in this 
[Act] shall be construed to limit or interfere with the authority of a 
health care practitioner to prescribe or administer any legally 
marketed device to a patient for any condition or disease within a 
legitimate health care practitioner-patient relationship,'' with 
several explicit limitations (21 U.S.C. 396).\59\ In general, the 
provision codifies FDA's longstanding recognition of the fact that 
healthcare providers prescribe and use medical products for unapproved 
uses when they judge that the unapproved use is medically appropriate 
for their particular patients.\60\ It thus limits FDA's oversight of 
certain practitioners' ``prescrib[ing] or administer[ing]'' of a 
``legally marketed device,'' but it does not reach all the activities 
that fall within commenters' broad conception of the practice of 
medicine--including, notably, the manufacturing of a device. The fact 
that Congress assigned specific meaning to the ``practice of medicine'' 
and laid out, in statutory text, exactly how that concept should apply 
in the context of FDA regulation belies the notion that there is some 
additional ``practice of medicine'' limitation on the Agency.
---------------------------------------------------------------------------

    \59\ The rest of 21 U.S.C. 396 provides: ``This section shall 
not limit any existing authority of the Secretary to establish and 
enforce restrictions on the sale or distribution, or in the 
labeling, of a device that are part of a determination of 
substantial equivalence, established as a condition of approval, or 
promulgated through regulations. Further, this section shall not 
change any existing prohibition on the promotion of unapproved uses 
of legally marketed devices.'' These limitations show that this 
provision does not operate as an across-the-board bar on FDA 
regulation of the prescribing or administration of legally marketed 
devices.
    \60\ See Ref. 17 at 17 (``January 2017 Memorandum'').
---------------------------------------------------------------------------

    Other statutory provisions confirm that understanding. In 
particular, if there were some generalized ``practice of medicine'' 
limitation that foreclosed FDA regulation of activities in a medical 
context, Congress would not have needed to issue exemptions specific to 
physician manufacturing. But the FD&C Act does contain exemptions for 
licensed practitioners who manufacture devices ``solely for use in the 
course of their professional practice.'' See, e.g., 21 U.S.C. 
360(g)(2). A generalized ``practice of medicine'' limitation would 
render these provisions superfluous. The exemptions are also limited in 
scope and do not, by their express terms, apply to all manufacturing by 
licensed practitioners. Id. (limiting exemption to ``use in the course 
of [the practitioner's] professional practice''); see also H.R. Rpt. 
94-853 at 24 (stating, with respect to the adverse-event reporting 
exemption, that ``[o]bviously, physicians and other licensed 
practitioners are not exempt from these requirements if their use of a 
device extends beyond ordinary professional practice into commercial 
activity''). A generalized ``practice of medicine''

[[Page 37346]]

prohibition would read out those limitations.
    As explained in response to comment 66, FDA recognizes that 
laboratories employ expert, trained personnel. We also recognize that 
laboratories prioritize the care of patients, may specialize in the 
development of testing methods, and may work closely with treating 
physicians. But these facts do not mean that, as a legal matter, FDA 
lacks authority over the IVDs manufactured by laboratories. The FD&C 
Act by its very nature affects medical practice. Cf. United States v. 
9/1 Kg. Containers, 854 F.2d 173, 176 (7th Cir. 1988) (``Congress gave 
the FDA comprehensive powers to license the manufacture of drugs and 
limit their sales. To regulate drugs is to be `involved' in the 
`practice of the healing arts.' ''). Thus, the fundamental question is 
the scope of authority Congress delegated, and the limitations it 
enacted, relevant to medical practice. As already explained, the FD&C 
Act contains no generalized limitation on FDA regulation of devices in 
a medical context. Cf. United States v. Regenerative Scis., 741 F.3d 
1314, 1320 (construing the FD&C Act not to apply to otherwise 
prohibited activities, because they were undertaken by doctors, would 
``create an enormous gap in the FDCA's coverage'').
    (Comment 75) One comment stated that Congress did not intend for 
FDA to regulate the ``practice of medicine,'' which (in the commenter's 
view) included all laboratory testing activities, as shown by: (1) 
legislative history for the FD&C Act, including legislative history 
associated with the 1938 Act and the 1962 Kefauver-Harris Amendments, 
(2) section 214 of the Food and Drug Administration Modernization Act 
(FDAMA), and (3) section 1111 of the Food and Drug Administration 
Amendments Act (FDAAA).
    (Response 75) As explained in response to comment 74, FDA does not 
agree that there is a generalized, atextual ``practice of medicine'' 
limitation on FDA's authority in ways other than those enumerated in 
the statute. The statute contains specific provisions related to 
healthcare practitioners' ``prescrib[ing] or administer[ing]'' a 
legally marketed device and ``manufactur[ing]'' a device ``solely for 
use in the course of their professional practice,'' and those 
provisions represent Congress's considered judgment about the scope of 
conduct that falls outside FDA authority. See West Virginia Univ. 
Hospitals, Inc. v. Casey, 499 U.S. 83, 98 (1991) (``The best evidence 
of [Congress's] purpose is the statutory text adopted by both Houses of 
Congress and submitted to the President.'').
    Comments cite statements in the legislative history related to the 
1938 Act and the 1962 Kefauver-Harris Amendments, but (among other 
things) those sources predate the MDA and FDAMA, when Congress 
specifically considered the practice of medicine in the device context 
and translated those considerations into legislative text. See 21 
U.S.C. 360(g)(2), 360i(c)(1), 374(a)(2)(B), 396.
    FDA agrees that section 214 of FDAMA, codified at 21 U.S.C. 396, 
reflects Congress's intent to protect certain practitioner prescribing 
and administration activities, but the provision does not extend to 
laboratory manufacturing of IVDs, including LDTs. The purpose of the 
provision is to ``ensure[ ] that once the FDA permits a device to be 
marketed for one use, health care practitioners have the flexibility to 
draw on their expertise to prescribe or administer the device'' for 
other uses for a specific patient. Judge Rotenberg Educ. Ctr., Inc. v. 
United States, 3 F.4th 390, 395 (D.C. Cir. 2021); see also Conf. Rep. 
105-399 at 97 (November 9, 1997) (provision intended to cover ``off-
label use of a medical device by a physician using his or her best 
medical judgment in determining how and when to use the medical product 
for the care of a particular patient''). It applies only in the context 
of use of a ``legally marketed device''--that is, a device that is 
already manufactured and lawfully on the market--and only applies to 
``prescrib[ing] or administer[ing] . . . within a legitimate health 
care practitioner-patient relationship.''
    The comment also cites section 1111 of FDAAA, 42 U.S.C. 247d-5a 
(2007), but that provision was repealed in 2016 by the Cures Act (Pub. 
L. 114-255, 130 Stat 1033 at 1121 ``Section 1111 of the Food and Drug 
Administration Amendments Act of 2007 (42 U.S.C. 247d-5a), relating to 
identification of clinically susceptible concentrations of 
antimicrobials, is repealed.''). In any event, that provision directed 
FDA to identify and periodically update ``clinically susceptible 
concentrations'' of antimicrobial drugs and did not address FDA's 
regulation of IVDs.
    (Comment 76) Various comments cited the role of state authorities, 
such as State laws and medical boards, in support of their conclusion 
that FDA cannot regulate the ``practice of medicine,'' which (in the 
commenters' view) included all laboratory testing activities. Several 
commenters asserted, for example, that the practice of medicine is 
regulated by state medical boards rather than FDA. Comments also argued 
that the proposed rule is inconsistent with existing state medical 
practice acts, such as a Utah law's definition of the practice of 
medicine. One commenter indicated that state law definitions of the 
practice of medicine should inform the applicability of 21 U.S.C. 396. 
Finally, one comment suggested that state tort law provides adequate 
oversight, noting that certain pathologists ``bear legal responsibility 
for the design and performance of LDTs'' and ``purchase medical 
malpractice insurance to cover these activities.''
    (Response 76) The scope of FDA's authority is defined by Federal 
law. See, e.g., City of Arlington v. Fed. Commc'ns Comm'n, 569 U.S. 
290, 297 (2013) (Agencies' ``power to act and how they are to act are 
authoritatively prescribed by Congress.''). Thus, the FD&C Act vests 
FDA with authority and dictates how that authority intersects with the 
``practice of medicine'' (see our response to comment 52 for a 
discussion of FDA's authority and our response to comment 74 for a 
description of this intersection). To the extent that comments were 
suggesting that State law defines those authorities and limitations, 
FDA disagrees.
    Comments appear to take the view that State law controls based on 
an assumption that state and Federal authorities cannot share 
jurisdiction, but that is not the case. Congress regularly enacts laws 
governing entities or activities that are also regulated under State 
law, and when it does so, the two regimes can coexist. See Wyeth v. 
Levine, 555 U.S. 555, 579 (2009) (``FDA [has] long maintained that 
state law offers an additional, and important, layer of consumer 
protection that complements FDA regulation.''). At least one comment 
indicated that there is a ``conflict'' between the State laws cited in 
the comments and this rulemaking, but the comment did not give any 
basis for the alleged conflict. State medical boards can perform their 
oversight function--and State law definitions of the ``practice of 
medicine'' can inform the application of State law--concurrent with 
FDA's exercise of its own authority under Federal law. Several comments 
inferred conflict from State law definitions, but if a State law 
defines particular activities to fall within the practice of medicine, 
that does not mean that FDA oversight of those same activities is 
impermissible, just as CMS's administration of CLIA with respect to 
laboratory activities that fall within the State's ``practice of 
medicine'' is not impermissible. See

[[Page 37347]]

Pharm. Mfrs. Ass'n v. FDA, 484 F. Supp. 1179, 1187-88 (D. Del.), aff'd, 
634 F.2d 106 (3d Cir. 1980) (``The fact that the practice of medicine 
is an area traditionally regulated by the states does not invalidate 
those provisions of the [statute] which may at times impinge on some 
aspect of a doctor's practice.''). Even assuming there were a conflict, 
it is Federal law, not State law, that would trump. Const. Art. VI, Cl. 
2 (``[T]he Laws of the United States . . . shall be the supreme Law of 
the land; and the Judges in every State shall be bound thereby, any 
Thing in the Constitution or Laws of any State to the Contrary 
notwithstanding.'').
    FDA also does not agree that it should read State law definitions 
of the ``practice of medicine'' into 21 U.S.C. 396. Section 396 does 
not prohibit regulation of the ``practice of medicine'' in general 
terms, nor does it explicitly or implicitly incorporate State law to 
define the scope of FDA authority. Instead, that provision carves out a 
specific and defined scope of physician conduct that falls outside 
FDA's statutory authority. See Lars Noah, Ambivalent Commitments to 
Federalism in Controlling the Practice of Medicine (February 21, 2004) 
(Provisions such as 21 U.S.C. 396 ``endorse deference to professional 
autonomy rather than the primacy of state regulation.'') (Ref. 142). 
Under the statute's plain language, State law does not control the 
analysis of FDA authority--nor would it be sensible to apply State law 
in this way given differences in definitions of the ``practice of 
medicine'' across the states. See United States v. Regenerative Scis., 
LLC, 741 F.3d 1314, 1319 (``[A]ppellants are wrong to suggest that the 
scope of the FDCA depends on state-by-state definitions of the 
`practice of medicine.' '').
    Finally, the presence of State tort law is not a reason to conclude 
that FDA lacks authority over IVDs manufactured by laboratories. The 
FD&C Act was enacted against the backdrop of State regulation and 
common-law liability. Wyeth v. Levine, 555 U.S. 555 at 566. Congress 
delegated power to FDA based on a view that the then-existing controls, 
including state controls, were not adequate to protect the public from 
dangerous products. Id. As explained in response to comment 53, 
Congress then increased FDA's powers over devices in the MDA based on 
concerns about unsafe and ineffective devices on the market, all while 
state tort liability continued. See Medtronic, Inc. v. Lohr, 518 U.S. 
470, 475-76 (1996). These facts show that the FD&C Act is not 
constrained by, but rather provides an extra layer of public-health 
protection over, state tort law.
    (Comment 77) Two comments argued that the statutory exemptions for 
licensed practitioners who manufacture products solely for use in the 
course of their professional practice apply for laboratories, or some 
subset of laboratories. One comment asserted that the exemptions apply 
to corporate and hospital laboratories that employ licensed 
practitioners, because construing the exemption to exclude corporate 
entities would impose liability on a solo practitioner's personal 
service corporation and would ``conflict[ ] with baseline common-law 
principles'' related to vicarious immunity. The same comment suggested 
that these statutory exemptions also should be construed to constitute 
an exemption from other ``more burdensome and costly provisions'' under 
the FD&C Act and FDA regulations.
    (Response 77) The statutory exemptions cited by comments exempt 
covered practitioners from several specific requirements: (1) 
establishment registration requirements (this exemption, by operation 
of law, also constitutes an exemption from listing and 510(k) 
requirements); (2) adverse-event reporting requirements; and (3) an 
expansive FDA inspection that ``extend[s] to all things'' within a 
relevant factory, warehouse, establishment, or consulting laboratory. 
21 U.S.C. 360(g)(2), 360i(c)(1), 374(a)(2)(B). These exemptions apply 
when a ``practitioner[ ]'' (1) is ``licensed by law to prescribe or 
administer'' a device, such as an IVD, (2) ``manufacture[s]'' that 
device, and (3) does so ``solely for use in the course of their [or 
his] professional practice.'' The exemptions are only relevant when a 
particular individual meets all three criteria. The language is precise 
and limited in scope; the possessive terms ``their'' and ``his,'' for 
example, make clear that the exemption applies only to specific 
individuals, not institutions. Thus, to the extent that comments are 
arguing that the exemptions apply to: (1) all activities of a 
laboratory that employs such an individual or (2) any laboratory 
activities in which personnel collectively meet the criteria (e.g., one 
individual is licensed to administer the device and others manufacture 
the device), FDA disagrees. By their plain terms, the exemptions do not 
apply to an institution or an entity; they apply only to an individual 
practitioner who meets all criteria. And construing the exemptions to 
apply more broadly would create a significant loophole: every device 
manufacturer could escape the relevant requirements simply by hiring 
the right personnel. That is not a rational understanding of Congress's 
intent: as one committee report made clear, the exemption was not 
intended to apply to ``commercial activity.'' H.R. Rpt. 94-853 at 24. 
This evidence of congressional purpose underscores the plain language 
of the statute.
    FDA also disagrees that exemptions from certain requirements in the 
FD&C Act should be read as exemptions from all, or any other, 
requirements of the FD&C Act. Congress included the licensed-
practitioner exemption for certain requirements and excluded it from 
others. This means that Congress knew how to apply the exemption when 
it wanted to, and did so only in particular circumstances. Interpreting 
the exemption to apply to other requirements, not specified by 
Congress, would directly conflict with Congress's intent as expressed 
through the statutory text. Courts have come to the same conclusion. 
See Cowan v. United States, 5 F. Supp. 2d 1235, 1240 (N.D. Okla. 1998) 
(``[T]he `medical practice exemption' referenced by Plaintiff is a very 
limited exemption from the registration requirements of the FDCA. 
Plaintiff's assertion that this exception provides a broad-based 
exemption to all physicians from the requirements of the Food, Drug, 
and Cosmetic Act is incorrect.''); cf. United States v. Algon Chem., 
Inc., 879 F.2d 1154, 1160 (3d Cir. 1989) (``the medical practitioner 
exemptions by their terms afford no more than the right to be free from 
inspection and registration requirements when veterinarians and other 
practitioners compound medicine with legally acquired materials, not 
the right to acquire unapproved drug substances'').
    One comment argued that it is not reasonable to say that a licensed 
practitioner acting within the scope of the exemption is exempt from 
``basic'' requirements such as registration, listing, and adverse-event 
reporting but still subject to ``more burdensome'' requirements, like 
De Novo review and premarket approval. FDA disagrees. De Novo review 
generally applies when FDA lacks experience with a device type, and 
premarket approval applies to class III devices, the highest-risk 
devices regulated by FDA. It is entirely reasonable for Congress to 
conclude that an exemption should apply with respect to some FD&C Act 
requirements but not with respect to FDA's premarket review of devices 
that are unknown or ``present[ ] a potential unreasonable risk of 
illness or injury,'' for example. See 21 U.S.C. 360c(a)(1)(C). FDA also 
notes that although the comment suggested that

[[Page 37348]]

the FD&C Act exempts licensed practitioners who are manufacturing 
solely within the course of their professional practice from 
``inspection[s],'' that is not the case. The licensed-practitioner 
inspection provision limits the scope of FDA's inspection--so that the 
inspection does not ``extend to all things therein''--but it does not 
eliminate FDA's authority to inspect (21 U.S.C. 374(a)(1)-(2)). In any 
event, reading these exemptions into other provisions of the FD&C Act 
would amount to rewriting the FD&C Act, which FDA cannot do.
    (Comment 78) Several comments argued that activities regulated 
under CLIA constitute the ``practice of medicine,'' implying that they 
are outside the scope of FDA's authority.
    (Response 78) CLIA does not constrain FDA's authority over devices, 
including LDTs, and that fact is true regardless of whether the 
activities regulated under CLIA are described as ``the practice of 
medicine.'' For further discussion of CLIA, please see section VI.D.8 
of this preamble.
7. Right of Healthcare Providers To Practice Medicine
    (Comment 79) One comment asserted that there is a right--based on 
several provisions of the Constitution--of healthcare providers to 
practice their profession without unwarranted interference. 
Specifically, the comment asserted that: the First Amendment guarantees 
the freedom of expression and the right to petition, which implicitly 
supports healthcare providers' rights to advocate for their patients 
and express concerns about regulations they view as capricious; the 
Fourth Amendment guards against unreasonable searches and seizures, 
which can be related to the privacy of patient records and the autonomy 
of healthcare providers in their practice; and the 14th Amendment 
ensures that no state may deprive any person of life, liberty, or 
property without due process of law. The comment asserted that, because 
the right to practice medicine is constitutionally protected, any 
limitation on that right must withstand strict scrutiny. The comment 
asserted that the LDT rule fails strict scrutiny because there is 
``nothing narrow'' in FDA's approach to LDTs.
    (Response 79) We disagree with this comment. First, this rule does 
not purport to regulate healthcare providers' practice of their 
profession. As the phaseout of the general enforcement discretion 
approach is implemented, laboratories that manufacture IVDs offered as 
LDTs generally will be expected to comply with several pre- and post-
market submission and reporting requirements applicable to devices for 
humans (including premarket notification/PMA requirements (as 
applicable), registration and listing, labeling requirements, reporting 
requirements regarding adverse events and corrections and removals, QS 
requirements, and certain IDE regulations), but this phaseout policy 
relates to statutory and regulatory requirements applicable to medical 
devices and the conduct of manufacturers and distributors, not 
healthcare providers. The medical profession is, of course, regulated, 
particularly under state law, but neither the amendment to Sec.  809.3 
nor the phaseout policy regulates healthcare providers acting in that 
capacity.
    Second, we disagree with the assertion that there is a 
constitutional right to practice medicine subject to regulation only 
under strict scrutiny. The comment did not support its conclusory 
assertion of a constitutional right to practice medicine with any case 
law citations, and we are not aware of any. See, e.g., Lars Noah, 
Ambivalent Commitments to Federalism in Controlling the Practice of 
Medicine, 53 U. Kan. L. Rev. 149, 192 (2004) (``[F]ederal expressions 
of deference to professional medical autonomy are rooted in politics 
rather than constitutional law.'') (Ref. 142). The comment's citation 
to various rights protected by the Constitution does not help bolster 
the argument. The right to petition, like other parts of the First 
Amendment, provides an ``assurance of a particular freedom of 
expression.'' McDonald v. Smith, 472 U.S. 479, 482 (1985). Nothing in 
this rule limits healthcare providers' ability to advocate for their 
patients and express concerns about regulations they view as 
capricious--in fact, that is just what the commenter did in submitting 
a comment on the proposed rule. Similarly, although ``private medical 
records warrant some privacy protection under the Fourth Amendment,'' 
Big Ridge, Inc. v. Fed. Mine Safety & Health Review Comm'n, 715 F.3d 
631, 648 (7th Cir. 2013), the comment failed to identify anything in 
the rule that constitutes a search or seizure of medical records or 
impinges on patients' privacy.
    Procedural due process guarantees ``the opportunity to be heard at 
a meaningful time and in a meaningful manner'' ``before an individual 
is finally deprived of a property interest.'' Mathews v. Eldridge, 424 
U.S. 319, 333 (1976) (cleaned up). Substantive due process protects 
rights that are ``deeply rooted in this Nation's history and 
tradition'' and ``implicit in the concept of ordered liberty'' ``such 
that neither liberty nor justice would exist if they were sacrificed.'' 
Washington v. Glucksberg, 521 U.S. 702, 721 (1997) (cleaned up). 
Nothing in this rule implicates either doctrine; the comment did not 
identify anything in the rule that would cause a deprivation of life, 
liberty, or property without notice and opportunity for hearing or any 
infringement on a fundamental right.
    Third, even if strict scrutiny were applied, that test would be 
satisfied here because the government has a compelling interest in 
protecting the public health, and premarket review and related 
requirements are narrowly tailored to achieve that result, as further 
explained elsewhere (see response to comment 93). The comment did not 
support its conclusory assertion to the contrary.
8. CMS/CLIA
    (Comment 80) Several comments argued that Congress delegated the 
regulation of IVDs offered as LDTs not to FDA but to CMS, and that the 
enactment of CLIA is evidence that Congress did not intend for such 
IVDs to be subject to the device authorities of the FD&C Act. Some 
argued that the FD&C Act's failure to specifically call out IVDs 
offered as LDTs, in contrast with CLIA's specific provisions regarding 
the regulation of laboratories, demonstrates that Congress intended 
IVDs offered as LDTs to be solely regulated by CMS under CLIA.
    (Response 80) FDA does not agree that Congress intended for IVDs 
offered as LDTs to be regulated solely by CMS under CLIA. CMS's CLIA 
authorities complement, rather than replace, FDA's regulation of 
laboratory-manufactured IVDs as devices under the FD&C Act. CMS 
determines whether a laboratory meets CLIA requirements, which is a 
specific role distinct from FDA's statutory responsibilities. FDA's 
device authorities under the FD&C Act are intended to help ensure that 
devices, including IVDs offered as LDTs, have appropriate assurance of 
safety and effectiveness. CMS's authorities under CLIA, by contrast, 
focus on the proficiency with which laboratories perform the testing 
activities. Unlike FDA can do under the FD&C Act, CMS does not regulate 
critical aspects of laboratory test development; does not evaluate the 
performance of a test before it is offered to patients and healthcare 
providers; does not assess clinical validity (i.e., the accuracy with 
which a test identifies, measures, or predicts the presence or absence 
of a clinical

[[Page 37349]]

condition or predisposition in a patient); does not regulate certain 
manufacturing activities, such as design controls and acceptance 
activities; does not provide human subject protections for patients who 
participate in clinical trials of tests; and does not require adverse 
event reporting.
    The lack of language in the FD&C Act specifically mentioning IVDs 
offered as LDTs does not change this conclusion. Congress did not 
define the scope of FDA's device authority by enumerating every device 
type subject to that authority; instead, it wrote a broad device 
definition at 21 U.S.C. 321(h)(1), which captures a wide range of 
articles without listing each one. FDA's device authorities thus are 
not limited to those few device types specifically mentioned in the 
FD&C Act. To the contrary FDA can, and does, regulate hundreds of 
device types that are not specifically mentioned in the FD&C Act. The 
controlling question is whether a product meets the FD&C Act's 
definition of device, and under the plain language of the statute as 
well as FDA's long-standing position this inquiry is resolved in the 
affirmative for IVDs offered as LDTs.
    As explained in the NPRM, CLIA does not expressly repeal FDA's 
authority, nor was FDA's authority repealed by implication, and the 
comments do not demonstrate otherwise (88 FR 68006 at 68019). ``An 
implied repeal will only be found where provisions in two statutes are 
in irreconcilable conflict, or where the latter Act covers the whole 
subject of the earlier one and is clearly intended as a substitute.'' 
Branch v. Smith, 538 U.S. 254, 273 (2003) (cleaned up). Here, as CMS 
itself has explained, ``the regulatory schemes of the two agencies are 
different in focus, scope and purpose'' and ``are intended to be 
complementary'' (Ref. 26). As explained above, CLIA puts a focus on the 
proficiency with which laboratories perform clinical testing, and the 
FD&C Act puts a focus on the tests themselves. CMS and FDA have 
different areas of expertise, and CLIA does not address a wide range of 
activities regulated under the FD&C Act, such as clinical validation 
and design activities. Thus, ``CLIA does not preempt the FDA's 
authority to regulate facilities like [Clinical Reference Laboratory]. 
When two statutes are `capable of co-existence, it is the duty of the 
courts, absent a clearly expressed congressional intent to the 
contrary, to regard each as effective.' '' Clinical Reference Lab., 791 
F. Supp. at 1509 (quoting Ruckelshaus v. Monsanto Co., 467 U.S. 986, 
1018, (1984)), aff'd in part and rev'd in part on other grounds sub 
nom. United States v. Undetermined No. of Unlabeled Cases, 21 F.3d 1026 
(10th Cir. 1994).
    (Comment 81) Some comments stated that CLIA's legislative history 
does not mention FDA jurisdiction over LDTs, or that it characterized 
CLIA as directing HHS ``to regulate all laboratories under a single 
statute,'' arguing that this is evidence that Congress did not intend 
for LDTs to be subject to the device authorities of the FD&C Act.
    (Response 81) FDA disagrees with the comments' characterization of 
CLIA's legislative history. As FDA has noted, CLIA serves a distinct 
role from FDA oversight and establishes requirements for laboratories 
and laboratory personnel pertaining to operations, inspections, and 
certification, with a focus on the proficiency with which laboratories 
conduct clinical testing, rather than on the test systems themselves, 
and its legislative history reflects this. The full context surrounding 
the enactment of CLIA reveals that Congress was not focused on the 
oversight of test systems themselves but rather on whether laboratory 
personnel were performing their jobs in a setting and in a manner that 
helped ensure accurate, reliable, and timely patient test results. 
CLIA's enactment was prompted in large part by Congress's concern with 
the low quality of cytology services associated with Pap testing for 
cervical cancer. For example, the Senate Report accompanying the bill 
noted: ``In too many instances, such errors [in pap smear testing] are 
the result of overworked and under-supervised cytotechnologists charged 
with the crucial responsibility of examining and categorizing cervical 
slides.'' S. Rep. No. 100-561, at 27 (1988). This concern led Congress 
to conclude that ``lack of quality assurance and quality control in the 
medical testing industry is pervasive.'' Id. at 20. Congress reaffirmed 
this intent in 1997 when it noted that ``[t]he purpose of CLIA quality 
control, proficiency testing, and personnel requirements is to ensure 
consistent, reliable, and appropriate use of a test system \61\ by 
users of the test.'' H.R. Rep. No. 105-310, at 76 (1997) (emphasis 
added). CMS has interpreted its authority consistent with this 
congressional intent, stating in the preamble to the final rule 
implementing the 1988 CLIA: ``CLIA specifically requires the regulation 
of the provision of laboratory services. On the other hand, CLIA and 
those implementing regulations are not intended to affect FDA's 
existing jurisdiction under the [FD&C Act] to regulate as devices, 
products used by providers of laboratory services.'' (57 FR 7002 at 
7010). CLIA's legislative history thus reflects a distinct and 
complementary role for CMS in the regulation of IVDs offered as LDTs.
---------------------------------------------------------------------------

    \61\ It is our understanding that CMS's role is, in part, to 
determine and ensure that a laboratory is following the 
manufacturer's instructions for a test (including how the test kit 
is stored, what specimens are used, how the specimens are stored, 
how the test is interpreted, and other aspects of the manufacturer's 
instructions). This is distinct from regulation by FDA, which 
focuses on the test itself and its manufacture.
---------------------------------------------------------------------------

    (Comment 82) Some comments argued that CLIA's quality control and 
assurance provisions are incompatible with or duplicative of, or were 
intended to apply to laboratories in place of, FDA's QS requirements, 
and therefore IVDs offered as LDTs cannot be regulated as devices.
    (Response 82) FDA disagrees. CLIA's quality control and assurance 
provisions do not supplant FDA's QS requirements, because FDA and CMS 
regulation, including these requirements, are complementary. Although 
the phaseout policy described in section V.C acknowledges that 
compliance with CLIA requirements provides certain quality assurances, 
FDA's QS requirements are neither duplicative of, nor incompatible 
with, CLIA. As noted in response to comment 12, the portion of CLIA 
that addresses quality systems relates to laboratory operations, 
laboratory personnel, and requirements for laboratory procedures 
relevant to testing. FDA's QS requirements are focused on the IVD 
offered as an LDT, including design control and validation, complaint 
handling, and other requirements intended to ensure that the IVD has 
appropriate assurance of safety and effectiveness for its intended use.
    Moreover, nothing in CLIA suggests that Congress intended it to 
supersede FDA's ability to apply its QSR to IVDs offered as LDTs. As 
described in more detail in response to comment 80 and in the NPRM, 
CLIA does not expressly repeal FDA's authority, nor was FDA's authority 
repealed by implication (88 FR 68006 at 68019).
    (Comment 83) FDA received comments asserting that IVDs offered as 
LDTs cannot be regulated under FDA's device authorities, because the 
application of FDA labeling requirements and prohibitions to these test 
systems would prevent manufacturers from complying with CMS's CLIA 
regulations requiring laboratories to offer consultation on 
interpreting test results and to provide pertinent updates on testing 
information that affect test results or their interpretation.

[[Page 37350]]

    (Response 83) FDA disagrees that these policies are in conflict. 
CMS's CLIA consultation regulations, 42 CFR 493.1445(e)(9) and 
493.1457(d), provide that laboratory directors and clinical consultants 
must ``[e]nsure that consultation is available to the laboratory's 
clients on matters relating to the quality of the test results reported 
and their interpretation concerning specific patient conditions.'' As 
noted in more detail in response to comment 93, a laboratory director 
or clinical consultant's ability to comply with the cited regulatory 
requirements is unaffected by FDA's oversight of LDTs. Premarket review 
for LDTs is intended to help assure that LDTs generate accurate and 
reliable test results. As noted in response to comment 93, FDA does not 
generally consider professional advice regarding a patient's results as 
evidence of a new intended use, and nothing in this rule is intended to 
change this practice.\62\ FDA recognizes that laboratory directors and 
clinical consultants help with interpretation and consulting to the 
healthcare provider, and they can and do give recommendations that are 
not limited to the content of FDA-required labeling.\63\
---------------------------------------------------------------------------

    \62\ In contrast, if a laboratory offers a test on its website 
for an unapproved use, FDA would likely consider that offer to be 
evidence of a new intended use.
    \63\ For products not subject to premarket approval, but instead 
subject to premarket notification (510(k)) requirements or exempt 
from premarket review, we use the term FDA-required labeling to 
include labeling that provides adequate directions for use and other 
information required to appear on the label or in labeling.
---------------------------------------------------------------------------

    CMS's CLIA test report requirements provide, in relevant part, that 
``[p]ertinent updates on testing information must be provided to 
clients whenever changes occur that affect the test results or 
interpretation of test results.'' 42 CFR 493.1291(e). As further 
explained in CMS's interpretive guidelines: ``When the laboratory 
changes methods, establishes a new procedure or refers tests to another 
laboratory, the laboratory must make the updated information concerning 
parameters such as patient preparation, preservation of specimens, 
specimen collection, or new `normal' ranges or units of measure 
available to its clients.'' CMS Manual Pub. 100-07. (Ref. 143). This 
requirement would not conflict with FDA requirements associated with 
certain labeling changes as the comment asserts. As noted above, 
interpretations and recommendations are not limited to the content of 
FDA-required labeling.
    (Comment 84) Some comments argued that IVDs offered as LDTs are not 
devices because the CLIA regulatory requirement for the establishment 
of performance specifications for tests that are not cleared or 
approved by FDA, 42 CFR 493.1253, indicates that such test systems are 
not intended to be regulated by FDA.
    (Response 84) FDA disagrees that the regulation of LDTs as devices 
is inconsistent with the CLIA regulatory requirements for the 
establishment of performance specifications for tests that are not FDA-
approved or -cleared. The CLIA regulation provides, ``[e]ach laboratory 
that modifies an FDA-cleared or approved test system, or introduces a 
test system not subject to FDA clearance or approval'' must establish 
performance specifications for certain performance characteristics 
specified in the regulation. See 42 CFR 493.1253(b)(2). Although the 
regulation uses the term ``not subject to FDA clearance or approval,'' 
the purpose of the regulation is not to state what tests are and are 
not devices that are required to undergo FDA premarket review (which 
would not be within CMS's expertise). It merely differentiates those 
tests that have not undergone FDA premarket review and thus must adhere 
to certain additional CLIA requirements. The regulation was issued in 
2003--long after FDA had publicly stated that IVDs offered as LDTs fall 
within the device authorities of the FD&C Act--but its preamble does 
not discuss any intent to overrule FDA on this issue (see 68 FR 3640 at 
3707). Instead, statements from CMS both preceding and following 
issuance of the CLIA regulation indicate that IVDs offered as LDTs are 
devices. See 57 FR 7002 at 7010 (``CLIA and those implementing 
regulations are not intended to affect FDA's existing jurisdiction 
under the [FD&C Act] to regulate as devices, products used by providers 
of laboratory services''); CMS, ``Laboratory Developed Tests (LDTs) 
Frequently Asked Questions'' (Ref. 26). (``Similar to other in vitro 
diagnostic tests, LDTs are considered `devices,' as defined by the 
FFDCA, and are therefore subject to regulatory oversight by FDA.''). 
Tests might not have undergone premarket review for a number of 
reasons, including a test not requiring premarket review due to its 
classification (or exemption from 510(k)) or a test being marketed 
without premarket authorization as a result of an FDA exercise of 
enforcement discretion.
    (Comment 85) A comment argued that the CLIA regulation requiring 
laboratory directors to ensure quality laboratory services for ``all 
aspects of test performance,'' 42 CFR 493.1407(e)(1), includes both 
analytical and clinical performance, and therefore FDA cannot regulate 
IVDs offered as LDTs. Another comment stated that CLIA assessments 
administered through CLIA-approved accrediting agencies, such as CAP, 
COLA, and the Joint Commission, account for clinical validity, and that 
laboratories whose tests are approved by NYS CLEP must show clinical 
validity.
    (Response 85) The comments are incorrect about the scope of CLIA 
regulation. CMS has stated explicitly that the ``CLIA program does not 
address the clinical validity of any test'' (Ref. 26). The NYS CLEP 
requirement to demonstrate clinical validity does not limit FDA's 
authority over laboratory-manufactured IVDs, as State requirements 
cannot preempt Federal law. Further, as noted in response to comment 
12, FDA and CMS enforce two different regulatory schemes, and there are 
many aspects of IVDs offered as LDTs that CMS does not regulate under 
CLIA, including, but not limited to, design control and validation and 
other requirements intended to ensure that the IVD has appropriate 
assurance of safety and effectiveness for its intended use.
    (Comment 86) One comment argued that Congress's establishment of a 
reimbursement system for laboratory tests that lack FDA clearance or 
approval, including section 216 of PAMA and CMS's reliance on Palmetto 
GBA's MolDX Program for local coverage determinations, indicates that 
Congress did not intend for IVDs offered as LDTs to be regulated as 
devices under the FD&C Act.
    (Response 86) FDA disagrees that the Medicare payment requirements 
established under section 216 of PAMA evidence a congressional intent 
to exclude IVDs offered as LDTs from FDA's device authorities, and, to 
the contrary, believes the requirements support an interpretation that 
such test systems are devices under the FD&C Act. PAMA established 
Medicare payment requirements for certain ``advanced diagnostic 
laboratory tests'' (ADLTs), which the statute defines as ``a clinical 
diagnostic laboratory test covered under this part that is offered and 
furnished only by a single laboratory and not sold for use by a 
laboratory other than the original developing laboratory (or a 
successor owner)'' and meets one of the following criteria: ``(A) The 
test is an analysis of multiple biomarkers of DNA, RNA, or proteins 
combined with a unique algorithm to yield a single patient-specific 
result. (B) The test is cleared or approved by the Food and Drug 
Administration. (C) The test meets other similar criteria established 
by the Secretary'' (see 42 U.S.C. 1395m-1(d)(5)). As ADLTs are 
developed,

[[Page 37351]]

offered, and furnished by a single laboratory they may include IVDs 
offered as LDTs. If ADLTs that are IVDs offered as LDTs were not 
subject to the FD&C Act's device authorities, FDA would have no 
jurisdiction to clear or approve the tests. If FDA lacked jurisdiction 
to clear or approve the tests, Congress would not have enacted 42 
U.S.C. 1395m-1(d)(5)(B), which includes FDA clearance or approval as a 
criterion for an ADLT and, thus, a basis for Medicare payment. Two 
allegedly conflicting statutes must be interpreted ``to give effect to 
each if [one] can do so while preserving their sense and purpose.'' 
Watt v. Alaska, 451 U.S. 259, 267 (1981). Because excluding IVDs 
offered as LDTs from FDA's device authorities could render part of 
PAMA's payment scheme a dead letter, this principle applies here.
    PAMA's inclusion of criteria other than FDA clearance or approval 
within the definition of an ADLT does not suggest that IVDs offered as 
LDTs are not devices under the FD&C Act. Nor does the fact that the 
MolDX program--which evaluates certain tests to determine whether the 
test meets Medicare's reasonable and necessary criteria--may list tests 
that are not cleared or approved by FDA. As noted in the response to 
comment 84, regarding the lack of a conflict with 42 CFR 
493.1253(b)(2), the marketing of a laboratory-manufactured IVD without 
FDA clearance or approval in certain situations is not incompatible 
with its regulation as a device by FDA.
    (Comment 87) FDA received comments asserting that the application 
of registration requirements and fees under FDA's device authorities to 
IVDs offered as LDTs would be duplicative of such requirements under 
CLIA.
    (Response 87) FDA disagrees that such requirements are duplicative, 
as they go to different regulators for different activities. As noted 
in response to comment 12, FDA's device authorities and CMS's CLIA 
authorities are complementary, not duplicative. CMS determines whether 
a laboratory and its personnel meet CLIA requirements, whereas FDA's 
statutory mandate is to review and evaluate the tests themselves, 
including IVDs offered as LDTs, to ensure that they have appropriate 
assurance of safety and effectiveness for their intended use.
    (Comment 88) Some comments, citing FDA v. Brown & Williamson 
Tobacco Corp., 529 U.S. 120 (2000), argued that FDA jurisdiction over 
IVDs offered as LDTs is precluded by the supposed inconsistency of FDA 
regulation of LDTs as devices with the regulatory structures for 
reimbursement for ADLTs and the regulation of clinical laboratories set 
forth in CLIA.
    (Response 88) FDA disagrees that FDA v. Brown & Williamson 
precludes FDA jurisdiction. In that case, the Supreme Court found that 
FDA's regulation of tobacco products as devices contravened the intent 
of Congress. The Court explained that Congress enacted six pieces of 
legislation, outside of the FD&C Act, regarding tobacco and human 
health, and did so against the ``backdrop of the FDA's consistent and 
repeated statements that it lacked authority under the [FD&C Act] to 
regulate tobacco absent claims of therapeutic benefit by the 
manufacturer.'' Id. at 144. The Court also concluded that the FD&C 
Act's mandate to ensure products are safe and effective for their 
intended use would require the removal of tobacco products from the 
market. See id. at 133-39. Because such a ``ban would contradict 
Congress' clear intent as expressed in its more recent, tobacco-
specific legislation,'' the ``inescapable conclusion'' was that tobacco 
products without therapeutic claims did not ``fit'' within the FD&C 
Act's regulatory scheme for medical products. Id. at 143.
    That is not the case here. FDA's regulation of LDTs as devices will 
not result in a categorical ban on LDTs. Moreover, FDA has long 
understood and publicly maintained that LDTs are devices, and Congress 
has not manifested a contrary intent. Indeed, as noted in response to 
comment 86, Congress has since enacted legislation that assumes LDTs 
are subject to FDA approval or clearance. As explained in response to 
comments 82-87, FDA regulation of IVDs offered as LDTs does not 
conflict with either the regulation of clinical laboratories under CLIA 
or the provisions for reimbursement for ADLTs cited in the comments to 
this rulemaking. The lack of a conflict here makes this situation 
clearly different from that in FDA v. Brown & Williamson.
    Moreover, to the extent that the supposed inconsistencies are based 
on CMS regulations, and not Federal statutes, FDA v. Brown & Williamson 
is inapposite. There, the Court turned to six pieces of Federal 
legislation outside of the FD&C Act in order to determine whether 
Congress intended tobacco products to be regulated as devices under the 
FD&C Act. See id. at 137-38. Here, comments citing to individual CMS 
regulations or the presence of unapproved, uncleared LDTs in the MolDX 
program are not compelling because, unlike statutes, those sources do 
not shed light on Congress's intent in enacting the FD&C Act or its 
amendments.
    (Comment 89) One commenter argued that because the performance of a 
test is a ``service'' or ``examination'' regulated under CLIA, even if 
a laboratory engages in IVD manufacturing or development activities, 
those activities should be understood to be governed by CLIA and not 
the FD&C Act because ``the lab's primary responsibility is still to 
perform the service.''
    (Response 89) FDA does not agree that a laboratory's ``primary 
responsibility'' is relevant to FDA's jurisdiction or that a laboratory 
engaged in both manufacturing an IVD and performing a medical service 
has greater or ``primary'' responsibility for performing the medical 
service such that it is no longer obligated to comply with requirements 
related to manufacturing the IVD. The mere fact that laboratories 
conduct a CMS-regulated activity--performing a test--does not exempt 
them from other relevant statutory or regulatory authorities related to 
test manufacturing or design.
    (Comment 90) One comment stated that, generally, Congress has 
appropriated sufficient funds for CMS to regulate clinical laboratories 
under CLIA, but it has not provided FDA with adequate funds to exercise 
regulatory authority over LDTs. This asserted disparity in funding, the 
comment argued, is evidence that Congress did not intend for FDA to 
have authority over LDTs.
    (Response 90) FDA fails to see how the amount of funds appropriated 
to CMS that are available to implement CLIA and the amount of funds 
appropriated to FDA that are available to regulate devices reflects a 
congressional intent that these tests are not regulated as devices 
under the FD&C Act. FDA's device program is funded through a 
combination of budget authority and user fees. As enforcement 
discretion is phased out, FDA will receive user fees associated with 
establishment registrations and premarket submissions for IVDs offered 
as LDTs. As with all products FDA regulates, FDA intends to prioritize 
its available resources to oversee LDTs in a risk-based manner. Even if 
FDA were not provided adequate funds, the Supreme Court recently 
acknowledged that funding does not always match apparent statutory 
mandates. See Biden v. Texas, 142 S. Ct. 2528, 2535 (2022) (``The INA 
states that if `an alien seeking admission is not clearly and beyond a 
doubt entitled to be admitted, the alien shall be detained for a 
proceeding.' Due to consistent and significant funding shortfalls, 
however, DHS has never had

[[Page 37352]]

`sufficient detention capacity to maintain in custody every single 
person described in section 1225.' '' (cleaned up)). Moreover, FDA's 
jurisdiction over devices and other products is established in the FD&C 
Act, and is not based on annual funding decisions and the relative 
amount of funding appropriated.
    (Comment 91) One comment suggested that, rather than regulate IVDs 
offered as LDTs under the FD&C Act, FDA should consult with CMS and CDC 
on an alternative approach whereby CLIA regulations are updated with 
additional requirements for validation of IVDs offered as LDTs, 
including modifications to authorized IVDs and novel LDTs.
    (Response 91) While FDA has consulted with CMS and CDC on the topic 
of IVDs offered as LDTs, including as part of this rulemaking, FDA 
disagrees that an alternative approach through updating CLIA 
regulations would suffice. As discussed in more detail in response to 
comment 10, CMS determines whether a laboratory and its personnel meet 
CLIA requirements, whereas FDA's statutory mandate is to review and 
evaluate the tests themselves, including IVDs offered as LDTs, to 
ensure that they have appropriate assurance of safety and effectiveness 
for their intended use. FDA has the resources and expertise to assess 
whether tests work for their intended clinical purpose; CMS does not.
9. Major Questions Doctrine
    (Comment 92) Various comments argued that this rulemaking 
implicates the ``major questions doctrine'' under West Virginia v. EPA, 
142 S. Ct. 2587 (2022). These comments asserted that: (1) the 
rulemaking presents the type of ``extraordinary case'' in which courts 
should hesitate before concluding that Congress granted the relevant 
authority to an agency and (2) the FD&C Act lacks the ``clear 
congressional authorization'' necessary to conclude that Congress 
granted this authority to FDA. To support their position, these 
comments generally focused on the facts that: (1) Congress previously 
has considered but declined to enact bills related to LDTs; (2) LDTs 
are a topic of congressional debate and therefore, in the commenters' 
view, a matter for Congress; (3) the claimed authority would affect a 
significant number of parties, ``would have a major impact on the 
delivery of healthcare,'' and would ``alter the market''; and (4) the 
Agency's approach would require billions of dollars in spending each 
year. Some comments also pointed to ``the overall FDCA regulatory 
scheme'' and ``subsequent legislation specific to clinical 
laboratories'' (i.e., CLIA). Several comments analogized to other cases 
such as FDA v. Brown and Williamson Tobacco Corp., 529 U.S. 120, 
Utility Air Regulatory Group v. EPA, 573 U.S. 302 (2014), and United 
States v. Franck's Lab, Inc., 816 F. Supp. 2d 1209 (M.D. Fla. 2011).
    (Response 92) FDA does not agree that it lacks authority for this 
rulemaking under the major questions doctrine. First, we do not agree 
that the major questions doctrine applies, because this is not the type 
of ``extraordinary case'' in which there is ``reason to hesitate'' 
before concluding that Congress intended to confer on FDA authority 
over laboratory-manufactured IVDs. Second, even if a court were to hold 
that the major questions doctrine applies, the FD&C Act supplies clear 
congressional authorization.
    a. This rulemaking is not ``extraordinary'' for purposes of the 
major questions doctrine. As explained by the Supreme Court, the major 
questions doctrine does not apply to every agency action, or even every 
agency action that involves significant costs and benefits and 
congressional interest. Rather, it applies only in those 
``extraordinary cases'' in which ``the history and the breadth of the 
authority that the agency has asserted, and the economic and political 
significance of that assertion, provide a reason to hesitate before 
concluding that Congress meant to confer such authority.'' West 
Virginia v. EPA, 142 S. Ct. 2587 at 2608 (cleaned up). The Court has 
indicated that whether there is a ``reason to hesitate'' depends on 
specific ``circumstances'' and ``common sense as to the manner in which 
Congress would have been likely to delegate.'' Id. at 2609 (cleaned 
up). It has identified specific factors that can signal such an 
extraordinary case, such as whether:
     The Agency appears to be assuming ``extravagant'' or 
``broad and unusual'' power--as measured in terms of cost, politics, or 
policy, for example--that Congress would have been ``highly unlikely'' 
to leave to Agency discretion. Id. at 2608-09, 2612 (internal 
quotations omitted).
     The asserted authority relies on an ``ancillary,'' 
``rarely . . . used'' or otherwise ``modest'' statutory provision. Id. 
at 2609-10 (internal quotations omitted).
     The Agency, through statements or practice, previously 
appeared to view the relevant language more narrowly, such that the 
Agency's new view seems ``unheralded'' or ``newly discovered.'' Id. at 
2610, 2612 (internal quotations omitted).
     Implementation of the Agency's decision will require 
``technical and policy expertise'' not traditionally within the 
Agency's wheelhouse. Id. at 2612 (internal quotations omitted).
     There is inconsistency between the asserted authority and 
the larger statutory scheme--for example, Congress has not ``conferred 
a like authority'' on the Agency elsewhere in the statute. Id. at 2613.
    Under the major questions doctrine, the Court has described these 
factors as indicating that Congress may not have meant to confer the 
power claimed by the Agency.
    Application of the factors here shows that courts should not 
hesitate before concluding that Congress granted FDA authority over 
laboratory-manufactured IVDs, consistent with the statute's plain 
language. In this rulemaking, FDA is not asserting any ``new'' 
authority at all. Over 30 years ago, FDA unambiguously stated that it 
has authority over laboratory-made IVDs, (Ref. 111), and in the last 
decade, it has applied that authority to hundreds of laboratory-made 
IVDs, including LDTs, without legal challenge (see, e.g., Refs. 144 to 
155). This Rule clarifies the statutory definition of a ``device,'' 
which is not an ``ancillary'' provision of the FD&C Act but rather the 
bedrock definition that governs the application of each device 
provision that FDA administers. As explained elsewhere in this 
preamble, the device definition encompasses diagnostic test systems, so 
there is nothing ``unusual'' or ``extravagant'' about concluding that 
it reaches test systems made by laboratories. In fact, that 
understanding is in lockstep with FDA's statutory mandate and the other 
authorities it implements, is consistent with FDA's longstanding 
approach, and makes the most of FDA's expertise. What would be 
``unusual'' is to read an atextual laboratory exemption into the FD&C 
Act--thus elevating laboratories above any other type of manufacturer--
of entirely amorphous breadth and scope. See Bostock v. Clayton Cty., 
140 S. Ct. 1731 at 1749 (inferring from ``broad language'' ``Congress's 
`presumed point [to] produce general coverage--not to leave room for 
courts to recognize ad hoc exceptions.' '') (quoting A. Scalia & B. 
Garner, Reading Law: The Interpretation of Legal Texts 101 (2012)). In 
the following paragraphs, FDA addresses each of the major questions 
factors to show why this is not an ``extraordinary case'' under that 
doctrine.
    First, FDA is not asserting ``extravagant'' or ``broad and 
unusual''

[[Page 37353]]

power that Congress would have been ``highly unlikely'' to leave to 
Agency discretion. Congress enacted the MDA ``to provide for the safety 
and effectiveness of medical devices intended for human use'' without 
qualification. Medical Device Amendments of 1976, Public Law 94-295 
(May 28, 1976) (purpose clause). In that legislation, it tasked FDA 
with overseeing the safety and effectiveness of all devices used in the 
United States--a substantial delegation that, according to FDA's 
estimates, encompasses a $374.5 billion industry today. Although FDA 
has estimated that this rule will have important public health impacts, 
the costs of the rule are not ``extravagant'' or ``unusual,'' 
particularly when viewed in the context of FDA's regulatory 
responsibility for devices overall. And device regulation is just one 
small part of FDA's overall remit: as of January 2024, FDA-regulated 
products accounted for about 21 cents of every dollar spent by U.S. 
consumers, and FDA had responsibility for ``more than $3.6 trillion in 
consumption of food, medical products, and tobacco.'' \64\ Given the 
breadth and scope of FDA's overall mandate, and its mandate with 
respect to devices, there is no reason to doubt that the mandate 
includes the subset of IVDs that are manufactured by laboratories, and 
the economic impact of this rule alone does not provide a reason to 
hesitate under the major questions doctrine.\65\
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    \64\ Ref. 156.
    \65\ One commenter's discussion of the major questions doctrine 
emphasized the Agency workload under the NPRM. Even assuming that 
were a relevant factor, the Agency's workload for purposes of this 
rule is not so great that it raises a question about whether 
Congress intended to confer authority on FDA to regulate laboratory-
manufactured IVDs. As stated, FDA's regulation of devices is just 
one small part of FDA's overall remit; and the regulation of the 
subset of IVDs that are manufactured by laboratories is just one 
part of that broader regulatory authority over devices.
---------------------------------------------------------------------------

    FDA also does not agree that ``political significance'' is a 
compelling factor here. Many comments pointed to recent legislative 
proposals related to IVDs, such as the Verifying Accurate, Leading-Edge 
IVCT Development Act of 2023 (VALID Act), H.R. 2369, 118th Cong. 
(2023). Some comments portrayed the VALID Act as a proposal to grant 
FDA new authority over LDTs, or interpreted Congress's decision not to 
enact the VALID Act as evidence that FDA lacks authority to issue the 
rule. These characterizations do not accurately describe the VALID Act. 
Congressional deliberations over the VALID Act involved the question 
whether a whole new statutory scheme, instead of the device framework 
in the FD&C Act, should apply to IVDs. Under the VALID Act, all IVDs, 
including LDTs, would have been carved out from the definition of a 
``device''--a step that would not have been necessary were they not 
covered by the existing definition--and would have been subject to a 
novel statutory framework including, for example, a new statutory 
approval standard, new types of premarket review (such as ``technology 
certification''), and different QS requirements. Thus, contrary to 
commenters' suggestions, the fact that Congress has not passed that 
bill does not represent a decision that FDA lacks authority over LDTs, 
but rather that Congress has not chosen to create a statutory scheme 
for IVDs that is different than for all other devices. Around the same 
time, Congress also considered, but did not pass, a bill that, as 
summarized by Congressional Research Service, would have ``shift[ed] 
the regulation of laboratory-developed testing procedures from the Food 
and Drug Administration (FDA) to the Centers for Medicare & Medicaid 
Services (CMS).'' \66\ In not passing that bill, Congress opted to 
maintain the longstanding, well-understood status quo: that IVDs, 
including LDTs, are devices subject to device requirements under the 
FD&C Act. Congress's consideration of these bills does not show that 
there is an open question whether Congress conferred this authority on 
FDA under the FD&C Act; instead, it provides additional evidence 
affirming that LDTs fall within FDA's existing authority.
---------------------------------------------------------------------------

    \66\ See Congressional Research Service summary, Verified 
Innovative Testing in American Laboratories (VITAL) Act, S. 1666, 
117th Cong. (introduced May 18, 2021), available at https://www.congress.gov/bill/117th-congress/senate-bill/1666.
---------------------------------------------------------------------------

    In any event, even if a court were to find the foregoing economic 
and political facts relevant under the major questions doctrine, FDA 
does not agree that they are sufficient to implicate that doctrine. The 
Court's major-questions cases examine a variety of factors to determine 
whether there is a ``reason to hesitate'' before concluding that 
Congress meant to confer the power claimed by the Agency. For example, 
in West Virginia, the Court cited a range of factors to conclude that 
the rulemaking there presented a ``major question.'' The Court did not 
rest the decision solely on the ``billions of dollars in compliance 
costs,'' EPA v. West Virginia, 142 S. Ct. 2587 at 2604, and the fact 
that Congress had ``consistently rejected proposals'' to create a cap-
and-trade scheme for carbon, id. at 2614. Instead, it devoted much 
attention to other factors, such as those described in the remaining 
paragraphs of this comment response. This fact suggests that economic 
and political factors, even where applicable, are not enough. And the 
other hallmarks of an ``extraordinary case'' are absent here.
    For example, FDA's asserted authority does not rely on an 
``ancillary,'' ``rarely . . . used'' or otherwise ``modest'' statutory 
provision, but on the meaning of ``device,'' which defines the scope of 
articles subject to device requirements under the FD&C Act. Congress 
knew this definition would play a central role in the application of 
FDA's authorities, so it gave the provision special attention in 1976, 
adding new terms and carefully distinguishing ``devices'' from 
``drugs.'' See, e.g., H.R. Rep. 94-853 at 13-15. Given the detailed 
nature of the definition and Congress's care in drafting it, this 
provision is very different from the ``vague statutory grant'' at issue 
in West Virginia, which, in the Court's view, was susceptible of 
interpretation in a manner that went ``beyond what Congress could 
reasonably be understood to have granted.'' EPA v. West Virginia, 142 
S. Ct. 2587 at 2609, 2614. Here, the definition's text is reasonably 
understood to reflect the true scope of FDA's authority as intended by 
Congress. See id. at 13 (``[T]he Committee has attempted to design 
device authority such that the law and the intent of the Congress is 
clear.''); see also United States v. Bacto-Unidisk, 394 U.S. 784, 798 
(1969) (``Congress fully intended that the [FD&C] Act's coverage be as 
broad as its literal language indicates.'').
    FDA is not exercising ``newly uncovered'' or ``unheralded'' 
authority. West Virginia v. EPA, 142 S. Ct. 2587 at 2610, 2614. FDA 
publicly communicated its view that test systems are subject to the 
Agency's authority over 50 years ago, see 38 FR 7096; that laboratories 
are subject to the Agency's authority almost 50 years ago, see 42 FR 
42521; and that laboratory ``in house'' tests are devices nearly 30 
years ago, see 62 FR 62249. And in the years since, FDA has 
consistently reiterated these assertions (see NPRM section III.D.1., 
``FDA's Longstanding Recognition That IVDs Manufactured by Laboratories 
Are Devices'' 88 FR 68006 at 68015-16). Over the last 10 years, FDA has 
applied its device authorities to hundreds of laboratory-manufactured 
tests. For example, dating back to at least 2014, it has granted 
premarket approval to IVDs offered as LDTs,\67\ and during the

[[Page 37354]]

COVID-19 public health emergency, the Agency issued EUAs for scores of 
IVDs offered as LDTs (see Ref. 18). All of these activities were 
predicated on the legal conclusion that test systems manufactured by 
laboratories are devices. See 21 U.S.C. 360e (premarket approval 
authority applicable to devices); 21 U.S.C. 360bbb-3 (EUA authorities 
applicable to drugs, devices, or biological products). Thus, this is 
not a situation in which ``the want of assertion of power by those who 
presumably would be alert to exercise it'' raises a question about 
``whether such power was actually conferred.'' Id. at 2608. FDA has 
repeatedly expressed its view of its authority, including in public 
statements and through public actions, and its consistent position over 
decades--without congressional intervention--suggests that there is no 
``reason to hesitate'' here. See, e.g., United States v. Tuente 
Livestock, 888 F. Supp. 1416, 1423 (S.D. Ohio 1995) (upholding FDA 
interpretation based on, among other things, the fact that ``Congress 
has been aware of the FDA's understanding and practice concerning live 
animals for almost twenty-five years, yet has in no way acted to limit 
the agency's jurisdiction'').\68\
---------------------------------------------------------------------------

    \67\ Ref. 157.
    \68\ One commenter attempted to discredit FDA's statement of 
authority in one preamble (62 FR 62243) on the basis that FDA lacked 
``any supporting analysis,'' among other things. But FDA is aware of 
no basis for the position that the major-questions doctrine requires 
an Agency to produce a detailed legal analysis in order to show its 
historical view. As the Supreme Court has described it, the question 
is whether the Agency's asserted authority is ``unheralded,'' 
``newly uncovered,'' or ``not previously exercised,'' West Virginia 
v. EPA, 142 S. Ct. 2587 at 2610, 2614, and that is not the case 
here. FDA also notes that the statement identified by the commenter 
was just one in a long line of public statements (see NPRM section 
III.D.1., ``FDA's Longstanding Recognition That IVDs Manufactured by 
Laboratories Are Devices'' 88 FR 68006 at 68015-16), and it was not 
the first statement of FDA's authority over laboratory-manufactured 
IVDs. See, e.g., (Ref. 111). Draft CPG: Commercialization of 
Unapproved In Vitro Diagnostic Devices Labeled for Research and 
Investigation (Aug 3, 1992) (stating that laboratory ``home brew'' 
products ``are subject to the same regulatory requirements as any 
unapproved medical device'').
---------------------------------------------------------------------------

    Implementation of this Rule involves technical and policy expertise 
traditionally within FDA's wheelhouse. FDA has amassed significant 
experience and expertise regulating IVDs (including test systems) over 
the course of five decades. This work is squarely within the expertise 
of FDA's OHT7. OHT7 employs staff across a wide range of disciplines to 
evaluate test systems and other IVDs, including the principles of their 
operation and the analytical validity, clinical validity, and safety 
data behind them. As explained in the NPRM, FDA's work in this area 
does not meaningfully differ whether an IVD comes from a laboratory or 
another manufacturer (88 FR 68006 at 68014) (see also responses to 
comments 67 and 71). Applying this sort of technical and scientific 
knowledge to devices is a quintessential function performed by FDA, and 
undoubtedly an area where FDA has ``comparative expertise.'' Id. at 
2613. Indeed, no other Federal Agency is similarly equipped to do it. 
These facts underscore the conclusion that FDA has a legitimate role to 
play--and value to add--in overseeing laboratory-made IVDs. They also 
reinforce the commonsense point that laboratory-manufactured IVDs fall 
within the basic mandate of the FD&C Act. Here, FDA is exercising 
authority, applying expertise, and serving its public-health mission in 
exactly the ways that are contemplated under the FD&C Act.
    Finally, the FD&C Act as a whole supports the conclusion that the 
Agency has authority for this rulemaking. Congress enacted both the 
FD&C Act and the MDA with public-health protection in mind. See United 
States v. Sullivan, 332 U.S. 689, 696 (1948) (``[T]he Act as a whole 
was designed primarily to protect consumers from dangerous 
products.''); Medtronic, Inc. v. Lohr, 518 U.S. 470, 476 (``In response 
to the mounting consumer and regulatory concern, Congress enacted the 
statute at issue here: the Medical Device Amendments of 1976.''). 
Congress tasked FDA with protecting the public with respect to certain 
defined categories of articles--as relevant here, ``devices''--and 
sought to avoid ``language which afforded loopholes for the escape of 
the unscrupulous.'' S. Rep. 74-361 at 2 (March 13, 1935). Given that 
risky products could originate from all corners of the country by all 
manner of ``persons,'' see 21 U.S.C. 321(e), Congress did not key the 
``device'' definition to any particular type of entity and did not 
limit FDA's enforcement authorities to particular actors, see 21 U.S.C. 
331 (listing ``prohibited acts'' generally without reference to the 
identity of an actor). Instead, it delegated broad authority and 
crafted exemptions from certain requirements as appropriate. See, e.g., 
21 U.S.C. 360(g)(2), 360i(c)(1), 374(a)(2)(B) (even licensed 
practitioners are subject to the FD&C Act, though their activities may 
be exempt). Consequently, the best reading of the FD&C Act is that it 
contains no carveout for laboratories, and Congress has enacted 
legislation supporting that interpretation. See 42 U.S.C. 1395m-
1(d)(5)(B) (certain tests developed by laboratories subject to FD&C 
Act). With respect to commenters' assertions regarding specific 
provisions of the FD&C Act and the enactment of CLIA, FDA has addressed 
those elsewhere in this preamble (see response to comment 54 and 
sections VI.D.3, VI.D.4, and VI.D.8 of this preamble).
    Some commenters also analogized FDA's proposed action to those in 
FDA v. Brown and Williamson Tobacco Corp., 529 U.S. 120 and Utility Air 
Regulatory Group v. EPA, 573 U.S. 302. But important factors 
influencing the Court's opinions in those cases are not present here. 
For instance, here, there is no inconsistency between the FD&C Act and 
FDA's regulation of laboratories as ``device'' manufacturers. See Brown 
and Williamson, 529 U.S. 120 at 125 (FDA ``may not exercise its 
authority in a manner that is inconsistent with the administrative 
structure that Congress enacted into law.'') (internal quotations 
omitted); Utility Air Regulatory Group, 573 U.S. 302 at 321 (Agency 
interpretation ``would be inconsistent with--in fact, would overthrow--
the Act's structure and design.''). Indeed, FDA has regulated in this 
way for years, and FDA has never disclaimed authority over laboratory-
manufactured IVDs. In addition, this final rule will not have the type 
of ``calamitous consequences'' that have caused the Court to consider 
other regulatory actions to be ``incompatible with the substance of 
Congress' regulatory scheme.'' \69\ 573 U.S. 302 at 322. Quite the 
opposite: FDA believes that a continuation of the status quo--or a 
construction of the FD&C Act that incorporates an atextual exemption 
for laboratories--would have serious consequences for the public, which 
is why FDA is issuing this rule.\70\
---------------------------------------------------------------------------

    \69\ One comment argued that this rulemaking will have practical 
consequences analogous to those in Utility Air--a significant 
increase in the number of applications, administrative costs, and 
the review period for applications--which shows that it presents a 
``major question.'' FDA disagrees. As already discussed, FDA does 
not agree that the current effects of this rule are a reliable 
indicator of Congress's intent in 1976. In addition, we do not agree 
that the practical effects here have the same weight as they did in 
Utility Air. See Utility Air Regulatory Group v. EPA, 573 U.S. 302, 
321-22 (2014) (``EPA described the calamitous consequences of 
interpreting the Act in that way.''). And in this rulemaking, unlike 
Utility Air, FDA has discretion to develop enforcement policies to 
address practical concerns about implementation, underscoring the 
point that practical concerns should not be understood to reflect a 
lack of jurisdiction. Id. at 326 (rule was not ``an exercise of 
EPA's enforcement discretion'' given the possibility of citizen 
suits).
    \70\ One comment also compared this rulemaking to the facts in 
United States v. Franck's Lab, Inc., 816 F. Supp. 2d 1209 (M.D. Fla. 
2011), which concerned FDA's authority over pharmacy compounding. 
However, that case was not a ``major questions'' case, and in any 
event, it was vacated by the Eleventh Circuit. United States v. 
Franck's Lab, Inc., 2012 U.S. App. LEXIS 27100 (11th Cir. 2012).

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[[Page 37355]]

    b. Even if the major-questions doctrine applies, the FD&C Act 
supplies ``clear congressional authorization'' for this rulemaking. In 
response to comment 52, FDA explained that the device definition, by 
its plain terms, encompasses IVDs manufactured by laboratories. This 
conclusion has more than ``a merely plausible textual basis.'' Id. at 
2609. It is the most reasonable reading of the text, and the one that 
matches congressional intent as expressed through the statutory scheme 
overall, the legislative history, and subsequent statements from 
Congress.
    Congress drafted the FD&C Act with broad reach, consistent with the 
remedial purpose of the legislation, and then exempted specific actors 
and activities as appropriate, but never exempted laboratories. In 
1938, Congress included the term ``diagnosis'' in the FD&C Act 
specifically to empower FDA to address articles producing false 
diagnostic results, without any carveout for laboratories. FD&C Act 
(June 25, 1938), Public Law 75-717, 52 Stat. 1040 (defining ``drug'' 
and ``device'' with reference to an intended use in ``diagnosis,'' 
among other things). In 1976, Congress reiterated that diagnostic 
articles should be regulated by FDA, now under the new, more robust 
device framework, and again made no distinction in the device 
definition between entities manufacturing those articles. See, e.g., 
H.R. Rep. 94-853 at 11 (February 29, 1976). As described in response to 
comment 53, the authorizing committees discussed concerns about 
diagnostic systems at length--and particularly the potential harms of 
faulty test results--but never mentioned that entities such as 
laboratories should fall outside the reach of the FD&C Act, even though 
laboratories were manufacturing tests at the time and FDA had recently 
announced, by regulation, that IVDs were devices regardless of their 
manufacturer. And in the over 30 years since FDA first stated its 
authority over LDTs specifically, Congress has not acted to limit the 
Agency's jurisdiction. Instead, in 2014, Congress passed legislation 
expressly recognizing that ``a clinical diagnostic laboratory test . . 
. offered and furnished only by a single laboratory'' can be ``cleared 
or approved by the Food and Drug Administration,'' 42 U.S.C. 1395m-
1(d)(5) & (d)(5)(B), and thus is within the definition of a device. 
Therefore, examining the text in context, the definition provides 
``clear congressional authorization'' for this rulemaking.

E. Other Legal Comments

    (Comment 93) Two comments raised First Amendment concerns. One 
comment asserted that LDTs are different from other devices in that the 
design and execution of LDTs, as well as the communication of test 
results, involve speech. In particular, the comment pointed to two CLIA 
regulations, 42 CFR 493.1445 and 493.1457, which provide that 
laboratory directors and clinical consultants must ``[e]nsure that 
consultation is available to the laboratory's clients on matters 
relating to the quality of the test results reported and their 
interpretation concerning specific patient conditions.'' The comment 
asserted that these communications will be restricted if FDA has not 
authorized them through premarket review. The comment then argued that 
the premarket review requirement for LDTs cannot survive First 
Amendment analysis. Although the comment conceded that there is a 
government interest in ensuring that test results do not include 
misleading information, the comment asserted that premarket review of 
LDTs would be too burdensome because such review would restrict 
laboratory directors and clinical consultants from sharing information 
about the meaning of test results. That outcome, the comment continued, 
would undermine the goal of providing healthcare practitioners with 
information relevant to treatment.
    The other comment focused on the right of physicians to receive 
information as part of their professional speech. The comment suggested 
that professional speech is subject to special protections under 
National Inst. of Family and Life Advocates v. Becerra, 138 S. Ct. 2361 
(2018) (NIFLA) and this special protection extends to physicians' right 
to receive information. Similar to the first comment, this comment 
asserted that an LDT is different from many other medical devices in 
that it is ``an informational service'' incorporating expert 
professional judgments. While the comment admitted that the FD&C Act 
properly places the burden on product sponsors to produce evidence that 
their products are safe and effective before they can be used, the 
comment asserted that ``the Constitution flips the burden of proof'' 
when regulating flows of medical information, so that FDA would bear 
the burden of establishing that an LDT is unsafe in order to regulate 
the LDT.
    (Response 93) We disagree with these comments, both in terms of the 
premises and the analyses. As an initial matter, it is important to 
clarify the limited impact that the application of the device 
authorities to LDTs will have on professional communications. As the 
phaseout of the general enforcement discretion approach is implemented, 
laboratories that manufacture IVDs offered as LDTs will be generally 
expected to comply with several pre- and post-market submission and 
reporting requirements applicable to devices for humans. As most 
relevant to this discussion, the premarket review requirements are 
intended to ensure that a device has a reasonable assurance of safety 
and effectiveness (or other assurances as required under the FD&C Act) 
for its intended uses prior to being offered for use. For IVDs, 
appropriate assurances of safety and effectiveness mean, among other 
things, that a test is not providing false results, which can stem from 
an analytical error or from a lack of clinical validity where a 
measured result is incorrectly associated with a particular clinical 
state. Accordingly, premarket review involves a scientific evaluation 
of the functioning of the device for accuracy and reliability. Where 
premarket requirements apply, a test may not be offered for use if 
those requirements have not been satisfied. But FDA does not generally 
consider professional advice regarding a patient's results as evidence 
of a new intended use, and nothing in this rule is intended to change 
this practice or otherwise limit the speech clinical professionals may 
employ in describing and interpreting the outputs of the devices that 
are lawful to employ. As discussed in more detail below, courts have 
upheld these premarket review requirements against First Amendment 
challenges.
    Both comments suggested that LDTs are different from other devices 
because they convey individuals' health information--that is, test 
results. The comments asserted that this information constitutes 
speech. But LDTs are not unique in conveying individuals' health 
information. So too do many non-laboratory IVDs have informational 
outputs, as well as numerous other types of diagnostic devices, such as 
radiological imaging devices (such as mammography, x-ray, CT, 
ultrasound machines), electrocardiograms, blood pressure cuffs, pulse 
oximeters, cardiac monitors including fetal heart rate monitors, and 
thermometers. These devices all communicate information--in the form of 
words, numbers, images, and/or sounds. Yet FDA's statutory authority to 
regulate diagnostic devices is well established. See 21 U.S.C. 321(h)

[[Page 37356]]

(defining ``device'' in part as an article ``intended for use in the 
diagnosis of disease or other conditions''). And the constitutionality 
of Congress's grant of authority to regulate these devices, and to 
prohibit their sale or use where applicable premarket requirements are 
not satisfied, has not been questioned. There is nothing about LDTs, as 
compared with these other devices (or with non-LDT IVDs that produce 
diagnostic results), that suggests they uniquely implicate the First 
Amendment. They do not.
    We are not aware of any instance in which a litigant has raised a 
First Amendment challenge to the application of the premarket review 
provisions of the FD&C Act for diagnostic devices based on the 
informational nature of their outputs. Any such challenge should fail 
on legal grounds. Even where LDTs or other diagnostic devices convey 
information about the health of patients, they do not convey ideas, 
creative expression, or editorial judgments--that is, they do not 
convey speech that implicates the First Amendment. Rather, they simply 
convey scientifically-generated test results purely as a function of 
the device. In this regard, they cannot be distinguished from a vast 
array of products whose regulation does not implicate the First 
Amendment: radar detectors, gas gauges, expiration lights for water 
filters, and so forth. Even though the very point of these products is 
to convey information, the Government may seek to ensure that they do 
so accurately and reliably--and may bar the sale of those that are not 
accurate and reliable--without triggering First Amendment scrutiny. 
Indeed, requirements of prior certification before commercial use of 
weighing and measuring devices--devices whose purpose is to convey 
information in ways analogous to diagnostic tests--are ubiquitous. See, 
e.g., Nat'l Inst. of Standards & Technology, Weights and Measures 
Program Requirements: A Handbook for the Weights and Measures 
Administrator 13-14 (2017) (``Before measuring instruments may be 
installed in stores or at business locations, most states require that 
the many types of measuring instruments have type evaluation 
certificates reporting that the models comply with the requirements of 
NIST Handbook 44,'' which provides ``the technical and performance 
requirements for commercial measuring instruments used in the United 
States''). But we are unaware of a single court that has even applied 
First Amendment scrutiny to these requirements. The application of the 
FD&C Act's medical device regulation to LDTs is the same in all 
relevant respects.\71\
---------------------------------------------------------------------------

    \71\ See also Winter v. G.P. Putnam's Sons, 938 F.2d 1033, 1035-
36 (9th Cir. 1991) (citing numerous courts that have applied 
products liability law, without First Amendment scrutiny, to 
aeronautical charts that contain erroneous information, noting that: 
``Aeronautical charts are highly technical tools. They are graphic 
depictions of technical, mechanical data. . . . The chart itself is 
like a physical `product.'. . . . [not] pure thought and 
expression.'').
---------------------------------------------------------------------------

    The comments also erred in their assessment of how the rule would 
affect professional speech. More specifically, the first comment was 
incorrect in suggesting that premarket review will preclude the 
laboratory directors and clinical consultants from consulting on the 
quality of the test results and their interpretation concerning 
specific patient conditions pursuant to the CLIA regulations. Premarket 
review for LDTs is intended to help assure that LDTs generate accurate 
and reliable test results. As noted, FDA does not generally consider 
professional advice regarding a patient's results as evidence of a new 
intended use, and nothing in this rule is intended to change this 
practice.\72\ FDA recognizes that laboratory directors and clinical 
consultants help with interpretation and consulting to the healthcare 
provider, and they can and do give recommendations that are not limited 
to the content of FDA-required labeling. This clinical consultation is 
unaffected by FDA's oversight of LDTs. Indeed, the CLIA provisions are 
not specific to LDTs and have coexisted with FDA regulation of other 
IVDs for some time. The commenter therefore was incorrect in construing 
the premarket review and related requirements discussed in this 
preamble as restricting laboratory directors and clinical consultants 
from sharing truthful and nonmisleading information about the meaning 
of a test result.
---------------------------------------------------------------------------

    \72\ In contrast, if a laboratory offers a test on its website 
for an unauthorized use, FDA would likely consider that offer to be 
evidence of a new intended use.
---------------------------------------------------------------------------

    In addition, with respect to speech by laboratories more generally, 
contrary to the first comment's suggestion, FDA does not take the 
position that communications by medical product manufacturers are 
strictly limited to the content of FDA-required labeling. For example, 
FDA has issued final guidance regarding medical product manufacturers 
sharing data and information about the authorized uses of their 
products that are not contained in their products' FDA-required 
labeling; the final guidance provides recommendations on how to share 
the information in a truthful and non-misleading way (see Ref. 62). FDA 
has also issued draft guidance with recommendations on how medical 
product manufacturers can share truthful and non-misleading information 
about unapproved uses of medical products (see, e.g., Refs. 158 and 
159).
    Essentially, then, the only content restriction is the requirement 
of premarket review itself--that laboratories cannot offer test results 
without first subjecting its device to premarket review to help assure 
that the device produces accurate and reliable results. A First 
Amendment challenge to the rule is therefore fundamentally a challenge 
to the FD&C Act's existing premarket requirements themselves, which 
prohibit the conduct of marketing devices absent satisfaction of those 
requirements. Even to the extent that the premarket requirements relate 
to speech in the form of labeling and marketing, they have long been 
upheld.
    Courts have upheld these premarket review requirements in the 
context of First Amendment challenges on a variety of grounds. The 
premarket review requirements do not burden free expression because 
they are directed to conduct and not to speech. United States v. 
Facteau, 89 F.4th 1, 29 (1st Cir. 2023), petition for cert. filed, __ 
U.S.L.W. __ (U.S. March 13, 2024) (No. 23-1016). A device is 
adulterated or misbranded ``if, among other things, it is intended for 
a use [subject to premarket review] that has not been approved or 
cleared by FDA.'' January 2017 Memorandum at 40; see generally id. at 
40-47 (Ref. 17). In this case, the relevant conduct includes making 
LDTs available for use and sale without premarket review when such 
review is required, which constitutes adulterating or misbranding the 
device while it is held for sale in violation of section 301(k) of the 
FD&C Act. ``[I]t has never been deemed an abridgment of freedom of 
speech'' to regulate conduct that involves language where the ``effect 
on speech would be only incidental to its primary effect on conduct.'' 
Expressions Hair Design v. Schneiderman, 581 U.S. 37, 47 (2017) 
(cleaned up). Accordingly, regulation of the conduct of making a device 
available without premarket review has only ``incidental effects'' on 
speech and ``do[es] not implicate the First Amendment.'' Facteau, 89 
F.4th 1 at 29 petition for cert. filed, __ U.S.L.W. __ (U.S. March 13, 
2024) (No. 23-1016) (cleaned up). See also Flytenow, Inc. v. FAA, 808 
F.3d 882, 894 (D.C. Cir. 2015) (any ``incidental burden'' that 
regulatory requirements impose on speech ``does not violate the

[[Page 37357]]

First Amendment'' where the requirements ``further an important 
government interest unrelated to the suppression of free expression,'' 
such as promoting safety). As explained above, premarket review helps 
assure medical products are safe and effective--which is a substantial 
government interest unrelated to the suppression of free expression.
    And it is ``constitutionally permissible'' to rely on speech to 
``infer intent,'' including where that intent establishes that the 
product is within a category that is subject to and violative of FDA 
premarket review requirements. Whitaker v. Thompson, 353 F.3d 947, 953 
(D.C. Cir. 2004). For example, charcoal products intended for emergency 
treatment of poisoning by ingestion are drugs regulated by FDA, but 
charcoal sold as fuel is not within FDA's jurisdiction. The product's 
intended use, which may be determined from the product's labeling, 
establishes whether the product is within FDA's jurisdiction (see Ref. 
17). The First Circuit recently observed that ``courts to consider the 
issue have uniformly concluded that using speech merely as evidence of 
a misbranding offense under the [FD&C Act] does not raise First 
Amendment concerns.'' United States v. Facteau, 89 F.4th 1 at 25, 
petition for cert. filed, __ U.S.L.W. __ (U.S. March 13, 2024) (No. 23-
1016). See, e.g., Nicopure Labs, 944 F.3d 267 at 282 (``FDA's reliance 
on a seller's claims about a product as evidence of that product's 
intended use, in order that the FDA may correctly classify the product 
and restrict it if misclassified, does not burden the seller's 
speech''); United States v. LeBeau, 2016 U.S. Dist. LEXIS 13612, *27 
(E.D. Wisc. February 3, 2016) (``A product's labeling can be used to 
infer the seller's intended use and whether the product is an 
unapproved drug under the FDCA.''), aff'd, 2016 U.S. App. LEXIS 12375 
(7th Cir. 2016); United States v. Cole, 84 F. Supp. 3d 1159, 1166 (D. 
Or. 2015); United States v. Livdahl, 459 F. Supp. 2d 1255 (S.D. Fla. 
2005); United States v. Lane Labs-USA, Inc., 324 F. Supp. 2d 547 
(D.N.J. 2004); U.S. v. Undetermined Quantities of Articles of Drug, 145 
F. Supp. 2d 692 at 703 (D. Md. 2001). See also Flytenow, Inc. v. FAA, 
808 F.3d at 894 (the ``evidentiary use of speech'' is ``well 
settled'').\73\
---------------------------------------------------------------------------

    \73\ Although the Second Circuit stated in United States v. 
Caronia, 703 F.3d 149, 169 (2d Cir. 2012) that ``the government 
cannot prosecute pharmaceutical manufacturers and their 
representatives under the [FD&C Act] for speech promoting the 
lawful, off-label use of an FDA-approved drug,'' the Second Circuit 
later confirmed that ``Caronia left open the government's ability to 
prove misbranding on a theory that promotional speech provides 
evidence that a drug is intended for a use that is not included on 
the drug's FDA approved label.'' United States ex rel. Polansky v. 
Pfizer, Inc., 822 F.3d 613 n.2 (2d Cir. 2016). The First Circuit 
likewise found that Caronia provides ``no basis to depart from the 
rule . . . that the evidentiary use of speech does not violate the 
First Amendment.'' Facteau, 89 F.4th at 24, petition for cert. 
filed, __ U.S.L.W. __ (U.S. March 13, 2024) (No. 23-1016).
---------------------------------------------------------------------------

    Nor does FDA's determination to exercise enforcement discretion 
with respect to premarket review in certain specific contexts (see 
discussion in section V.B) restrict or burden speech. As the First 
Circuit recently explained in rejecting a First Amendment challenge to 
an FDA final guidance describing an enforcement discretion policy, the 
enforcement policy does not ``burden[ ] what [medical product] 
manufacturers may say,'' but instead ``expands, rather than contracts, 
the domain of speech that the government shields from being used as 
evidence'' of intended use. Facteau, 89 F.4th at 28, petition for cert. 
filed, __ U.S.L.W. __ (U.S. March 13, 2024) (No. 23-1016). The court 
held that ``a policy that limits the consideration of [certain] speech 
as evidence of intended use does not raise First Amendment concerns.'' 
Id. at 25. The D.C. Circuit similarly held, regarding an earlier 
iteration of the enforcement policy, that a policy that provides a 
``safe harbor'' from the use of certain speech as evidence of intended 
use did not establish ``independent authority to regulate manufacturer 
speech'' and therefore was not subject to First Amendment scrutiny. 
Washington Legal Found. v. Henney, 202 F.3d 331, 336 (D.C. Cir. 2000).
    Moreover, to be protected under the First Amendment, commercial 
speech must ``concern lawful activity.'' Central Hudson Gas & Elec. 
Corp. v. Pub. Serv. Comm'n, 447 U.S. 557, 566 (1980). Where Congress 
requires FDA premarket review of a product, making the LDTs available 
for use or sale without such review ``renders the sale-as-labeled 
unlawful.'' Nicopure Labs. v. FDA, 944 F.3d 267, 284 (D.C. Cir. 2019). 
The speech proposing an illegal sale of such a product is ``related to 
illegal activity'' and therefore is ``not subject to constitutional 
protection.'' Id.; accord United States v. LeBeau, 654 Fed. App'x 826, 
831 (7th Cir. 2016) (``Because [defendant]'s statements promoted the 
unlawful sale of an unapproved drug, they were not entitled to 
protection.''); United States v. Caputo, 517 F.3d 935, 940-41 (7th Cir. 
2008) (the unapproved device ``could not lawfully be sold at all'' and 
therefore ``[t]here was no lawful activity for speech to promote''); 
United States v. Cole, 84 F. Supp. 3d 1159, 1166-67 (D. Or. 2015) 
(``[d]efendants' speech concerns an illegal activity--the introduction 
into interstate commerce of unapproved new drugs[,] . . . the First 
Amendment is not violated.'').
    And commercial speech is protected under the First Amendment only 
to the extent that it is ``not . . . misleading.'' Central Hudson, 447 
U.S. 557 at 566. The labeling and advertising for unapproved medical 
products may be considered misleading where the labeling or advertising 
``claim [the product] to be safe and effective without any scientific 
support.'' United States v. Undetermined Quantities of Articles of 
Drug, 145 F. Supp. 2d 692, 703. In such instances, the labeling and 
advertising is ``entitled to no First Amendment protections.'' Id.
    Even if the premarket review and related requirements for devices 
were subject to First Amendment scrutiny, they would easily pass muster 
under Central Hudson and even more exacting levels of scrutiny. Under 
the Central Hudson framework, if the speech is truthful, not inherently 
or actually misleading, and relates to lawful activity, the government 
may impose restrictions that advance a ``substantial'' government 
interest and are no ``more extensive than is necessary to serve that 
interest.'' Central Hudson, 447 U.S. 557 at 566. As FDA has explained 
elsewhere, premarket review and related requirements for medical 
products advance several substantial government interests including 
motivating the development of robust scientific data on safety and 
efficacy; maintaining the premarket review process for safety and 
efficacy to prevent harm, protect against fraud, misrepresentation, and 
bias, and to prevent the diversion of healthcare resources toward 
ineffective treatments; and ensuring required labeling is accurate and 
informative. See January 2017 Memorandum at 3; see also id. at 4-11 
(Ref. 17); Nicopure Labs, 944 F.3d 267 at 285 (premarket and labeling 
requirements ``directly advance[ ] the government's interest in 
accuracy and public health''). These interests apply to LDTs: as 
explained above, premarket review and related requirements help assure 
the safety and effectiveness of IVDs offered as LDTs.
    These premarket review and related requirements are appropriately 
tailored to achieve these goals. To the extent that premarket review 
requirements relate to speech at all, they implicate speech only by 
firms responsible for the product's development and/or distribution--
the parties best able to conduct the research and gather information 
necessary for premarket review and otherwise take steps necessary to 
assure that the

[[Page 37358]]

medical product is safe and effective (see Ref. 17 at 24-25). In this 
way, these requirements are similar to other Federal regulatory 
programs that are directed to particular regulated industry and the 
products those companies produce. Moreover, these requirements do not 
operate to ban speech but rather to establish a process for evaluating 
medical products that fosters truthful, non-misleading, and 
appropriately substantiated speech. See Nicopure Labs, 944 F.3d 267 at 
289 (products subject to premarket review are ``not excluded from the 
marketplace of information, only evaluated first to prevent them from 
misleading consumers''); Ref. 160 (``Commercial speech serves an 
`informational function' and can be regulated to ensure that the public 
has access to accurate information. The FDA serves exactly this end. 
The agency aims not to censor company speech, but to foster the 
development of accurate and reliable information, and channel that 
information into settings where it can be rigorously evaluated.'').
    The Agency has also considered a variety of alternative approaches 
and has determined that they would not optimally advance the government 
interests described above. One alternative would be to continue to 
exercise enforcement discretion in perpetuity regarding premarket 
review requirements for IVDs offered as LDTs and instead rely on 
postmarket remedies, such as enforcement actions for LDTs shown to be 
unsafe. However, FDA has carefully tailored this final rule to balance 
competing interests important to the protection of the public health 
and determined to exercise enforcement discretion with respect to 
premarket review in certain specific contexts (see discussion in 
section V.B); FDA has determined that, in other contexts, exclusive 
reliance on post-market remedies would not be in the best interest of 
public health because it does not provide a reasonable assurance of 
safety and effectiveness prior to the introduction of an IVD to the 
market.
    One comment suggested, as an alternative approach to premarket 
review, that LDT regulation should ``replicate CLIA's reliance on 
private ordering solutions (e.g., private accreditation) and rely on 
postmarketing assessment (rather than premarket review) of LDT safety 
and effectiveness.'' Another alternative would be to enforce premarket 
review requirements only for the highest risk LDTs. Yet another 
alternative would be for FDA to continue to exercise enforcement 
discretion for IVDs offered as LDTs but have unauthorized LDTs disclose 
that they are not FDA-reviewed. All of these potential alternatives, 
like FDA's continuing to exercise enforcement discretion in perpetuity, 
would fall short in achieving FDA's public health objectives: by 
forgoing most or all premarket review except in the limited 
circumstances covered by the enforcement discretion policies described 
in section V.B of this preamble (or other enforcement discretion 
policies that FDA may adopt), these approaches would not sufficiently 
address the safety and effectiveness concerns that have led to the 
issuance of this rule.
    More specifically, the steps suggested by the comment--replicating 
CLIA's reliance on private ordering solutions and relying on 
postmarketing assessments--would be inadequate substitutes for 
premarket review. Among other things, CLIA inspections are conducted 
biennially, so that, if a laboratory has not developed a safe and 
effective test, it could be giving false or invalid results to 
healthcare providers or patients for up to 2 years before the 
laboratory's CLIA inspection. Also, CLIA inspectors typically pick a 
sample of tests for detailed review. Therefore, an LDT from a 
laboratory test manufacturer that has added multiple new tests since 
its last inspection may not have any review of the underlying 
documentation for that test. For additional discussion of why CLIA does 
not provide sufficient assurances of safety and effectiveness for IVDs 
offered as LDTs, see our responses to comments in section VI.C.2 of 
this preamble.
    Now we turn to the remaining arguments made in the comments. As 
noted, one comment suggested that the rule would impermissibly 
interfere with physicians' right to receive information as part of 
their professional speech. As discussed above, however, this comment 
failed to acknowledge that premarket review relates to a scientific 
evaluation of the accuracy and reliability of the test results, which 
is the function of the device; FDA does not intend to consider 
professional advice regarding a patient's results as evidence of a new 
intended use. In addition, framing the issue from the perspective of 
the healthcare practitioner receiving information, as opposed to the 
perspective of the speaker, does not change the First Amendment 
analysis. For example, the origin of the commercial speech doctrine was 
based largely on the interests of consumers in receiving information. 
See Virginia State Bd. of Pharmacy v. Virginia Citizens Consumer 
Council, 425 U.S. 748, 757 (1976). Accordingly, focusing on the 
interests of the listener, as opposed to the interests of the speaker, 
does not render the Central Hudson analysis inapplicable in evaluating 
the constitutionality of premarket review.
    It also makes no difference whether the recipient of the 
information is a healthcare practitioner or a patient. Congress enacted 
the FD&C Act to cover medical products directed to both healthcare 
practitioners and patients. For example, FDA regulates the labeling of 
medical products to help assure that they are used safely and 
effectively, whether the labeling is directed to healthcare 
practitioners or patients. And the government interest in providing a 
reasonable assurance of safety and effectiveness of devices applies no 
matter who is the audience for the information.
    Contrary to one comment's suggestion, the Supreme Court's opinion 
in NIFLA is inapposite. On the topic of professional speech, that 
decision merely held that ``neither California nor the Ninth Circuit 
has identified a persuasive reason for treating professional speech as 
a unique category that is exempt from ordinary First Amendment 
principles'' but the Court did not ``foreclose the possibility that 
some such reason exists.'' NIFLA, 138 S. Ct. 2361 at 2375. In any 
event, our analysis does not rely on treating professional speech as a 
unique category that is exempt from ordinary First Amendment 
principles.
    We also disagree with the comments' assertions that strict scrutiny 
should apply because the speech regarding test results is not itself 
commercial. As discussed above, these devices produce scientifically-
generated informational outputs as their function; they do not convey 
the type of speech that might justify heightened scrutiny. Moreover, 
courts do not apply the concept of commercial speech so narrowly: 
information disclosed ``in connection with a proposed commercial 
transaction'' constitutes commercial speech, even where the relevant 
speech itself does not propose a commercial transaction. See N.Y. State 
Rest. Ass'n v. N.Y. City Bd. of Health, 556 F.3d 114, 131 (2d Cir. 
2009) (a requirement to post calorie content information on menus ``is 
clearly commercial speech''). More specifically, courts have held that 
FDA's premarket review requirements are subject to review under the 
commercial speech doctrine rather than strict scrutiny, even where the 
manufacturer's speech involves matters of science. See Discount Tobacco 
v. United States, 674 F.3d 509, 532-33 (6th Cir. 2012) (Central Hudson 
was the appropriate test for premarket review of tobacco harm reduction 
claims where the claims

[[Page 37359]]

were ``consumer-directed'' and ``regarding a manufacturer's specific 
products''); Washington Legal Foundation v. Friedman, 13 F. Supp. 2d 
51, 62-65 (D.D.C. 1998) (finding manufacturers' dissemination of 
scientific information about their products to health practitioners to 
be commercial speech), vacated in part on other grounds, 202 F.3d 331 
(D.C. Cir. 2000). Nevertheless, even if this rule were subject to First 
Amendment scrutiny (which, as explained above, it is not) and even if 
strict scrutiny were then applied, that test would be satisfied here 
because the government has a compelling interest in protecting the 
public health, and premarket review is narrowly tailored to achieve 
that result, for the reasons explained above.
    Finally, we are not aware of any authority to support the flipped-
burden-of-proof theory regarding premarket review. Congress established 
the premarket review requirements under the FD&C Act, which places the 
burden on the manufacturer to establish the safety and effectiveness of 
medical products. To the extent a stakeholder challenges those 
requirements under the First Amendment, it is the government's burden 
to establish that the requirements are constitutionally permissible. 
That is, the government bears the burden on the Central Hudson analysis 
or other applicable First Amendment doctrine of making the required 
showing, e.g., that the premarket review requirement directly advances 
a substantial government interest. But there is no First Amendment 
principle that would result in a court or an agency rewriting the 
premarket review provisions of the FD&C Act to require FDA to prove 
that an individual LDT is unsafe.
    In sum, FDA's premarket review and related requirements for medical 
devices do not violate the First Amendment, and the action FDA is 
taking today to clarify their application to LDTs does not raise any 
constitutional concerns.
    (Comment 94) One comment suggested that the rule might raise 
concerns under Equal Protection principles on the ground that the rule 
unduly favors large entities over smaller ones without a rational basis 
for the distinction. The comment similarly suggested the rule may have 
antitrust implications by disproportionately affecting smaller 
laboratories to the benefit of larger entities because the costs of 
entry or operation will be too high for the small laboratories to 
compete.
    (Response 94) The rule does not raise either Equal Protection or 
antitrust concerns. Under Equal Protection jurisprudence, the 
government has ``considerable leeway'' to issue rules that ``may appear 
to affect similarly situated people differently.'' Clements v. Fashing, 
457 U.S. 957, 962-963 (1982). The case law refers to such an effect as 
a ``classification.'' Where the classification involves a suspect 
class, such as race or nationality, or infringes on a fundamental 
right, the law will be subject to heightened scrutiny. Massachusetts 
Bd. of Retirement v. Murgia, 427 U.S. 307, 312 (1976). In the absence 
of those circumstances, a law containing a classification is ``accorded 
a strong presumption of validity,'' Heller v. Doe, 509 U.S. 312, 319 
(1993), and will be upheld if it ``bears some fair relationship to a 
legitimate public purpose.'' Plyler v. Doe, 457 U.S. 202, 216 (1982).
    We disagree with the comment's suggestion that this rule involves a 
classification. Neither the underlying provisions of the FD&C Act, nor 
the gradual phaseout of FDA's general enforcement discretion approach, 
treats smaller entities differently from larger ones. Thus, Equal 
Protection principles have no application here.
    But even assuming that the rule involved a classification in the 
form of a different effect on smaller entities, the rule would be 
subject to rational basis review. The comment did not claim that this 
rule involves any suspect classification or fundamental right. Although 
the comment stated that certain diseases are more prevalent in certain 
``ethnic groups,'' and the rule must be implemented in a non-
discriminatory manner to the extent it may affect IVDs offered as LDTs 
that are intended for those diseases, the comment does not explain how 
these facts would support a suspect classification theory. Even if the 
rule were to have a disproportionate impact, a disproportionate impact, 
by itself, does not trigger strict scrutiny under Equal Protection 
principles. Washington v. Davis, 426 U.S. 229, 242 (1976).
    Accordingly, even if the rule involved a classification (which it 
does not), the rule would be subject to rational basis review, which 
the rule would easily satisfy. FDA rationally concluded that the 
phaseout policy will help to ensure the safety and effectiveness of 
IVDs offered as LDTs and more accurate diagnoses, which will lead to 
better care and advance public health overall. The rule therefore is 
rationally related to a legitimate purpose.
    FDA also disagrees that the rule raises antitrust concerns. 
Antitrust law is directed toward preserving free and unfettered 
competition by curtailing anti-competitive conduct by private entities, 
such as precluding private arrangements among companies that 
unreasonably restrain competition. See, e.g., Northern Pac. Ry. Co. v. 
United States, 356 U.S. 1, 4-5 (1958). Antitrust law does not concern 
and does not curtail the Federal government's oversight in the interest 
of protecting and promoting the public health.
    (Comment 95) One comment asserted that the LDT rule would 
constitute a ``taking'' under the Fifth Amendment to the U.S. 
Constitution because it would disadvantage smaller, more specialized 
laboratories to the benefit of larger laboratories and AMCs. The 
comment contended that this would be a regulatory taking in that it 
would significantly diminish the value of property without a valid 
public purpose.
    (Response 95) We disagree that the rule would constitute a taking. 
The Fifth Amendment to the U.S. Constitution prohibits the Government 
from taking private property for public use without just compensation. 
The Supreme Court has held that the Government effects a ``per se'' 
taking when it physically appropriates property, which is the 
``clearest sort of taking.'' Cedar Point Nursery v. Hassid, 141 S. Ct. 
2063, 2071 (2021). The Court has also recognized that there may be a 
regulatory taking where regulations that ``restrict an owner's ability 
to use his own property'' go ``too far.'' Id. at 2071-72. In such 
cases, a taking may be found based ``on a complex of factors, 
including: (1) the economic impact of the regulation on the claimant; 
(2) the extent to which the regulation has interfered with distinct 
investment-backed expectations; and (3) the character of the 
governmental action.'' Murr v. Wisconsin, 582 U.S. 383, 393 (2017) 
(cleaned up) (referred to as the ``Penn Central factors'' after Penn 
Central Transp. Co. v. New York City, 438 U.S. 104, 124 (1978)). The 
force of any one of these three Penn Central factors may be ``so 
overwhelming . . . that it disposes of the taking question.'' 
Ruckelshaus v. Monsanto Co., 467 U.S. 986, 1005.
    As the phaseout of the general enforcement discretion approach is 
implemented, laboratories that manufacture IVDs offered as LDTs 
generally will be expected to comply with several pre- and post-market 
submission and reporting requirements applicable to devices for humans, 
including premarket notification/PMA requirements (as applicable), 
registration and listing, labeling requirements, reporting requirements 
regarding adverse events and corrections and removals, QS

[[Page 37360]]

requirements, and certain IDE regulations. To our knowledge, the FD&C 
Act's premarket review and related requirements have never been held to 
effectuate a taking of property. It has long been established that the 
government may regulate products in the interests of public health and 
safety and such regulation ``cannot, in any just sense, be deemed a 
taking.'' Mugler v. Kansas, 123 U.S. 623, 668 (1887). The takings 
doctrine is based on the concept that, when the government seizes 
property for the public benefit, such as land for a road or a dam, the 
public should compensate the owner. But that is a different scenario 
from where the government limits the use of property to protect public 
health and safety. See id. at 669. As the Supreme Court has elaborated, 
``[l]ong ago it was recognized that all property in this country is 
held under the implied obligation that the owner's use of it shall not 
be injurious to the community, and the Takings Clause did not transform 
that principle to one that requires compensation whenever the State 
asserts its power to enforce it.'' Keystone Bituminous Coal Ass'n v. 
DeBenedictis, 480 U.S. 470, 491-92 (1987) (cleaned up). As a result, 
restrictions on ``uses of personal property'' that are ``directed at 
the protection of public health and safety'' are ``the type of 
regulation in which the private interest has traditionally been most 
confined and governments are given the greatest leeway to act without 
the need to compensate those affected by their actions.'' Rose Acre 
Farms, Inc. v. United States, 559 F.3d 1260, 1281 (Fed. Cir. 2009).
    The phaseout of the general enforcement discretion approach for 
LDTs is intended to protect public health and safety and to prevent 
injuries to the community. FDA is taking this action to help ensure the 
safety and effectiveness of IVDs offered as LDTs and to achieve more 
accurate diagnoses, which will lead to better care and advance the 
public health overall. Accordingly, the character of the government's 
action here--to advance the public health--weighs heavily, if not 
conclusively, against finding that the phaseout effects a taking.
    The other Penn Central factors also weigh in favor of finding no 
taking here. With regard to economic impact, the comment asserted that 
the value of the property of small laboratory manufacturers will be 
diminished. However, many changes in government laws, regulations, and 
policies have economic consequences, and the Supreme Court has long 
recognized that ``[g]overnment hardly could go on if to some extent 
values incident to property could not be diminished without paying for 
every such change in the general law.'' Pennsylvania Coal Co. v. Mahon, 
260 U.S. 393, 413 (1922). The Supreme Court has explained that ``mere 
diminution in the value of property, however serious, is insufficient 
to demonstrate a taking.'' Concrete Pipe & Prods. v. Constr. Laborers 
Pension Trust, 508 U.S. 602, 645 (1993). Similarly, a ``loss of 
profit'' does not establish a taking. 74 Pinehurst LLC v. New York, 59 
F.4th 557, 566 (2d Cir. 2023). And courts have rejected regulatory 
takings claims even where the government's action ``impose considerable 
costs on private actors in the regulated industry.'' Mobile Relay 
Assocs. v. FCC, 457 F.3d 1, 12 (D.C. Cir. 2006). Instead, in evaluating 
the economic impact of a regulation, courts have explained that the 
``touchstone'' is ``proportionality'': ``the size of a liability only 
weighs in favor of finding a taking insofar as it is out of proportion 
to the legitimate obligations society may impose on individual 
entities.'' B&G Constr. Co. v. Dir., OWCP, 662 F.3d 233, 260 (3d Cir. 
2011) (cleaned up).
    In enacting the FD&C Act, Congress determined that manufacturers of 
medical products should bear the costs of ensuring that their products 
are appropriately safe and effective, and these costs are proportional 
to the resulting benefits of FDA oversight to the public health. 
Furthermore, as discussed elsewhere in this preamble, FDA has taken 
several steps to address the economic impact of the final phaseout 
policy--for example, by including certain enforcement discretion 
policies in the final phaseout policy (see section V.B of this 
preamble). Accordingly, the phaseout policy does not place 
disproportionate costs on laboratory manufacturers.
    With respect to the last Penn Central factor, a ``reasonable 
investment-backed expectation must be more than a unilateral 
expectation or an abstract need.'' Ruckelshaus v. Monsanto Co., 467 
U.S. 986 at 1005 (cleaned up). Courts have held that those who do 
business in highly regulated fields are on notice that changes are 
possible. Connolly v. Pension Ben. Guar. Corp., 475 U.S. 211, 226-27 
(1986) (``Those who do business in the regulated field cannot object if 
the legislative scheme is buttressed by subsequent amendments to 
achieve the legislative end'') (cleaned up).
    Laboratory manufacturers have been on notice for some time that 
their tests could be subject to increased oversight. As a legal matter, 
FDA has long taken the position that LDTs are devices subject to 
regulation under the FD&C Act, over which it was exercising enforcement 
discretion. Moreover, laboratory manufacturers have been on notice that 
their tests could be subject to increased oversight at various times--
e.g., after issuance of the preamble to the ASR rule nearly 30 years 
ago, stating that ``FDA believes that clinical laboratories that 
develop [in-house] tests are acting as manufacturers of medical devices 
and are subject to FDA jurisdiction under the act'' (62 FR at 62249), 
and after two draft guidance documents were issued by FDA on October 3, 
2014, entitled ``Framework for Regulatory Oversight of Laboratory 
Developed Tests (LDTs)'' (79 FR 59776) and ``FDA Notification and 
Medical Device Reporting for Laboratory Developed Tests (LDTs)'' (79 FR 
59779) (Refs. 38 and 112). Accordingly, laboratory manufacturers did 
not have reasonable investment-backed expectations that they would not 
ever be subject to FDA oversight.
    Accordingly, application of the Penn Central factors confirms that 
FDA's phaseout of the general enforcement discretion approach for LDTs 
will not effect a taking.
    (Comment 96) Various comments requested, or stated that FDA should 
have granted,\74\ an extension of the 60-day comment period. Most of 
these comments requested a 60-day or longer extension. The comments 
argued for an extension given the following: (1) the complex and 
multifaceted nature of the proposed rule, which required review by 
experts in various fields; (2) the significant implications that the 
final rule will have on stakeholders; (3) the numerous legal issues 
raised by the rule; (4) differences in FDA's proposal compared to its 
previous proposals (e.g., with respect to tests currently on the market 
and the timeline for premarket review expectations); (5) a longer 
comment period would be in line with Agency precedent (e.g., the 
comment period for the 2014 draft LDT guidance documents was 120 days, 
and other FDA rulemakings ``with more modest impact'' had longer than 
60-day comment periods); (6) the length of time that FDA has been 
working on the proposed rule (at least 7 months, according to one 
comment); and/or (7)

[[Page 37361]]

the comment period spanned the Thanksgiving holiday season. Various 
comments described what they would do with additional time, which 
included surveying small businesses and investors to better understand 
the implications of the costs of the rule; estimating added costs to 
the U.S. healthcare system from the loss of competition resulting from 
the rule; and assessing the harm to patients resulting from small 
entities exiting the market and/or reducing operations. Several 
comments stated that FDA's denial of requests for extensions raised 
concerns about the thoroughness of stakeholder engagement and noted 
that the denials were based on FDA's ``manufactured sense of urgency.''
---------------------------------------------------------------------------

    \74\ FDA received 14 requests for extensions soon after 
publication of the NPRM. For those requests, FDA responded directly 
to the requesters (and submitted a sample of such a response to the 
docket, see e.g. Ref. 161) and posted an update to its website 
stating that ``[a]fter considering the [request/requests] and other 
factors, including the extensive background of public comment on 
this topic and the public health benefits of proceeding 
expeditiously, the FDA has determined to proceed with the standard 
60-day comment period'' (Ref. 113).
---------------------------------------------------------------------------

    (Response 96) After reviewing the public comments and the requests 
for additional time for comment, FDA does not believe that extending or 
reopening the comment period is necessary for the public to receive a 
meaningful opportunity to comment on the NPRM. Consequently, and in 
light of the public health benefits of proceeding expeditiously, FDA is 
again declining to extend the comment period.
    Under the APA, agencies are required to provide interested persons 
an opportunity to participate in the rulemaking through submission of 
comments. 5 U.S.C. 553(c). Although the APA does not delineate a 
minimum number of days that a comment period must run, courts have said 
that the length of a comment period must provide a meaningful 
opportunity to comment. See Rural Cellular Ass'n v. FCC, 588 F.3d 1095, 
1101 (D.C. Cir. 2009). And while some courts have found comment periods 
of less than 30 days to be appropriate, various courts have observed 
that 30 days is generally the shortest time period for interested 
persons to meaningfully review a proposed rule and provide informed 
comment. See, e.g., Nat'l Lifeline Ass'n v. FCC, 921 F.3d 1102, 1117 
(D.C. Cir. 2019). FDA's own regulations require that the Agency 
generally provide 60 days for comment on proposed regulations, see 21 
CFR 10.40(b)(2), and E.O. 12866 generally recommends a comment period 
of at least 60 days for most rulemaking, see E.O. 12866, sec. 6(a), 58 
FR 51735, October 4, 1993.
    The Supreme Court has stated that the APA ``sets forth the full 
extent of judicial authority to review executive agency action for 
procedural correctness.'' FCC v. Fox Television Stations, Inc., 556 
U.S. 502, 513 (2009). Moreover, the Court has emphasized that beyond 
the APA's minimum requirements, courts lack authority ``to impose upon 
[an] agency its own notion of which procedures are `best' or most 
likely to further some vague, undefined public good.'' Vermont Yankee 
Nuclear Power Corp. v. NRDC, 435 U.S. 519, 549 (1973). Under this 
rubric, many courts have refused to find an APA violation where an 
agency provides a 60-day (or even shorter) comment period and otherwise 
provides a meaningful opportunity to comment. See Little Sisters of the 
Poor Saints Peter & Paul Home v. Pennsylvania, 140 S. Ct. 2367, 2386 
(2020) (``The Departments complied with each of these statutory 
procedures. They `request[ed] and encourag[ed] public comments on all 
matters addressed' in the rules. . . . They also gave interested 
parties 60 days to submit comments.'') (internal citations omitted); 
see also Chamber of Com. of United States v. United States Sec. & Exch. 
Comm'n, 85 F.4th 760, 779-80 (5th Cir. 2023) (``We cannot conclude that 
the initial [45-day] comment period was so short as to deprive 
petitioners of a meaningful opportunity to comment on the proposed 
rulemaking. Petitioners may have hoped for more time, but it is not for 
us to decide whether an agency has chosen a maximally net beneficial 
comment period.'').
    FDA has determined that the 60-day comment period for the NPRM 
allowed sufficient time for a meaningful opportunity to comment. There 
was ample time for the submission of more than 6,500 comments. A 
variety of entities submitted comments, including medical device 
associations, industry, medical and healthcare professional 
associations, other advocacy organizations, government agencies, and 
individuals, and they offered a broad array of perspectives on FDA's 
proposal. In addition, FDA has determined that an extension would not 
be appropriate in light of the public health benefits of proceeding 
expeditiously in finalizing this rulemaking.
    We note that many of the complex policy and legal issues have been 
discussed by FDA and stakeholders for over a decade.\75\ In addition, 
after publication of the NPRM, FDA worked to ensure that stakeholders 
fully understood the proposal, including by hosting a webinar (see Ref. 
162). The webinar addressed, among other things, the various 
differences in FDA's proposal compared to its previous proposals.
---------------------------------------------------------------------------

    \75\ As discussed in the NPRM (88 FR 68006 at 68016) and 
elsewhere in this preamble, the Agency held a 2-day public meeting 
and opened a docket for public comment in 2010 regarding FDA's plans 
to develop a broad approach to the oversight of LDTs (75 FR 34463, 
June 17, 2010). Input received through those proceedings informed 
two draft guidance documents issued by FDA on October 3, 2014, 
entitled ``Framework for Regulatory Oversight of Laboratory 
Developed Tests (LDTs)'' (79 FR 59776) and ``FDA Notification and 
Medical Device Reporting for Laboratory Developed Tests (LDTs)'' (79 
FR 59779). FDA solicited public feedback on the draft guidance 
documents and held a public workshop on January 8 and 9, 2015 (79 FR 
69860, November 24, 2014). From October 2014 through 2016, FDA 
analyzed more than 300 sets of comments on the draft guidance 
documents, as well as discussion from the public workshop, and 
engaged extensively with stakeholders in meetings and conferences. A 
number of interested parties provided feedback, including 
laboratories, healthcare providers, patients, conventional IVD 
manufacturers, government agencies, and members of Congress. The 
feedback ranged generally from strong opposition to strong support 
for FDA's proposed increased oversight of LDTs and addressed a wide 
range of topics, including FDA's authority to regulate LDTs, the 
risks posed by LDTs without increased FDA enforcement, the effect of 
a new enforcement approach on test access and innovation, the 
potential interplay between FDA regulation and CLIA, and the 
implications of increased FDA oversight for competition in the IVD 
market. FDA also has received and responded to multiple citizen 
petitions raising some of the same policy and legal issues raised in 
this rulemaking. See Refs. 114-115.
---------------------------------------------------------------------------

    We are not persuaded by the other arguments made in the comments. 
For example, we do not believe it would be appropriate to extend the 
comment period for this NPRM to align it with the comment period of 
other FDA proposed rules or the 2014 LDT draft guidance documents. The 
appropriate length for a comment period is not a one-size-fits-all 
analysis but rather depends on many relevant factors, which were all 
considered in choosing a 60-day comment period for this NPRM and 
considering extension requests. In addition, we disagree that the 
length of time that FDA spent developing, drafting, and publishing the 
NPRM suggests that a meaningful opportunity to comment was not provided 
to interested persons or that an extension is appropriate based on that 
timing. Finally, as noted above, one comment argued for an extension 
because the comment period was over Thanksgiving, and also because 
various small laboratories would be preparing during the 60-day comment 
period for a January conference. Although the 60-day comment period 
covered Thanksgiving, it ended on December 4, 2023, and a 30- or 60-day 
extension would have extended the comment period through the December/
January holiday season. Moreover, although certain small laboratories 
impacted by this rulemaking may have participated in a January 
conference, we do not believe that an extension to accommodate such a 
commitment would have been appropriate in light of the public health 
benefits of proceeding expeditiously in finalizing this rulemaking.

[[Page 37362]]

    (Comment 97) One comment stated that a 180-day extension of the 
comment period was appropriate (and preferred a 9 to 12-month 
extension), noting that such a request aligns with the Federal 
Register's Guide to the Rulemaking Process.
    (Response 97) For the reasons set forth in response to comment 96, 
after reviewing the public comments and the requests for additional 
time for comment, FDA does not believe that extending the comment 
period is necessary for the public to receive a meaningful opportunity 
to comment on the NPRM. Consequently, and in light of the public health 
benefits of proceeding expeditiously, FDA is again declining to extend 
the comment period.
    Notably, in its Guide to the Rulemaking Process, the Federal 
Register acknowledges that comment periods on proposed rules typically 
range from 30 to 60 days: ``[i]n general, agencies will specify a 
comment period ranging from 30 to 60 days in the `Dates' section of the 
Federal Register document, but the time period can vary'' (Ref. 163). 
Although the Federal Register states that for complex rulings, agencies 
may provide for longer periods, such as 180 days or more, see id., the 
Federal Register is clear that this is not a requirement.
    (Comment 98) Several comments emphasized that a 60-day comment 
period was insufficient specifically for practitioners, who are 
directly impacted by the rule. These comments noted that practitioners 
are busy taking care of patients, some were uncertain regarding the 
details of the proposed rule, and many were not aware of the proposed 
rule when it issued.
    (Response 98) For the reasons discussed in response to comment 96, 
FDA disagrees that the 60-day comment period was insufficient. 
Moreover, we note that to help ensure stakeholders understood the 
proposal, FDA held a webinar on October 31, 2023, providing information 
on and answering questions about the NPRM (see Ref. 162). In addition, 
although certain individual practitioners may not have been aware of 
the proposal after it was issued, FDA received numerous lengthy and 
substantive comments from practitioners, trade groups, and other 
organizations representing practitioners, and those comments have 
helped to shape the final phaseout policy.
    (Comment 99) One comment urged FDA to hold a public meeting (not 
less than 60 days before the comment deadline) to educate laboratories 
on the specifics of the ``regulatory requirements FDA plans to 
impose,'' among other things.
    (Response 99) To help stakeholders understand and comment on the 
NPRM, FDA held a webinar on October 31, 2023, to provide stakeholders 
with information on and answer questions about the NPRM (see Ref. 162). 
The presentation, printable slides, and transcript from the Webinar 
have been available on FDA's website since that date (see Ref. 72).
    (Comment 100) One comment stated that the initial categorization of 
the proposed rule as not ``Section 3(f)(1) significant'' was 
inconsistent with E.O. 12866 and the Office of Information and 
Regulatory Affairs' (OIRA's) April 6, 2023 memorandum regarding 
implementation of that E.O. because the proposed rule impacts the three 
listed categories of significant regulatory actions and exceeds the 
threshold for economic significance. The comment noted that although 
the proposed rule was later re-assigned a categorization of ``Section 
3(f)(1) significant,'' the original categorization demonstrates ``a 
lack of consideration of all relevant factors by the FDA'' and 
``portrays a lack of partnership in helping to identify and establish a 
regulatory framework that could work for the industry being 
regulated.''
    (Response 100) The proposed rule was originally categorized as 
``Other significant'' in the Spring 2023 Unified Agenda--i.e., as 
significant under a provision of E.O. 12866 other than section 
3(f)(1)--and then categorized as ``Section 3(f)(1) significant'' in all 
subsequent Unified Agendas. For the Spring 2023 Unified Agenda, the 
exact proposal was still under development and it was not clear whether 
the proposed rule would be ``Section 3(f)(1) significant.'' As such, 
FDA categorized it as ``Other significant.'' As discussed in section 
VIII, OIRA has determined that the final rule is a significant 
regulatory action under E.O. 12866 section 3(f)(1). In any event, the 
comment does not explain, and it is otherwise unclear to FDA, how this 
initial categorization demonstrates a lack of consideration by FDA of 
``relevant factors'' or a ``lack of partnership'' with industry to 
establish an appropriate policy.
    (Comment 101) One comment stated that FDA failed to conduct the 
required federalism analysis under E.O. 13132 and the Agency 
erroneously stated in the NPRM that ``this proposed rule does not 
contain policies that have substantial direct effects on the States, on 
the relationship between the National Government and the States, or on 
the distribution of power and responsibilities among the various levels 
of government.'' \76\ The comment stated that because the proposed rule 
has such effects, and would preempt state law under section 521 of the 
FD&C Act (21 U.S.C. 360k), FDA must comply with all of the requirements 
of sections 6(c) \77\ and 8(a) \78\ of E.O. 13132. Another comment 
stated that the conclusions in the proposed rule regarding federalism 
``do not reflect the impact on practice of medicine'' given that the 
proposed rule conflicts with certain state medical practice acts as 
well as NYS CLEP that currently permits the review, approval, and use 
of LDTs.
---------------------------------------------------------------------------

    \76\ Another comment agreed with this comment to the extent FDA 
was asserting authority to regulate States and State-owned entities 
(see comment 106).
    \77\ Section 6(a) of E.O. 13132 states that ``[t]o the extent 
practicable and permitted by law, no agency shall promulgate any 
regulation that has federalism implications and that preempts State 
law, unless the agency, prior to the formal promulgation of the 
regulation'' meets certain prescribed requirements.
    \78\ Section 8(a) of E.O. 13132 states that ``[i]n transmitting 
any draft final regulation that has federalism implications to the 
Office of Management and Budget pursuant to Executive Order 12866 of 
September 30, 1993, each agency shall include a certification from 
the official designated to ensure compliance with this order stating 
that the requirements of this order have been met in a meaningful 
and timely manner.''
---------------------------------------------------------------------------

    (Response 101) Although E.O. 13132 contains principles that apply 
broadly to ``policies that have federalism implications,'' which means 
``regulations, legislative comments or proposed legislation, and other 
policy statements or actions that have substantial direct effects on 
the States, on the relationship between the national government and the 
States, or on the distribution of power and responsibilities among the 
various levels of government,'' a federalism summary impact statement 
is required for a ``regulation'' that has federalism implications and 
that meets certain additional criteria. Because the requirement for a 
federalism summary impact statement applies specifically to 
``regulation'' and not to policy, the requirement for a federalism 
summary impact statement applies to the proposed amendment to Sec.  
809.3 and not to the proposed phaseout policy. And because the proposed 
amendment to Sec.  809.3 would not establish any new requirements, it 
would not have any federalism implications under E.O. 13132 (see 
section XI).
    Even if the requirement for a federalism summary impact statement 
were to apply to the phaseout policy, the policy does not have 
federalism implications because it is not establishing any new 
requirements. Rather, the phaseout policy is about increasing oversight 
of existing requirements under the FD&C Act and

[[Page 37363]]

FDA regulations. All laboratory manufacturers, including State-owned 
laboratories, have been legally subject to these requirements even 
though the Agency generally has not enforced them. As such, the 
enforcement policy is not changing their legal obligations.
    Moreover, we note that E.O. 12866, section 11 makes clear that the 
order ``is intended only to improve the internal management of the 
executive branch, and is not intended to create any right or benefit, 
substantive or procedural, enforceable at law by a party against the 
United States, its agencies, its officers, or any person.''
    For additional discussion regarding NYS CLEP, see sections V.B.2 
and VI.F.5 of this preamble.
    (Comment 102) Several comments stated that FDA has violated the MDA 
General Rule because the proposed rule is unduly burdensome and lacks 
flexibility.
    (Response 102) The ``general rule'' provision for records and 
reports in the MDA states that: ``Every person who is a manufacturer, 
importer, or distributor of a device intended for human use shall 
establish and maintain such records, make such reports, and provide 
such information, as the Secretary may by regulation reasonably require 
to assure that such device is not adulterated or misbranded and to 
otherwise assure its safety and effectiveness,'' and that ``Regulations 
prescribed under the preceding sentence--(1) shall not impose 
requirements unduly burdensome to a device manufacturer, importer, or 
distributor taking into account his cost of complying with such 
requirements and the need for the protection of the public health and 
the implementation of this Act. . . .'' Section 2 of the MDA, Public 
Law 94-295 (1976), codified at section 519 of the FD&C Act. Section 519 
has since been amended and this provision now appears at section 519(a) 
and (a)(4).
    As an initial matter, the ``general rule'' provision referenced in 
the comment is not applicable to this rulemaking. FDA is not 
prescribing new regulations under section 519 of the FD&C Act regarding 
records and reports, but rather is amending Sec.  809.3 and phasing out 
the general enforcement discretion approach for IVDs offered as LDTs.
    In any event, FDA disagrees with the assertion that the proposed 
rule is overly burdensome and lacks flexibility such as might violate 
this provision. For additional discussion of FDA's adherence to least 
burdensome principles, see the response to comment 12.
    (Comment 103) Several comments stated that FDA violated the 
Unfunded Mandates Reform Act of 1995 (Pub. L. 104-4) (UMRA) because it 
did not assess all regulatory options and select the least burdensome 
avenue in its proposal. Some of these comments asserted that the 
proposal shows no evidence of consideration of viable alternatives.
    (Response 103) Under the UMRA, before issuing any rule for which a 
written statement is required under section 202 of the UMRA, agencies 
must ``identify and consider a reasonable number of regulatory 
alternatives and from those alternatives select the least costly, most 
cost-effective or least burdensome alternative that achieves the 
objectives of the rule.'' See 2 U.S.C. 1535. Under section 202 of the 
UMRA, unless otherwise prohibited by law, a written statement 
containing certain prescribed information must be prepared before an 
agency issues any general notice of proposed rulemaking that ``is 
likely to result in promulgation of any rule that includes any Federal 
mandate that may result in the expenditure by State, local, and tribal 
governments, in the aggregate, or by the private sector, of 
$100,000,000 or more (adjusted annually for inflation) in any 1 year.''
    As an initial matter, the UMRA requirement referenced in the 
comment is not applicable to this rulemaking. This rulemaking is not 
likely to result in a final rule that includes any Federal mandate, as 
that term is defined in the UMRA (see 2 U.S.C. 658(6)), and so a 
written statement is not required under section 202 and the 
requirements at 2 U.S.C. 1535 do not apply.
    Even if the requirements applied, however, FDA disagrees with the 
assertion that it did not assess all regulatory options and select the 
least burdensome avenue in its proposal such as might violate the UMRA. 
FDA identified and considered a reasonable number of regulatory 
alternatives and selected the most cost-effective or least burdensome 
alternative that achieves the objective of this rule, as required by 
the UMRA. Specifically, FDA considered five different regulatory 
alternatives, comparing the total costs, benefits, and transfers with 
one option that would be more stringent and three options that would be 
less stringent than the proposal. See section II.J of the PRIA (Ref. 
60). FDA also sought comments on various additional policies and has 
considered those comments and made changes to the proposal based on 
some of the comments submitted.
    (Comment 104) One comment stated that the NPRM fails to comply with 
a new provision of the APA, codified at 5 U.S.C. 553(b)(4), which 
requires that an NPRM include a website with a 100-word or less, plain 
language summary of the NPRM that is posted on regulations.gov.\79\ The 
comment asserted that this failure undermines the ability of 
stakeholders--particularly smaller laboratories and their employees--to 
understand FDA's proposal and participate meaningfully in the public 
comment process. As such, the comment stated that FDA must publish a 
concise summary of its proposal, reissue the NPRM with the mandatory 
internet address included, and restart this proceeding with a new 
public comment period.
---------------------------------------------------------------------------

    \79\ On July 23, 2023, the ``Providing Accountability Through 
Transparency Act of 2023,'' Public Law 118-9, amended section 553(b) 
of the APA, adding the requirement that an NPRM include ``the 
internet address of a summary of not more than 100 words in length 
of the proposed rule, in plain language, that shall be posted on the 
internet website under section 206(d) of the E-Government Act of 
2002 (44 U.S.C. 3501 note) (commonly known as regulations.gov).'' 
Section 553(b)(4) of the APA.
---------------------------------------------------------------------------

    (Response 104) We disagree. FDA substantially complied with this 
new APA requirement by including an 89-word, plain-language summary of 
the NPRM on its website (see Ref. 115), which is included as Ref. 56 of 
the NPRM, posted on regulations.gov.80 81 That suffices, but 
even if it did not, any insufficiency would not have undermined the 
ability of stakeholders to understand FDA's proposal and participate 
meaningfully in the public comment process. During the comment period, 
a summary of the NPRM was included on FDA's LDT web page (see Ref. 
134), a summary of the NPRM was included at the beginning of the NPRM, 
FDA's press release for the NPRM provided high-level information 
regarding the content of the NPRM (see Ref. 164), and FDA held a 
webinar after issuance of the NPRM to provide stakeholders with 
information on and

[[Page 37364]]

answer questions about the NPRM (see Ref. 162). In light of all of 
this, we disagree that stakeholders, particularly smaller laboratories 
and their employees, were deprived of a meaningful public comment 
process. In fact, the sheer number of comments submitted on the NPRM, 
including by small laboratories and their employees, contradicts such 
an assertion. Nor did any commenter identify any way in which the 
comments they submitted would have differed in any way had FDA 
published a 100-word summary on https://www.regulations.gov. For these 
reasons, FDA declines to reissue the comment period.
---------------------------------------------------------------------------

    \80\ Under the ``Increased FDA Oversight to Help Ensure Safety 
and Effectiveness of LDTs'' heading, which was posted the same day 
of publication of the NPRM, FDA included the following summary of 
the NPRM: ``On September 29, 2023, the FDA announced a proposed rule 
aimed at helping to ensure the safety and effectiveness of these 
tests. The proposed rule seeks to amend the FDA's regulations to 
make explicit that IVDs are devices under the Federal Food, Drug, 
and Cosmetic Act, including when the manufacturer of the IVD is a 
laboratory. Along with this amendment, the FDA is proposing a policy 
under which the FDA intends to provide greater oversight of LDTs 
through a phaseout of its general enforcement discretion approach 
for most LDTs.'' (Ref. 113).
    \81\ On March 11, 2024, a summary was added to the ``Docket 
Details'' of the LDT NPRM. See https://www.regulations.gov.
---------------------------------------------------------------------------

    (Comment 105) Several comments stated that State-owned and academic 
institutions should not fall under the jurisdiction of FDA. One of 
these comments stated that FDA's regulation of State governmental 
entities is constrained by the text of the FD&C Act, which the comment 
stated does not treat states as ``persons'' subject to various 
significant medical device provisions of the FD&C Act (e.g., 
registration requirements under section 510(c), premarket notification 
requirements under section 510(k), premarket approval requirements 
under section 515(c), and adverse event reporting requirements in part 
803). The comment stated that these provisions regulate ``persons,'' 
not sovereign states, and that the Supreme Court's ``longstanding 
presumption'' against treating U.S. states as ``persons'' can be 
``disregarded only upon some affirmative showing of statutory intent to 
the contrary.'' \82\ The comment stated that the FD&C Act provides no 
affirmative showing of congressional intent for FDA to regulate 
laboratories owned by State agencies and State universities.
---------------------------------------------------------------------------

    \82\ See Vermont Agency of Natural Resources v. US ex rel 
Stevens, 529 U.S. 765, 766 (2000).
---------------------------------------------------------------------------

    (Response 105) FDA disagrees. The comment does not include several 
key points that, when taken together, indicate that a state is properly 
understood as a ``person'' under the FD&C Act.
    The comment relies on the Supreme Court's decision in Vt. Agency 
for Nat. Res. v. U.S. ex rel. Stevens to support the assertion that the 
term ``person'' does not encompass States. After its decision in 
Stevens, however, the Court made clear that ``qualification of a 
sovereign as a `person' . . . depends not upon a bare analysis of the 
word `person,' but on the legislative environment in which the word 
appears.'' Inyo County v. Paiute-Shoshone Indians of the Bishop Cmty. 
of the Bishop Colony, 538 U.S. 701, 711 (2003) (citations and internal 
quotations omitted); see also Pfizer, Inc. v. Gov't of India, 434 U.S. 
308, 313 (1978) (``In light of the law's expansive remedial purpose, 
the Court has not taken a technical or semantic approach in determining 
who is a `person' entitled to sue for treble damages. Instead, it has 
said that `[t]he purpose, the subject matter, the context, the 
legislative history, and the executive interpretation of the statute 
are aids to construction which may indicate' the proper scope of the 
law.'') (quoting United States v. Cooper Corp., 312 U.S. 600, 605 
(1941)).
    There are two key features of the ``legislative environment'' of 
the FD&C Act that, taken together, make clear that the statute's 
reference to ``person'' encompasses States--a position long reflected 
in FDA's regulations. See Sec.  814.3(h) (issued in 1986) (defining 
``[p]erson'' to include, among other things, ``any . . . scientific or 
academic establishment, Government agency, or organizational unit 
thereof, or any other legal entity''). First, the definition of 
``person'' in the FD&C Act uses the term ``includes.'' 21 U.S.C. 321(e) 
(``[t]he term `person' includes individual, partnership, corporation, 
and association''). It is a longstanding rule of statutory construction 
that, ``[i]n definitive provisions of statutes and other writings, 
`include' is frequently, if not generally, used as a word of extension 
or enlargement rather than as one of limitation or enumeration.'' Am. 
Sur. Co. of New York v. Marotta, 287 U.S. 513, 517 (1933). Accordingly, 
in choosing to define ``person'' in the FD&C Act as ``includ[ing]'' 
individuals, partnerships, corporations, and associations, Congress 
indicated the term could be construed broadly to include entities in 
addition to the enumerated ones. This is particularly clear in light of 
the other definitions in section 201 of the FD&C Act, most of which use 
the term ``means'' (i.e., ``The term X means. . . .''). If Congress had 
intended a limited meaning, it would have used the much more 
restrictive sentence structure that appears in all of the surrounding 
definitions and said: ``The term person means individuals, 
partnerships, corporations, and associations'' (emphasis added). 
Indeed, in Vermont Agency of Natural Resources, the Supreme Court 
acknowledged that very distinction in Stevens--definitions of person 
that used the term ``means,'' as in the example in that case, point to 
a different result from those that use the term ``includes.'' 529 U.S. 
765, 786 n.17 (2000) (citing California v. United States, 320 U.S. 577, 
585-86 (1944)).\83\
---------------------------------------------------------------------------

    \83\ Similarly, in Return Mail, Inc. v. USPS, the Court invoked 
the presumption that a person does not include governmental entities 
where the statute did not define ``person.'' 139 S. Ct. 1853, 1861 
(2019).
---------------------------------------------------------------------------

    Second--and crucially--Congress demonstrated its understanding that 
the FD&C Act's reference to ``person'' includes government entities 
when it enacted provisions involving the payment of fees in connection 
with the submission of certain premarket review submissions to FDA. The 
FD&C Act requires that ``[e]ach person'' who submits several different 
types of premarket review submissions shall be subject to a fee. See 21 
U.S.C. 379h(a)(1)(A), 379j(a)(2)(A), 379j-42(a)(1)(A), 379j-
52(a)(1)(A). The FD&C Act then exempts ``State and Federal'' government 
entities from the payment of fees for submissions relating to products 
that will not be distributed commercially. See 21 U.S.C. 379g(1), 
379j(a)(2)(B), 379j-41(1)(b)(ii), 379j-51(4)(b)(iv). These exemptions 
would be superfluous if the term ``person'' already excluded 
governmental entities. In addition, under the terms of the statute, 
governmental entities are subject to fees for submissions related to 
products to be distributed commercially. See, e.g., 21 U.S.C. 
379j(a)(2)(B)(iii). These provisions, too, demonstrate that Congress 
intended their devices to be subject to premarket review under the FD&C 
Act.
    (Comment 106) One comment cited a June 2020 memorandum from Robert 
Charrow (then-HHS General Counsel) to Stephen Hahn, MD (then-
Commissioner of Food and Drugs) that said that the FDA likely had 
limited to no authority to regulate states and state-owned entities. 
The comment noted that FDA omitted any discussion of this potential, 
significant legal limitation in the proposed rule and regulatory impact 
analysis and did not comment on whether the current HHS General Counsel 
or FDA accepted or rejected the prior legal analysis. The comment noted 
that this limitation would have a profound impact on State-owned AMCs 
and other State-owned laboratory entities and stated that the issue 
should be subject to more significant administrative or judicial 
consideration prior to advancing any proposed rule.
    (Response 106) FDA referenced the memorandum from the HHS Office of 
the General Counsel in the proposed rule, noting that it informed HHS' 
August 2020 posting of a statement on its website entitled ``Rescission 
of Guidances and Other Informal Issuances.'' 88 FR 68006 at 68016. FDA

[[Page 37365]]

stated that in November 2021, based on new advice from the HHS Office 
of the General Counsel, HHS leadership determined that the August 2020 
statement no longer represented the Department's policy or legal views. 
Id. As stated in the response to comment 105, FDA does not agree that 
it has limited to no authority to regulate States and State-owned 
entities, and we do not agree that additional consideration of this 
issue is necessary or appropriate prior to advancing this rulemaking.
    (Comment 107) One comment stated that FDA has significant conflicts 
of interest associated with the rulemaking because the final rule will 
significantly increase the Agency's acquisition of fees and likely also 
its Federal appropriations, as increased oversight will require 
additional funding. The comment noted that FDA's relationships with 
manufacturers are also a conflict of interest as the final rule will 
primarily benefit test manufacturers from who FDA currently receives 
significant user fees. Finally, the comment noted that a rule that 
increases test manufacturers' market share in laboratory testing and 
which may result in increased submissions to the FDA from such 
manufacturers provides additional financial incentives to FDA.
    (Response 107) We disagree. FDA frequently issues rules, like this 
final rule, that have significant implications on the number of 
applications and submissions (many of which have associated user fees) 
that it receives. The fact that a rule may result in increased 
submissions/applications (with associated user fees) does not mean that 
there are conflicts of interest at issue.
    To the extent the comment is suggesting that the motivation behind 
the rulemaking is some type of financial gain, we also disagree. As FDA 
has noted in the NPRM and elsewhere in this preamble, we are issuing 
this rule to help ensure the safety and effectiveness of IVDs offered 
as LDTs and to achieve more accurate diagnoses, which will lead to 
better care and advance public health overall (88 FR 68006 at 68012). 
Although the final rule is expected to increase the number of 
applications and submissions FDA receives, the collection of those fees 
is not the driver behind this rulemaking. Finally, FDA does not control 
the amount of funds appropriated by Congress, so it is unclear how this 
rulemaking could be argued to be motivated by FDA's desire for an 
increase in appropriated funds.
    (Comment 108) One comment stated that FDA provides no legal basis 
or justification for excluding certain tests from its definition of an 
LDT (i.e., an IVD that is intended for clinical use and that is 
designed, manufactured, and used within a single laboratory that is 
certified under CLIA and meets the regulatory requirements under CLIA 
to perform high complexity testing). The comment also stated that FDA 
excludes certain tests from its definition that are specifically 
recognized under CLIA regulations. Another comment expressed concern 
about the definition, and specifically the lack of clarity regarding 
the meaning of ``clinical use'' and the process for assessing 
``intent'' when applied to genomics.
    (Response 108) As noted in the NPRM and in this preamble, FDA has 
generally considered an LDT to be an IVD that is intended for clinical 
use and that is designed, manufactured, and used within a single 
laboratory that is certified under CLIA and meets the regulatory 
requirements under CLIA to perform high complexity testing (88 FR 68006 
at 68009). Although FDA's general enforcement discretion approach has 
been focused on LDTs, FDA's phaseout policy has a broader scope. 
Specifically, FDA is applying the phaseout policy to IVDs that are 
manufactured and offered as LDTs by laboratories that are certified 
under CLIA and that meet the regulatory requirements under CLIA to 
perform high complexity testing, and used within such laboratories, 
even if those IVDs do not fall within FDA's traditional understanding 
of an LDT because they are not designed, manufactured, and used within 
a single laboratory. Whether a test falls within FDA's traditional 
understanding of an LDT therefore is inapposite for purposes of the 
phaseout policy. Moreover, for the enforcement discretion policies 
included in this rule that apply to certain types of ``LDTs,'' FDA has 
included its rationale for those policies and their scopes in section 
V.B.
    (Comment 109) One comment stated that the final rule should 
explicitly state the legal authority supporting the regulation and 
should highlight the urgency of ``addressing LDT regulation given that 
it currently falls within a regulatory gap.''
    (Response 109) FDA has included a discussion of the legal authority 
for the rule (see sections I.C and IV of this preamble) as well as a 
discussion of the need for the rule (section III.B of this preamble).
    (Comment 110) One comment stated that this rule cannot become a 
binding regulation until it is subjected to the centralized regulatory 
review process, which consists of a benefit-cost analysis and Office of 
Management and Budget (OMB) review.
    (Response 110) To the extent the comment is implying that this 
rulemaking did not include centralized regulatory review, it is 
incorrect. FDA has gone through that process. As part of that process, 
it has prepared preliminary and final regulatory impact analyses under 
EOs 12866, 13563, and 14094, as well as the Regulatory Flexibility Act 
and the Unfunded Mandates Reform Act. OIRA has reviewed those analyses 
and this rule.
    Although this rule has been issued in accordance with the 
centralized regulatory review process described in E.O. 12866 and its 
amendments, FDA disagrees with the assertion that a rule would not be 
``binding'' were it not subjected to all aspects of centralized 
regulatory review as specified by E.O. 12866. Legal requirements for 
rulemaking are set forth in the APA and related statutes, organic 
statutes such as the FD&C Act, and applicable regulations. 
Additionally, Section 10 of E.O. 12866 provides: ``This Executive order 
is intended only to improve the internal management of the Federal 
Government and does not create any right or benefit, substantive or 
procedural, enforceable at law . . . . '' See also Alliance for Natural 
Health U.S. v. Sebelius, 775 F. Supp. 2d 114, 135 n.10 (D.D.C. 2011) 
(citing Section 10 in rejecting challenge to FDA regulation for alleged 
violation of E.O. 12866); E.O. 13563 section 7(f) (noting that the E.O. 
does not create any right or benefit enforceable at law or in equity); 
E.O. 14094 section 4(c) (same). E.O. 12866 thus does not establish 
legally enforceable requirements for rulemaking.
    (Comment 111) One comment argued that, to phase out the general 
enforcement discretion approach for IVDs offered as LDTs, FDA would 
have to provide data ``to cross a predetermined threshold for action,'' 
and the data should be presented ``along with the minutes of meetings 
around it.''
    (Response 111) There is no requirement--in the APA, FD&C Act, or 
otherwise--establishing a ``predetermined threshold'' for changing an 
enforcement discretion approach. As FDA explained in section III.B of 
this preamble as well as the NPRM, the LDT landscape has evolved 
significantly since the enactment of the MDA (88 FR 68006 at 68009), 
and several factors justify this rule, including, but not limited to, 
the increased complexity of IVDs offered as LDTs and their growing 
share of the testing market. The documents supporting FDA's findings, 
including sources such as peer-reviewed literature and FDA memoranda, 
were

[[Page 37366]]

published in the docket for this rulemaking.
    (Comment 112) One comment expressed concern with FDA characterizing 
the proposed rule, if finalized, as not establishing any requirements. 
The comment stated that ``applying a panoply of regulations to an 
entirely new class that had not hitherto been regulated is, from the 
perspective of laboratories, imposing entirely new requirements.''
    (Response 112) To the extent the commenter is suggesting that FDA 
is required to go through notice-and-comment rulemaking to phase out 
the general enforcement discretion approach for applicable 
requirements, we disagree. The phaseout policy does not impose any 
binding requirements on the Agency or LDT manufacturers, but rather 
describes how FDA intends to phase out the general enforcement 
discretion approach for existing requirements under the FD&C Act that 
apply to LDTs as devices. The phaseout policy described in the NPRM, 
and this preamble, is a general statement of policy and therefore, it 
is exempt from the rulemaking procedures of the APA. 5 U.S.C. 
553(b)(3)(A). Moreover, the phaseout policy is an enforcement policy, 
and the FD&C Act's enforcement provisions commit broad discretion to 
FDA to decide how and when they should be exercised. See Heckler v. 
Chaney, 470 U.S. 821, 835 (1985). In any event, such an argument is 
misplaced given that FDA is in fact engaging in notice-and-comment 
rulemaking here.
    To the extent the comment is instead suggesting that FDA's 
characterization means that the Agency is underestimating the costs of 
the phaseout, we also disagree. The economic analyses in the proposed 
and final rules do not assume zero costs to laboratories because FDA is 
not changing any legal requirements. Rather, these analyses account for 
all of the costs associated with changes in FDA's enforcement approach.
    (Comment 113) One comment stated that two sources--an overview of 
Federal law related to IVDs and clinical laboratories appearing in 
Clinical Chemistry, and a white paper written on behalf of ACLA--
provide a good alternative to FDA's position.
    (Response 113) It is not clear if this comment was saying that 
these sources provide an alternative policy FDA should consider, or if 
the comment was saying that these papers undermine FDA's legal 
position. In any event, to the extent those sources make significant 
arguments that have been advanced by other comments submitted to the 
docket for this rulemaking, those arguments have been addressed. In 
particular, the express purpose of the referenced journal article is 
``to provide a legislative and regulatory history of IVDs to foster a 
foundational basis for future LDT discussions,'' and FDA addresses 
comments it received regarding the history of its statements on LDTs 
elsewhere in this preamble. The argument that LDTs are not devices and 
are therefore outside FDA's jurisdiction, which is advanced in the 
white paper written on behalf of ACLA, has likewise been addressed 
elsewhere in this preamble.

F. Phaseout Policy

1. General Comments on the Phaseout Policy
    (Comment 114) Some comments stated that FDA's approach to phasing 
out the general enforcement discretion approach for LDTs is too broad 
and does not appropriately account for differences in the types of IVDs 
offered as LDTs. Some comments stated that FDA should utilize a risk-
based approach in its oversight of IVDs offered as LDTs.
    (Response 114) FDA does not agree with these comments. FDA has 
crafted a tailored phaseout policy intended to better protect the 
public health by helping to assure the safety and effectiveness of IVDs 
offered as LDTs, while also accounting for other important public 
health considerations such as patient access and reliance. Notably, the 
phaseout policy includes several new, targeted enforcement discretion 
policies, based in part on comments submitted on the NPRM regarding 
whether and how FDA should phase out the general enforcement discretion 
approach for more than a dozen specific types of tests (see section 
VI.L). FDA's reasons for adopting these policies are discussed further 
in section V.B. For other categories of IVDs, for the reasons discussed 
throughout this preamble, including responses to comments in sections L 
and F, FDA is not adopting enforcement discretion policies.
    (Comment 115) Some comments suggested that FDA's phaseout of the 
general enforcement discretion approach should only apply to 
``commercial'' manufacturers and for-profit laboratories, and that FDA 
should establish a separate framework for oversight of LDTs that are 
offered in laboratories that work closely with treating physicians and 
are directly integrated into patient care. One comment suggested that 
FDA continue its enforcement discretion approach for tests that are 
designed and overseen by physicians and laboratories for the care of 
their patients in consultation with their clinical providers.
    (Response 115) FDA disagrees that the Agency should phase out the 
general enforcement discretion approach only for conventional 
manufacturers and for-profit laboratories. The need for greater FDA 
oversight to better assure the safety and effectiveness of IVDs offered 
as LDTs applies to IVDs offered as LDTs by non-profit laboratories as 
well as other types of laboratories.
    Regarding the comments about LDTs manufactured by laboratories that 
work closely with treating physicians or that are directly integrated 
into patient care, we note that FDA is adopting an enforcement 
discretion policy for LDTs manufactured and performed by a laboratory 
integrated within a healthcare system to meet an unmet need of patients 
receiving care within the same healthcare system. As discussed in 
section V.B.3, FDA has determined that an enforcement discretion policy 
for premarket review requirements and QS requirements (except for 
requirements under part 820, subpart M (Records)) for such LDTs is 
appropriate given the likelihood that laboratories would stop 
manufacturing unmet need LDTs under the proposed phaseout policy (given 
the limited market for such LDTs and perceived costs of compliance with 
premarket review and QS requirements), the risk mitigations present in 
these circumstances, and the lack of available FDA-authorized IVDs to 
meet the patient's need.
    (Comment 116) Several comments suggested alternatives to the 
phaseout policy, including combining a quality framework like ISO 9001 
with a risk-based self-regulation model; utilizing a targeted program 
focusing on areas of concern by providing tools to qualify both LDTs 
and other IVDs for specific indications; updating the CLIA regulations 
or otherwise tightening the regulation of laboratories and 
standardizing best practices; ``leveraging'' existing quality assurance 
programs and programmatic guardrails for lower risk tests; 
``exempting'' tests that have been reviewed and approved by NYS CLEP 
and providing for other ``categorical exemptions''; exercising 
enforcement discretion for LDTs developed and offered locally in small 
volumes; creating a framework for LDT manufacturers to make their 
validation studies public (which FDA could then utilize for risk-based 
enforcement); incorporating principles from the proposed VALID Act; 
establishing national accuracy laboratories or partnering with existing 
organizations to

[[Page 37367]]

serve as independent entities dedicated to evaluating and verifying the 
performance of diagnostic tests; or establishing regional market zones 
for LDTs (by state or locality) to facilitate conversations between 
laboratories and clinicians.
    (Response 116) Many of the suggestions provided in these comments 
are outside of FDA's authority to implement. For example, FDA does not 
have the statutory authority to implement specific provisions of the 
VALID Act bill (e.g., technology certification), as the bill was never 
enacted. Similarly, regarding the comments about CLIA, FDA is not the 
agency in charge of administering that statute. Other suggestions may 
fall outside of FDA's authority and also lack sufficient clarity, such 
as suggestions that FDA establish national accuracy laboratories or 
regional market zones for LDTs. With respect to making validation 
studies public, adopting a risk-based self-regulation model, or 
utilizing a targeted program focusing on areas of concern by providing 
tools to qualify LDTs and other IVDs for specific indications, FDA 
disagrees that these measures reduce the public health need for 
additional FDA oversight of IVDs offered as LDTs. These measures would 
not include critical aspects of FDA's oversight (such as requirements 
for premarket review, QS, registration and listing or centralized 
adverse event reporting), would not provide for oversight by 
independent experts, and would not address the risks associated with 
IVDs for indications that do not fall within specific ``areas of 
concern.''
    Likewise, with respect to standardizing best practices or 
``leveraging'' existing quality assurance programs and programmatic 
guardrails for lower risk tests, FDA disagrees that such mechanisms 
mitigate the need to phase out the general enforcement discretion 
approach for LDTs, as explained in sections VI.C.1 and VI.C.3. FDA also 
disagrees that an enforcement discretion policy for LDTs that are 
developed and offered locally in small volumes would be appropriate, as 
FDA has concerns that there would not be sufficient risk mitigations in 
such circumstances.
    With respect to the comment about LDTs that have been reviewed and 
approved by NYS CLEP, we agree that an enforcement discretion policy 
for LDTs approved by NYS CLEP is appropriate, as explained in section 
V.B.2.
    (Comment 117) FDA received a comment from DoD stating that FDA 
should continue the general enforcement discretion approach for LDTs 
used within DoD. Specifically, DoD explained that its ``use of LDTs is 
based on unique, military-relevant scenarios not encountered within the 
civilian or commercial sectors, therefore, there is no commercial 
market or incentive for private development of such tests. For example, 
DoD, on behalf of the United States, is a party to international 
agreements that require deployed service members to test negative for 
certain infectious diseases prior to deployment . . . In addition, with 
DoD personnel and US citizens deployed worldwide, to sometimes austere 
environments, isolated cases of rare infectious diseases require LDT 
testing without the benefit of a declared emergency and access to the 
FDA EUA pathway.'' DoD further explained that ``Department of Defense 
Instruction (DoDI) 6640.02, establishes the Center for Clinical 
Laboratory Medicine (CCLM),'' and that ``DoD would work with FDA to 
establish standards within the DoD unique internal program to achieve 
stated objectives that provide for clinical validity of LDTs.''
    (Response 117) For the reasons discussed further in section V.B.1, 
FDA intends to exercise enforcement discretion and generally not 
enforce applicable requirements for LDTs manufactured and performed 
within DoD.
    (Comment 118) FDA received several comments stating that FDA should 
continue the general enforcement discretion approach for LDTs 
manufactured and performed within VHA. Two comments suggested that FDA 
should not continue the general enforcement discretion approach for 
LDTs manufactured and performed within VHA because VHA's program is not 
in alignment with FDA regulation (though one of these comments 
supported ``leveraging'' outside programs ``in principle''). One 
comment asked whether continuation of the general enforcement 
discretion approach for LDTs manufactured and performed within VHA 
would extend beyond the administrative boundaries for which VHA's 
program is currently limited.
    (Response 118) FDA agrees with those comments that stated that FDA 
should have an enforcement discretion policy for LDTs manufactured and 
performed within VHA. For the reasons discussed in more detail in 
section V.B.1, FDA intends to exercise enforcement discretion and 
generally not enforce applicable requirements for LDTs manufactured and 
performed within VHA. With respect to concerns that VHA's program is 
not currently in alignment with FDA regulation, FDA notes that VHA is 
taking steps in consultation with FDA to track all LDTs in its system 
and to ensure both the analytical and clinical validity of its LDTs, 
the quality manufacturing of its LDTs, and the central reporting of 
adverse events. As noted in section V.B.1, this enforcement discretion 
policy applies only to LDTs used for patients that are being tested and 
treated within the VHA program.
    (Comment 119) One comment requested that FDA provide more clarity 
``for LDTs where the testing laboratory does [not] manufacture any 
parts of the tests.''
    (Response 119) As discussed in the responses to comments in section 
VI.D.2, a test system is a device regardless of who manufactures it or 
its components, and is subject to applicable requirements in the FD&C 
Act and implementing regulations.
2. Continued Enforcement Discretion for Currently Marketed IVDs Offered 
as LDTs
    (Comment 120) We received many comments urging FDA to maintain the 
general enforcement discretion approach with respect to applicable 
requirements (or a subset thereof) for currently marketed IVDs offered 
as LDTs. Many of these comments stated that continuing the general 
enforcement discretion approach for such IVDs is critical to prevent 
patients from losing access to certain valuable tests. Several of these 
comments also suggested that ``the for-profit sector'' would not step 
in to fill the gaps left by market withdrawal of IVDs for which there 
are ``small markets.'' Other comments stated that it is important to 
continue the general enforcement discretion approach for currently 
marketed IVDs offered as LDTs to sustain successful patient outcomes. 
Some of these comments asserted that certain IVDs offered as LDTs have 
become the standard of care, and some stated that losing access to 
certain currently marketed IVDs offered as LDTs could require the use 
of inferior tests. Other comments argued that currently marketed IVDs 
offered as LDTs that are already integrated into clinical practice pose 
a minimal safety risk, as many have been used effectively for years 
without causing harm, and/or already satisfy accreditation criteria 
from recognized accreditation bodies. A few comments noted that some 
currently marketed IVDs offered as LDTs address unmet needs for which 
authorized tests do not exist, or for which authorized tests do not 
reflect the latest advances in science, suggesting that FDA ought to 
continue the general enforcement

[[Page 37368]]

discretion approach to currently marketed IVDs offered as LDTs to avoid 
disrupting access to these IVDs.
    Some comments asserted that not continuing the general enforcement 
discretion approach for currently marketed IVDs offered as LDTs would 
negatively impact specific populations, such as children, individuals 
with rare diseases, individuals requiring transplantation, and oncology 
patients. Comments stated that certain IVDs offered as LDTs for use in 
children are the gold standard, and that essential, time-sensitive 
testing conducted by pediatric laboratories is performed most 
effectively if done rapidly in house.
    Comments also stated that laboratories have substantial reliance 
interests in currently marketed IVDs offered as LDTs, having made 
business decisions against the backdrop of FDA's decades-long general 
enforcement discretion approach. These comments asserted that 
discontinuing the general enforcement discretion approach for currently 
marketed IVDs offered as LDTs would not recognize these reliance 
interests. Other comments stated that patients have reliance interests 
in IVDs offered as LDTs that would be ``suddenly rendered 
uneconomical,'' and that these reliance interests would not be 
recognized if FDA did not continue the general enforcement discretion 
approach for these IVDs.
    In addition, many comments stated that FDA should continue the 
general enforcement discretion approach for currently marketed IVDs 
offered as LDTs to reduce the demands on FDA resources. Some comments 
described concerns based on experiences with EUA requests during the 
COVID-19 pandemic. Other comments highlighted the estimated number of 
premarket submissions in FDA's PRIA. The comments generally argued that 
continuing the general enforcement discretion approach for currently 
marketed IVDs offered as LDTs would help to ensure that FDA has 
sufficient resources to conduct timely reviews of other submissions and 
would avoid bottlenecks such as those that have been observed in other 
jurisdictions. Many comments also stated that FDA should continue the 
general enforcement discretion approach for currently marketed IVDs 
offered as LDTs to reduce the burden on laboratories. These comments 
generally emphasized the many submissions that laboratories might 
reasonably need to prepare within the applicable timeframe and stated 
that user fee payments would be too high. One comment added that 
although it is ``critical'' that FDA not enforce against IVDs offered 
as LDTs for lacking premarket authorization while a submission for that 
IVD is reviewed, such an approach does not mitigate the need to 
continue the general enforcement discretion approach for currently 
marketed IVDs offered as LDTs, as it does not address the burden of 
preparing and reviewing submissions. Several comments argued that 
continuing the general enforcement discretion approach for currently 
marketed IVDs offered as LDTs would help to reduce the need for 
laboratories to divert resources from innovation to support the 
compliance of currently marketed IVDs.
    Other comments supported continuing the general enforcement 
discretion approach for currently marketed IVDs offered as LDTs 
because, according to these comments, validation studies may otherwise 
need to be repeated that would be impossible or unethical to repeat; 
financial costs to patients and legal costs to providers would 
otherwise increase; and because FDA previously expressed support for 
continuing the general enforcement discretion approach with respect to 
certain requirements for currently marketed LDTs (see Ref. 57).
    (Response 120) As discussed in section V.B.3, FDA generally intends 
to exercise enforcement discretion with respect to premarket review and 
QS requirements (except for requirements under part 820, subpart M 
(Records)) for currently marketed IVDs offered as LDTs that were first 
marketed prior to the date of issuance of this rule and that are not 
modified, or that are modified as described in section V.B.3 The scope 
of and basis for this policy are set forth in section V.B.3.
    Although FDA is adopting this policy, it does not necessarily agree 
with all of the statements made in comments supporting an enforcement 
discretion policy for currently marketed IVDs offered LDTs. For 
example, we do not agree that currently marketed IVDs offered as LDTs 
that are already integrated into clinical practice pose a minimal 
safety risk, or that meeting accreditation criteria from recognized 
accreditation bodies eliminates the need for FDA oversight for the 
reasons discussed in response to comments under section VI.C.3. Rather, 
FDA is including this enforcement discretion policy in consideration of 
other factors, as discussed in section V.B.3.
    (Comment 121) In contrast, FDA received several comments that did 
not support continuing the general enforcement discretion approach for 
currently marketed IVDs offered as LDTs, or favored significantly 
limiting the number of IVDs that would fall under the continued 
enforcement discretion approach. Comments expressed concern that 
continuing the general enforcement discretion approach would be 
inappropriate given the evidence of ``low-performing'' IVDs offered as 
LDTs currently on the market. Other comments expressed concern that 
continuing the general enforcement discretion approach for these IVDs 
may cause certain IVDs to appear to be FDA-authorized even when they 
have not been authorized, and that laboratories might extensively 
modify their IVDs and avoid compliance with applicable requirements for 
these modified IVDs. One comment opposed continuing the general 
enforcement discretion approach for currently marketed IVDs offered as 
LDTs ``particularly for commercial testing''; other comments asserted 
that continuing the general enforcement discretion approach for 
currently marketed IVDs offered as LDTs would inappropriately focus on 
where or by whom an IVD was developed, rather than the risk of the IVD, 
and stated that it would be more ``effective'' to narrowly tailor any 
continued enforcement discretion approach to LDTs that are not 
associated with safety or effectiveness concerns.
    Finally, a few comments did not completely oppose or support an 
enforcement discretion policy for currently marketed IVDs offered as 
LDTs. For example, some comments stated that continuing the general 
enforcement discretion approach for currently marketed IVDs offered as 
LDTs would not be sufficient to address other problems with the 
phaseout policy, including laboratories' inability to make 
``necessary'' updates to their IVDs or respond to changing public 
health needs. Other comments suggested that FDA should continue the 
general enforcement discretion approach for currently marketed IVDs 
offered as LDTs only if FDA does not establish other more specific 
policies.
    (Response 121) FDA has also carefully considered the comments 
recommending against the inclusion of a policy for currently marketed 
IVDs offered as LDTs. FDA agrees that there is evidence in the record 
demonstrating that there are problematic IVDs offered as LDTs that are 
currently marketed. However, FDA remains concerned about the potential 
harms from loss of access to beneficial IVDs offered as LDTs on which 
patients are currently relying. Therefore, FDA has determined that it 
best serves the public health to adopt a more targeted expectation of 
compliance for currently marketed IVDs offered as LDTs. As noted in 
section V.B.3, FDA

[[Page 37369]]

anticipates that adverse event reporting, information contained in 
labeling, and other sources of information (including public reports 
and any relevant information from the healthcare community) will help 
the Agency identify problematic currently marketed IVDs offered as LDTs 
for which enforcement or other action is warranted. FDA intends to take 
such action as appropriate. In this way, FDA's policy is consistent 
with one comment's recommendation to ``narrowly tailor'' the approach, 
taking into account ``safety or effectiveness concerns'' with currently 
marketed IVDs offered as LDTs.
    One comment argued against an enforcement discretion policy for 
currently marketed IVDs offered as LDTs because such a policy may cause 
these IVDs to appear to be FDA-authorized even when they have not been 
authorized. FDA disagrees. Devices marketed under an enforcement 
discretion policy are not lawfully on the market, and should not be 
understood to share the same legal status as lawfully marketed devices. 
Statements in labeling that an unauthorized IVD is authorized by FDA, 
or suggestions along those lines, would misbrand the IVD under section 
502(a) of the FD&C Act. We believe that enforcing this and other 
labeling requirements would help to address the concern raised in the 
comment.
    Another comment stated that a policy for currently marketed IVDs 
offered as LDTs could be problematic because laboratories might 
extensively modify their IVDs and avoid compliance with applicable 
requirements for these modified IVDs. As described in section V.B.3, 
the enforcement discretion policy for currently marketed IVDs offered 
as LDTs is limited to instances in which the IVD is unmodified, or the 
IVD is modified only in certain limited ways. If an IVD is modified in 
more significant ways, FDA intends to phase out the general enforcement 
discretion approach with respect to all requirements for that IVD. We 
believe this policy addresses the concern raised in the comment.
    FDA also acknowledges that under this policy, its compliance 
expectations for currently marketed IVDs will differ depending on 
whether the IVD is offered by a laboratory or a conventional 
manufacturer. However, in light of the reliance interests engendered by 
FDA's longstanding enforcement discretion approach for LDTs, as 
described in the comments, we have determined that this differential 
treatment is warranted. Over time, FDA anticipates that IVDs will 
evolve and eventually come into compliance with FDA requirements, such 
that IVDs manufactured by laboratories will generally fall under the 
same enforcement approach as other IVDs. In the FRIA, we estimate that 
50 percent of currently marketed IVDs offered as LDTs will be submitted 
to FDA for premarket review (e.g., due to significant modifications as 
described in section V.B.3) over the course of 20 years.
    To the extent that some comments indicated that this policy is 
appropriate to address unmet needs, FDA notes that discussion regarding 
tests for unmet needs can be found in section VI.L.5 of this preamble. 
Also, discussion regarding potential impacts on specific patient 
populations can be found in section VI.K.
    (Comment 122) Some comments stated that FDA should continue the 
general enforcement discretion approach for currently marketed IVDs 
offered as LDTs only with respect to premarket review requirements. 
Other comments stated that the enforcement discretion policy for 
currently marketed IVDs offered as LDTs should be for premarket review 
requirements and all QS requirements, though one comment recommended 
that the policy apply for premarket review requirements and QS 
requirements related only to design controls. Most comments that 
supported continuing the general enforcement discretion approach for 
currently marketed IVDs offered as LDTs were focused on premarket 
review and QS requirements, and not all requirements. However, a few 
comments suggested that the general enforcement discretion approach 
continue for all applicable requirements. Several comments stated that 
MDR requirements and registration and listing requirements should be 
enforced, as these requirements would provide important information 
about the testing landscape. One comment suggested that while 
registration and listing requirements should still be enforced, 
currently marketed IVDs offered as LDTs from hospital and health system 
laboratories should not be ``subject to overly burdensome 
requirements'' for registration and listing; for example, FDA should 
limit the amount of listing information expected for those IVDs. 
Another comment expressed concern that enforcing registration 
requirements for laboratories manufacturing currently marketed IVDs 
offered as LDTs could ``be prohibitive'' for some laboratories. One 
comment stated that laboratories that have a system for reporting 
errors, and that are integrated into a health system, generally should 
not be expected to comply with adverse event reporting requirements (it 
is not clear if this comment was intended to be specific to currently 
marketed IVDs offered as LDTs, but the organization of the comment 
suggests that it was).
    (Response 122) FDA agrees that it should phase out the general 
enforcement discretion approach for all applicable requirements other 
than premarket review and QS requirements (except for requirements 
under part 820, subpart M (Records)) for currently marketed IVDs 
offered as LDTs that were first marketed prior to the date of issuance 
of this rule and that are not modified, or that are modified as 
described in section V.B.3. This policy reflects a careful balancing of 
relevant considerations, as discussed in section V.B.3 and in response 
to comment 120.
    We note that the costs of compliance with premarket review and QS 
requirements are a significant portion of the overall anticipated costs 
to laboratories of complying with applicable FDA requirements (see 
section II.F.5 of the FRIA (Ref. 10)). Of the total estimated 
discounted costs to industry of $1.17 billion, the average estimated 
costs of compliance with stages 1 and 2 are approximately $9,522 per 
test ($74,783 per laboratory) and the average estimated costs of 
compliance with premarket review and QS requirements are approximately 
$3.02 million per test ($1.26 million per laboratory). As a result, FDA 
has concluded that focusing the policy on these requirements should 
address the concerns about widespread market exit. As noted above, FDA 
expects compliance with requirements under part 820, subpart M 
(Records), including compliance with QS requirements regarding 
complaint files. This will facilitate compliance with MDR requirements, 
because complaints will then be reviewed to determine whether they are 
MDR reportable. FDA intends to review complaint files during an 
inspection to assess compliance with relevant QS and MDR requirements.
    FDA intends to phase out the general enforcement discretion 
approach for requirements other than premarket review and most QS 
requirements in order to gather information about, and take appropriate 
action with respect to, currently marketed IVDs offered as LDTs. FDA 
has determined that the public-health value of compliance with these 
requirements outweighs any concerns raised in the comments. In 
particular, based on the information in the FRIA, we do not believe 
compliance with these other requirements will cause laboratories to 
stop offering IVDs on which patients currently rely. In addition, FDA 
disagrees that

[[Page 37370]]

laboratories that have a system for reporting errors and are integrated 
into a health system should not be expected to submit MDRs to FDA for 
currently marketed IVDs offered as LDTs (or for other IVDs). 
Centralized reporting of adverse events enables FDA to track trends 
across devices of the same type, identify when issues arise, and work 
with stakeholders to address those issues. For example, as discussed in 
section III.B, FDA was able to identify a biotin interference issue 
through analysis of MDRs indicating inaccurate test results. Biotin is 
commonly used in immunoassays as part of the test technology. 
Therefore, when high dose biotin supplements (advertised for hair and 
nail growth) became more popular, FDA began seeing inaccurate test 
results associated with these immunoassays. FDA's investigation 
revealed that this biotin interference affected dozens of tests across 
multiple manufacturers. This led to a multiyear interactive effort to 
have manufacturers address the issue through assay re-design. Notably, 
it is likely many RUO immunoassay kits still use biotin that would be 
affected in the same manner by these supplements, and it is likely that 
those manufacturers have not addressed this issue. These RUO kits 
currently may be offered as LDTs by laboratories. Enforcement of 
adverse event reporting and registration and listing requirements for 
these currently marketed IVDs offered as LDTs will help FDA identify 
where this problem may still be occurring, and where other problems are 
occurring, so that these problems can be addressed.
    For additional discussion of FDA's phaseout of the general 
enforcement discretion approach with respect to registration and 
listing requirements and adverse event reporting requirements, see 
sections VI.F.7 and VI.F.8 of this preamble.
    (Comment 123) Some comments recommended that FDA continue the 
general enforcement discretion approach with respect to certain 
requirements for currently marketed IVDs offered as LDTs that were 
first marketed prior to publication of the proposed rule whereas other 
comments recommended such an approach should be for currently marketed 
IVDs offered as LDTs that were first marketed prior to publication of 
the final rule, or prior to the effective date of the final rule. One 
comment suggested that FDA continue the general enforcement discretion 
approach with respect to certain requirements for IVDs offered as LDTs 
that are marketed within the next 4 years. Another comment suggested 
that FDA continue the general enforcement discretion approach with 
respect to certain requirements for IVDs offered as LDTs that have been 
marketed for at least 3 years prior to March 31, 2024, and that are 
supported by post-market data that provide evidence of device 
performance and safety.
    (Response 123) As discussed in section V.B.3, FDA has keyed the 
policy for currently marketed IVDs offered as LDTs to the date of this 
final rule, rather than the proposed rule. FDA chose this date because 
patients and the healthcare community may have begun relying on these 
IVDs during the period between publication of the proposed and final 
rule. Patients and the healthcare community also may have begun relying 
on IVDs offered as LDTs that were marketed before March 31, 2024 (and 
that are currently marketed), even if such IVDs were marketed for fewer 
than 3 years prior to that date. By contrast, for IVDs offered as LDTs 
that are introduced after the date of issuance of the final rule (e.g., 
within the next 4 years), the decisions of laboratories, patients, and 
the healthcare community would be made taking into account the 
expectation of compliance and not presuming the same reliance. 
Furthermore, given the timing of the phaseout policy and the 
enforcement discretion policy for currently marketed IVDs offered as 
LDTs, FDA anticipates that laboratories should be able to comply with 
premarket review and QS requirements by the time of stages 3-5 for IVDs 
offered as LDTs that are marketed after the publication date for this 
final rule.
    (Comment 124) Some comments stated that if FDA were to continue the 
general enforcement discretion approach for currently marketed IVDs 
offered as LDTs, the approach should apply to such IVDs even if the 
IVDs are modified. One comment argued that modifications are essential 
to the evolution of patient care. However, most comments suggested that 
a general enforcement discretion approach for currently marketed IVDs 
offered as LDTs should not apply to such IVDs after certain types of 
modifications are made. These comments generally proposed that an 
enforcement discretion approach should not apply to currently marketed 
IVDs offered as LDTs after any changes to intended use, indications for 
use, and/or performance. One comment proposed that a general 
enforcement discretion approach for currently marketed IVDs offered as 
LDTs apply to those IVDs if modified in ways that do not significantly 
change the indications for use, except for some changes to specimen 
type; that do not significantly change performance claims or 
significantly and adversely change performance; or that do not 
adversely change the safety for individuals who come in contact with 
the IVD. Another comment proposed that a general enforcement discretion 
approach for currently marketed IVDs offered as LDTs apply to those 
IVDs if modified in ways that do not alter methodology, intended use, 
or performance, arguing that this would allow laboratories to continue 
innovating and address emerging scientific understanding and patient 
needs. One comment suggested that a laboratory manufacturing a 
currently marketed IVD offered as an LDT should not be expected to 
submit a premarket submission for modifications that are properly 
validated by the laboratory, stating that the utility of currently 
marketed IVDs offered as LDTs will diminish over time if overly 
restrictive constraints are placed on modifications.
    Some comments emphasized that FDA should provide clear guidance 
regarding what IVDs offered as LDTs would fall within an enforcement 
discretion policy for currently marketed IVDs offered as LDTs, 
including regarding the types of modifications that would be included 
within that policy.
    (Response 124) FDA agrees that the policy should apply to currently 
marketed IVDs offered as LDTs when they are modified in certain limited 
ways.
    As discussed in response to comment 261, FDA's regulations require 
premarket review when an authorized device is modified in a way that 
affects safety and effectiveness (for a device approved under a PMA, 
with certain exceptions) or in a way that could significantly affect 
safety and effectiveness (for a device subject to 510(k)). Following a 
similar approach in this context, and as discussed in more detail in 
section V.B.3, FDA generally intends to exercise enforcement discretion 
with respect to premarket review and QS requirements (except for 
requirements under part 820, subpart M (Records)) for currently 
marketed IVDs offered as LDTs that were first marketed prior to the 
date of issuance of this rule and that are not modified, or that are 
modified in relatively minor ways. This policy is intended to preserve 
access to beneficial IVDs on which patients and the healthcare 
community currently rely, including versions of that IVD with minor 
changes. However, once the IVD is changed in certain, more significant 
ways that could affect its basic safety and effectiveness profile, the 
policy no longer applies. Thus, FDA generally expects compliance with 
premarket review and QS requirements for currently marketed IVDs 
offered as

[[Page 37371]]

LDTs when a laboratory's modifications (individually or in aggregate) 
change the indications for use of the IVD, alter the operating 
principle of the IVD (e.g., changes in critical reaction components), 
include significantly different technology (e.g., addition of 
artificial intelligence/machine learning to the test algorithm, a 
change from targeted sequencing to whole genome sequencing, a change 
from immunoassay to mass spectrometry, or a change from manual to 
automated procedures), or adversely change the performance or safety 
specifications of the IVD. These modifications are generally consistent 
with the types of modifications that comments suggested should not fall 
within an enforcement discretion policy for currently marketed IVDs 
offered as LDTs. Although some comments suggested that the policy 
should encompass all modifications to currently marketed IVDs offered 
as LDTs, FDA does not agree that this type of broad policy would 
appropriately serve the public health purpose of this rulemaking.
    (Comment 125) FDA received several comments that proposed specific 
circumstances under which FDA might continue the general enforcement 
discretion approach with respect to certain requirements for currently 
marketed IVDs offered as LDTs. Some comments stated that FDA should 
continue the general enforcement discretion approach for currently 
marketed IVDs offered as LDTs that are ``standard of care'' or 
otherwise well established in the literature; that are widely adopted 
and incorporated into professional society treatment guidelines; that 
are developed and offered locally; that are ``already in known 
published medical classifications''; that have ``proven performance 
serving a vital part of healthcare''; for which there are long-term 
safety and effectiveness records, or evidence of analytical and 
clinical validity and clinical utility; and/or that are not high risk. 
One comment stated that FDA should continue the general enforcement 
discretion approach for currently marketed IVDs offered as LDTs that, 
among other types of IVDs, have been modified from FDA-authorized 
devices with respect to certain parameters (in some cases supported by 
further studies), or that have been developed by a government or 
reference laboratory in good standing under CLIA. Another comment 
stated that FDA should continue the general enforcement discretion 
approach for currently marketed IVDs offered as LDTs that have 
``demonstrated concordance with FDA-approved companion diagnostics.'' 
Yet another comment suggested FDA continue the general enforcement 
discretion approach for currently marketed IVDs offered as LDTs that 
are used ``without issues'' within public health laboratories.
    (Response 125) As discussed in section V.B.3, FDA intends to 
exercise enforcement discretion and generally not enforce premarket 
review requirements and QS requirements (except for requirements under 
part 820, subpart M (Records)) for currently marketed IVDs offered as 
LDTs as long as they are not modified following issuance of this final 
rule, or are modified but only as described in section V.B.3. FDA is 
adopting this policy based on careful consideration of the comments and 
the economic projections in the proposed rule, and after weighing 
competing interests at issue here, as described in section V.B.3.
    FDA does not believe that the alternative policies suggested by 
stakeholders in the comments summarized above would strike the 
appropriate balance between these competing interests. For example, 
policies only for some currently marketed IVDs offered as LDTs would 
not adequately address concerns that patients and providers may have 
reasonably made choices based on an assumption of continued access to 
certain IVDs that may not be offered as a result of the phaseout 
policy, and specifically if FDA were to expect compliance with 
premarket review and most QS requirements. These include policies that 
are limited only to currently marketed IVDs offered as LDTs that are 
offered by certain types of laboratories; that have been modified from 
FDA-authorized devices with respect to certain parameters; or that have 
``demonstrated concordance'' with certain FDA-authorized IVDs. For 
discussion of FDA's determination not to phase out the general 
enforcement discretion approach only for IVDs that are high-risk, see 
section VI.L.4.
    In addition, many of the policies suggested in comments would be 
difficult to administer or would not set clear expectations for 
stakeholders. For example, a policy for currently marketed IVDs offered 
as LDTs that are ``standard of care,'' or otherwise well established in 
the literature, may not be clear for stakeholders. There may be 
different opinions regarding what IVDs offered as LDTs are standard of 
care or well established in the literature, and defining those terms in 
a manner that could be consistently and predictably applied may not be 
feasible. Similar concerns apply to policies for currently marketed 
IVDs offered as LDTs that are ``widely adopted'' and incorporated into 
professional society treatment guidelines; that are developed and 
offered locally; that are ``already in known published medical 
classifications''; that have ``proven performance serving a vital part 
of healthcare''; or for which there are ``long-term'' safety and 
effectiveness records or evidence.
    (Comment 126) One comment suggested that FDA should continue the 
general enforcement discretion approach for currently marketed IVDs 
offered as LDTs upon request.
    (Response 126) FDA believes that continuing the general enforcement 
discretion approach for currently marketed IVDs offered as LDTs only 
upon request would not set clear expectations for stakeholders and 
would be administratively difficult to implement.
    (Comment 127) Some comments suggested that FDA should continue the 
general enforcement discretion approach only for specific types of 
currently marketed IVDs offered as LDTs (depending on the impact to 
different patient populations), or for currently marketed IVDs offered 
as LDTs that are intended for unmet needs or for rare diseases or 
indications or where there is a strong public health need for the IVD, 
linked to ensuring access to accurate and reliable IVDs and 
facilitating a smooth transition for FDA oversight. Other comments 
suggested that FDA should continue the general enforcement discretion 
approach for currently marketed IVDs offered as LDTs that have been 
approved by other regulatory bodies, Federal agencies, or certain other 
programs or entities, in some cases only when the IVD has been offered 
for a minimum period of time without any reported adverse consequences, 
or when there is no credible information establishing a lack of 
validity, false or misleading claims, or a probability that the IVD 
will cause serious adverse health consequences.
    (Response 127) Regarding the comments about a policy for LDTs for 
unmet needs, we note that FDA is adopting a policy for LDTs 
manufactured and performed by a laboratory integrated within a 
healthcare system to meet an unmet need of patients receiving care 
within the same healthcare system. Moreover, regarding the comment 
about a policy for currently marketed IVDs offered as LDTs that have 
been approved by other regulatory bodies, FDA is adopting an 
enforcement policy for LDTs that are approved by NYS CLEP. In addition,

[[Page 37372]]

FDA is adopting an enforcement policy for LDTs offered within DOD's and 
VHA's oversight programs. For further discussion of these aspects of 
the phaseout policy, see sections V.B.2 and V.B.3.
    Further, similar to our response to comment 125, FDA is concerned 
that a policy for IVDs offered as LDTs for a certain period of time 
without issues or that meet a strong public health need would be 
difficult to administer and would not set clear expectations for 
stakeholders as there may be different opinions regarding what IVDs 
offered as LDTs meet these, or any similar, descriptions.
    (Comment 128) One comment suggested that IVDs falling within the 
policy for currently marketed IVDs offered as LDTs be labeled with a 
statement disclosing they have not been authorized by FDA.
    (Response 128) The Agency does not believe such a policy would be 
appropriate at this time. FDA expects that most IVDs offered as LDTs 
subject to premarket review requirements will lack required FDA 
authorization for several years following issuance of this final rule. 
Under the phaseout policy described in section V.C, the phaseout of 
enforcement discretion with respect to premarket review requirements 
will begin 3.5 years (for high-risk IVDs offered as LDTs) to 4 years 
(for other IVDs offered as LDTs subject to premarket review) from the 
date of issuance of this rule. After a complete premarket submission 
for an IVD offered as an LDT has been submitted within these 
timeframes, FDA generally does not intend to enforce against the IVD 
for lacking FDA authorization during the pendency of FDA review. Thus, 
in the context of the phaseout policy, including such a statement in 
the labeling for currently marketed IVDs offered as LDTs could create 
confusion by suggesting a distinction that does not exist between those 
IVDs that are in the process of coming into compliance with premarket 
review requirements and those that are not. If our experience with 
implementation of the phaseout policy indicates that a different 
approach to inclusion of such a statement is warranted as more IVDs 
offered as LDTs come into compliance with premarket review 
requirements, FDA would consider making appropriate policy changes in 
accordance with good guidance practices (Sec.  10.115).
    To the extent anyone may seek information regarding whether a 
particular test has been authorized by FDA, such information can be 
found in FDA databases. For example, tests that have been approved, 
cleared, or had a De Novo request granted by FDA appear in the PMA, 
510(k), and De Novo databases, respectively (Refs. 165,166, and 224). 
We expect that most tests, including those offered without premarket 
review (e.g., because they are exempt from premarket notification or 
fall within an enforcement discretion policy), will be listed in the 
Registration & Listing database in Stage 2 of the phaseout policy. 
Where a test has been approved, cleared, or had a De Novo request 
granted, this database will also indicate the applicable premarket 
submission number.
    (Comment 129) Several comments stated that if FDA continues the 
general enforcement discretion approach for currently marketed IVDs 
offered as LDTs, ``FDA should retain the authority to require 
additional regulatory evaluation where there is a need to do so.''
    (Response 129) We agree that regardless of the policy for currently 
marketed IVDs offered as LDTs or any other enforcement discretion 
policy included in the phaseout policy, FDA retains the authority to 
enforce any applicable requirements and pursue enforcement action at 
any time against violative IVDs. Moreover, we note that as discussed 
above, suggestions that an unauthorized IVD is authorized by FDA would 
misbrand the IVD under section 502(a) of the FD&C Act.
    (Comment 130) One comment stated that if FDA continues the general 
enforcement discretion approach with respect to premarket review 
requirements for currently marketed IVDs offered as LDTs, FDA should 
allow submission of predetermined change control plans (PCCPs) for 
currently marketed IVDs offered as LDTs without additional submissions, 
to allow for ``controlled, pre-approved test modifications.''
    (Response 130) Under section 515C of the FD&C Act, FDA may approve 
or clear a PCCP that is submitted in a PMA, supplemental PMA, or 510(k) 
notification. A PMA supplement or new 510(k) is not required for a 
modification to a device that would otherwise be required if the change 
is consistent with a PCCP previously approved or cleared by FDA. As set 
forth in section 515C, a PCCP can only be approved under section 515 of 
the FD&C Act or cleared under section 510(k) of the FD&C Act. For 
additional discussion of PCCPs, see our response to comments in section 
VI.M. FDA notes, however, that the policy for currently marketed IVDs 
offered as LDTs does encompass modifications to such IVDs when the 
modification involves a minor change, as discussed in section V.B.3.
    (Comment 131) One comment stated that if FDA continues the general 
enforcement discretion approach with respect to premarket review for 
currently marketed IVDs offered as LDTs, those IVDs should be able to 
serve as predicate devices if laboratories subsequently modify the IVDs 
and submit 510(k)s for those modified IVDs.
    (Response 131) Under section 513(i) of the FD&C Act and part 807, 
subpart E of FDA's regulations, a predicate device (for purposes of FDA 
clearance of a 510(k) submission) is a ``legally marketed'' device. 
FDA's regulations establish that ``[a] legally marketed device to which 
a new device may be compared for a determination regarding substantial 
equivalence is a device that was legally marketed prior to May 28, 
1976, or a device which has been reclassified from class III to class 
II or I (the predicate), or a device which has been found to be 
substantially equivalent through the 510(k) premarket notification 
process'' (Sec.  807.92(a)(3)). An IVD that does not satisfy this 
definition, including a currently marketed IVD offered as an LDT that 
requires but does not have premarket authorization, would not be 
eligible to serve as a predicate device.
3. Small Laboratories
    (Comment 132) FDA received comments stating that FDA should 
structure the phaseout of the general enforcement discretion approach 
for LDTs differently for small laboratories, as such laboratories will 
be more heavily affected by the phaseout. Some comments stated that 
small laboratories often develop and validate innovative assays or 
modify existing tests to serve specific populations, which can be 
costly. One comment stated that compliance with FDA requirements is a 
large and costly undertaking which only the largest corporations would 
be able to do, and that providing a longer phaseout period for LDTs 
offered by laboratories with annual receipts below $150,000 would still 
not be sufficient for small laboratories to come into compliance. 
Another comment recommended FDA have a ten-year phaseout for IVDs 
offered as LDTs by small laboratories and define small laboratory using 
the definition proffered by the Small Business Administration.
    (Response 132) FDA recognizes that some small laboratories may be 
disproportionately impacted by the phaseout of the general enforcement 
discretion approach for LDTs from a financial perspective, as discussed 
in section III of the FRIA (Ref. 10). However, the final phaseout 
policy includes several enforcement discretion

[[Page 37373]]

policies that we anticipate will reduce costs for laboratories compared 
to what was estimated in the PRIA, including for small laboratories 
(see section V.B). As shown in table 48 of the FRIA, annualized costs 
per entity under the final phaseout policy (taking into account the 
enforcement discretion policies described in section V.B of this 
preamble) are estimated to be about 6 percent of receipts for small 
laboratories (for further discussion see section III.B of the FRIA).
    In light of the anticipated costs to small laboratories associated 
with the final phaseout policy, and the additional considerations 
discussed in comment 133, FDA does not believe it is appropriate to 
adopt an enforcement discretion policy for small laboratories' IVDs 
offered as LDTs or to extend the phaseout policy to 10 years for such 
laboratories.
    We understand that small laboratories may manufacture innovative 
LDTs or modify existing IVDs to serve specific populations. For small 
laboratories that are integrated within a healthcare system, certain of 
their LDTs may fall within the unmet need policy, discussed further in 
section V.B.3. Small laboratories that are not integrated within a 
healthcare system would fall outside that policy including because 
there are not the same risk mitigations present in such situations (see 
further discussion in section V.B.3).
    (Comment 133) Some comments expressed opposition to FDA having a 
different enforcement approach for small laboratories and advocated for 
uniform treatment of all laboratories. Several comments stated that the 
size of the laboratory should not determine how certain tests are 
treated, noting that this type of approach would not be acceptable if 
applied to non-laboratory manufacturers and would be inconsistent with 
a risk-based approach. Some comments also stated that the harm to 
patients from faulty tests does not change based on the size of the 
laboratory and remarked that a longer phaseout period may allow for 
continued patient harm due to problematic IVDs offered as LDTs. One 
comment stated that small laboratories with fewer LDTs may actually be 
better able to comply with FDA requirements than larger laboratories 
and AMCs with hundreds of LDTs and suggested that any extension of the 
implementation period be based on the number of LDTs that a laboratory 
performs rather than annual receipts. Another comment noted that some 
small laboratories are associated with large hospital systems, which 
may prevent them from qualifying for any exemption or special 
considerations afforded to small laboratories.
    (Response 133) FDA agrees that the phaseout of the enforcement 
discretion approach for LDTs should not be determined by laboratory 
size, as a different enforcement approach for small laboratories would 
not be in the best interest of the public health where we are unaware 
of any evidence supporting that IVDs manufactured by small laboratories 
are any less likely to be problematic than IVDs manufactured by large 
laboratories. We note that this approach is generally consistent with 
FDA's device regulations and policies, which generally do not 
distinguish small businesses from other regulated entities (though 
small businesses are eligible for a waiver or reduction of certain 
MDUFA user fees as a matter of statute). FDA also anticipates that 
features of the final phaseout policy will address many of the concerns 
of small laboratories as discussed in response to comment 132 above. 
FDA's phaseout policy is described in detail in section V.
4. Academic Medical Centers
    (Comment 134) We received many comments responding to the questions 
posed in the NPRM (88 FR 68006 at 68023-24) about whether FDA should 
continue the general enforcement discretion approach with respect to 
any requirements for tests manufactured by AMC laboratories. We 
received a wide variety of comments spanning all sides of the issue: 
comments in favor of continuing an enforcement discretion approach for 
tests manufactured by AMC laboratories, comments recommending that FDA 
also continue an enforcement discretion approach for tests manufactured 
by other similarly situated laboratories, comments that suggested 
limitations to an enforcement discretion approach for tests 
manufactured by AMC laboratories, and comments against the continuation 
of an enforcement discretion approach for tests manufactured by AMC 
laboratories. We also received various suggestions on possible ways to 
define an AMC.
    (Response 134) As stated in section V.B, FDA is adopting several 
enforcement discretion policies that may apply to certain IVDs 
manufactured by AMC laboratories. First, FDA intends to exercise 
enforcement discretion and generally not enforce premarket review 
requirements and QS requirements (except for requirements under part 
820, subpart M (Records)) for currently marketed IVDs offered as LDTs 
as long as they are not modified following issuance of this rule, or 
are modified but only in certain limited ways as described in section 
V.B.3. This includes IVDs currently offered as LDTs by AMC 
laboratories. Second, FDA intends to exercise enforcement discretion 
and generally not enforce premarket review requirements for LDTs 
approved by NYS CLEP, as described in section V.B.2. We anticipate that 
some LDTs manufactured by AMC laboratories may fall within this policy. 
Third, FDA intends to exercise enforcement discretion and generally not 
enforce premarket review requirements and QS requirements (except for 
requirements under part 820, subpart M (Records)) for LDTs manufactured 
and performed by a laboratory integrated within a healthcare system to 
meet an unmet need of patients receiving care within the same 
healthcare system. We anticipate many LDTs made in AMC laboratories 
will fall within this policy.
    For the reasons set forth in section V.B and discussed in the 
response to comment 135, FDA does not think it is appropriate to have 
an enforcement discretion policy for: all LDTs manufactured by AMC 
laboratories; all requirements for LDTs manufactured by AMCs 
laboratories; or LDTs manufactured by AMC laboratories but not LDTs 
manufactured by other laboratories integrated within a healthcare 
system (as such, and because we are not adopting an enforcement policy 
for AMC laboratories, we have not included a definition of AMCs in the 
phaseout policy).
    (Comment 135) Comments suggested that FDA should continue its 
general enforcement discretion approach with respect to tests 
manufactured by AMC laboratories for various reasons. Some argued that 
a continued enforcement discretion approach for AMCs is necessary 
because increased FDA oversight of their LDTs would negatively impact 
the public health, access, medical training, and innovation. Comments 
also claimed that AMC laboratories cannot afford the cost of compliance 
with FDA requirements as they perform tests on hospitalized patients, 
with no additional revenue stream or resources to cover the cost of 
compliance with FDA requirements. Other comments claimed that 
continuing an enforcement discretion approach is necessary because AMC 
laboratories already operate with tight budgets, are short staffed, and 
struggle to find qualified talent. Similar comments indicated that due 
to budgets, AMC laboratories may be prevented from performing FDA-
authorized alternative tests where such tests require specialized 
capital equipment,

[[Page 37374]]

additional training, and inventory management, whereas a continued 
enforcement discretion approach for LDTs made by AMC laboratories would 
account for consolidation of testing platforms for efficiency. Comments 
hypothesized that increased FDA oversight would cause AMC laboratories 
to limit their testing offerings, detrimentally impacting the most 
vulnerable populations, raising costs to patients, and hurting access. 
Many comments stated that AMC laboratories manufacture and provide 
tests for unmet needs to provide care for the most complex adult and 
pediatric patients. This includes tests for rare diseases, which are 
low volume or do not have a ``commercial'' alternative. For example, a 
comment indicated that there are less than 20 laboratories that perform 
advanced immunologic testing, and all such laboratories are AMC 
laboratories. Comments expressed concern that patients might not 
otherwise have access to these and other tests. Other comments focused 
on the role of AMCs in training medical students, research, and 
innovation. Some pointed out that AMC laboratories create and develop 
test methods that ``commercial'' laboratories later adopt and use for 
their tests, and that AMC laboratories are nimble and able to explore 
and employ creative applications of new technology to enhance clinical 
testing. These comments expressed concern that increased FDA oversight 
would inhibit training and research to the detriment of the public 
health.
    Comments also stated that the integration of AMC laboratories into 
patient care at the AMC provides a direct feedback loop between 
providers and patients that helps to mitigate the risks of the tests by 
providing context about the patient, their condition, and the 
particular purpose a test serves in this patient's care, and thereby 
allowing for conversation about the interpretation of results between 
the physician, patient, and test manufacturer. The commenters posit 
that these factors allow test manufacturers to troubleshoot as needed.
    (Response 135) As described in response to comment 134, FDA is 
adopting several enforcement discretion policies that may apply to 
certain IVDs manufactured by AMC laboratories, including an enforcement 
discretion policy for LDTs manufactured and performed by a laboratory 
integrated within a healthcare system to meet an unmet need of patients 
receiving care within the same healthcare system. As discussed in 
section V.B.3, in the circumstances described in the unmet needs 
policy, FDA has greater confidence that ordering physicians will 
communicate any questions about LDTs or concerns regarding the safety 
and effectiveness of the LDT (e.g., when the patient's symptoms point 
to another diagnosis; when subsequent test results contradict the 
original test result) to a laboratory given the built-in communication 
mechanisms present. Moreover, FDA generally has greater confidence that 
laboratories will communicate any limitations of the LDT or other 
relevant information to the ordering physician given these mechanisms. 
We think this is particularly likely to happen in the context of LDTs 
for unmet needs, which are likely to be a focus of attention and 
communication between laboratorians and providers given the uncommon 
nature of the issues presented.
    FDA anticipates that this and other enforcement discretion policies 
(described in response to comment 134) that may apply to IVDs 
manufactured by AMC laboratories will help to avoid the access concerns 
discussed in the comments. Specifically, FDA anticipates that these 
policies will reduce the compliance costs associated with the phaseout 
policy for many laboratories, including AMC laboratories, thereby 
addressing many of the financial concerns referenced in the comments. 
As described in the FRIA, the costs of compliance with premarket review 
and QS requirements are a significant portion of the overall 
anticipated costs to laboratories of complying with applicable FDA 
requirements (see section II.F.5 of the FRIA (Ref. 10)). Of the total 
estimated discounted costs to industry of $1.17 billion, the average 
estimated costs of compliance with stages 1 and 2 are approximately 
$9,522 per test ($74,783 per laboratory) and the average estimated 
costs of compliance with premarket review and QS requirements are 
approximately $3.02 million per test ($1.26 million per laboratory). 
Therefore, these policies may help to avoid AMC laboratories from no 
longer offering currently marketed IVDs or from manufacturing LDTs for 
unmet needs in the future due to the perceived costs of compliance with 
premarket review and QS requirements, as discussed further in section 
V.B.3. We also anticipate these policies will help to address the other 
concerns raised in comments, such as regarding AMC laboratories' role 
in training medical students to understand tests.
    As discussed in the response to comment 142, we believe that for 
unmet need LDTs, the risk mitigations present in laboratories 
integrated within healthcare systems will help to address some of the 
concerns raised regarding problematic IVDs offered as LDTs discussed in 
the NPRM and this preamble. Notably, this policy is limited to 
exercising enforcement discretion for premarket review and most QS 
requirements (not all FDA requirements) and LDTs for unmet needs (not 
LDTs for which there are available FDA-authorized alternatives).
    FDA believes it is important that an enforcement discretion policy 
for laboratories integrated within a healthcare system be limited to 
premarket review and QS requirements. Compliance with other applicable 
requirements will help provide assurances regarding safety and 
effectiveness and help FDA monitor for potentially poor performing LDTs 
that should be addressed. Moreover, we understand that compliance with 
premarket review and QS requirements are what is likely to lead 
laboratories integrated within a healthcare system to stop 
manufacturing LDTs for unmet needs in the future due to perceived 
compliance costs.
    (Comment 136) Other comments pointed out features they assert 
mitigate the risk of tests manufactured by AMC laboratories. Comments 
noted that such laboratories are already regulated under/by CLIA, CAP, 
and other state and local accreditation bodies and that most hospital 
systems have mechanisms for reporting and tracking of events that have 
the potential for negative patient impact in order to comply with 
accreditation requirements. Some pointed to the not-for-profit nature 
of AMCs and the fact that AMCs are working to educate providers and 
enhance patient care--not generate profit or ``commercialize'' the 
tests they manufacture. Some claimed AMC laboratories have a 
demonstrated track record for developing safe and effective tests. 
Comments stated that AMCs were not subject to the lawsuits involving 
misleading information which FDA cited in the NPRM. Another posited 
that tests developed by AMCs do not have the problems observed in 
``commercial'' tests.
    (Response 136) FDA does not agree with comments that assert that an 
enforcement discretion policy is appropriate for all requirements for 
all LDTs manufactured and performed by AMC laboratories. FDA does not 
agree with the assertion that there are no problems with IVDs offered 
as LDTs by AMC laboratories nor does FDA agree that CLIA and other 
accreditations and the not-for-profit nature of AMCs are sufficient 
mitigations to justify such a policy. As described in the NPRM and

[[Page 37375]]

memorandums to file prepared by FDA that were included in the docket 
for this rulemaking, we are aware of problems with certain IVDs offered 
as LDTs manufactured and performed by AMC laboratories (see Refs. 16 
and 18).
    FDA does not believe it would be appropriate to have an enforcement 
discretion policy for all LDTs manufactured by AMC laboratories because 
such laboratories must comply with CLIA, as some comments asserted. In 
our response to comments in section VI.C, we explain that CLIA 
requirements and accreditation activities serve a complementary and 
distinct purpose from FDA oversight, and are therefore insufficient on 
their own to justify FDA continuing its general enforcement discretion 
approach for IVDs offered as LDTs.
    Although healthcare systems may already have mechanisms addressing 
the reporting and tracking of adverse events, that does not negate the 
need for FDA oversight, including of MDR requirements. FDA uses adverse 
event information to monitor safety signals and identify trends, so 
that we can inform healthcare providers about issues the Agency has 
identified and work with manufacturers to correct problems with their 
devices. Reports to FDA about corrections and removals are also 
important in assuring that healthcare providers, patients, and 
caregivers are aware of problems and how to address them.
    Finally, we note that even if an AMC is a not-for-profit entity, as 
raised in the comments, whether or not a test is sold for profit does 
not determine the quality of the test itself, which is the focus of 
FDA's attention.
    (Comment 137) In response to FDA's question whether to continue its 
general enforcement discretion approach for tests made by AMC 
laboratories, many comments made various suggestions to FDA about 
continuing its general enforcement discretion for LDTs made by other 
types of health systems that are responsible for patients' complete 
clinical course of care. Some comments asserted that FDA should 
continue its general enforcement discretion approach for LDTs: (1) made 
by laboratories within hospitals that provide immediate patient care or 
any community healthcare delivery system, (2) manufactured by 
laboratories in accredited hospitals and healthcare systems where the 
laboratory directors meet prerequisite education and experience 
requirements, or (3) manufactured by CLIA-certified laboratories that 
are integrated as part of a healthcare organization providing direct 
medical care. These comments claimed that a continued enforcement 
discretion approach for these LDTs would be appropriate, either because 
an AMC is too hard to define, or because some of the aspects of AMCs 
described in the NPRM, i.e., integration into patient care, and CLIA 
certification and meeting requirements to perform high-complexity 
testing, also apply to clinical laboratories in other health systems.
    (Response 137) For the reasons discussed further in section V.B.3, 
FDA is adopting an enforcement discretion policy for LDTs manufactured 
and performed by laboratories integrated within a healthcare system to 
meet an unmet need of patients receiving care within the same 
healthcare system. FDA is not adopting an enforcement policy specific 
to AMC laboratories based on FDA's understanding that AMCs are not the 
only healthcare systems in which integrated laboratories make LDTs to 
meet the needs of patients being cared for in the same healthcare 
system.
    FDA believes that the risk mitigations present when the patient 
tested is receiving care within the same healthcare system as the 
laboratory offering the unmet need LDT, along with the other risk 
mitigations discussed in section V.B.3, help to address some of the 
concerns raised regarding problematic IVDs offered as LDTs discussed in 
the NPRM and this preamble. Specifically, in such situations, FDA 
generally has greater confidence that ordering physicians will 
communicate any questions about LDTs or concerns regarding the safety 
and effectiveness of the LDT (e.g., when the patient's symptoms point 
to another diagnosis; when subsequent test results contradict the 
original test result) to a laboratory given the built-in communication 
mechanisms present. Moreover, FDA generally has greater confidence that 
laboratories will communicate any limitations of the LDT or other 
relevant information to the ordering physician given these mechanisms. 
We think this is particularly likely to happen in the context of LDTs 
for unmet needs, which are likely to be a focus of attention and 
communication between laboratorians and providers given the uncommon 
nature of the issues presented. For further discussion on these risk 
mitigations, please refer to section V.B.3. While we recognize that 
these features do not mitigate all risk and there may still be some 
uncertainty about the performance of tests subject to this policy, we 
believe that these features support enforcement discretion for 
premarket review and quality system requirements in the specific 
context of LDTs for unmet needs.
    Thus, and as described further in section V.B.3, FDA intends to 
exercise enforcement discretion and generally not enforce premarket 
review and most QS requirements for LDTs manufactured and performed by 
a laboratory integrated within a healthcare system to meet an unmet 
need of patients receiving care within the same healthcare system. This 
policy may include, but is not limited to, AMC laboratories' LDTs. We 
believe this policy generally encompasses the scenarios described in 
the comments summarized above (e.g., where LDTs are made by 
laboratories within hospitals or that are part of a healthcare 
organization providing direct medical care), albeit it applies only to 
LDTs that are intended to meet an unmet need of patients receiving care 
within the same healthcare system as the laboratory. As described in 
section V.B.3, an enforcement discretion policy whereby FDA generally 
would not enforce premarket review and most QS requirements for any 
LDTs manufactured by laboratories integrated within healthcare systems 
would appear to be overly broad, including because it would encompass 
LDTs for which there are FDA-authorized alternatives that we know have 
appropriate assurances of safety and effectiveness.
    (Comment 138) Some comments suggested that FDA should continue a 
general enforcement discretion approach only with respect to premarket 
review, but phase in other requirements, such as reporting of adverse 
events, for LDTs manufactured by AMC laboratories.
    (Response 138) FDA is adopting an enforcement discretion policy for 
premarket review and most QS requirements for certain unmet need LDTs 
manufactured and performed by laboratories integrated within a 
healthcare system where the patient is receiving care. Among other 
things, this enforcement discretion policy is intended to avoid 
laboratories that manufacture unmet need LDTs from no longer 
manufacturing such LDTs as a result of the phaseout policy and 
perceived costs with premarket review and QS requirements. FDA is 
concerned that including premarket review requirements only in the 
policy would not sufficiently address this concern. As noted in section 
V.B.3, FDA expects compliance with all other applicable requirements as 
described in the phaseout policy.
    For the reasons discussed in section V.B.3, FDA is not adopting an 
enforcement discretion policy for all LDTs manufactured and performed 
by

[[Page 37376]]

AMC laboratories (or other laboratories integrated within healthcare 
systems).
    (Comment 139) Another comment suggested that FDA continue the 
general enforcement discretion approach for all regulatory 
requirements, but only for low-risk tests offered by AMC laboratories.
    (Response 139) FDA disagrees that it would be appropriate to adopt 
an enforcement discretion policy for all FDA requirements for low-risk 
tests offered by AMC laboratories. As an initial matter, FDA does not 
believe that AMC laboratories would stop offering low-risk tests as a 
result of the phaseout policy (including because most low-risk tests 
are exempt from premarket notification, meaning premarket submissions 
are not required). Moreover, for the reasons discussed throughout this 
preamble, compliance with other applicable requirements, such as 
registration and listing and adverse event reporting, among others, 
will provide critical assurances regarding these tests and allow FDA to 
monitor and take action in the event a problematic IVD is offered.
    (Comment 140) A comment urged FDA to recognize that some hospitals 
and integrated patient facilities, including AMCs, may need to use 
devices ``off label,'' and asked how certain provisions, like the 
custom device exemption and IDE expanded access, apply to laboratories.
    (Response 140) FDA recognizes that, under the FD&C Act, healthcare 
practitioners may prescribe or administer a legally marketed device to 
a patient for any condition or disease within a legitimate healthcare 
practitioner-patient relationship (see section 1006 of the FD&C Act (21 
U.S.C. 396)). As discussed further in section VI.D.6, however, section 
1006 of the FD&C Act does not reach the manufacturing of a device, 
including by a laboratory.
    Regarding the custom device exemption and IDE expanded access, FDA 
has issued a final guidance document on the custom device exemption 
(Ref. 168) and has provided information on its website about expanded 
access for medical devices (Ref. 169) as resources to device 
manufacturers, including laboratory manufacturers, among others.
    (Comment 141) Some comments claimed that AMCs engage in the 
practice of medicine when they modify or use FDA-authorized tests off-
label and so AMCs are not subject to FDA laws and requirements when 
they engage in these activities. Another comment stated that there are 
exclusions in the FD&C Act that apply to AMCs. Specifically, the 
comment quoted the following provision from the FD&C Act: 
``practitioners licensed by law to prescribe or administer drugs or 
devices and who manufacture, prepare, propagate, compound or process 
drugs or devices solely for use in the course of their professional 
practice,'' and cited the following provisions in the FD&C Act: 21 
U.S.C. 360(g)(2), 360i(c)(2),\84\ and 374(a)(2)(B).
---------------------------------------------------------------------------

    \84\ Although this comment cited 21 U.S.C. 360(i)(c)(2), we 
believe the commenter may have intended to reference 21 U.S.C. 
360(i)(c)(1), which refers to ``any practitioner who is licensed by 
law to prescribe or administer devices intended for use in humans 
and who manufactures or imports devices solely for use in the course 
of his professional practice.''
---------------------------------------------------------------------------

    (Response 141) We do not agree that the ``practice of medicine'' 
provision in the FD&C Act is so broad as to encompass all of the 
activities raised in the comments (see response to comment 74 for a 
further discussion of this provision). Section 1006 of the FD&C Act 
expressly states what conduct within the practice of medicine falls 
outside of FDA's statutory authority. See 21 U.S.C. 396 (``Nothing in 
this [Act] shall be construed to limit or interfere with the authority 
of a health care practitioner to prescribe or administer any legally 
marketed device to a patient for any condition or disease within a 
legitimate health care practitioner-patient relationship,'' with 
several explicit limitations). Notably, the provision limits FDA's 
oversight of certain practitioners' ``prescrib[ing] or 
administer[ing]'' of a ``legally marketed device,'' but it does not 
reach the manufacturing of a device. Thus, to the extent that an AMC or 
AMC laboratory is manufacturing a device, including by modifying 
another entity's device, its actions do not fall within the ``practice 
of medicine'' provision.
    Regarding the comment asserting that various referenced exemptions 
in the FD&C Act generally apply to AMCs or AMC laboratories, we note 
that these exemptions apply when a ``practitioner[ ]'': (1) is 
``licensed by law to prescribe or administer'' a device, such as an 
IVD, (2) ``manufacture[s]'' that device, and (3) does so ``solely for 
use in the course of their [or his] professional practice.'' As 
discussed in response to comment 77, these exemptions are only relevant 
when a particular individual meets all three criteria and, by their 
plain terms, do not apply to an institution or an entity. Thus, to the 
extent the commenter is asserting that all AMCs or all AMC laboratories 
generally fall within these exemptions, we disagree.
    (Comment 142) Several comments suggested that AMCs should be 
subject to the same enforcement approach as all other IVD manufacturers 
because it is important that patients be able to depend on tests 
regardless of who develops them. One comment stated that applying the 
same oversight approach would help to ``standardize the development and 
validation of LDTs.'' Another comment thought that FDA should not 
continue an enforcement discretion approach for LDTs manufactured and 
used in an AMC laboratory because it falsely gives the impression that 
LDTs manufactured by AMCs are superior to LDTs manufactured by non-
AMCs. Another comment highlighted that FDA's memorandum to file 
entitled ``Summary of 2020 Assessment of the First 125 EUA Requests 
from Laboratories for Molecular Diagnostic Tests for SARS-CoV-2'' 
concluded that the deficiencies found in design, validation, and 
performance of COVID-19 tests were similar across all types of 
laboratories, including AMCs (see Ref. 18). Other comments suggested 
that any continuation of enforcement discretion should be test-based, 
with comments highlighting that FDA should focus on continuing its 
enforcement discretion approach for tests developed to meet needs of 
those impacted by pediatric and rare diseases, regardless of where the 
test is manufactured.
    (Response 142) FDA agrees that patients should be able to depend on 
IVDs regardless of who manufactures them, which is why FDA is phasing 
out the general enforcement discretion approach for LDTs. This phaseout 
policy includes several enforcement discretion policies for certain 
requirements for specific categories of IVDs manufactured by a 
laboratory. This phaseout policy is intended to better protect the 
public health by helping to assure the safety and effectiveness of IVDs 
offered as LDTs, while also accounting for other important public 
health considerations such as patient access and reliance.
    Regarding the enforcement discretion policies FDA is adopting, as 
discussed further in section V.B.3, FDA intends to exercise enforcement 
discretion and generally not enforce premarket review requirements and 
QS requirements (except for requirements under part 820, subpart M 
(Records)) for LDTs manufactured and performed by a laboratory 
integrated within a healthcare system to meet an unmet need of patients 
receiving care within the same healthcare system. We understand that 
AMCs generally integrate their laboratories within their

[[Page 37377]]

respective healthcare systems, and so this policy generally applies to 
their LDTs for unmet needs, as well as the unmet need LDTs manufactured 
and performed by other laboratories integrated within a healthcare 
system.
    As discussed further in section V.B.3, FDA understands that 
laboratories integrated within a healthcare system may no longer 
manufacture and perform many critical LDTs for unmet needs due to a 
lack of financial incentive and the perceived costs of premarket review 
and QS requirements for such tests if expected to comply with such 
requirements. FDA is aware, however, of problems with certain IVDs 
offered as LDTs manufactured and performed by AMC laboratories (see 
response to comment 32). Certain evidence of problematic IVDs offered 
as LDTs described in the NPRM addressed tests from AMCs, including the 
memorandum described above entitled ``Summary of 2020 Assessment of the 
First 125 EUA Requests from Laboratories for Molecular Diagnostic Tests 
for SARS-CoV-2'' (Ref. 18). In addition, another FDA memorandum and 
several of the studies referenced in the NPRM referenced IVDs 
manufactured by AMC laboratories (see Refs. 20 and 92). We believe the 
risk mitigations present in laboratories integrated within healthcare 
systems, and various other risk mitigations, as described in section 
V.B.3, help to address some of the concerns raised regarding 
problematic IVDs offered as LDTs discussed in the NPRM and this 
preamble.
    As discussed further in section V.B.3, while we recognize that 
these features do not mitigate all risk and there may still be some 
uncertainty about the performance of tests subject to this policy, we 
believe that these features support enforcement discretion for 
premarket review and quality system requirements in the specific 
context of LDTs for unmet needs. FDA considers an LDT to be for an 
unmet need where there is no available FDA-authorized IVD that meets 
the patient's needs. This may be because: (1) there is no FDA-
authorized IVD for the disease or condition (for example, because it is 
for a rare disease or condition); (2) there is an FDA-authorized IVD 
for the disease or condition but it is not indicated for use on the 
patient, or a unique attribute needs to be added to the LDT to meet the 
patient's needs; or (3) there is an FDA-authorized IVD but it is not 
available to the patient.
    We also acknowledge statements in the comments that applying the 
same oversight approach would help to standardize the development and 
validation of LDTs. In light of unique validation issues for many IVDs 
for unmet needs, FDA intends to consider whether issuing additional 
guidance regarding validation of tests, including those for rare 
diseases that takes into consideration the challenges in obtaining a 
robust number of samples for validation, would be helpful, as discussed 
in section V.B.3. In the event FDA were to issue any such guidance, FDA 
would do so in accordance with good guidance practices (see Sec.  
10.115). FDA anticipates that such guidance could result in more 
consistently robust validation practices across laboratories that 
develop tests for unmet needs and reduce the potential for introduction 
of poorly performing LDTs.
    Finally, we do not think it is appropriate to adopt an enforcement 
discretion policy for all LDTs developed to meet the needs of those 
impacted by pediatric and rare diseases, regardless of where the LDT is 
manufactured and performed. As discussed further in section V.B.3, such 
a policy would appear to be overly broad, as there are not the same 
risk mitigations present for all such LDTs that would help address and 
avoid the use of problematic LDTs.
    (Comment 143) A number of comments expressed concern that if FDA 
were to continue its general enforcement discretion approach for AMCs, 
it would distort the market and negatively impact underserved and rural 
regions. Comments indicated that AMCs are generally concentrated in 
urban areas and that many patients in rural areas are not able to 
access AMCs due to lack of proximity or insurance coverage. Another 
comment stated that community health centers provide more cancer 
treatment than AMCs. The comments expressed fear that continuing an 
enforcement discretion approach for AMCs will exacerbate the 
disparities in care between urban and rural regions and would be 
detrimental to the ability of community centers to provide tests for 
cancer patients. Similarly, another comment stated that non-AMCs will 
have trouble attracting talent if FDA continues to exercise enforcement 
discretion for AMCs.
    (Response 143) As discussed in section V.B.3, FDA intends to 
exercise enforcement discretion and generally not enforce premarket 
review requirements and QS requirements (except for requirements under 
part 820, subpart M (Records)) for LDTs manufactured and performed by a 
laboratory integrated within a healthcare system to meet an unmet need 
of patients receiving care within the same healthcare system.
    FDA believes that this policy will help to address the concerns 
raised in the comments for patients in underserved and rural regions 
and should mitigate concerns about attracting talented laboratorians. 
The policy applies to all laboratories integrated within a healthcare 
system, not only AMCs. FDA anticipates that this policy will help to 
avoid laboratories integrated within healthcare systems, wherever such 
healthcare systems are located, from no longer manufacturing LDTs to 
meet the unmet needs of patients receiving care within the same 
healthcare system due to the costs of compliance with premarket review 
and QS requirements.
    (Comment 144) Several comments suggested that FDA not extend its 
general enforcement discretion approach to AMCs if AMCs were to 
``commercialize'' the tests they develop at a significant volume.
    (Response 144) FDA believes that an enforcement discretion policy 
for LDTs manufactured and performed by a laboratory integrated within a 
healthcare system should be limited only to those LDTs for which there 
is an unmet need, and should not apply when there is an FDA-authorized 
test available that meets the needs of the patient. There may be an 
unmet need because--(1) there is no FDA-authorized IVD for the disease/
condition (for example, because it is for a rare disease/condition); 
(2) there is an FDA-authorized IVD for the disease/condition but it is 
not indicated for use on the patient, or a unique attribute needs to be 
added to the test to meet the patient's needs; or (3) there is an FDA-
authorized IVD but it is not available to the patient. Moreover, as 
described in section V.B.3, this enforcement discretion policy is 
limited to LDTs for patients who are receiving care within the same 
healthcare system as the laboratory offering the test.
    (Comment 145) Multiple comments indicated that it will be difficult 
to develop a consistently implementable definition of AMCs. Many other 
comments stated that AMC laboratories serve patients beyond a single 
physical location and that such a ``requirement'' would be too narrow. 
These comments indicated that it is rare for specimen collection, 
testing in a clinical laboratory, and treatment of the patient to all 
take place in the same building. Comments also pointed out that real 
estate availability and patient needs may force AMCs to take advantage 
of multiple physical spaces. Other comments indicated that while AMCs 
may span multiple physical locations, they may all be connected by one

[[Page 37378]]

electronic management record system. Some comments suggested FDA 
consider an enforcement discretion policy for AMCs that have closely 
affiliated health systems or where the laboratories work directly or in 
coordination or collaboration with the academic institution. Other 
comments questioned what it meant to have a medical residency training 
or fellowship program involving test development, and whether this 
applied to pathology. Others wanted clarity on the meaning of ``direct 
patient care.''
    We also received many comments providing various possible 
definitions of an AMC. Common across many comments was that AMCs are 
high-complexity CLIA-accredited laboratories and that the leadership or 
a portion of the laboratory leadership have an academic appointment at 
an Accreditation Council for Graduate Medical Education (ACGME)-
accredited school with a training program in pathology or laboratory 
medicine. Some comments suggested an AMC laboratory should provide 
testing for patients in their AMCs. Another comment suggested an AMC 
laboratory should accept at least 50 percent of its samples from 
patients being tested within the institution-affiliated healthcare 
system. Another comment suggested that FDA should not limit an 
enforcement discretion policy to tests where samples come from within 
the AMC because AMCs are often referral centers. A comment suggested 
that an AMC be defined as a nonprofit 501(c)(3) with a Liaison 
Committee on Medical Education-accredited medical school, teaching 
hospital, residency training program, and a mission to educate medical 
professionals. Other comments suggested an AMC use a single EMR where 
testing is performed within the system and reported into the system 
EMR. Another comment suggested an AMC is a unit where the physician 
ordering the specimen is either employed by the healthcare system or 
has active clinical privileges at a hospital owned by the healthcare 
system.
    (Response 145) Based on these and other comments submitted to the 
docket for this rulemaking and for the reasons described in section 
V.B.3, FDA will not have a separate enforcement discretion policy for 
AMC laboratories. Instead, FDA intends to exercise enforcement 
discretion and generally not enforce premarket review requirements and 
QS requirements (except for requirements under part 820, subpart M 
(Records)) for LDTs manufactured and performed by a laboratory 
integrated within a healthcare system to meet an unmet need of patients 
receiving care within the same healthcare system. As such, FDA is not 
defining an AMC in this preamble and many of the concerns raised in the 
comments summarized above have been addressed or are no longer relevant 
(e.g., concerns regarding limiting the policy to manufacturers at a 
single physical location; questions regarding what it means to have a 
medical residency training or fellowship program involving test 
development; questions regarding the meaning of ``direct patient 
care'').
5. New York State Department of Health Clinical Laboratory Evaluation 
Program (NYS CLEP)
    (Comment 146) FDA received several comments in support of 
``leveraging'' LDT approval under established programs, specifically 
NYS CLEP, in lieu of ending FDA's general enforcement discretion 
approach for LDTs with respect to premarket review requirements, in 
order to prevent duplicative efforts and reduce burden for both FDA and 
laboratories. Some comments expressed general support for relying on 
established programs such as NYS CLEP, but noted that these programs 
would need to be aligned with FDA's regulatory review standards. Some 
comments noted that NYS CLEP provides a robust system of oversight and 
furthers the same goals as FDA's 510(k) process, but they suggested 
that adverse event data collection and registration and listing should 
be conducted at the Federal level. Other comments recommended using NYS 
CLEP as a model when structuring FDA's enforcement of requirements for 
IVDs offered as LDTs. Some comments supported the idea of continuing 
the general enforcement discretion approach for all FDA requirements 
for tests that have already been approved by NYS CLEP. One comment 
noted that relying on existing programs and continuing enforcement 
discretion for these tests would reduce concerns about bottlenecks in 
FDA's review capacity and constraints on innovation and alleviate 
concerns about increased costs.
    NYS provided a comment indicating support for continued enforcement 
discretion with respect to premarket review requirements for LDTs they 
have reviewed and approved. They explained that their ``technical 
review is designed to determine whether the test is analytically and 
clinically valid. The laboratory must submit all applicable standard 
operating procedures, validation data demonstrating accuracy and 
reliability of the test results, documentation that the results are 
associated with a clinical or public health need, examples of reports, 
and other material necessary to evaluate the tes t. . . . CLEP's LDT 
oversight process is designed to address the risk for each LDT and 
considers all parts of the test, including test method, intended use, 
specimen type, and claims, as well as the laboratory performing the 
test. Each LDT application is reviewed by subject matter experts with 
post-graduate experience and training in the field and reviews are not 
conducted during onsite survey. An LDT approval is specific to the 
laboratory. . . . Tests that cannot meet CLEP requirements are denied. 
Approval may be revoked or modified if an approved test is found 
subsequently to be no longer analytically and/or clinically valid.'' 
However, NYS supported the collection of adverse event information and 
registration and listing information at a national level.
    (Response 146) As discussed in section V.B.2, FDA intends to 
exercise enforcement discretion with respect to premarket review 
requirements for LDTs approved by NYS CLEP. FDA notes that this is an 
enforcement discretion policy and not a substitute for FDA premarket 
review. FDA believes that the term ``leveraging'' in the NPRM (88 FR 
68006 at 68024) might have caused confusion. FDA recognizes that NYS 
CLEP's regulatory framework is not the same as FDA's (e.g., NYS CLEP 
has a different risk classification and premarket review program). 
However, as explained in section V.B.2, FDA believes that NYS CLEP has 
a program that provides for certain mitigations that help reduce the 
risk of harm from inaccurate and unreliable LDTs. Specifically, NYS 
CLEP has a program under which high risk and moderate risk LDTs 
generally are evaluated for analytical and clinical validity. Based on 
the available information, FDA believes that generally NYS CLEP's 
review of analytical and clinical validity of LDTs helps to mitigate 
the risk of harm from inaccurate and unreliable LDTs and that, rather 
than enforcing premarket review requirements by FDA, it would be more 
efficient and effective to use our resources for other oversight 
activities regarding IVDs offered as LDTs. See section V.B.2. for 
further information. We have accounted for this enforcement discretion 
policy in the FRIA. Specifically, as discussed in appendix A of the 
FRIA (Ref. 10), we estimate that 12.1 percent of IVDs offered as LDTs 
would not experience new costs associated with submission preparation 
and review as a result of FDA's enforcement discretion policy with 
respect to LDTs approved by NYS CLEP.

[[Page 37379]]

    However, as discussed in section V.B.2, FDA intends to phase out 
its general enforcement discretion approach with respect to other 
regulatory requirements, such as registration and listing and MDR 
requirements, for these LDTs. Enforcement of other requirements will 
help to protect and promote the public health, e.g., by providing FDA 
and the public with important information about these tests. See 
section V.B.2 for further information.
    (Comment 147) Some comments stated that an external program such as 
NYS CLEP should not ``replace FDA regulation,'' but noted that such 
programs could be used to streamline FDA review or provide additional 
``flexibility'' to tests certified under such regimes. Some comments 
expressed concern that such external programs would be unable to handle 
the volume of requests from laboratories, and others noted that if FDA 
were to ``leverage'' such external programs and continue its general 
enforcement discretion approach, this may lead to an overly broad 
approach with FDA accepting foreign standards like the EU CE 
Certificate.
    (Response 147) FDA's policy with regard to LDTs approved by NYS 
CLEP does not ``replace FDA regulation.'' As described in section 
V.B.2, FDA intends to exercise enforcement discretion with respect to 
premarket review requirements, but not other FDA requirements such as 
MDR reporting, for LDTs approved by NYS CLEP. See section V.B.2. for 
further information. Additionally, as noted above, this is an 
enforcement discretion policy and not a substitute for FDA premarket 
review. As described in section V.B.2, FDA intends to exercise 
enforcement discretion and generally not enforce the premarket review 
requirements for LDTs approved by NYS CLEP because NYS CLEP has a 
program under which high risk and moderate risk LDTs generally are 
evaluated for analytical and clinical validity. Based on the available 
information, FDA believes that generally NYS CLEP's review of 
analytical and clinical validity of LDTs helps to mitigate the risk of 
harm from inaccurate and unreliable LDTs and that, rather than 
enforcing premarket review requirements by FDA, it would be more 
efficient and effective to use our resources for other oversight 
activities regarding IVDs offered as LDTs. Further, as stated in 
section V.B.2, FDA retains its discretion to pursue enforcement action 
at any time against violative IVDs when appropriate.
    This enforcement discretion policy for LDTs approved by NYS CLEP 
does not apply to tests with foreign approvals if those tests are not 
approved by NYS CLEP. With respect to concerns regarding potentially 
overwhelming NYS CLEP, the likelihood of this result is unclear. 
However, FDA anticipates collaborative communication with NYS CLEP. 
Should experience with this policy indicate that changes are warranted, 
FDA would consider appropriate policy changes through guidance in 
accordance with good guidance practices (see Sec.  10.115).
    (Comment 148) A few comments stated that FDA should not 
``leverage'' outside programs and continue applying the general 
enforcement discretion approach for tests under those programs. They 
stated that these programs as they exist today do not have the same 
scope and standards as FDA's device regulations. Further, they stated 
that ``allowing'' external programs with different standards to ``stand 
in for FDA regulation'' would not further the goal of implementing a 
single risk-based regulatory framework.
    (Response 148) As discussed in the response to comment 146, FDA 
believes that the term ``leveraging'' in the NPRM (88 FR 68006 at 
68023) might have caused confusion. FDA recognizes that NYS CLEP's 
regulatory framework is not the same as FDA's (e.g., NYS CLEP has a 
different risk classification and premarket review program). However, 
as discussed in section V.B.2, FDA intends to exercise enforcement 
discretion with respect to premarket review requirements for LDTs 
approved by NYS CLEP because FDA believes that NYS CLEP has a program 
that provides for certain mitigations that help reduce the risk of harm 
from inaccurate and unreliable LDTs. See section V.B.2 for further 
information. FDA notes that this is an enforcement discretion policy 
and not a substitute for FDA premarket review or a ``stand in for FDA 
regulation.'' Further, as described in section V.B.2, FDA generally 
intends to exercise enforcement discretion with respect to premarket 
review requirements, but not other FDA requirements such as MDR 
reporting, for LDTs approved by NYS CLEP. See section V.B.2 for further 
information.
    (Comment 149) One comment asked whether an enforcement discretion 
policy for NYS CLEP-approved LDTs would include those used on people 
across all states, or whether the policy would be limited to NYS CLEP-
approved tests used only in New York State.
    (Response 149) FDA generally intends to exercise enforcement 
discretion with respect to premarket review requirements for LDTs 
approved by NYS CLEP. As explained in section V.B.2, these are LDTs 
with NYS CLEP approval, conditional approval, or within an approved 
exemption from full technical documentation granted by NYS CLEP. The 
enforcement discretion policy with respect to LDTs approved by NYS CLEP 
applies regardless of whether that LDT is performed on specimens from 
NYS or elsewhere, as the risk mitigations upon which the policy is 
based apply regardless of where the specimens are coming from. This 
enforcement discretion policy only applies to the version of the LDT 
approved by NYS CLEP. If the laboratory is offering and using a 
different version of the LDT that is not approved by NYS CLEP, this 
enforcement discretion policy would not apply.
    (Comment 150) FDA received comments suggesting that NYS CLEP should 
be granted ``deemed'' status and tests subject to NYS CLEP should be 
exempt from the phaseout of FDA's general enforcement discretion 
approach for LDTs.
    (Response 150) As described in section V.B.2, FDA generally intends 
to exercise enforcement discretion with respect to premarket review 
requirements for LDTs approved by NYS CLEP. FDA's policy with respect 
to LDTs approved by NYS CLEP is an enforcement discretion policy and 
not a substitute for FDA premarket review. Further, FDA intends to 
phase out its general enforcement discretion approach with respect to 
other regulatory requirements, such as registration and listing and MDR 
requirements, for these LDTs. Enforcement of other requirements will 
help to protect and promote the public health, e.g., by providing FDA 
and the public with important information about these tests. For 
additional discussion of FDA's policy with respect to LDTs approved by 
NYS CLEP, see section V.B.2.
6. Timing and Structure of the Phaseout Policy
    (Comment 151) FDA's proposed phaseout policy described a gradual 
phaseout of the general enforcement discretion approach for LDTs that 
would occur in stages over a total period of 4 years. FDA received 
several comments stating that this timeline is too short and should be 
extended. These comments generally proposed that FDA modify the 
phaseout period to last a total of 7-10 years, though at least one 
comment proposed a significantly longer phaseout period of 15 years. 
One

[[Page 37380]]

comment suggested that each stage of the phaseout period should be 
extended by an additional year. These comments generally characterized 
the length of the phaseout period as unreasonable or not workable, and 
emphasized laboratories' lack of experience and infrastructure for 
complying with FDA requirements; the number of tests that laboratories 
will have to address and associated resource demands; FDA's resource 
limitations; the time required for laboratories to become familiar with 
applicable requirements; and general uncertainty regarding how 
laboratories will navigate the phaseout process. One comment noted that 
in a survey of 39 laboratories, only 1 laboratory stated that it would 
likely be able to implement all applicable requirements within the 4-
year timeframe (this survey is described in Ref. 170). In describing 
this survey finding, the comment characterized the proposed phaseout 
timeline as ``unrealistic since the requirements for FDA approval 
cannot be conducted in a timely fashion due to the large number of LDTs 
and insufficient resources,'' and further stated that ``[FDA's] review 
process is also lengthy once data is submitted.'' Some comments 
suggested that the length of the phaseout period be extended for 
certain types of tests, such as diagnostic flow cytometry leukemia and 
lymphoma immunophenotyping tests, due to the challenges associated with 
preparing premarket submissions for such tests.
    In addition, one comment noted that the average time to bring a 
medical device to market has been estimated to range from 2-7 years, 
and several comments noted that FDA had proposed a longer phaseout 
period of 9 years in 2014. One comment noted that the VALID Act had 
proposed a transition period of up to 10 years. Another comment stated 
that the reliance interests of laboratories would be harmed if the 
length of the phaseout period were not extended, given the challenges 
that laboratories would face from competing demands for limited 
resources.
    FDA also received comments stating that the overall length of the 
phaseout period should be reduced. One comment stated that if 
laboratories have been doing ``the right thing,'' they should not 
require 4 years to comply with applicable requirements, and patients 
should not have to wait 4 years to be able to rely on accurate tests. 
Another comment suggested that FDA consider the Agency's expectations 
for a startup conventional IVD manufacturer and apply the same 
expectations to laboratory manufacturers, stating that a conventional 
manufacturer could not take 4 years to come into compliance. One 
comment stated that FDA should shorten the phaseout period for 
premarket approval requirements for tests that pose a higher risk of 
harm from 4 years to 1-2 years.
    FDA also received a comment that agreed with FDA's phaseout 
timeline. This comment stated that the timeline would give laboratories 
adequate time to come into compliance with applicable requirements 
while allowing FDA to gather information on the LDT market and 
prioritize review of high-risk tests.
    (Response 151) After considering the public comments and the impact 
of new enforcement discretion policies included in the final phaseout 
policy, FDA has determined that it should retain a 4-year, gradual 
phaseout of the Agency's general enforcement discretion approach for 
LDTs.
    As described in section II.F of the FRIA (Ref. 10), FDA has 
estimated the time and resources that will be required for laboratories 
to comply during each stage of the phaseout policy. We estimate total 
costs to be approximately $101 million for stage 1 in year 1 for 1,275 
affected laboratories, $113 million for stages 1 and 2 in year 2 for 
1,275 affected laboratories, $386 million for stages 1 through 4 in 
year 3 for 858 affected laboratories, and $1.65 billion for stages 1 
through 5 for 849 affected laboratories with 7,554 premarket 
submissions in subsequent years (year 4 to year 20).
    Based on these estimates, and in consideration of the factors 
discussed for each stage of the phaseout policy in section V.C, FDA has 
determined that the time allotted for each stage of the phaseout will 
give laboratories adequate time to comply with the requirements that 
are the focus of that stage. For example, FDA has determined that a 1-
year time period is adequate to phase out the general enforcement 
discretion approach for LDTs with respect to MDR requirements and 
correction and removal reporting requirements under stage 1 of the 
phaseout policy, given that laboratories should already have some 
processes in place for detecting problems with their IVDs to comply 
with CLIA regulations, and in stage 1 laboratories will be reporting 
adverse events and malfunctions to FDA in accordance with part 803. 
Additional discussion of the timeframe associated with stage 1 and the 
timeframes associated with other stages of the phaseout policy is 
provided in response to comments 154-159. Additional discussion of 
FDA's phaseout of the general enforcement discretion approach with 
respect to particular requirements under each stage of the phaseout 
policy is provided in sections VI.F.7-13 of this preamble.
    In addition, changes have been made to the phaseout policy that 
directly address the concerns raised in comments that laboratories' 
reliance interests will be harmed if the phaseout period is not 
extended, and that laboratories will not be able to come into 
compliance during the time periods set forth in the phaseout policy 
(e.g., due to the lack of experience with FDA oversight, the cost of 
compliance, etc.). FDA recognizes that some laboratories may lack 
familiarity, experience, or existing infrastructure for complying with 
FDA requirements. However, we note that, as discussed elsewhere in this 
preamble, there are numerous existing final guidance documents and 
educational resources made available by FDA to help companies comply 
with requirements applicable to devices. FDA also intends to issue 
guidance documents or make other resources available to provide further 
clarity to stakeholders regarding implementation of certain aspects of 
the phaseout policy following issuance of this rule. FDA also 
recognizes that the time and resource demands associated with each 
stage of the phaseout policy may be significant for laboratories, and a 
laboratory's efforts to come into compliance with the requirements 
associated with different stages of the phaseout policy may need to 
take place concurrently. However, as described in section V.B.3, FDA 
intends to exercise enforcement discretion and generally not enforce 
premarket review requirements and QS requirements (except for 
requirements under part 820, subpart M (Records)) for currently 
marketed IVDs offered as LDTs. As discussed further in section V.B.3, 
this policy takes into account that laboratories may have made 
financial investments and other decisions based on a past assumption 
about the presence of the general enforcement discretion approach.
    In addition, FDA intends to exercise enforcement discretion and 
generally not enforce premarket review and QS requirements (except for 
requirements under part 820, subpart M (Records)) for LDTs manufactured 
and performed by a laboratory integrated within a healthcare system to 
meet an unmet need of patients receiving care within the same 
healthcare system. FDA also intends to exercise enforcement discretion 
and generally not enforce premarket review requirements for LDTs that 
are approved by NYS CLEP. As a result of these policies, the time and 
resources associated with stages 3, 4, and 5 of the phaseout policy are 
estimated to be significantly reduced as

[[Page 37381]]

compared to the estimates in the PRIA (see sections II.F.3, 4, and 5 of 
the FRIA (Ref. 10)). With fewer competing demands, laboratories may be 
better able to comply with the requirements that are the focus of 
stages 1 and 2 of the phaseout policy.
    While the Agency appreciates the information provided in a comment 
regarding a survey in which only 1 out of 39 laboratories stated that 
the laboratory would likely be able to implement all applicable 
requirements within the proposed 4-year phaseout period, this survey 
did not take into account the enforcement discretion policies described 
in the preceding paragraph. The comment that described this survey 
emphasized the perceived burden of compliance with FDA's premarket 
review requirements, yet under many of the enforcement discretion 
policies included in the final phaseout policy, FDA intends to exercise 
enforcement discretion and generally not enforce premarket review 
requirements. FDA also notes that this survey was conducted with a 
small sample size and reflects the subjective views of entities that 
would be subject to increased FDA oversight under the phaseout policy.
    Regarding the comments on extending the phaseout policy in light of 
demands on FDA resources, we note that the enforcement discretion 
policies included in the final phaseout policy will significantly 
reduce these demands. The annualized costs to FDA over 20 years are 
approximately $408 million less than the estimates in the PRIA (in the 
FRIA, the primary estimate for FDA review costs over 20 years at a 7 
percent discount rate are $121 million, as compared to $530 million in 
the PRIA). These policies, and in particular the policy for currently 
marketed IVDs offered as LDTs, also address concerns that FDA should 
modify the length of the phaseout period for certain types of tests to 
account for perceived challenges associated with preparing premarket 
submissions for such tests.
    FDA does not believe it would be in the best interest of public 
health to adopt a longer phaseout period or to extend the time allotted 
for any of the stages in the phaseout policy. Based on information 
currently available to the Agency regarding the risks associated with 
IVDs offered as LDTs (as discussed in the NPRM and sections III.B and 
VI.C of this preamble), an extension of the phaseout policy to a period 
longer than 4 years would be inconsistent with FDA's mission to protect 
the public health. FDA encourages manufacturers to begin working 
towards compliance with applicable requirements as early as possible, 
and to engage with FDA through a Pre-Submission or other available 
mechanism.
    FDA recognizes that the Agency proposed a different timeline for 
phasing out its general enforcement discretion approach for LDTs in 
2014, which, if finalized, would have involved a longer overall 
phaseout period. However, as noted in section III.B and described in 
the NPRM, FDA's concerns regarding the risks associated with IVDs 
offered as LDTs have grown in recent years, and more recent evidence 
from a variety of sources underscores the pressing need to better 
assure the safety and effectiveness of IVDs offered as LDTs (88 FR 
68006 at 68009). Diagnostic testing is increasingly important; for 
example, as time goes on, more novel treatments will require use of a 
specialized test to identify patients likely to benefit from those 
treatments.\85\ Furthermore, IVDs offered as LDTs are a growing sector 
of the diagnostic testing market (Ref. 4). FDA anticipates that IVDs 
will continue to become more complex and play a greater role in modern 
healthcare (Ref. 3). The U.S. LDT market size is anticipated to grow 6 
percent from 2023 to 2030 due to varying factors including increased 
use in personalized medicine and rising prevalence of chronic diseases. 
(Id.) FDA is therefore taking steps to oversee the safety and 
effectiveness of IVDs regardless of where they are manufactured, so 
that both now and in the future, patients can have confidence about the 
tests used in their care.
---------------------------------------------------------------------------

    \85\ See, e.g., Ref. 23 (``Demand is increasing in the CDx 
market, due to the paradigm shift to precision medicine.'').
---------------------------------------------------------------------------

    Moreover, the longer timeline proposed in 2014 included a phaseout 
of enforcement discretion for LDTs already on the market, whereas the 
phaseout policy described in this preamble phases out enforcement 
discretion with respect to premarket review for IVDs offered as LDTs 
entering the market after publication of the final rule.
    We disagree with comments that the time to bring a device to market 
or any timing provisions in the proposed VALID Act should dictate the 
timeline of the phaseout policy. For example, we note that even if the 
average time to bring a medical device to market ranges from 2-7 years, 
as one comment asserted, this does not mean that 7 years is needed to 
prepare and submit a premarket submission to FDA, even if new data must 
be collected to support the submission. FDA is aware of estimates that 
refer to the time required to bring a new device all the way from 
concept to market as 3-7 years (Ref. 171). Not only does this cover 
development time prior to FDA review, but it is also based on all 
devices including permanent implants, which generally take longer to 
develop and evaluate than IVDs.
    FDA also does not agree that the length of the phaseout period 
should be reduced to less than 4 years. A reduced timeline would mean 
phasing out the general enforcement discretion approach with respect to 
premarket review requirements before the start of a new user fee cycle, 
which would not provide industry with a prior opportunity to 
participate in user fee negotiations with the knowledge that laboratory 
manufacturers will be expected to comply with premarket review 
requirements for new IVDs offered as LDTs. A shorter overall phaseout 
timeline would also place greater concurrent demands on laboratory 
resources. For the same reasons, FDA does not believe that the phaseout 
period for premarket review requirements for high-risk IVDs offered as 
LDTs should be shortened from 4 years to 1-2 years. FDA notes that the 
phaseout policy already prioritizes phasing out the general enforcement 
discretion approach for high-risk IVDs offered as LDTs by phasing out 
enforcement discretion with respect to premarket review requirements 
for high-risk tests prior to doing so for moderate-risk and low-risk 
tests.
    Finally, some comments suggested that the length of the phaseout 
period be extended for certain types of tests, such as diagnostic flow 
cytometry leukemia and lymphoma immunophenotyping tests, due to the 
challenges associated with preparing premarket submissions for such 
tests. We believe the timelines for premarket review are reasonable and 
appropriate, as discussed further in section V.C and the responses to 
comments in section VI.F.13. Moreover, providing different timelines 
for the phasing out of the enforcement discretion approach for 
different types of IVDs would be overly complicated for laboratories to 
follow and for FDA to implement.
    (Comment 152) FDA received comments stating that the timing of 
certain stages of the phaseout policy should be measured from when FDA 
issues final guidance documents or other educational materials 
regarding implementation of the phaseout policy, rather than from 
publication of the phaseout policy itself.
    (Response 152) FDA disagrees with these comments. Although FDA 
intends to issue guidance documents or make

[[Page 37382]]

other resources available to provide further clarity to stakeholders 
regarding implementation of certain aspects of the phaseout policy, and 
intends to issue any such guidance documents or provide other resources 
expeditiously, there are numerous existing final guidance documents and 
educational resources on FDA's website to help companies comply with 
FDA requirements applicable to devices. Moreover, this preamble 
includes extensive information about the phaseout policy and FDA's 
expectations, as well as references to final guidance documents and 
resources available to laboratories.
    (Comment 153) One comment stated that it was unclear whether FDA 
intended the stages of the phaseout policy to run concurrently or 
consecutively. The comment requested that FDA clarify this point.
    (Response 153) The timing for each stage of the phaseout policy is 
based on the date that FDA publishes this final rule and not when the 
previous stage ends. For example, stage 3 will begin after 3 years, 
measured from the date of publication of this final rule and not 
relative to the timing of any other stages. However, because each stage 
will begin after a different length of time has passed from the date of 
publication of this final rule, the stages will commence in sequence. 
For example, as described in section V.C, stage 1 will commence 1 year 
after publication of this final rule. Upon the start of stage 1, FDA 
will generally expect compliance with applicable MDR requirements, 
correction and removal reporting requirements, and QS requirements 
under Sec.  820.198 (complaint files). Stage 2 will commence 2 years 
after publication of this final rule. Upon the start of stage 2, FDA 
will generally expect compliance with applicable requirements discussed 
under stage 2, in addition to continued compliance with MDR 
requirements, correction and removal reporting requirements, and QS 
requirements under Sec.  820.198 (complaint files) for which the 
general enforcement discretion approach was phased out at the beginning 
of stage 1.
    (Comment 154) One comment stated that ending the general 
enforcement discretion approach with respect to MDR requirements and 
correction and removal reporting requirements 1 year after publication 
of the phaseout policy is appropriate, as this timeline will enable FDA 
to quickly identify LDTs potentially associated with safety or 
performance issues. This comment further stated that laboratories that 
are in compliance with CLIA requirements should already have systems in 
place for detecting problems with their tests. Another comment stated 
that FDA should end the general enforcement discretion approach with 
respect to MDR requirements and correction and removal reporting 
requirements 6 months after publication of the phaseout policy. 
According to this comment, 6 months is more than adequate to establish 
procedures for identifying events that need to be reported and for 
implementing a reporting mechanism (e.g., through the FDA eSubmitter 
software). In addition, this comment recommended that all subsequent 
stages of the phaseout policy commence 6 months sooner than proposed by 
FDA, as a result of the shorter timeline for phasing out the general 
enforcement discretion approach with respect to MDR requirements and 
correction and removal reporting requirements under stage 1.
    (Response 154) FDA agrees with the comment that stated that phasing 
out the general enforcement discretion approach with respect to MDR 
requirements and correction and removal reporting requirements 1 year 
after publication of the phaseout policy is appropriate, for the 
reasons discussed in section V.C. FDA also agrees that most 
laboratories should be able to establish and implement procedures for 
complying with MDR requirements and correction and removal reporting 
requirements within 6 months; however, we also believe it is 
appropriate to provide a little more time to help to ensure compliance 
with the requirements.\86\ In recognition that phasing out the general 
enforcement discretion approach with respect to MDR requirements and 
correction and removal reporting requirements too quickly may lead to 
less effective reporting, FDA has determined to phase out the general 
enforcement discretion approach with respect to these requirements 1 
year after publication of this final rule. As such, FDA also disagrees 
that all subsequent stages of the phaseout policy should commence 6 
months sooner than proposed by FDA in the proposed phaseout policy.
---------------------------------------------------------------------------

    \86\ Some comments submitted on the draft guidance documents 
that FDA issued in 2014, in which FDA proposed a 6-month timeframe 
for laboratory compliance with MDR requirements, suggested that a 
longer period would be appropriate.
---------------------------------------------------------------------------

    (Comment 155) FDA received one comment which expressed concern that 
FDA had not proposed to phase out the general enforcement discretion 
approach with respect to the requirements addressed in stage 2 of the 
phaseout policy in a manner that would distinguish between IVDs of 
different risk levels. The comment stated that a decision not to pursue 
such an approach, which FDA had previously considered, would be 
arbitrary and not justified.
    (Response 155) FDA does not agree that the phaseout of the general 
enforcement discretion approach with respect to the requirements 
addressed in stage 2 of the phaseout policy should be conducted in a 
manner that distinguishes between IVDs of different risk levels, or 
that the Agency's decision not to structure the phaseout policy in the 
manner suggested by the comment is arbitrary and unjustified. The 
requirements for which FDA will expect compliance in stage 2 of the 
phaseout policy, including registration and listing requirements under 
21 U.S.C. 360, part 607, and part 807 (excluding subpart E), labeling 
requirements under 21 U.S.C. 352 and parts 801 and 809, subpart B, and 
investigational use requirements under 21 U.S.C. 360j(g) and part 812, 
are general controls under section 513(h)(1) of the FD&C Act, and are 
thus generally applicable to all devices. FDA has determined that it 
would best serve the public health to phase out the general enforcement 
discretion approach with respect to these requirements 2 years after 
publication of this final rule, irrespective of the risk classification 
of the device.
    In the NPRM, FDA acknowledged that this proposal was different from 
FDA's prior statements in the 2017 Discussion Paper (88 FR 68006 at 
68025), wherein FDA discussed a scenario in which the timing of FDA's 
expectations for compliance with certain requirements might depend on 
the type of premarket review applicable to the device (Ref. 57). FDA 
anticipates that 2 years is adequate time for laboratories to come into 
compliance with the requirements addressed in stage 2, and structuring 
the phaseout policy in this manner is easier for laboratories to 
comprehend and follow, easier for FDA to implement, and more responsive 
to the pressing need for additional FDA oversight of IVDs offered as 
LDTs.
    (Comment 156) One comment requested clarification as to whether FDA 
intends to phase out the general enforcement discretion approach with 
respect to QS provisions regarding complaint files under Sec.  820.198 
during stage 1 of the phaseout policy (when FDA generally intends to 
phase out the general enforcement discretion approach with respect to 
MDR requirements), rather than during stage 3 of the phaseout policy, 
given that FDA's regulations regarding MDR requirements state that 
``[i]f you are a manufacturer, you may maintain MDR

[[Page 37383]]

event files as part of your complaint file, under part 820 of this 
chapter, if you prominently identify these records as MDR reportable 
events. We will not consider your submitted MDR report to comply with 
this part unless you evaluate an event in accordance with the quality 
system requirements described in part 820 of this chapter'' (Sec.  
803.18(e)).
    (Response 156) FDA has modified the phaseout policy to clarify that 
while FDA generally intends to phase out the general enforcement 
discretion approach with respect to QS requirements in stage 3 of the 
phaseout policy (as described in section V.C), FDA intends to phase out 
the general enforcement discretion approach with respect to the QS 
requirements under Sec.  820.198 (complaint files) in stage 1 of the 
phaseout policy, given the connection between the complaint 
investigation and complaint file requirements and the MDR reporting 
regulations.
    (Comment 157) FDA received one comment which stated that it could 
take up to a year for a sizable healthcare system to prepare a list of 
LDTs, before the healthcare system could list those LDTs with FDA.
    (Response 157) FDA appreciates that it may take time for 
laboratories to identify and prepare a list of their IVDs offered as 
LDTs before being able to comply with device listing requirements under 
the FD&C Act and FDA's regulations. Under FDA's phaseout policy, FDA is 
phasing out the general enforcement discretion approach with respect to 
registration and listing requirements 2 years after publication of this 
final rule, which will provide sufficient time for laboratories to come 
into compliance even if a year is needed for some laboratories to 
prepare a comprehensive list of their IVDs offered as LDTs.
    (Comment 158) One comment stated that 3 years could be sufficient 
to develop a quality management system that complies with QS 
requirements, but that developing a quality management system that is 
both QS-compliant and CLIA-compliant will be complex and require 
uncommon knowledge and expertise. This comment also stated that to 
develop a quality management system that meets FDA's expectations, 
laboratories will require guidance from FDA with detailed descriptions 
of the differences that exist between QS requirements and CLIA 
regulations. The comment urged FDA to phase out the general enforcement 
discretion approach with respect to QS requirements 4 years after 
publication of the phaseout policy or 1 year after FDA issues a 
guidance document regarding the differences that exist between the QS 
requirements and CLIA regulations, whichever comes later. The comment 
also stated that this approach should provide FDA sufficient time to 
amend the QSR to harmonize with international standards.
    (Response 158) FDA does not agree that the Agency should phase out 
the general enforcement discretion approach with respect to QS 
requirements 4 years after publication of the phaseout policy, or 1 
year after issuance of a guidance document describing differences that 
exist between QS requirements and CLIA regulations, rather than 3 years 
after publication of the phaseout policy as proposed by FDA. While FDA 
recognizes that laboratories will be complying with applicable CLIA 
requirements as well as applicable QS requirements, laboratories 
already comply with CLIA requirements.
    Moreover, as discussed in section V.C, compliance with CLIA 
requirements provides certain quality assurances that may be relevant 
to laboratories' manufacturing practices, and laboratories may be able 
to apply concepts set forth under CLIA requirements to manufacturing 
activities regulated by FDA. As such, and as further discussed in 
section V.C.3, FDA intends to phase out the general enforcement 
discretion approach with respect to only a subset of QS requirements 
rather than all applicable requirements for LDTs. This subset of QS 
requirements is listed in section V.C.3.
    FDA also notes that it has already finalized amendments to the QSR 
(effective in February 2026), and the amended QS requirements, which 
align more closely with international consensus standards for devices, 
will be in effect prior to the beginning of stage 3 (see 89 FR 7496). 
FDA anticipates providing to all its stakeholders, including 
laboratories, timely guidance on compliance with the regulatory 
requirements in that rule. In addition, several educational resources 
regarding the QS requirements currently applicable under part 820 are 
currently available on FDA's website (see Ref. 72).
    (Comment 159) One comment stated that FDA should phase out the 
general enforcement discretion approach with respect to premarket 
review requirements after 4 years for PMAs and after 9 years for 
510(k)s and De Novo submissions. Another comment stated that FDA should 
phase out the general enforcement discretion approach with respect to 
premarket review requirements after 5 years for PMAs, after 7 years for 
De Novo requests, and after 9 years for 510(k)s. In addition, one 
comment stated that if FDA does not continue the general enforcement 
discretion approach with respect to premarket review and QS 
requirements for ``existing LDTs,'' FDA should, in the alternative, 
consider ``exempting or more gradually phasing in premarket review and 
QSR requirements for LDTs that meet certain criteria,'' such as those 
``certified by [NYS CLEP].'' Another comment stated that FDA should 
extend the phaseout by 5 years for premarket review and QS requirements 
for LDTs introduced or modified after the effective date of the rule 
that have approval from NYS CLEP, receive coverage from the MolDx 
Program, or are performed in a CLIA-certified clinical laboratory 
accredited by CAP, unless there is credible information establishing 
that the LDT is marketed with insufficient evidence of analytical or 
clinical validity, that the LDT is marketed with false or misleading 
analytical or clinical claims, or that it is probable that the LDT will 
cause serious adverse health consequences.
    (Response 159) After considering the public comments and the impact 
of other policies included in the phaseout policy, for the reasons 
discussed in section V.C, FDA has determined that it should phase out 
the general enforcement discretion approach: (1) with respect to QS 
requirements (other than requirements under Sec.  820.198 (complaint 
files)), 3 years after publication of this final rule; (2) with respect 
to premarket review requirements for high-risk IVDs, 3\1/2\ years after 
publication of this final rule; and (3) with respect to premarket 
review requirements for moderate-risk and low-risk IVDs (that require 
premarket submissions), 4 years after publication of this final rule. 
For further discussion of these stages and the QS and premarket review 
requirements, see sections V.C.3-5, VI.F.12, and VI.F.13.
    FDA disagrees that the phaseout policy should be modified as 
suggested by these comments. As discussed in response to comment 151, 
FDA has determined that extending the timelines for stages of the 
phaseout policy is not necessary to provide an adequate opportunity for 
laboratories to comply with applicable requirements or to effectively 
implement the phaseout policy, and is not in the best interest of the 
public health. This is true even in the case of IVDs offered as LDTs 
covered by the MolDx Program or performed in a CAP-accredited CLIA-
certified laboratory. As discussed in response to comments in section 
VI.C.3, neither the MolDx Program nor CAP accreditation

[[Page 37384]]

provides a substitute for FDA oversight or mitigates the need for FDA 
oversight. With respect to LDTs approved by NYS CLEP, as described in 
section V.B.2, FDA intends to exercise enforcement discretion and 
generally not enforce premarket review requirements for LDTs approved 
by NYS CLEP. As further discussed in section V.B.2, compliance with the 
QS requirements that FDA intends to enforce for these LDTs will help 
provide for quality manufacturing of these LDTs. FDA understands that 
NYS CLEP's clinical laboratory standards (which exceed CLIA 
requirements in certain respects) and its premarket review requirements 
collectively could generally satisfy these QS requirements except as to 
certain aspects of design control documentation, and FDA therefore does 
not anticipate significant additional burden with respect to compliance 
with these QS requirements for laboratories offering LDTs approved by 
NYS CLEP.
    We further note that the absence of ``credible information'' 
establishing a lack of evidence of analytical or clinical validity, 
false or misleading claims, or a probability that the IVD offered as an 
LDT will cause serious adverse health consequences does not justify 
delaying the phaseout of FDA's general enforcement discretion approach 
with respect to QS and premarket review requirements. Even in the 
absence of such ``credible information,'' risks may exist that will be 
mitigated by compliance with applicable QS and premarket review 
requirements.
    In addition, as described above, one comment submitted to the 
docket suggested that FDA exempt or more gradually phase in premarket 
review and QS requirements for certain LDTs as an alternative option in 
the event that FDA determined not to continue the general enforcement 
discretion approach with respect to premarket review and QS 
requirements for existing tests. As described in section V.B.3, FDA 
intends to exercise enforcement discretion and generally not enforce 
premarket review and QS requirements (except for requirements under 
part 820, subpart M (Records)) for currently marketed IVDs offered as 
LDTs that were first marketed prior to the date of issuance of this 
rule and that are not modified, or that are modified in certain limited 
ways.
    (Comment 160) FDA received several comments which stated that the 
Agency should end the general enforcement discretion approach with 
respect to MDR requirements and/or registration and listing 
requirements prior to deciding whether and when to phase out the 
general enforcement discretion approach with respect to other 
applicable requirements. These comments generally asserted that FDA 
lacks certain information necessary to inform the feasibility of the 
phaseout policy. For example, one comment stated that FDA is missing 
information regarding how many clinical laboratories currently offer 
LDTs, how many LDTs are on the market, how frequently LDTs are 
modified, the nature of those modifications, and the intended use(s) of 
those LDTs. In addition to these comments, a comment suggested that 
FDA's 4-year phaseout policy should apply only to high-risk IVDs 
offered as LDTs, after which FDA should determine how best to proceed 
with respect to other IVDs offered as LDTs.
    (Response 160) FDA does not agree that the Agency should phase out 
the general enforcement discretion approach only with respect to MDR 
requirements and/or registration and listing requirements prior to 
determining how to proceed with respect to other applicable 
requirements. Although FDA is prioritizing the phaseout of the general 
enforcement discretion approach with respect to MDR requirements and 
correction and removal reporting requirements (followed by registration 
and listing requirements) to obtain additional information about 
potentially harmful IVDs offered as LDTs as soon as feasible (see 
discussion in section V.C), FDA already possesses enough information to 
determine that there is no longer a sound basis to generally treat LDTs 
differently from other IVDs and that the general enforcement discretion 
approach for LDTs does not best serve the public health. As discussed 
in response to comment 151, recent evidence from a variety of sources 
underscores the pressing need to better assure the safety and 
effectiveness of LDTs. Adopting a phaseout policy that only addresses 
MDR and registration and listing requirements at this time would 
inevitably delay the phaseout of the general enforcement discretion 
approach for other requirements beyond a 4 year period, and thus would 
be inconsistent with FDA's mission to protect the public health.
    In addition, the FRIA (Ref. 10) provides estimates of much of the 
information that the comments characterized as ``missing,'' such as how 
many laboratories currently offer IVDs as LDTs and how many IVDs 
offered as LDTs are on the market. Although we acknowledge that these 
are estimates, and we do not have exact numbers, we do not believe that 
should delay the phaseout of the general enforcement discretion 
approach, which we have determined is not in the best interest of 
public health. FDA also does not agree that certain information, such 
as the intended use(s) of all IVDs offered as LDTs, is necessary for 
FDA to determine whether and when to phase out the general enforcement 
discretion approach with respect to certain requirements.
    FDA likewise does not agree that the Agency should phase out the 
general enforcement discretion approach for high-risk IVDs offered as 
LDTs prior to determining how to proceed with respect to other IVDs 
offered as LDTs. As FDA explained in the NPRM and in this preamble, the 
Agency is aware of information showing that there is a high variability 
in the performance of IVDs offered as LDTs even in circumstances where 
the test technology is relatively simple and well-understood, and where 
the tests are low risk (88 FR 68006 at 68010-11).
    (Comment 161) Some comments suggested that FDA consider stratifying 
the phaseout policy by annual test volume, due to the potential impact 
of high-volume LDTs on larger patient populations.
    (Response 161) FDA does not agree that FDA's general enforcement 
discretion approach for LDTs should be phased out on a different 
timeline, in a different sequence, or otherwise in a different manner 
based on annual test volume. The importance of having assurances 
regarding the safety and effectiveness of IVDs offered as LDTs does not 
depend on whether IVDs are offered in low or high volume. Moreover, we 
think stratifying the phaseout in this way would be overly complicated 
for laboratories to comprehend and follow, and for FDA to implement.
    (Comment 162) Some comments stated that FDA did not provide 
sufficient clarity or specificity regarding how it intends to implement 
the phaseout policy, resulting in uncertainty among laboratories which 
may have a ``chilling effect.'' Another comment stated that the 
phaseout policy is too complicated for laboratories to follow.
    (Response 162) We believe the information included in the phaseout 
policy, including the timeline for the various stages in the phaseout 
policy and information regarding enforcement discretion policies 
described in this preamble, provides clear expectations for 
laboratories that offer IVDs as LDTs. FDA appreciates that additional 
guidance regarding implementation of the phaseout policy may facilitate

[[Page 37385]]

efforts by laboratories to comply with applicable requirements. As 
discussed more fully in response to comment 291, FDA anticipates 
issuing a small entity compliance guidance, issuing guidance documents, 
and/or making additional resources available on specific topics over 
the course of the phaseout period.
    (Comment 163) A comment sought clarification regarding how the 
phaseout policy will apply to LDTs that are developed during the 
phaseout period, for example, LDTs that are developed between issuance 
of the rule and the start of stage 1 of the phaseout policy, or that 
are developed between successive stages of the phaseout policy.
    (Response 163) Laboratories that first introduce IVDs offered as 
LDTs after the publication of the final rule and during the phaseout 
period will be expected to comply with requirements consistent with the 
dates identified for each stage of the phaseout policy. For example, an 
IVD offered as an LDT introduced 2\1/2\ years after publication of this 
final rule, which would be after the start of stage 2 of the phaseout 
policy but before the start of stage 3, would be expected to comply 
with requirements for which FDA has already phased out the general 
enforcement discretion approach under stages 1 and 2. FDA would expect 
compliance with QS requirements upon the start of stage 3 (other than 
requirements under Sec.  820.198 (complaint files), for which FDA would 
have already phased out the general enforcement discretion approach 
under stage 1), and so on for stages 4 and 5 as applicable. 
Laboratories should also be aware of the enforcement discretion 
policies included in the phaseout policy, including those set forth in 
section V.B.
7. MDR Requirements
    (Comment 164) Many comments supported FDA's proposal to end its 
general enforcement discretion approach with respect to the MDR 
requirements within 1 year from publication of the final rule. A 
comment suggested that this approach was reasonable regardless of the 
risk or volume of the LDTs the laboratory distributed. However, another 
comment suggested that FDA would need to provide additional guidance on 
the types of events it is interested in to avoid being flooded with 
reports about events that are of the type that are within CLIA's 
purview. This comment stated that the vast majority of laboratory 
adverse events are due to human error (e.g., manual mispipetting or a 
lost specimen) and not due to a design flaw with an LDT. Along these 
lines, another comment requested that FDA provide definitions of 
certain terms in the context of laboratories, such as: FDA reportable 
adverse event, causal for MDR requirements, malfunction, and recall. 
Another suggested that such definitions align with reporting for 
``conventional'' IVDs. Yet another comment suggested that FDA continue 
the general enforcement discretion approach for the MDR requirements 
until FDA provides education on this topic.
    (Response 164) FDA agrees with the comments supporting FDA's 
proposed phaseout of enforcement discretion regarding MDR reporting for 
IVDs offered as LDTs. As stated in section V.C, FDA is phasing out the 
general enforcement discretion approach with respect to the MDR 
requirements within one year from publication of the final rule for 
IVDs offered as LDTs. FDA acknowledges that some laboratories may not 
be familiar with FDA's MDR requirements in part 803. However, FDA 
disagrees that this justifies waiting to phase out the general 
enforcement discretion approach with respect to those requirements. 
Laboratories should already have some processes in place for detecting 
problems with their IVDs to comply with CLIA regulations. In addition, 
FDA already has a number of resources to assist manufacturers in 
complying with MDR requirements, including guidance, information on 
FDA's website, and webinars. These include, for example, FDA's final 
guidance document entitled ``Medical Device Reporting for 
Manufacturers'' (Ref. 172), and information on ``How to Report Medical 
Device Problems'' on the Agency's website (Ref. 173). Laboratories can 
better understand their responsibilities under part 803 by consulting 
these resources. FDA also intends to develop additional educational 
resources on MDR reporting to assist laboratories transitioning to 
compliance with these requirements.
    With respect to the comment requesting that FDA provide definitions 
of certain terms in the context of laboratories, we note that the 
following terms are already defined in part 803 for purposes of MDR 
reporting requirements: ``MDR reportable event'' (Sec.  803.3(o)(2)), 
``caused or contributed'' (Sec.  803.3(c)), and ``malfunction'' (Sec.  
803.3(k)). These definitions apply to MDR reporting requirements 
regardless of whether the manufacturer of a device is a laboratory and 
regardless of whether the device at issue is an IVD or another kind of 
device. Although the term ``recall'' is not used in FDA's MDR 
regulations, we note that FDA regulations define the term ``recall'' at 
21 CFR 7.3(g) (voluntary recalls) and 21 CFR 810.2(k) (mandatory device 
recalls). FDA has multiple resources for industry regarding recalls 
available on its website (see, e.g., Ref. 174).
    Further, we note that MDR reportable events can include events 
caused by user error and are not limited to events resulting from a 
flaw in device design. For example, under the regulations, a device 
manufacturer must submit a report to FDA when it becomes aware of 
information that reasonably suggests that the manufacturer's device may 
have caused or contributed to a death or serious injury (Sec.  
803.50(a)(1)). Section 803.3(c) defines ``caused or contributed,'' to 
specifically include death or serious injury events occurring as a 
result of labeling or user error, among other things. However, if the 
manufacturer determines that an event is solely the result of user 
error with no other performance issue, and there has been no device-
related death or serious injury, the manufacturer is not required to 
submit an MDR report. It would therefore generally be unlikely that a 
laboratorian losing a specimen (as referenced in the comment) would be 
considered a reportable event.
    Importantly, CLIA does not require laboratories to report suspected 
device-associated adverse events to any Federal oversight authority. 
Therefore, we disagree with the comment suggesting that the phaseout of 
enforcement discretion for MDR requirements will result in a flood of 
MDRs for events ``of the type within CLIA's purview.''
    (Comment 165) Several comments argued that MDR requirements should 
not apply to laboratories. Some of these comments indicated that the 
framework is not appropriate for laboratories, while others asserted 
that CLIA already covers the MDR activities. In particular, a comment 
stated that CLIA requires laboratories to identify, document, and 
perform corrective measures for any laboratory errors, including 
patient harm and that this documentation is reviewed by a CLIA 
inspector, its accrediting bodies, or exempt States. Further, the 
comment stated that CMS-approved accrediting organizations are required 
to notify CMS within 10 days of any deficiency identified in an 
accredited or CLIA-exempt laboratory if the deficiency poses an 
immediate jeopardy to the patient or a hazard to the general public. 
Another comment suggested that FDA should not ``subject'' laboratories 
that have a system for reporting errors, and which are integrated 
within a health system, to the MDR requirements. Another comment opined 
that compliance with the MDR requirements was not

[[Page 37386]]

warranted because events were rare and for most laboratories never 
occur.
    (Response 165) FDA disagrees with the suggestion that laboratory 
compliance with the MDR requirements is not warranted. MDR reporting is 
an important postmarket surveillance tool that FDA uses to monitor 
device performance, detect potential device-related safety issues, and 
contribute to benefit-risk assessments of medical devices. FDA also 
disagrees that CLIA ``covers'' activities equivalent to complying with 
MDR reporting requirements. As explained in our responses to comments 
in section VI.C.2, the CLIA requirements are geared towards identifying 
issues and problems with the laboratory operations, not with an LDT 
itself. Further, unlike FDA's MDR regulations, CLIA regulations do not 
require centralized reporting of suspected, device-associated adverse 
events to inform tracking and trending by a Federal oversight 
authority. FDA's MDR regulations require that a manufacturer report to 
FDA within specified timeframes when the manufacturer receives or 
otherwise becomes aware of information reasonably suggesting that a 
device it markets may have caused or contributed to a death or serious 
injury, or has malfunctioned and the device or a similar device that 
the manufacturer markets would be likely to cause or contribute to a 
death or serious injury, if the malfunction were to recur (Sec. Sec.  
803.50(a) and 803.53). It is important that FDA receive this 
information to enable it to identify trends and detect safety signals. 
For example, FDA received MDRs regarding incorrect test results due to 
``carryover'' in automated test systems. ``Carryover'' is when a 
falsely high result is obtained due to residual analyte from a high 
concentration sample that was tested immediately prior. Upon review of 
trends across MDRs and further investigation, FDA found that 
``carryover'' caused inaccurate results across multiple automated test 
systems. Based on this finding, FDA worked to ensure that manufacturers 
of affected automated test systems addressed this issue. This included 
FDA classification of recalls for affected tests and manufacturer 
notification to users. As another example, FDA received MDRs indicating 
that ambient temperature in laboratories was affecting test results for 
common tests. Upon review of trends across MDRs and further 
investigation, we found that temperature interference caused inaccurate 
results across different tests that used different instruments from 
different manufacturers in different laboratories. Based on this 
finding, manufacturers redesigned affected tests to address this issue 
and submitted the changes for FDA review.
    For similar reasons, FDA disagrees that there generally should be 
continued enforcement discretion for MDR requirements for laboratories 
that have a system for reporting errors, and which are integrated 
within a health system. Being integrated within a health system does 
not ensure centralized reporting of suspected, device-associated 
adverse events to inform tracking and trending by a Federal oversight 
authority in accordance with the manufacturer reporting requirements in 
part 803. Continuing to exercise enforcement discretion for the MDR 
requirements for all the entities identified in the comment would 
undermine FDA's ability to identify trends or issues with the 
performance of IVDs offered as LDTs.
    Moreover, FDA disagrees with the comment indicating that adverse 
events associated with LDTs are rare. In the absence of the type of 
reporting required by the MDR regulations, FDA has no assurance that 
adverse events associated with IVDs offered as LDTs are ``rare.'' 
Laboratories may not be tracking or reporting these adverse events 
currently, but that does not mean that they do not occur. However, if 
MDR reportable events are truly rare for certain laboratories, that 
should minimize additional burden of complying with the MDR 
requirements.
8. Registration and Listing Requirements
    (Comment 166) FDA received many comments supporting the need for 
and rationale behind the proposal to phase out the enforcement 
discretion approach for registration and listing requirements. One 
comment emphasized the need to create an active and accurate account of 
LDTs offered. Some comments voiced the need for FDA to identify and 
address poorly performing tests and the importance of transparency in 
terms of LDTs currently in use and any related adverse events.
    (Response 166) FDA agrees that registration and listing information 
will provide FDA with a better understanding of the exact universe of 
IVDs offered as LDTs and facilitate oversight. FDA is phasing out the 
general enforcement discretion approach with respect to registration 
and listing requirements under 21 U.S.C. 360 and part 807 (excluding 
subpart E) 2 years after publication of this final rule. Under this 
timeline, FDA will be able to utilize registration and listing 
information to obtain an understanding of the universe of IVDs offered 
as LDTs to facilitate premarket review of those IVDs.
    FDA also agrees with comments supporting FDA addressing poorly 
performing IVDs offered as LDTs and noting the importance of 
transparency in terms of any IVD adverse events. Beginning 1 year after 
the publication date of this final rule, FDA no longer intends to have 
the general enforcement discretion approach for MDR requirements, among 
other requirements. Enforcement of MDR requirements will enable FDA to 
systematically monitor significant adverse events to identify 
problematic IVDs offered as LDTs, such as those with poor performance 
or other safety issues.
    (Comment 167) One comment suggested that FDA accelerate the 
phaseout timeline for registration and listing requirements, 
emphasizing the importance of this information in implementing the rest 
of the phaseout policy. Some comments agreed with the need to enforce 
registration and listing requirements but requested that FDA enforce 
only the elements that are currently required for IVDs and other 
devices, as it is ``not appropriate to require more elements for LDTs 
than are currently required for IVDs and medical devices.''
    (Response 167) As described in section V.C, FDA has determined that 
it will best serve the public health to phase out the general 
enforcement discretion approach with respect to registration and 
listing requirements 2 years after publication of this final rule. We 
believe laboratories will have sufficient time to come into compliance 
with these requirements, and that any less time may not be sufficient. 
Moreover, FDA is first prioritizing the phaseout of the enforcement 
discretion approach for MDR requirements (and related complaint file 
requirements) and correction and removal requirements to obtain 
information about potentially harmful IVDs offered as LDTs as soon as 
possible (stage 1).
    We note that the registration and listing requirements applicable 
to IVDs offered as LDTs are the same as those applicable to other IVDs 
and other devices; FDA is not establishing any new registration and 
listing requirements as part of this rulemaking.
    (Comment 168) Several comments supported the enforcement of 
registration and listing requirements but urged FDA to phase out the 
general enforcement discretion approach for registration and listing 
requirements before phasing out the general enforcement discretion 
approach for

[[Page 37387]]

other requirements. In particular, some comments suggested phasing out 
the general enforcement discretion approach with respect to 
registration and listing requirements before MDR requirements.
    (Response 168) Under the final phaseout policy, FDA intends to 
phase out the general enforcement discretion approach for registration 
and listing requirements in stage 2, after first phasing out the 
general enforcement discretion approach for MDR requirements and 
correction and removal reporting requirements (as well as requirements 
regarding complaint files, given the connection between the complaint 
investigation and complaint file requirements and the MDR reporting 
regulations) in stage 1. FDA does not agree that the phaseout policy 
should address registration and listing requirements before the 
requirements described in stage 1. FDA has structured the phaseout 
policy to facilitate obtaining information about potentially harmful 
IVDs offered as LDTs as soon as feasible. As detailed in this preamble, 
FDA is concerned that some LDTs on the market may be posing risks to 
patients. Phasing out the general enforcement discretion approach for 
MDR requirements and correction and removal reporting requirements 
(stage 1) will help FDA to systematically monitor significant adverse 
events and identify problematic IVDs offered as LDTs. In addition, 
under this phaseout structure, laboratory manufacturers will have 
sufficient time to comply with registration and listing requirements 
(stage 2).
    FDA therefore intends to phase out the general enforcement 
discretion approach with respect to MDR requirements and correction and 
removal reporting requirements before registration and listing 
requirements. We note that, as stated in section V.C, FDA generally 
does not intend to enforce requirements to include certain information 
(e.g., registration numbers, premarket submission numbers) in reports 
or other submissions to the Agency until the information is addressed 
in a later stage of the phaseout policy.
    (Comment 169) FDA received comments requesting guidance on the 
information required for registration and listing. One comment 
suggested that FDA consider creating temporary product codes in order 
to advance the registration and listing process while product codes are 
developed.
    (Response 169) FDA has instructions and educational resources 
relating to registration and listing requirements available on FDA's 
website (Ref. 175). For more information on product codes, see FDA's 
final guidance on ``Medical Device Classification Product Codes.'' FDA 
intends to consider creating product codes to be used during the 
registration and listing process where no product code exists for a 
given test type. FDA also intends to consider providing additional or 
more targeted resources on registration and listing requirements over 
the course of the phaseout period, as appropriate.
    (Comment 170) One comment encouraged FDA to establish a clear and 
publicly available mechanism that would allow patients and providers to 
``ascertain the test's level of review.''
    (Response 170) As detailed in section V.C, FDA intends to phase out 
the general enforcement discretion approach with respect to 
registration and listing requirements 2 years after publication of this 
final rule. The registration and listing database generally will 
provide patients and healthcare providers with information about 
specific IVDs as required by FDA regulation (see, e.g., Sec.  
807.26(g)), including information regarding an IVD's ``level of 
review.'' In particular, we note that the device listing database 
includes information indicating the type of premarket submission (if 
any) for the listed device. We recognize that this information may not 
be included for currently marketed IVDs offered as LDTs, as well as for 
IVDs offered as LDTs after the publication of the final rule prior to 
stages 4 and 5.
    (Comment 171) FDA received comments regarding the potentially 
prohibitive costs of registration and listing for some laboratories. 
One comment recommended FDA enforce ``limited'' registration and 
listing requirements for existing tests and allow laboratories to 
provide an ``electronic, internet-based test menu'' housed on the 
laboratory's website in lieu of individual test listings. Another 
comment noted that some laboratories maintain publicly available test 
catalogs online that include such information on tests' intended use, 
test method, and specimen requirements, and urged FDA to continue to 
exercise enforcement discretion if laboratories submit links to these 
test catalogs instead of providing all the information required for 
listing.
    (Response 171) FDA disagrees with these comments. As described in 
section II.F.2.a of the FRIA, FDA estimates the cost of compliance with 
registration and listing requirements (this does not include 
registration fees) to range between $0.20 million and $0.82 million in 
initial costs and between $0.08 million and $0.34 million in recurring 
costs for between 590 and 2,362 affected laboratories (as well as 
between $0.02 million and $0.07 million in initial costs for between 47 
and 189 new affected laboratories each year). This amounts to less than 
$500 per laboratory for compliance with initial registration and 
listing requirements and slightly over $100 per laboratory for 
compliance with annual requirements. In addition, under current user 
fee rates, laboratories must pay an annual establishment registration 
fee of $7,653. FDA believes it is unlikely for these costs of 
registration and listing to be prohibitively expensive for 
laboratories.
    FDA also disagrees with the suggestions provided in these comments. 
FDA has determined that collecting registration and listing information 
for all laboratories and IVDs offered as LDTs in a uniform and 
systematic manner will provide the Agency with a holistic and 
comprehensive view of the universe of IVDs offered as LDTs and better 
enable FDA to help assure the safety and effectiveness of LDTs. FDA 
does not believe ``limited'' registration and listing information or 
the submission of electronic internet-based test menus/catalogs would 
allow the Agency to have such a comprehensive view.
    (Comment 172) One comment stated that laboratories with multiple 
locations operating under a common quality management system should be 
allowed to register as a single entity with multiple sites.
    (Response 172) With the phaseout of the general enforcement 
discretion approach, manufacturers of IVDs offered as LDTs generally 
will be expected to comply with registration and listing requirements 
under 21 U.S.C. 360, part 607, and part 807 (excluding subpart E) in 
the same way as other medical device manufacturers. FDA's regulations 
define establishment in the registration context as ``a place of 
business under one management at one general physical location at which 
a device is manufactured, assembled, or otherwise processed.'' 21 CFR 
807.3(c); see also 21 CFR 607.3(c) (defining ``establishment'' in the 
context of registration requirements for licensed devices as ``a place 
of business under one management at one general physical location''). 
To the extent a laboratory has multiple sites in different physical 
locations, each of these sites would be registered separately. This 
information is important to inform FDA's oversight, including with 
respect to conducting inspections. If a laboratory with multiple sites 
were to register as a single entity that would impede such oversight 
and FDA's ability to conduct

[[Page 37388]]

inspections in a timely and efficient manner.
    (Comment 173) One comment suggested that FDA should reduce the 
burden of registration and listing for clinical laboratories by 
continuing an enforcement discretion approach for low-risk tests with 
regard to registration and listing requirements if the laboratory 
``documents'' all low-risk LDTs it performs as required by CAP 
accreditation.
    (Response 173) As discussed in section VI.L.4, FDA does not think 
it is appropriate to continue an enforcement discretion approach for 
low-risk LDTs, including with respect to registration and listing 
requirements. Moreover, specifically regarding registration and listing 
requirements, comprehensive registration and listing is critical to 
inform FDA's understanding of the universe of IVDs offered as LDTs and 
to help FDA identify, monitor, and address any issues with IVDs offered 
as LDTs. In addition, as discussed in response to comment 171, FDA does 
not anticipate the costs of registration and listing to be 
prohibitively expensive for laboratories. We also note that under the 
phaseout policy, FDA expects compliance with registration and listing 2 
years after publication of the final rule (stage 2), which we 
anticipate will be sufficient time to come into compliance with the 
registration and listing requirements.
9. Corrections and Removals Reporting Requirements
    (Comment 174) A comment stated that it did not agree with FDA's 
proposal to end the general enforcement discretion approach with 
respect to the correction and removal reporting requirements because it 
perceives CLIA as adequately covering these requirements. Another 
comment suggested that FDA continue the general enforcement discretion 
approach for correction and removal reporting requirements if 
laboratories have documented corrective action and removal processes.
    (Response 174) FDA disagrees with these comments. As described in 
sections V.C, VI.C.2, and VI.D.8, CLIA requirements are complementary 
and distinct from FDA requirements. They do not provide adequate 
oversight of IVDs offered as LDTs to render FDA oversight unnecessary. 
Under the FD&C Act, certain entities are required to report device 
malfunctions, adverse events, and corrections and/or removals of a 
device. Moreover, FDA has authority to take steps when a device 
presents a risk to the public health, including utilizing its mandatory 
recall authority. There are not the same requirements and authorities 
under CLIA.
    Enforcement of correction and removal reporting requirements along 
with the MDR requirements will enable FDA to systematically monitor 
adverse events, identify problematic IVDs offered as LDTs, and monitor 
corrections and removals of IVDs offered as LDTs. Moreover, as FDA 
stated in response to comment 165, MDR is one of the postmarket 
surveillance tools that FDA uses to monitor device performance, detect 
potential device-related safety issues, and contribute to benefit-risk 
assessments of medical devices. Under Sec.  806.10, manufacturers and 
importers are required to submit a written report to FDA of any 
correction or removal of a device initiated by such manufacturer or 
importer if the correction or removal was initiated: (1) to reduce a 
risk to health posed by the device or (2) to remedy a violation of the 
FD&C Act caused by the device which may present a risk to health 
(subject to the limitation and exemption described in Sec.  
806.10(a)(2)), within 10 working days of initiating such action. This 
information is critical to FDA's ability to assure that patients, 
healthcare providers, and other stakeholders have information about 
safety or other issues with a device, and to monitor the effectiveness 
of corrective actions.
    Laboratories having ``documented processes'' relating to 
corrections and removals does not provide the same types of critical 
assurances. If laboratories do have existing internal processes, 
however, that should ease the burden of complying with FDA's correction 
and removal reporting requirements.
10. Investigational Device Exemption Requirements
    (Comment 175) Several comments suggested clarification around when 
investigational use requirements apply to IVDs offered as LDTs. One 
comment requested that FDA address how the phaseout would impact 
laboratories that validate reagents for use in a clinical trial where 
the reagent has been labeled by its manufacturer as being RUO, or 
validate kits that have been manufactured by a third party but which 
are validated by the laboratory for a specific purpose for use in a 
clinical trial, e.g., for clinical trial stratification, inclusion/
exclusion determinations, or safety assessments of enrolled subjects. 
This comment further stated that FDA should be cognizant of the time 
that is required to get a test ready for use in a clinical trial. 
Another comment sought clarification regarding potential impacts of the 
phaseout on clinical research organizations (CROs). This comment 
observed that it would be redundant for both CROs and their clients to 
make submissions to FDA for the same IVDs, and further stated that if 
``CRO LDTs'' are ``restricted'' by the phaseout, there could be 
significant delays with respect to drug and IVD development. The 
comment recommended that FDA consider granting all accredited CRO 
laboratories ``an exemption'' from applicable requirements. Multiple 
comments requested clarification regarding clinical trial assays that 
have no direct impact on patient care, such as for pharmacokinetic 
analyses for dosing studies. Others cited the importance of IVDs 
offered as LDTs in drug trials and suggested continued enforcement 
discretion to support therapeutic product development.
    (Response 175) The IDE requirements under section 520(g) of the 
FD&C Act and part 812 apply to clinical investigations of devices. 
However, certain categories of clinical investigations of devices are 
exempt from most IDE requirements under Sec.  812.2(c), and certain 
other categories of device investigations are deemed to have an 
approved IDE application under Sec.  812.2(b) if the conditions therein 
are met. Sponsors and investigators of investigational devices have 
obligations under the IDE regulations (and related regulations such as 
parts 50 and 56 (21 CFR parts 50 and 56), regarding protection of human 
subjects and institutional review boards, respectively). Thus, if a 
laboratory is a sponsor or investigator of an investigational IVD 
(including a reagent or instrument), that laboratory is responsible for 
ensuring compliance with all applicable requirements under the FD&C Act 
and FDA's regulations. Investigational IVDs may include an IVD that was 
previously labeled RUO by a third-party manufacturer, an IVD that was 
previously labeled by a third party manufacturer for a use different 
from the use in the clinical investigation, or an IVD manufactured by a 
third party but modified by the laboratory for purposes of the clinical 
investigation. Additional information regarding RUO-labeled products is 
available in FDA's final guidance document entitled ``Distribution of 
In Vitro Diagnostic Products Labeled for Research Use Only or 
Investigational Use Only'' (Ref. 176).
    Under the phaseout policy described in section V.C, FDA expects 
compliance with applicable IDE requirements and other applicable 
requirements, such as parts 50 and 56, for investigations that involve 
investigational IVDs offered as

[[Page 37389]]

LDTs 2 years after publication of this final rule. FDA has several 
resources available to help sponsors comply with IDE requirements in 
the context of clinical investigations of IVDs, including a final 
guidance document entitled ``In Vitro Diagnostic (IVD) Device Studies--
Frequently Asked Questions,'' which has been available to stakeholders 
since June 2010 (see Ref. 177).
    We recognize that some sponsors of clinical investigations of 
investigational IVDs may choose to engage with a CRO, including a CRO 
laboratory, to perform certain duties, including certain obligations 
under the IDE regulations. It is up to the sponsor and CRO to decide 
which duties and obligations the CRO will undertake. The obligations 
that apply under the IDE regulations must be met regardless of which 
party performs them. If an IDE application is required, either the 
sponsor or the sponsor's CRO may submit the application, i.e., it is 
not necessary for both parties to submit an IDE application for the 
same clinical investigation of the investigational IVD. We note that to 
the extent a CRO submits an IDE application to FDA, this application 
would be distinct from the premarket submission (such as a 510(k), De 
Novo, or PMA) that the CRO's client may subsequently submit to FDA if 
the client intends to offer the IVD.
    With respect to use of IVDs offered as LDTs in clinical 
investigations of drugs, FDA has issued a draft guidance document 
entitled ``Investigational IVDs Used in Clinical Investigations of 
Therapeutic Products'' (this guidance has not been finalized at this 
time but it includes information that may be helpful, such as a 
discussion of certain IDE requirements) and a final guidance document 
entitled ``Investigational In Vitro Diagnostics in Oncology Trials: 
Streamlined Submission Process for Study Risk Determination Guidance 
for Industry,'' which provide additional information regarding 
investigational use requirements in such settings (see Refs. 178 and 
179). As FDA has explained, sponsors should already be aware that all 
investigational IVDs used in therapeutic product trials are subject to 
IDE requirements, and may require the submission of an IDE application 
separate from an investigational new drug application (IND) to the 
extent an IDE application is required under part 812 of FDA's 
regulations (Ref. 178). When an IDE application is not required, a 
therapeutic product trial that uses an investigational IVD must still 
comply with other IDE requirements as applicable under part 812. An IDE 
and an IND may be held by the same entity or may be held by different 
entities (for example, a CRO and its client); however, IDE and IND 
applications may cross-reference each other through a letter of 
authorization, or in cases where either an IND or an IDE application is 
not required, information may be provided through the use of a master 
file (MAF). As explained in section V.C, FDA generally expects 
compliance with the device investigational use requirements 2 years 
after publication of the final rule. Given this time period to prepare, 
FDA does not anticipate that compliance with IDE requirements will 
meaningfully delay drug or IVD development activities. Further, FDA 
notes that investigations of diagnostic devices are exempt from most 
IDE requirements, provided that certain labeling requirements are met 
and the testing: is noninvasive, does not require an invasive sampling 
procedure that presents significant risk, does not by design or 
intention introduce energy into a subject, and is not used as a 
diagnostic procedure without confirmation of the diagnosis by another, 
medically established diagnostic product or procedure (Sec.  
812.2(c)(3)). Additionally, investigations of diagnostic devices that 
are not significant risk are deemed to have an approved IDE (without 
submission of an IDE application) if the conditions in Sec.  812.2(b) 
are met.
    Finally, in response to comments that inquired regarding the 
applicability of IDE requirements to certain types of assays, FDA would 
generally need additional information regarding the specific assay and 
the investigation in which the assay is intended to be used. FDA 
encourages stakeholders to consult the materials that have been made 
available by the Agency regarding IDE requirements, including the final 
guidance documents referenced above. Laboratories may also contact FDA 
with product-specific questions, as discussed elsewhere in this 
preamble.
11. Labeling Requirements
    (Comment 176) FDA received several comments inquiring about 
labeling requirements for LDTs and requesting clear guidance on the 
required information and where such information needs to be located. 
One comment asked whether labeling for LDTs should be written with the 
performing laboratory as the audience or the ordering physician, noting 
that this distinction ``is critical as it directly impacts the 
communication of clinical information, essential for accurate patient 
diagnosis and treatment.'' Another comment stated that FDA should not 
consider the ``test menu, educational and interpretive information, and 
scientific publications included on the laboratory website'' as 
labeling and must not treat this information in the same way as product 
advertisement. Another comment stated that information listed as part 
of test menus ``cannot be subject to rigid labeling requirements and 
should not be considered `promotional.'''
    (Response 176) FDA appreciates the comments requesting 
clarification regarding the labeling requirements for LDTs. FDA's 
regulations in Sec.  809.10 set forth specific labeling requirements 
for IVDs, including specific information that must be included. FDA 
anticipates that this information might be encompassed in more than one 
document, such as the test protocol, test report template, and test 
menu.
    FDA intends to provide more targeted guidance and/or additional 
resources regarding the applicable labeling requirements prior to stage 
2 of the phaseout period.
    (Comment 177) One comment expressed concern that FDA labeling 
requirements would be duplicative because similar information is 
provided in the test ordering form or as part of the electronic order 
entry process. The comment also expressed concern that FDA labeling 
requirements would be impractical because there is limited space on the 
label after compliance with CLIA and other requirements, and that data 
elements of electronic health records would need to be added and then 
standardized and harmonized. This comment recommended FDA continue the 
general enforcement discretion approach for labeling requirements if 
the ``LDTs' information'' is documented and made available to FDA upon 
request.
    (Response 177) FDA disagrees with this suggestion. FDA is phasing 
out the general enforcement discretion approach with respect to 
labeling requirements under 21 U.S.C. 352 and parts 801 and 809, 
subpart B. FDA believes that generally enforcing the labeling 
requirements for IVDs offered as LDTs will provide for consistent and 
comprehensive information that will benefit healthcare providers and 
patients and help FDA to better protect and promote the public health. 
As noted in response to comment 176, FDA anticipates that the 
information required under Sec.  809.10 might be encompassed in more 
than one document, such as the test protocol, test report template, and 
test menu. In addition, in the case of insufficient space with respect 
to the label, to the extent there is an immediate container onto which 
a label could be affixed, we note that Sec.  809.10(a)(10) provides 
that some of the

[[Page 37390]]

required information may appear on the outer container labeling. These 
and other labeling requirements are additionally discussed in FDA's 
final guidance document entitled ``Labeling: Regulatory Requirements 
for Medical Devices'' (Ref. 180).
    As noted in response to comment 176, FDA intends to provide more 
targeted guidance and/or additional resources regarding labeling 
requirements prior to stage 2 of the phaseout period.
    (Comment 178) FDA received one comment stating that significant 
problems for laboratories could be expected when ``adhering to guidance 
for manufacturers regarding labeling practices.'' The comment also 
stated that LDTs cannot reasonably be expected to adhere to the label 
requirements under Sec.  809.10 as there is no physical container onto 
which a label could be affixed. Similarly, the comment noted that 
creation of a package insert would not be practical in a laboratory 
setting.
    (Response 178) It is unclear what ``guidance'' the comment is 
referring to as the comment did not identify any specific guidance. To 
the extent the comment is referring to the labeling requirements in 
Sec.  809.10, as noted in response to comment 176, FDA anticipates that 
the information required under Sec.  809.10 might be encompassed in 
more than one document, such as the test protocol, test report 
template, and test menu.
    FDA's IVD labeling requirements in Sec.  809.10(b) specify the 
information that must be included in labeling and provides a package 
insert as an example of labeling. However, the regulations do not 
require that the labeling be a package insert.
    FDA recognizes that guidance and/or additional resources on the 
labeling requirements for LDTs would be helpful for laboratory 
manufacturers. Therefore, FDA intends to provide more targeted guidance 
and/or additional resources on labeling requirements, including label 
requirements, prior to phase 2 of the phaseout period.
    (Comment 179) One comment requested that FDA clarify expectations 
regarding compliance with UDI requirements for IVDs offered as LDTs.
    (Response 179) FDA recognizes that the labeling requirements under 
part 801 of FDA's regulations, for which FDA intends to phase out the 
general enforcement discretion approach under stage 2 of the phaseout 
policy (see section V.C), include UDI requirements. FDA intends to 
provide more targeted guidance and/or additional resources regarding 
UDI requirements prior to stage 2 of the phaseout period.
12. Quality System Requirements
    (Comment 180) A number of comments agreed with FDA that 
laboratories should have quality systems to help ensure that there are 
less errors with IVDs offered as LDTs. These comments went on, however, 
to express concerns with FDA's proposal to exercise enforcement 
discretion with respect to certain QS requirements in part 820 for 
those IVDs for which all design and manufacturing activities occur 
within a single CLIA-certified laboratory that meets the regulatory 
requirements to perform high complexity testing and for which 
distribution of the IVD does not occur outside that single laboratory. 
In particular, comments thought that having two different systems could 
result in confusion about what is ``required.''
    (Response 180) FDA agrees that quality systems are important to 
assuring that a manufacturer consistently manufactures IVDs that have 
appropriate assurance of safety and effectiveness, and FDA generally 
expects laboratories to comply with the QS requirements at the 3-year 
mark under stage 3 of the phaseout policy (other than requirements 
under Sec.  820.198 (complaint files), for which FDA will phase out the 
general enforcement discretion approach under stage 1 of the phaseout 
policy). As stated in section V.C, FDA is also finalizing the QS policy 
for LDTs as proposed. For LDTs, FDA will expect compliance at the 3-
year mark with some, but not all, of the QS requirements.
    FDA recognizes that this policy creates a more nuanced approach in 
terms of expectations for QS compliance, but we believe this nuance is 
justified because it may be important for some laboratories while still 
serving FDA's public-health goals. FDA has set forth the reasoning for 
this policy, which is based on certain quality assurances provided 
through compliance with CLIA requirements, in section V.C. This policy 
is consistent with the Agency's least burdensome approach for devices. 
FDA also welcomes compliance with the full QSR, including to avoid 
confusion. As with any enforcement discretion policy, this policy is 
subject to change as circumstances warrant.
    (Comment 181) Many comments sought additional clarity about the QS 
requirements. These comments explained that laboratories do not have 
experience with FDA's QS requirements and may need substantial 
assistance in understanding the requirements and whether they can 
``leverage'' their existing quality system to meet FDA's requirements. 
Another comment questioned the requirements that would be included in 
FDA's final rule amending part 820 and whether FDA would require 
certification to the relevant ISO standard (i.e., ISO 13485). A similar 
comment asked whether FDA would make guidance available to clinical 
laboratories on this topic and whether such guidance would be issued 
with enough time for laboratories to take necessary actions to come 
into compliance. Another comment requested that FDA provide guidance on 
the gaps that exist between the QSR and CLIA.
    (Response 181) FDA understands that compliance with the FD&C Act 
and its implementing regulations, including part 820, is unfamiliar for 
many laboratories. We intend to engage in various educational 
activities, including issuing timely guidance, to assist laboratories 
with understanding and complying with applicable requirements. 
Additionally, FDA has just issued its final rule amending part 820 (see 
89 FR 7496). This rule will take effect 2 years from publication on 
February 2, 2026. FDA anticipates providing to all its stakeholders, 
including laboratories, timely guidance on compliance with the 
regulatory requirements in that rule. Laboratories can take advantage 
of these efforts to obtain a better understanding of the applicable 
requirements.
    As for the specific question about certification to ISO 13485, FDA 
is not requiring certification and such certification will not 
substitute for an FDA routine inspection under section 704 of the FD&C 
Act (89 FR 7496, 7518).
    (Comment 182) We received several comments about the relationship 
between FDA's QSR and CLIA. A comment suggested that FDA should 
harmonize its QSR with CLIA. Another comment stated that FDA should 
specify whether compliance with part 820 obviates the need to maintain 
CLIA certification.
    (Response 182) First, the requirement to comply with part 820 does 
not obviate the need for a laboratory to maintain CLIA certification. 
CMS administers CLIA and its implementing regulations, whereas FDA 
administers the FD&C Act and its implementing regulations, including 
the QSR. As FDA has explained elsewhere in this preamble, the schemes 
implemented by CMS and FDA are complementary and not duplicative; both 
are important to help assure quality testing with laboratory-
manufactured tests.

[[Page 37391]]

    Second, FDA disagrees that the QSR and CLIA regulations require 
harmonization because, as stated previously, the two schemes are 
complementary, not duplicative or conflicting. In addition, to the 
extent that the comments were suggesting that FDA needs to revise the 
QSR in light of CLIA, FDA disagrees. CLIA and its implementing 
regulations and FDA's QSR are two different regulatory frameworks based 
in different statutory authorities intended to achieve different goals. 
Unlike CLIA and its implementing regulations, the QSR provides a basic 
framework of requirements critical for a quality system for 
manufacturing devices. These requirements are flexible, apply to many 
device types, and recognize that manufacturing circumstances may vary. 
Under the QSR, manufacturers are responsible for complying with those 
parts of the regulation that are applicable to their operations, and 
the QSR is intended to be sufficiently flexible to be applied to the 
spectrum of devices as well as manufacturers of varying size and 
operation type. Although FDA has adopted a policy described in this 
preamble that takes into account certain assurances provided by CLIA 
for LDTs (see section V.C), that policy does not mean that the 
requirements are duplicative or conflicting or that amendments to the 
QSR are required (see comment response 82).
    (Comment 183) Some comments argued that the QSR is not appropriate 
for laboratory testing and it does not cover all aspects of laboratory 
operation. A comment suggested that this is because laboratories that 
develop LDTs do not engage in manufacturing. Other comments stated that 
ISO 15189: Medical Laboratories (ISO 15189) is the more appropriate 
standard.
    (Response 183) As stated above, the QSR provides a basic framework 
of requirements critical for a quality system for manufacturing 
devices. These requirements are flexible, applying to many device 
types, and recognize that manufacturing circumstances may vary. Under 
the QSR, manufacturers are responsible for complying with those parts 
of the regulation that are applicable to their operations, and the 
regulation is intended to be sufficiently flexible to be applied to the 
spectrum of devices as well as manufacturers of varying size and 
operation type. In this manner, the QSR is suited to the manufacture of 
IVDs in laboratories. Furthermore, because the QSR focuses on assuring 
the quality of the device itself, it need not cover ``all aspects of 
laboratory operation.''
    FDA also disagrees with the comment that laboratories that develop 
LDTs do not engage in device manufacturing. Section 820.3(o) defines a 
manufacturer as ``any person who designs, manufactures, fabricates, 
assembles, or processes a finished device. Manufacturer includes but is 
not limited to those who perform the functions of contract 
sterilization, installation, relabeling, remanufacturing, repacking, or 
specification development, and initial distributors of foreign entities 
performing these functions.'' As explained in the NPRM and in section 
VI.D. of this preamble, LDTs are devices (88 FR 68006 at 68015-16). As 
such, when laboratories design, assemble, or process an LDT, they are 
manufacturers of a finished device and as such are subject to the QSR 
(for further discussion, see comment response 71).
    ISO 15189, similar to CLIA, specifies requirements for quality and 
competence in medical laboratories, focusing on the competencies and 
qualifications of laboratory personnel and testing processes. The QSR 
is focused on a robust quality system that promotes safety and 
effectiveness of the device itself through controls such as adequate 
management oversight, procedures for validating changes, monitoring, 
and audits, and plans for handling non-conformances. In contrast, ISO 
15189 does not address the processes involved in manufacturing an IVD, 
including design controls. Thus, ISO 15189 is not the appropriate 
standard for laboratory activities relating to device manufacturing.
    (Comment 184) Several comments suggested that compliance with the 
QSR is not warranted because of the quality management systems 
laboratories already have in place. One comment went on to state that 
such systems comply with Federal and State facility licensure 
requirements, CLIA certification, medical test site requirements, CAP 
accreditation, and participation in CLIA-required proficiency testing 
surveys/challenges. Another suggested that CLIA regulation and CAP 
combined are sufficient. Another comment suggested that FDA did not 
present scientific data that having multiple quality systems produces a 
better test result.
    (Response 184) FDA disagrees with these comments. As explained 
throughout this preamble, none of the requirements the comments 
referenced address the quality and manufacturing of the device itself. 
For example, the focus of CLIA is on the testing process as it is 
implemented in a given laboratory, focusing on the qualifications, 
responsibilities, and ongoing competencies of laboratory personnel, 
rather than the manufacture of the IVD itself. For more information 
about the differences between CLIA and FDA regulation, see our 
responses to comments in section VI.C.2.
    Some commenters pointed to participation in CLIA-required 
proficiency testing surveys/challenges, but those surveys/challenges 
are only required for certain analytes; the majority of IVDs offered as 
LDTs test for analytes that do not have required proficiency testing 
(Refs. 181 and 182). Proficiency testing events are performed on a 
regularly scheduled basis to assess whether laboratories are performing 
tests appropriately. Such testing is not intended to assess a 
laboratory's ability to continually manufacture safe and effective 
IVDs, nor does it establish the performance of a particular test, as 
further described in response to comment 9.
    With regard to CAP accreditation, as discussed in more detail in 
response to comment 18, CAP accreditation addresses the manner in which 
the laboratory performs a test and does not assess the laboratory's 
processes for making the test. Further, CAP accreditation is voluntary.
    As for state licensure requirements, the comment did not identify 
specific states or their requirements for FDA to assess. When FDA 
considered comments about New Jersey's laboratory certification program 
and Washington's medical test site program, it concluded that they are 
focused on laboratory operations, like CLIA, and do not provide 
assurances regarding the analytical and clinical validity of LDTs (Ref. 
84), see response to comment 22. FDA has included a policy for LDTs 
that are approved by NYS CLEP (see section V.B.2).
    While none of the existing requirements discussed here are 
duplicative of the QSR, FDA is adopting an enforcement discretion 
policy with respect to QS requirements for LDTs in recognition that 
compliance with CLIA requirements provides some quality assurances that 
may be relevant to laboratories' manufacturing practices, as described 
in section V.C.
    Finally, we disagree that FDA is required to produce or cite 
scientific data showing that ``having multiple quality systems produces 
a better test result.'' Regardless of the presence of other quality 
systems, the question is whether laboratory compliance with the quality 
system requirements under the FD&C Act, as applicable, will advance 
public health by helping assure that

[[Page 37392]]

IVDs are safe and effective. FDA has determined that it will, based on 
the evidence before it. FDA need not ``conduct or commission [its] own 
empirical or statistical studies'' to draw this conclusion. FCC v. 
Prometheus Radio Project, 141 S. Ct. 1150 at 1160.
    (Comment 185) A comment concurred with the QS requirements that FDA 
proposed to focus on for LDTs; however, the comment indicated that FDA 
should also focus on Sec.  820.70; production and process controls. The 
comment went on to state that CLIA does not fully address any of these 
regulations.
    (Response 185) FDA agrees that CLIA does not duplicate QS 
requirements. However, CLIA does provide some relevant assurances, 
including with respect to Sec.  820.70, in the context of manufacturing 
activities occurring within a single CLIA-certified laboratory that 
meets the regulatory requirements to perform high complexity testing 
and for which the IVD is not transferred outside that single 
laboratory. Section 820.70 requires manufacturers to develop, conduct, 
control, and monitor production processes to ensure that a device 
conforms to its specifications and to establish and maintain process 
control procedures where deviations from device specifications can 
occur due to the manufacturing process. This provision also has 
requirements addressing environmental controls, personnel cleanliness, 
contamination control, building suitability, equipment sufficiency, 
manufacturing material use and removal, and validation of software used 
in automated processes. CLIA regulations require that the laboratory 
have control procedures to monitor test accuracy and precision and 
detect immediate errors that occur due to test system failure, adverse 
environmental conditions, and operator performance (42 CFR 493.1256). 
This provision also addresses requirements for supply checks. 
Additionally, other CLIA requirements address facility requirements, 
including equipment, and personnel competency (42 CFR 493.1101 and 
1235). FDA determined that these requirements, in combination with the 
QS requirements on which FDA is focusing oversight (such as the design 
controls in Sec.  820.30), provide assurances relevant to Sec.  820.70.
    (Comment 186) Several comments raised concerns about the costs of 
compliance with the QSR. A comment took issue with FDA's statement, as 
characterized by the comment, that the final rule amending part 820 
would not impose new requirements because that was a comparative 
statement about the differences between FDA's proposed rule and the 
current part 820, but that many LDT manufacturers would be complying 
with part 820 for the first time. Other comments asserted that the cost 
of QS compliance will prohibit small companies from marketing tests, 
hurting patients.
    (Response 186) FDA acknowledges that many laboratories may not have 
experience with part 820. In the NPRM, FDA stated that FDA's proposed 
amendment of part 820 was substantially similar to the current QS 
requirements simply to explain that laboratories can use the current 
part 820 to understand FDA's requirements with respect to quality 
systems, and to prepare for compliance even though the final QS rule 
had not been issued at that time--not to diminish the effort needed to 
comply (see 88 FR 68006 at 68026).
    FDA continues to believe that QS compliance is important to help 
assure the safety and effectiveness of IVDs offered as LDTs, as 
explained throughout this preamble (see, e.g., section III.B.1). 
However, FDA has also considered the costs associated with QS 
compliance for laboratories, and has taken those costs into account in 
developing the policy for currently marketed IVDs offered as LDTs (see 
section V.B.3). Under that policy, FDA intends to exercise enforcement 
discretion and generally not enforce premarket review and QS 
requirements (except for requirements under part 820, subpart M 
(Records)), for currently marketed IVDs offered as LDTs that were first 
marketed prior to the date of issuance of this rule and that are not 
modified, or that are modified as described in section V.B.3. This 
policy applies to all laboratories, including small laboratories. In 
light of this policy, FDA disagrees that the cost of compliance with 
the QSR, alone, would cause small laboratories to close. (For more 
information about impacts on small businesses, see section VI.G). We 
note that in the FRIA, we estimate $71 million less in one-time costs 
for compliance with QS requirements for all affected entities compared 
to the PRIA, and $354 million less in annual recurring costs (see Ref. 
60).
    Further, as discussed in the NPRM and in this preamble, FDA intends 
to exercise enforcement discretion with respect to certain QS 
requirements for LDTs as discussed in section V.C.3, which may reduce 
costs for such laboratories.
    (Comment 187) A comment indicated that enforcing QS requirements 
for laboratories could have negative impacts on manufacturers of 
laboratory tools and instruments, and on producers of reagents and 
antibodies, because they may not be able to meet the supplier 
requirements. Another comment stated that the supplier requirements in 
Sec.  820.50 (purchasing controls) expand the responsibility of the 
laboratory professional beyond the CLIA requirements, and 
inappropriately place ``liability'' on laboratory professionals, who 
are acting as healthcare providers, for ensuring the quality of 
reagents instead of placing that responsibility on suppliers.
    (Response 187) The manufacturers of test components that are 
themselves finished devices, such as instruments, reagents, and 
antibodies, intended for clinical purposes should already be complying 
with the QSR, including requirements in Sec.  820.50, and thus we would 
not expect negative impacts on suppliers as a result of this phaseout 
policy. FDA agrees that when a laboratory manufacturer makes a test 
system using components that are not intended for clinical use, such as 
components labeled RUO, the laboratory is subject to the purchasing 
controls set forth in Sec.  820.50, which may require validation of 
such components for the clinical use.\87\ FDA acknowledges that 
laboratory manufacturers may prefer to source components manufactured 
under a QS to help assure the quality of their test.
---------------------------------------------------------------------------

    \87\ See Ref. 176, which states that it is important that 
research and investigational use only products should not be 
distributed for clinical diagnostic uses.
---------------------------------------------------------------------------

    Section 820.50 (purchasing controls) requires that manufacturers of 
finished devices assess the capability of their suppliers to produce 
acceptable components. When the manufacturer ensures that components, 
such as laboratory instruments, reagents, and antibodies, are adequate 
for the IVD's intended use, this helps to ensure the accuracy of the 
IVD being manufactured. Ultimately, the laboratory manufacturer cannot 
be sure that the specifications for a finished IVD are met if they did 
not take steps to ensure that the individual components of the finished 
device meet specifications. As such, FDA disagrees that such a supplier 
requirement is inappropriate. Enforcement of supplier requirements will 
provide assurances that IVDs continue to be manufactured with quality 
components over time.
    (Comment 188) A comment argued that the QSR does not translate well 
to laboratory activities, and that CLIA addresses many of the QS 
requirements on which FDA proposed to focus in the QS policy for LDTs. 
The comment stated that the acceptance activities in Sec. Sec.  820.80 
and 820.86 do not translate well to laboratories, specifically

[[Page 37393]]

highlighting the requirements in Sec.  820.80(d) and indicating, 
according to the commenter, that it is unclear how a laboratory might 
comply with the requirement that manufacturers establish and maintain 
procedures for finished device acceptance to ensure that each 
production run, lot, or batch of finished devices meets acceptance 
criteria. The comment also specified that a number of CLIA provisions 
in 42 CFR part 493, subparts J and K serve the same purposes as or 
cover the activities in Sec.  820.30 (design controls), Sec.  820.100 
(corrective and preventive action), and part 820, subpart M (records 
requirements).
    (Response 188) FDA disagrees that the CLIA regulations cited in the 
comment provide assurances relevant to the cited QS requirements in 
part 820. CLIA covers laboratory operations, including processes for 
handling and dealing with components and specimens, as well as 
documenting and responding to patient test result errors as a result of 
laboratory operations. None of the CLIA provisions include requirements 
for designing or monitoring issues with the IVD itself. For example, 42 
CFR 493.1241 addresses the need for a test request, 42 CFR 493.1242 
addresses policies for specimen handling, storage, and processing, 42 
CFR 493.1252 addresses proper storage of reagents and specimens, 42 CFR 
493.1253 addresses performance specification with regards to accuracy, 
precision, and range (without tying those specifications to the design 
of the test and without addressing design input and output review), and 
42 CFR 493.1290 and 1291 address other issues related to laboratory 
operations rather than faulty device design, including the content of 
test reports, handling of abnormal results, error reporting 
requirements, and assessment and resolution of identified problems with 
regard to patient test result errors.
    In contrast, the design controls in Sec.  820.30, at a high level, 
address: design and development planning, procedures for ensuring that 
the design requirements are appropriate for the device intended use, 
including design inputs, procedures for defining and documenting design 
outputs, procedures for design review, verification, and validation, 
and procedures for documenting and validating design changes. Each of 
these requirements aims to ensure that devices perform as intended, 
which is a concept not covered by the CLIA requirements.
    Similarly, the CLIA requirements on correcting errors (42 CFR 
493.1291) and records requirements (42 CFR 493.1251 (procedure manual), 
42 CFR 493.1101 (facilities), 42 CFR 493.1105 (retention requirements), 
42 CFR 493.1291 (test report), and 42 CFR 493.1283 (test records)) are 
focused on addressing laboratory errors and laboratory recordkeeping. 
The QS requirements are focused on assuring the quality of the IVD 
offered as an LDT itself, and compliance with these requirements 
addresses issues of device quality. As detailed in comment 182, CLIA 
and the QSR are complementary but different in focus.
    While FDA acknowledges that the terminology of the QSR may not be 
familiar to many laboratories, as stated in comment 181, FDA intends to 
engage in educational activities to assist laboratories in 
understanding compliance with the QSR. FDA disagrees that lack of 
familiarity means that the requirements are inappropriate for 
laboratories. The QSR is written in a flexible manner and there are 
many ways that a laboratory may comply with the QSR. For example, the 
comment cited uncertainty about how a laboratory would comply with 
acceptance activities in Sec. Sec.  820.80 and 820.86 generally, and 
specifically questioned the ability for laboratories to comply with 
finished device acceptance requirements in Sec.  820.80(d), which 
requires that manufacturers, including laboratories, establish and 
maintain procedures for finished device acceptance to ensure that each 
production run, lot, or batch of finished devices meets specified 
requirements; in other words, assessing whether the finished device is 
what you expected. For example, laboratories procure reagents from 
external sources for use as part of their LDT. The laboratory would 
need suitable methods to identify reagents in a way that distinguishes 
between those that have just been received and not yet evaluated, those 
that have been received and found unacceptable according to their 
purchasing controls, and those that have been received and found 
acceptable according to their purchasing controls and are therefore 
adequate for use as part of the final LDT. Manufacturers have the 
flexibility to choose a combination of methods to comply with these 
requirements, including finished device inspection and testing, 
acceptance criteria, and identification methods, provided such methods 
will accomplish the required result. For example, for final acceptance 
activities, laboratories may have a procedure that specifies the 
methods and materials and acceptance criteria (including confidence 
intervals) that would be used to assess whether the final LDT meets 
those specified acceptance criteria, prior to the LDT being used for 
clinical use.
    (Comment 189) A comment recommended that FDA establish an 
``umbrella approval'' for CGMP and software modules from each 
laboratory and that FDA should recognize results from third party 
quality efforts.
    (Response 189) In general, FDA does not ``approve'' manufacturing 
practices, although they are reviewed within the context of a PMA. We 
note that, in premarket applications, manufacturers may rely on 
information that they previously submitted to FDA by referencing where 
the information was provided in a previous submission. Establishment of 
an ``umbrella approval'' for CGMP and software modules is outside the 
scope of this rulemaking.
    With regards to third-party quality efforts, to the extent that the 
comment is referring to CAP accreditation or NYS CLEP assessments, see 
our response to comment 18 and section V.B.2 for more information on 
that topic.
13. Premarket Review Requirements
    (Comment 190) Several comments expressed concern that compliance 
with premarket review requirements would be infeasible and cost-
prohibitive for laboratories with limited resources and stated that FDA 
should take into account that these laboratories also pay fees to CMS 
associated with CLIA. One comment stated that FDA should ``[s]et 
reasonable pricing for LDT review and registration.'' One comment 
suggested that FDA should consider temporarily reducing user fees for 
premarket submissions during the phaseout timeline.
    (Response 190) In the final phaseout policy, in recognition of 
patient reliance and cost considerations, among other things, FDA has 
included policies for enforcement discretion with respect to premarket 
review for several categories of IVDs, as described in section V.B. 
These policies should help address some of the concerns raised by the 
comments.
    With respect to fees, FDA is unable to unilaterally change user fee 
amounts or adjust user fees to take into consideration other fees that 
laboratories may pay to CMS pursuant to CLIA. User fees associated with 
establishment registrations and certain premarket submissions are 
established by Congress in MDUFA. Under the current reauthorization of 
MDUFA, payment of either a standard fee or a small business fee is 
required for each submission type identified in 21 U.S.C.

[[Page 37394]]

379j(a)(2)(A) (unless the applicant qualifies for a fee waiver or for 
an exception under 21 U.S.C. 379j(a)(2)(B)). Payment of an 
establishment registration fee is required at the time of initial or 
annual registration (as applicable), except as provided in 21 U.S.C. 
379j(a)(3)(B). More information about user fees is available on FDA's 
user fee website (see Ref. 183). However, FDA will have an opportunity 
to negotiate with industry regarding user fees at the time of the next 
reauthorization of MDUFA, which will occur in advance of stages 4 and 5 
of the phaseout policy (when FDA intends to phase out the general 
enforcement discretion approach for premarket review requirements).
    FDA disagrees that compliance with premarket review requirements is 
likely to be infeasible for laboratories with limited resources. As 
just noted, the existing program incorporates a different user fee 
amount for small businesses (see 21 U.S.C. 379j(d) and (e)), and review 
can occur relatively quickly when an IVD has been appropriately 
validated for its intended use. In addition, FDA implements premarket 
review consistent with several ``least burdensome'' statutory 
provisions and in accordance with Agency policy. This topic is 
discussed in detail in FDA's final guidance document entitled ``The 
Least Burdensome Provisions: Concept and Principles,'' which defines 
``least burdensome'' to mean the minimum amount of information 
necessary to adequately address a relevant regulatory question or issue 
through the most efficient manner at the right time (Ref. 72). FDA also 
encourages IVD manufacturers to take advantage of FDA's industry 
resources, including final guidance documents and resources available 
through the Division of Industry and Consumer Education within CDRH 
(see Ref. 184). These resources may facilitate efforts by laboratories 
to comply with premarket review requirements and other applicable 
requirements. Ultimately, FDA recognizes that laboratories will need to 
make investments to comply with premarket review requirements, but 
these investments are important to help ensure that IVDs are 
appropriately safe and effective, so that patients and providers can 
rely on test results for clinical decision-making.
    (Comment 191) We received several comments asking specific 
questions about what and how different types of data should be 
presented in premarket submissions, and how to know when a premarket 
submission is required, especially for modifications. For example, 
comments asked what specific data are necessary to bridge a premarket 
authorization to new specimen types, how to handle database curation 
for sequencing assays, and what types of software applications are 
considered part of a test system. Another comment stated that the NPRM 
did not provide sufficient guidance on what amount or type of data may 
be required.
    (Response 191) FDA appreciates that many laboratory manufacturers 
may not be familiar with FDA's regulations and the premarket submission 
process. FDA intends to consider providing guidance on various topics 
and making additional resources available over the course of the 
phaseout period as appropriate, including on the topic of premarket 
review of IVDs offered as LDTs. FDA has already made resources 
available on several of the specific topics identified by the comments, 
including FDA's final guidance documents entitled ``Deciding When to 
Submit a 510(k) for a Change to an Existing Device'' and 
``Modifications to Devices Subject to Premarket Approval (PMA)--The PMA 
Supplement Decision-Making Process,'' regarding modifications to 
devices (Refs. 61 and 185); information regarding the CLSI EP35 
standard (1st Edition), ``Assessment of Equivalence or Suitability of 
Specimen Types for Medical Laboratory Measurement Procedures,'' 
regarding bridging to new specimen types (Ref. 186); FDA's final 
guidance document entitled ``Use of Public Human Genetic Variant 
Databases to Support Clinical Validity for Genetic and Genomic-Based In 
Vitro Diagnostics,'' regarding database curation (Ref. 187); and FDA's 
final guidance documents entitled ``Clinical Decision Support 
Software,'' ``General Principles of Software Validation,'' and 
``Content of Premarket Submissions for Device Software Functions,'' 
regarding software (Refs. 188 to 190). The amount and type of data 
needed in premarket submissions varies depending on the circumstances. 
For questions that are specific to a particular IVD, laboratory 
manufacturers may request feedback from FDA through a Pre-Submission, 
which is further explained in FDA's final guidance document entitled 
``Requests for Feedback and Meetings for Medical Device Submissions: 
The Q-Submission Program'' (Ref. 65).
    (Comment 192) One comment questioned how premarket submissions may 
account for the various components of a test (e.g., extraction kits, 
instrument platform, software, or reagent) when those components may 
not be manufactured by the laboratory manufacturer and the laboratory 
manufacturer may consider them to be interchangeable.
    (Response 192) In the scenario described in the comment, the 
laboratory manufacturer is expected to establish specifications for 
such components and have purchasing and acceptance controls to ensure 
each component meets specifications. This is critical to help ensure 
the quality of the test over time. While evidence of purchasing and 
acceptance controls are generally not part of premarket review for 
510(k) and De Novo submissions, they are required elements of a quality 
system. In addition, under the design control provisions of the QSR, 
the laboratory would be expected to validate its test system, including 
all components per established specifications, for its intended use. 
During premarket review, FDA would review analytical and clinical 
validation information for the test system. For PMAs, FDA would also 
review applicable quality system information.
    (Comment 193) Some comments addressed what FDA should consider as 
evidence of a reasonable assurance of safety or effectiveness in 
premarket submissions for IVDs offered as LDTs. Some comments stated 
that clinical trials ``should not be required'' because they are too 
burdensome. One comment stated that FDA should expect less information 
in premarket submissions when tests are designed for use on 
``commercially'' available instruments and using ``commercially'' 
available reagents. Another comment suggested that FDA consider peer-
reviewed evidence of clinical validity and clinical utility and prior 
reviews by other regulatory bodies.
    (Response 193) The content that must be included in a premarket 
submission can vary greatly based on several factors, including the 
type of submission and the type of device. Data relevant to the 
evaluation of a submission for one type of test may not be relevant to 
evaluating submissions for other types of tests. However, in general, 
FDA does not agree that the amount and type of evidence included in a 
particular submission should vary based on whether the IVD is 
manufactured by a laboratory or another manufacturer. FDA encourages 
IVD manufacturers to request feedback on individual submissions through 
FDA's Pre-Submission program, which is further explained in FDA's final 
guidance document entitled ``Requests for Feedback and Meetings for 
Medical Device Submissions: The Q-Submission Program'' (Ref. 65). FDA 
also implements premarket review consistent with several ``least

[[Page 37395]]

burdensome'' statutory provisions and in accordance with Agency policy. 
This topic is discussed in detail in FDA's final guidance document 
entitled ``The Least Burdensome Provisions: Concept and Principles'' 
(Ref. 72).
    With respect to the consideration of peer-reviewed evidence, FDA 
would not expect laboratories to generate additional clinical validity 
data when available literature is adequate to demonstrate that the IVD 
is clinically valid. In reviewing submissions for IVDs, FDA considers 
applicable information from the literature submitted by the applicant. 
In addition, as discussed in response to comment 203, FDA has published 
a final guidance document describing a recognition program for publicly 
accessible databases of human genetic variants as sources of valid 
scientific evidence for genetic and genomic tests (Ref. 188). Under 
this policy, test manufacturers can use information in FDA-recognized 
databases to support the clinical validity of their tests.
    FDA disagrees that FDA should expect less information in premarket 
submissions when tests are designed for use on ``commercially'' 
available instruments and with ``commercially'' available reagents. 
FDA's expectations for validation apply to the test system, which 
includes use of all components together. Any given instrument or 
reagent may be a part of a test system that works well and part of 
another test system that does not.
    With respect to the comment suggesting that FDA consider prior 
reviews by other regulatory bodies, as described elsewhere in this 
preamble, FDA anticipates expanded use of the Third Party review 
program and intends to exercise enforcement discretion with respect to 
premarket review requirements for LDTs approved by NYS CLEP. Further, 
FDA will continue ongoing efforts towards international harmonization 
with other regulatory bodies.
    (Comment 194) One comment expressed concern that FDA does not have 
the level or depth of expertise necessary to review premarket 
submissions for highly complex LDTs. Another comment stated that the 
NPRM was focused largely on clinical pathology, and that FDA has not 
considered that the large quantity of premarket submissions FDA will 
receive will be more varied and challenging, and include digital 
pathology products incorporating artificial intelligence/machine 
learning, liquid biopsies, multiplex assays, multianalyte tests 
incorporating complex algorithms, and whole genome sequencing.
    (Response 194) FDA disagrees with the comment's suggestion that FDA 
has failed to consider a wide range of IVDs in connection with this 
rulemaking, such as the products listed in the comment. FDA is familiar 
with these products, as discussed below, and has taken into account its 
experience with IVDs generally in issuing this rule. FDA also notes 
that the term ``clinical pathology'' is broad. According to the 
Association of Academic Medical Centers, clinical pathology includes 
many subspecialties, including blood banking-transfusion medicine, 
chemical pathology, clinical informatics, cytopathology, hematology, 
microbiology, and molecular genetic pathology, among others.
    FDA also disagrees that it lacks the level or depth of expertise 
necessary to evaluate premarket submissions for a wide variety of 
challenging and varied highly complex IVDs offered as LDTs. FDA employs 
hundreds of scientists with expertise in the review of IVD safety and 
effectiveness, including those who have worked in clinical laboratories 
and developed LDTs. This expertise includes knowledge of digital 
pathology products, liquid biopsy-based tests, multiplex assays, multi-
analyte tests incorporating complex algorithms, and whole genome 
sequencing, among other things. FDA also works with experts across 
offices, including experts in the Digital Health Center of Excellence 
on artificial intelligence/machine learning matters. For example, FDA 
has already authorized artificial intelligence/machine learning-based 
software (see Ref. 191), digital pathology tests incorporating 
artificial intelligence/machine learning (see Ref. 192), liquid biopsy 
assays (see, e.g., Refs. 144 and 193), multiplex assays (see, e.g., 
Refs. 194 and 195), multi-analyte tests incorporating complex 
algorithms (see, e.g., Refs. 196 and 197), and exome sequencing based 
NGS tests (see, e.g., Refs. 198 and 199).
    (Comment 195) Several comments requested clarity around device 
classification and offered suggestions for how FDA should classify IVDs 
offered as LDTs, including what factors should be considered. One 
comment suggested FDA determine and continuously seek input on 
classification of tests through a public process. Another comment 
suggested FDA use a request for information process to gather 
information on currently available IVDs offered as LDTs and use that 
data to establish classification panels that IVD manufacturers could 
look to as a resource in the premarket submission process, which would 
save them time and resources. Some comments stated that, when 
classifying tests, FDA should consider context, including how widely a 
test is distributed; whether it is offered by a laboratory that is 
integrated into patient care; and the history of the test manufacturer, 
including with respect to validation generally and for specific tests.
    (Response 195) As discussed more fully in section VI.P of this 
preamble, FDA already has processes in place and has made multiple 
resources available to industry to help manufacturers determine the 
classification of their devices. FDA notes that some IVDs offered as 
LDTs may already be classified under existing classification 
regulations. FDA recommends that stakeholders consult FDA's 
classification database for more information (Ref. 200). Laboratory 
manufacturers may also seek feedback from FDA through a Pre-Submission, 
or may submit a request for information regarding the class in which a 
device is classified or the requirements applicable to a device under 
section 513(g) of the FD&C Act.
    We note that standards for classification of a device are set forth 
in statute (21 U.S.C. 360c(a)). The existing device classification 
processes focus on the risk of the IVD itself and availability of 
controls to address such risk. In classifying devices, FDA considers, 
among other things, the device's intended use and indications for use, 
which includes consideration of the intended patient population. The 
risk the device poses to the patient and/or the user is a major factor 
in the class it is assigned. Refer to FDA's web page for more 
information on classification (Ref. 201).
    With regard to the request for FDA to continuously seek input on 
classification of tests through a public process, we agree that public 
input can be important, and in fact required, in certain circumstances.
    Among other things, there is a public process when FDA classifies a 
preamendments device for the first time under section 513(d) of the 
FD&C Act. This process involves a public meeting of the appropriate 
advisory committee panel and notice and comment rulemaking.
    Postamendments devices are deemed to be class III by operation of 
law under section 513(f)(1) of the FD&C Act, but such devices can be 
reclassified under different processes. Under section 513(f)(3) of the 
FD&C Act, for example, stakeholders can petition FDA to change the 
classification of these devices (see Sec.  860.134(b) (21 CFR 
860.134(b))). FDA can also initiate reclassification under section 
513(f)(3) of the FD&C Act, and

[[Page 37396]]

under that process, the public would have an opportunity to review and 
comment on the proposed classification and special controls, if 
applicable, which are published first by proposed order in the Federal 
Register (see Sec.  860.134(c)). In addition, a manufacturer can submit 
a De Novo classification request under section 513(f)(2) of the FD&C 
Act requesting reclassification to class II or class I. FDA acts on 
such requests through written order, without a public comment process.
    (Comment 196) Some comments stated that FDA's three-tier 
classification system for devices does not translate well to IVDs 
offered as LDTs. These comments expressed concern that FDA would 
inappropriately classify many IVDs offered as LDTs as high risk ``when 
in reality their risk is mitigated by the fact that they are part of a 
multi-faceted medical assessment and are rarely used in isolation for 
clinical decision-making.'' Some comments stated that most LDTs should 
be considered low- or moderate-risk because they are typically used as 
only one part of a more comprehensive patient evaluation and not the 
singular factor for clinical decisions. One comment stated that ``LDTs 
are comprised of not only medical products, but also analytic 
processes,'' and suggested that ``A regulatory review process for LDTs 
should consider both and achieve an appropriate balance between the two 
given where the risk lies in a particular test.''
    (Response 196) FDA disagrees that FDA's device classification 
system does not translate well to IVDs offered as LDTs. FDA determines 
the risk class of devices, including IVDs, by applying the statutory 
standards set forth in the FD&C Act, including standards for class I 
(low-risk), class II (moderate-risk), and class III (high-risk) 
devices. See 21 U.S.C. 360c(a)(1). FDA's classification decisions take 
into account the risk of a device, which may depend on whether the 
device is the sole determinant for clinical decision-making, among 
other things. FDA is not aware of any unique feature of IVDs offered as 
LDTs that renders the statutory standards less applicable or less 
appropriate for these IVDs.
    To the extent that the comments were suggesting that IVDs offered 
as LDTs are unique because they are ``part of a multi-faceted medical 
assessment and are rarely used in isolation for clinical decision-
making,'' FDA disagrees. Many IVDs are indicated for use in conjunction 
with clinical assessments and not as the sole basis for clinical 
decisions, so IVDs offered as LDTs are not unique in that respect. For 
example, class III prostate specific antigen tests are intended to be 
used in conjunction with a digital rectal exam to aid in the detection 
of prostate cancer in men aged 50 years and older. Class II Duchenne 
muscular dystrophy newborn screening tests are intended to be used in 
conjunction with other clinical and diagnostic findings to aid in the 
screening of newborns. Class I cholesterol tests are intended to be 
used to aid in the diagnosis of lipid disorders. In general, any IVD, 
regardless of class, that is indicated to ``aid in the diagnosis'' of a 
clinical condition is intended to be used in conjunction with clinical 
assessments. Therefore, use in the context of a ``multi-faceted medical 
assessment'' is not unique to IVDs offered as LDTs.
    FDA also disagrees that IVDs offered as LDTs should be considered 
low or moderate risk whenever they are part of a multifaceted medical 
assessment (i.e., are not used in isolation for clinical decision-
making). Even if such tests are used as a part of a multifaceted 
medical assessment and are not the sole determinant for clinical 
decision-making, false positive or false negative test results can 
still lead to unwarranted interventions or progression of disease 
without necessary intervention. Given the role that IVDs offered as 
LDTs play in modern medical care, test validity has a significant 
impact on the public health. However, FDA notes that most currently 
classified IVDs have been determined by FDA to be low or moderate risk 
(class I or class II).
    With regard to the suggestion that FDA's regulatory review process 
should consider that LDTs are comprised of both ``medical products'' 
and ``analytic processes,'' the comment provided no additional 
discussion of these terms, and FDA is not clear on the distinction the 
commenter intended to draw. To the extent the commenter meant to 
distinguish between medical devices and the ``practice of medicine,'' 
see our responses to comments in section VI.D.6. With regard to the 
suggestion that FDA take a balanced approach in light of a test's 
risks, FDA agrees. We take a risk-based approach to the devices we 
regulate and determine the level of regulation warranted to provide 
reasonable assurance of safety and effectiveness. On January 31, 2024, 
FDA announced that it is undertaking an effort to initiate the process 
to reclassify most IVDs that are currently class III into class II 
because FDA believes there is sufficient information to establish 
special controls that, together with general controls, will provide a 
reasonable assurance of safety and effectiveness for these tests. The 
majority of these tests are infectious disease and CDx IVDs (Ref. 66). 
FDA aims to complete this reclassification process before stage 4 of 
the phaseout policy.
    (Comment 197) One comment questioned how a high-risk IVD offered as 
an LDT that uses a class I instrument could be classified into a 
different class than the instrument, and whether the instrument would 
need to go through premarket review based on the classification of the 
high-risk IVD offered as an LDT.
    (Response 197) The regulatory requirements applicable to a 
particular device can vary depending on the device's intended use. For 
example, the same instrument may be subject to certain requirements 
when it is not intended for use as part of a particular test system and 
subject to a different set of requirements when it is intended for use 
as part of a particular test system. Most instruments not intended for 
use as part of a particular test system are classified as class I 
510(k)-exempt. However, if a manufacturer seeks to market a test system 
that includes such an instrument as a component, the instrument would 
be reviewed under the standards applicable to the overall test system. 
For example, in the context of a submission for a high-risk test 
system, FDA would review information to support use of the instrument 
in that test system.
    (Comment 198) Several comments proposed that FDA streamline 
premarket submission or review for some or all IVDs offered as LDTs. 
Comments stated that FDA review should be expedited so that care is not 
delayed, and that quick turnaround times are particularly needed for 
infection prevention and control. Some comments suggested specific 
approaches FDA could take. One comment asked FDA to consider 
maintaining a MAF containing core data submitted by a manufacturer, 
which other laboratories could then draw from and use rather than 
repeat a data collection. Another comment suggested FDA provide 
standardized templates to help the manufacturers of IVDs offered as 
LDTs present data in a consistent and understandable format. Another 
comment suggested that FDA identify strategies to streamline validation 
of tests when there are well characterized biomarkers or numerous tests 
with a similar intended use.
    (Response 198) Premarket pathways and certain submission 
requirements are

[[Page 37397]]

set forth in the FD&C Act,\88\ and FDA cannot change those 
requirements. In addition, to the extent that the comments were 
suggesting that FDA should have a different approach to implementing 
premarket review for IVDs offered as LDTs compared with other IVDs, FDA 
disagrees.
---------------------------------------------------------------------------

    \88\ Some devices that are also biological products are licensed 
under the PHS Act.
---------------------------------------------------------------------------

    However, in general, FDA supports tools for more efficient 
premarket review as consistent with applicable law. For example, FDA's 
device MAF system is available to device manufacturers, including 
laboratory sponsors of IVDs offered as LDTs. A laboratory sponsor can, 
with the data owner's permission, reference specific MAFs in a 
premarket submission for a third party's data and other information 
related to the subject IVD offered as an LDT. The MAFs would allow 
FDA's confidential review of such information to facilitate scientific 
evaluation of the IVD without disclosing trade secret or confidential 
information to the sponsor laboratory (see Ref. 202 for more details). 
Such use of MAFs in a manner that eliminates unnecessary burdens is 
consistent with the least burdensome principles directed by Congress.
    FDA appreciates that standardized templates or additional guidance 
regarding data presentation and test validation may facilitate efforts 
by laboratories to comply with applicable premarket review 
requirements. As discussed more fully in response to comment 291, FDA 
anticipates issuing a small entity compliance guide, and intends to 
consider issuing additional guidance documents as appropriate and 
making additional resources available on specific topics, including 
test validation, over the course of the phaseout period. As described 
further in response to comment 293, there are multiple resources to 
help manufacturers, including laboratories, understand the type of data 
and information, including validation data and information, that is 
included in support of premarket submissions for IVDs. As stated 
elsewhere, FDA implements premarket review, including its review of 
analytical and clinical validation data, consistent with several 
``least burdensome'' statutory provisions and in accordance with Agency 
policy. This topic is discussed in detail in FDA's final guidance 
document entitled ``The Least Burdensome Provisions: Concept and 
Principles,'' which defines ``least burdensome'' to mean the minimum 
amount of information necessary to adequately address a relevant 
regulatory question or issue through the most efficient manner at the 
right time (Ref. 75). Consistent with FDA's least burdensome 
principles, if available literature is adequate to demonstrate that the 
clinical validity of the biomarker detected by the test is well-
established, FDA considers such applicable information from the 
literature submitted by the applicant.
    (Comment 199) One comment suggested that FDA collaborate with CDC 
and other Federal agencies so that each public health laboratory does 
not need to submit a separate PMA to obtain premarket approval for 
their shared test types. The comment noted that this suggested approach 
would alleviate challenges when the public health laboratory does not 
hold the validation dataset, which, for some test types, is validated 
by Homeland Security and the Laboratory Response Network.
    (Response 199) When a laboratory submits an application for 
premarket approval of an IVD, that application can include information 
to support the distribution of that IVD to other laboratories; for 
example, CDC can obtain approval for a test that involves the 
distribution of that test to the Laboratory Response Network. In 
addition, as discussed above, data owners may choose to submit a MAF 
and provide a right of reference to specific laboratories, which in 
turn can reference the data and information in the MAF in their PMA 
applications.
    (Comment 200) One comment suggested that FDA work with CMS, CAP, 
and the Joint Commission to align requirements for clinical 
laboratories when performing validation experiments to avoid creating 
redundant and misaligned regulations that will lead to costly delays.
    (Response 200) FDA is responsible for implementing the requirements 
of the FD&C Act with respect to IVDs, including requirements for safety 
and effectiveness of IVDs offered as LDTs. FDA takes a least burdensome 
approach in its implementation of premarket review requirements, in a 
manner that strives to eliminate redundancy and unnecessary burdens. 
However, this approach does not change the applicable statutory and 
regulatory requirements for premarket review, including premarket 
submission content requirements and requirements for valid scientific 
evidence. As discussed more fully in sections VI.C.2 and VI.C.3, CMS 
and laboratory accreditation bodies, such as CAP and the Joint 
Commission, address clinical laboratory operations and personnel, but 
do not address critical aspects of laboratory development, such as 
clinical validity. FDA has both the authority and the expertise to 
oversee IVDs offered as LDTs to better assure the safety and 
effectiveness of these devices. In addition, FDA and CMS meet regularly 
to share information and coordinate our approaches, as appropriate, and 
will continue to do so upon implementation of this rule.
    FDA appreciates that additional guidance regarding IVD validation 
may facilitate efforts by laboratories to comply with premarket review 
requirements. FDA intends to consider issuing additional guidance 
documents as appropriate, and making additional resources available on 
specific topics, which may include clinical validity, over the course 
of the phaseout period. See our response to comment 291.
    (Comment 201) We received comments asking what standard FDA will 
apply for IVDs offered as LDTs that remain on the market while FDA 
reviews a premarket submission for that IVD. One comment urged FDA to 
``allow'' these IVDs to remain on the market while the laboratory 
manufacturer addresses FDA's questions unless there is a likelihood of 
serious harm. Another comment asked FDA to confirm whether the Agency 
commits to take action on premarket submissions during the same stage 
in which sponsors are expected to submit them (e.g., during stage 4 for 
high-risk LDTs).
    (Response 201) As described in section V.C, in stage 4 of the 
phaseout policy (3\1/2\ years after publication of this final rule), 
FDA is phasing out the general enforcement discretion approach with 
respect to premarket review requirements for high-risk IVDs offered as 
LDTs. In stage 5 (4 years after publication of this final rule), FDA is 
phasing out the general enforcement discretion approach with respect to 
premarket review requirements for moderate-risk and low-risk IVDs 
offered as LDTs (that are subject to premarket submission 
requirements). As described in section V.C, FDA generally does not 
intend to enforce against IVDs offered as LDTs for lacking premarket 
authorization after a complete PMA, HDE application, 510(k), BLA, or De 
Novo request has been submitted to FDA (by the corresponding stage of 
the phaseout policy) until FDA completes review of the submission. We 
note, however, that regardless of the phaseout timeline and enforcement 
discretion policies in this preamble, FDA retains discretion to pursue 
enforcement action at any time against violative IVDs when appropriate.
    The phaseout policy does not address the timeframe within which FDA 
will complete review of premarket

[[Page 37398]]

submissions. FDA's timeline for phasing out the general enforcement 
discretion approach with respect to premarket review requirements 
aligns with the next reauthorization of MDUFA, which will provide an 
opportunity for FDA and industry to negotiate regarding user fees and 
performance goals with the knowledge that laboratory manufacturers will 
generally be expected to comply with applicable premarket review 
requirements.
    (Comment 202) Several comments asked how premarket authorization 
will work when it is possible FDA will receive several De Novo requests 
for the same type of test. One comment stated that there would be a 
disincentive to being the first to submit a De Novo request for novel 
tests (specifically in reference to laboratories creating new intended 
uses for FDA-authorized tests) because such requests require payment of 
a higher user fee than 510(k) submissions. FDA also received comments 
asking about the logistics of the premarket review process when 
sponsors may not know whether another entity has submitted a De Novo 
request for the same type of test.
    (Response 202) FDA has issued multiple final guidance documents 
outlining our policies for De Novo requests, including ``De Novo 
Classification Process (Evaluation of Automatic Class III 
Designation)'' (Ref. 203) and ``Acceptance Review for De Novo 
Classification Requests'' (Ref. 204), in addition to a final rule 
entitled ``Medical Device De Novo Classification Process'' (86 FR 
54826, October 5, 2021).
    With respect to the comments asking about the logistics of the 
premarket review process when multiple sponsors have submitted De Novo 
requests for the same type of IVD, FDA generally would not disclose the 
existence of a De Novo request under review to other submitters, but 
would notify them if/when a De Novo request for the same device type is 
granted. As further explained in our final guidance document entitled 
``De Novo Classification Process (Evaluation of Automatic Class III 
Designation),'' when a De Novo request is granted while other devices 
of the same type are under review in additional De Novo requests, the 
additional De Novo requests will be declined. The submitters of the 
declined De Novo requests will be required to demonstrate substantial 
equivalence to the IVD that was granted a De Novo in a 510(k) 
submission, and comply with any applicable special controls for the 
device type; the sponsor may use all information in their initial De 
Novo request by incorporating it by reference into the new 510(k) 
submission.
    To the extent this process and the higher user fees associated with 
De Novo requests compared to 510(k) submissions may disincentivize 
submission of De Novo requests for novel IVDs, as suggested in one 
comment, this concern is not specific to IVDs offered as LDTs, but 
rather relates to all devices. FDA is not changing the De Novo and 510k 
frameworks through this rulemaking.
    (Comment 203) One comment requested guidance on how to handle 
database curation for sequencing assays, specifically regarding adding 
to databases without having to submit an application to FDA, and 
regarding regulations for curated databases pertaining to the 
authenticity and security of data and obtaining proper documentation 
for database submissions prior to inclusion in the database.
    (Response 203) FDA has published a final guidance document entitled 
``Use of Public Human Genetic Variant Databases to Support Clinical 
Validity for Genetic and Genomic-Based In Vitro Diagnostics,'' which 
describes a recognition program for publicly accessible databases as 
sources of valid scientific evidence for genetic and genomic tests 
(Ref. 187). This final guidance addresses recommendations for 
appropriate curation of publicly accessible databases using human 
expert evaluation, including recommendations around database procedures 
and operations, data quality and security, variant evaluation and 
assertions, and professional training and conflicts of interest. FDA 
recognition of a database indicates that FDA believes the data and 
assertions contained in the database can be considered valid scientific 
evidence. Test manufacturers can use the assertions within FDA-
recognized databases to support the clinical validity of their tests.
    We note that the clearance/approval of a PCCP may help 
manufacturers avoid the need for PMA supplements or new 510(k)s for 
modifications to a database that is used as part of test result 
generation. PCCPs provide the opportunity for a manufacturer to 
prospectively outline how changes to a device will be validated and 
implemented. This may include how a database that is used as part of 
the test result generation may be updated, such as to add variants. FDA 
can review and clear or approve the PCCP during review of a premarket 
submission. Manufacturers would not need to submit a PMA supplement or 
new 510(k) for subsequent changes when such changes are in accordance 
with the authorized PCCP. This approach has been successfully employed 
for various FDA-authorized IVDs.
    (Comment 204) FDA received comments with specific questions about 
FDA premarket review, including the review process, FDA response 
timelines, associated user fees, and appeal rights, among other 
subjects.
    (Response 204) Notably, neither the regulation amendment nor the 
phaseout policy changes applicable FDA requirements for IVDs or IVD 
manufacturers. As noted throughout this preamble, FDA has published 
numerous final guidance documents and resources for industry with 
information on how to comply with applicable requirements, including 
requirements for premarket review. We encourage interested parties to 
consult these materials, including final guidance documents and 
resources available through the Division of Industry and Consumer 
Education within CDRH (see Ref. 184). As appropriate, FDA also intends 
to develop guidance documents specific to the final phaseout policy, 
which will be forthcoming during implementation.

G. Impact on Small Businesses

    (Comment 205) FDA received comments expressing concern that phasing 
out the general enforcement discretion approach for LDTs will put 
financial and administrative pressure on small laboratories, resulting 
in laboratory closures, consolidation of smaller entities, and 
monopolies in the testing space as large laboratories take more of the 
market share. Several comments stated that large laboratories will be 
advantaged as they have the resources to afford the necessary staffing 
and other costs related to test development and regulatory submission 
and emphasized the thin financial margins with which small laboratories 
operate. Some comments stated that the impact on small laboratories 
will result in a loss of expertise and infrastructure. In addition, 
comments noted that such centralization of LDTs at large laboratories 
may negatively impact medical education and training in pathology.
    (Response 205) FDA appreciates the concerns regarding financial and 
administrative challenges for smaller laboratories. FDA anticipates 
that the enforcement discretion policies discussed in section V.B will 
sufficiently address these concerns and help to avoid undue disruption 
to the testing market. For example, FDA intends to exercise enforcement 
discretion and generally not enforce premarket review and QS 
requirements (except for requirements under part 820,

[[Page 37399]]

subpart M (Records)) for currently marketed IVDs offered as LDTs that 
were first marketed prior to the date of issuance of this rule and that 
are not modified, or that are modified as described in section V.B.3. 
Premarket review costs and QS costs are a significant portion of the 
overall costs associated with compliance with applicable requirements 
under the FD&C Act and FDA's regulations, as described in section 
II.F.5 of the FRIA (see Ref. 10). Small laboratories that do not incur 
such costs will face significantly less of the financial and 
administrative pressure that the comments describe, reducing the 
likelihood of laboratory closures, laboratory consolidation, and 
monopolies predicted by the comments. For further discussion see 
section III.B of the FRIA. FDA also intends to issue a small entity 
compliance guide, which will assist small entities in complying with 
applicable requirements. For discussion of the potential impact of the 
phaseout policy on medical education and training, see our response to 
comment 301.
    (Comment 206) Some comments enumerated specific questions for FDA 
regarding compliance and requested clarification as to whether FDA will 
make materials available to help small businesses come into compliance.
    (Response 206) FDA intends to provide additional resources on 
specific topics that may be useful as laboratories come into compliance 
with applicable requirements, as discussed in response to comment 291. 
In addition, as noted in response to comment 205, FDA intends to issue 
a small entity compliance guide to provide additional guidance to small 
businesses.

H. Impact on Pricing

    (Comment 207) Several comments stated that ending the general 
enforcement discretion approach for LDTs will lead to higher prices for 
clinical tests due to the costs of complying with applicable FDA 
requirements. Some comments further stated that the costs of complying 
with applicable requirements will result in the closure of many 
laboratories, the outsourcing of certain laboratory testing, or other 
supply chain contractions, which in turn will increase the costs of 
tests due to decreased test availability, decreased market competition, 
and increased handling costs (e.g., costs associated with shipping 
samples to a centralized laboratory), or supply chain contractions. One 
comment expressed skepticism regarding FDA's statement that any losses 
may be offset by the market entry of IVDs from other manufacturers. FDA 
also received a comment which argued that increased prices for clinical 
tests will disincentivize people from seeking preventive care until 
they suffer an emergency, which will increase costs for the overall 
healthcare system. Collectively, these comments suggested that 
laboratories will pass increased costs to their customers, which some 
comments noted could result in higher insurance premiums. However, one 
comment stated that insurance companies will be more likely to cover 
tests (because they will have FDA authorization), which may allow for 
greater access to more affordable testing. Payors themselves commented 
in support of the rule ``given the proliferation of laboratory 
developed tests (LDTs) and concerns about the reliability of certain 
LDTs.'' One comment noted that it is inaccurate to assume that LDTs are 
always cheaper.
    (Response 207) FDA recognizes that laboratories may pass the costs 
of compliance with applicable requirements, including the specific 
examples listed in the comments, to their customers by raising prices 
for IVDs offered as LDTs. We also recognize that if many laboratories 
reduce operations or exit the market, production may be concentrated in 
a few large laboratories, which may cause prices for certain IVDs 
offered as LDTs to increase. As we noted in section II.F.6 of the PRIA 
and the FRIA (Ref. 60 and 10), the exact effect of the phaseout policy 
on the price of IVDs offered as LDTs is unknown. A few comments 
received by FDA included discussion of the price differential between 
unauthorized LDTs and FDA-authorized tests, but comments did not 
otherwise provide empirical data to inform FDA's assessment of effects 
on test prices.
    However, we note that in the final phaseout policy, after 
considering the public comments received on the NPRM, FDA has included 
certain enforcement discretion policies. As described in section V.B.3, 
FDA intends to exercise enforcement discretion and not enforce 
premarket review and QS requirements (except for requirements under 
part 820, subpart M (Records)) for currently marketed IVDs offered as 
LDTs that were first marketed prior to the date of issuance of this 
rule and that are not modified, or that are modified in certain limited 
ways as described in section V.B.3. In addition, FDA intends to 
exercise enforcement discretion and generally not enforce premarket 
review requirements for LDTs approved by NYS CLEP. FDA also intends to 
exercise enforcement discretion and generally not enforce premarket 
review requirements and QS requirements (except for requirements under 
part 820, subpart M (Records)) for LDTs manufactured and performed by a 
laboratory integrated within a healthcare system to meet an unmet need 
of patients receiving care within the same healthcare system.
    As noted in response to comment 205, the costs of compliance with 
premarket review requirements (as well as QS requirements) are a 
significant portion of the overall anticipated costs to laboratories of 
complying with applicable FDA requirements (see section II.F.5 of the 
FRIA (Ref. 10)). As a result, FDA's determination to include the 
enforcement discretion policies described above in the final phaseout 
policy may significantly reduce the costs of compliance under the final 
phaseout policy, thus reducing the number of laboratories that scale 
back operations or exit the market. FDA estimates the annualized cost 
over 20 years to be $4.6 billion less than the estimates in the PRIA 
(Ref. 60).
    In addition, we anticipate that FDA oversight could help to support 
coverage and reimbursement determinations for IVDs offered as LDTs, 
which we anticipate will make certain IVDs offered as LDTs for which 
there is a reasonable assurance of safety and effectiveness more 
affordable for patients. As a result, FDA does not agree that patients 
will necessarily be disincentivized from seeking preventive care 
resulting in increased costs to the healthcare system as a result of 
the phaseout policy.
    In addition, phasing out the general enforcement discretion 
approach for LDTs will help to reduce other healthcare costs. Greater 
oversight by FDA will help to address the hidden costs associated with 
unsafe or ineffective IVDs (including IVDs promoted with false or 
misleading claims), such as costs incurred from inappropriate 
treatments, additional or repeat testing, unnecessary consultations 
with providers, or additional treatments that become necessary due to 
the progression or worsening of a disease or condition following 
misdiagnosis. While certain costs may be passed on to individuals and 
insurers, we expect some of these costs will be offset by the 
associated benefits.
    A more fulsome discussion of the estimated costs and benefits is 
provided in FDA's FRIA (Ref. 10).
    (Comment 208) FDA received one comment which stated that some 
laboratories may decide to utilize tests that are more expensive for 
patients, regardless of medical necessity, in order

[[Page 37400]]

to recoup the costs of complying with applicable FDA requirements.
    (Response 208) FDA does not agree that phasing out the general 
enforcement discretion approach for LDTs will cause laboratories to 
utilize more expensive tests regardless of medical necessity. FDA 
anticipates that, to the extent some laboratories may attempt to recoup 
costs by utilizing more expensive tests regardless of medical 
necessity, such laboratories would be likely to engage in such 
practices irrespective of FDA's determination to phase out the general 
enforcement discretion approach for LDTs. In addition, the use of any 
particular test is a decision to be made between patients and their 
healthcare providers. Finally, FDA anticipates that third party payors 
may review the medical necessity of tests for which claims for 
reimbursement are submitted.

I. Impact on Access and Innovation

    (Comment 209) Several comments expressed concern that ending the 
general enforcement discretion approach for LDTs will negatively impact 
patient access to clinical testing. These comments generally asserted 
that the cost or complexity of complying with FDA requirements, and the 
burdens that may fall on laboratories from the phaseout of the general 
enforcement discretion approach, will cause many laboratories to reduce 
activities and stop offering some or all IVDs offered as LDTs, 
particularly in the context of other challenges that laboratories face 
with respect to staffing, supply chains, and other challenges. Several 
comments stated that in a recent American Society for Microbiology 
survey of its members, over 80 percent of the microbiology laboratories 
surveyed said they would consider discontinuing LDTs if FDA finalized 
its proposal. Another comment stated that in an internal survey of 
members of the Association of Pathology Chairs, out of 39 laboratories 
surveyed, 37 reported that more outsourcing of tests would be necessary 
if FDA finalized its proposal. Some comments stated that the impact 
would be particularly significant for laboratories that currently lack 
the infrastructure to comply with applicable requirements and for 
emerging companies.
    Based on these concerns, many comments stated that patient access 
to tests will be reduced, and patients will potentially be deprived of 
important health-related information. Some comments stated that this 
would result in worse patient outcomes and higher healthcare costs; 
comments suggested that patients would lose access to IVDs offered as 
LDTs that perform well, even some IVDs offered as LDTs that may perform 
better than FDA-authorized IVDs, while other comments stated that 
patients would lose access to testing that supports rapid care 
decisions. A few comments asserted that harm may result from losing 
access to certain types of tests, such as infectious disease tests or 
genetic tests. Other comments suggested that reduced access to tests 
would mean less choice, flexibility, competition, or ability to 
withstand disruptions to the test market. One comment stated that more 
tests would be offered by large laboratories that prioritize financial 
profits over accountability or patient care and that cannot ``keep up 
with the necessary fine-tuned evolution of these tests.'' Another 
comment suggested that by reducing access to testing, the phaseout 
policy would infringe on patient and physician ``rights to timely and 
adequate care and the freedom to exercise clinical judgment.'' Other 
comments reiterated the suggestion that the phaseout policy would limit 
access and thereby constrain a physician's ability to use his or her 
discretion to make treatment decisions. Some comments questioned 
whether the market withdrawal of some IVDs offered as LDTs would be 
counterbalanced by the introduction of new IVDs.
    In addition, some comments stated that by reducing the availability 
of IVDs offered as LDTs, the phaseout policy would lead to delays in 
testing, including by potentially increasing reliance on reference 
laboratories which may increase the time for individuals to obtain test 
results. Other comments argued that delays will result from FDA's 
premarket review process, which will slow down the ability of patients 
to access tests that they need. Comments also stated that if FDA were 
to finalize its proposal, delays could result due to less competition, 
and that if the phaseout policy results in centralization of tests to 
certain locations, patients who are not in the local area could face 
additional hurdles.
    (Response 209) As described in section V, FDA has made several 
changes to the phaseout policy that was described in the NPRM, 
including the addition of certain enforcement discretion policies. 
These changes significantly reduce the economic impact of the phaseout 
policy, and thus the likelihood that laboratories may reduce their test 
offerings or exit the market. Based in part on the inclusion of these 
enforcement discretion policies in the final phaseout policy, FDA 
disagrees with concerns that the phaseout of the general enforcement 
discretion approach for LDTs will have a significant net negative 
impact on patient access to IVDs that have appropriate assurance of 
safety and effectiveness.
    Most notably, FDA intends to exercise enforcement discretion and 
generally not enforce premarket review and QS requirements (except for 
requirements under part 820, subpart M (Records)) for currently 
marketed IVDs offered as LDTs that were first marketed prior to the 
date of issuance of this rule and that are not modified, or that are 
modified as described in section V.B.3.
    FDA also intends to exercise enforcement discretion and generally 
not enforce premarket review requirements for LDTs approved by NYS 
CLEP, and premarket review requirements and QS requirements (except for 
requirements under part 820, subpart M (Records)) for LDTs manufactured 
and performed by a laboratory integrated within a healthcare system to 
meet an unmet need of patients receiving care within the same 
healthcare system, as discussed in sections V.B.2 and V.B.3.
    FDA anticipates that these aspects of the final phaseout policy 
will substantially reduce the overall impact of the phaseout policy on 
patient access to clinical tests. In addition, FDA notes that, as 
explained in the NPRM and discussed in the FRIA, the FD&C Act and FDA's 
regulations do not require premarket review for all IVDs (88 FR 68006 
at 68013). FDA estimates that approximately 50 percent of IVDs offered 
as LDTs will not require premarket review (see section II.F.2 of the 
FRIA (Ref. 10)). Moreover, under FDA's phaseout policy, FDA does not 
intend to phase out the general enforcement discretion approach for 
premarket review requirements for IVDs offered as LDTs until several 
years after publication of this final rule. FDA also generally does not 
intend to enforce against IVDs offered as LDTs for lacking premarket 
authorization after a complete PMA, HDE application, 510(k), BLA or De 
Novo request has been submitted to FDA by the start of the 
corresponding stage of the phaseout policy, until FDA completes review 
of the submission, so as not to interrupt access to IVDs that are 
already on the market and available to patients.
    To the extent that some IVDs offered as LDTs come off the market 
because, for example, the IVD cannot meet applicable requirements under 
the FD&C Act and its implementing regulations, or the laboratory does 
not invest resources to meet those requirements, the value of access to 
such IVDs is diminished in the absence

[[Page 37401]]

of assurances regarding the IVDs' safety and effectiveness. Neither 
patients nor providers are helped by access to tests that are not safe 
and effective for their intended use. In addition, in the event some 
IVDs offered as LDTs exit the market, FDA expects that other 
manufacturers may fill the need with IVDs that comply with applicable 
FDA requirements. FDA also anticipates that applying the same general 
oversight approach to both laboratory and non-laboratory manufacturers 
of IVDs will encourage genuine innovation and facilitate access to IVDs 
for which there is a reasonable assurance of safety and effectiveness, 
as discussed further in response to comment 218 (see Refs. 15, 22, 88 
to 90).
    Finally, it is unclear to FDA how generalizable the survey data 
cited in comments may be. While comments stated that the American 
Society for Microbiology's survey of its members found that over 80 
percent of the microbiology laboratories surveyed would consider 
discontinuing most LDTs if FDA finalized its proposal, only 88 of the 
American Society for Microbiology's 36,000 members (0.2 percent) 
responded to the survey (Ref. 205). Similarly, the Association of 
Pathology Chairs' survey of its members produced only 39 responses 
(Ref. 170), while their comment states that the Association of 
Pathology Chairs ``represents the entire academic pathology leadership 
team of over 160 departments nationwide.'' Regardless, the policy 
changes to the phaseout policy, including the addition of certain 
enforcement discretion policies, help address the concerns identified 
in these surveys as described above.
    (Comment 210) A few comments stated that laboratories may begin 
offering their tests for ``surveillance use only,'' in reference to a 
category of tests that FDA proposed in the NPRM would not be affected 
by the phaseout policy.
    (Response 210) Tests for public health surveillance are limited to 
tests manufactured and offered for use exclusively for public health 
surveillance and are distinct from tests used for other purposes in 
that they are intended solely for use on systematically collected 
samples for analysis and interpretation of health data in connection 
with disease prevention and control, and tests results are not reported 
to patients or their healthcare providers. Tests for which results are 
returned to a patient or healthcare provider would not be considered 
public health surveillance tests. Laboratories could not simply label 
tests ``for surveillance use'' to avoid oversight of broader use of the 
tests.
    (Comment 211) FDA received a comment which stated that FDA should 
analyze the totality of circumstances that currently exist ``in 
healthcare'' before phasing out the general enforcement discretion 
approach for LDTs. This comment suggested that such circumstances 
support the conclusion that the phaseout policy will contribute to a 
``total disruption'' in patient access to tests. Another comment asked 
whether the Agency has performed, or intends to perform, an impact 
analysis on patient care, patient access, and patient safety, and one 
comment expressed concern that action by FDA in the absence of 
comprehensive data regarding the use of LDTs will result in severe 
restrictions on access.
    (Response 211) As described elsewhere in this preamble, the Agency 
has determined that increased FDA oversight is necessary to better 
assure the safety and effectiveness of IVDs offered as LDTs, and that 
maintaining the general enforcement discretion approach for LDTs is not 
in the best interest of the public health. In finalizing FDA's policy 
for phasing out the general enforcement discretion approach for LDTs, 
FDA has carefully considered issues related to patient care and access, 
including through the Agency's review and analysis of more than 6,500 
comments submitted to the docket for this rulemaking. As discussed in 
response to comment 209, FDA's final phaseout policy includes several 
policies that will substantially reduce the overall impact of the 
phaseout policy on patient access to IVDs offered as LDTs. FDA has also 
conducted a detailed regulatory impact analysis that considers costs 
and benefits; please see discussion in the FRIA (Ref. 10).
    (Comment 212) FDA received a comment which stated that ending the 
general enforcement discretion approach for LDTs would impact 
laboratories' willingness to share new methods and rare reagents with 
each other. The comment stated that as a result, the phaseout policy 
may impede efforts that aim to address barriers to care, such as the 
Cancer Moonshot Initiative.
    (Response 212) FDA does not agree that ending the general 
enforcement discretion approach for LDTs will result in less scientific 
exchange between laboratories, or negatively impact initiatives such as 
the Cancer Moonshot Initiative. FDA anticipates that the phaseout 
policy will help to advance the Cancer Moonshot Initiative, as cancer 
care is often personalized based on the genetic makeup of the tumor, 
and helping to ensure that IVDs offered as LDTs have appropriate 
assurance of safety and effectiveness will help patients with cancer 
get the optimal treatment. Although FDA's phaseout of the general 
enforcement discretion approach may lead laboratories to incur 
additional costs, including in connection with premarket review 
requirements in some cases, FDA does not anticipate that these factors 
will necessarily cause laboratories that currently share new methods, 
rare reagents, or other information or materials to cease doing so.
    Moreover, better assuring the safety and effectiveness of LDTs may 
foster test innovation and facilitate the collective efforts of the 
scientific and medical communities to identify promising technologies, 
new therapies, or areas worthy of future research (see Refs. 15, 22, 88 
to 90). The FD&C Act's premarket review requirements provide an impetus 
for manufacturers to conduct scientifically sound and robust research 
to establish the safety and effectiveness of their devices, including 
IVDs. Basing decisions on scientifically reliable information can help 
to eliminate or reduce harms to health, such as misdiagnosis or delayed 
diagnosis with a lost opportunity for effective treatment, as well as 
the diversion of limited resources to ineffective treatments. See 
January 2017 Discussion Paper at 5-6 (Ref. 57).
    (Comment 213) One comment stated that during a past recall of a 
particular IVD, FDA recommended the use of an LDT as an alternative to 
the recalled device. The comment expressed concern that ending the 
general enforcement discretion approach for LDTs may impede FDA's 
ability to respond to similar recalls.
    (Response 213) FDA disagrees with this comment. By phasing out the 
general enforcement discretion approach for LDTs, FDA seeks to better 
protect the public health by helping to assure the appropriate safety 
and effectiveness of LDTs, including IVDs offered as LDTs, which may 
serve as alternatives to IVDs that are the subject of a recall. 
Moreover, as discussed in response to comment 209, FDA's final phaseout 
policy includes several policies that will substantially reduce the 
overall impact of the phaseout policy on patient access to IVDs offered 
as LDTs.
    (Comment 214) FDA received comments stating that the phaseout 
policy would have a negative impact on innovation in the testing space, 
as laboratories working to come into compliance would be either unable 
or

[[Page 37402]]

unwilling to engage in innovative test development. Some comments 
stated that the regulatory constraints associated with the phaseout 
policy would cause laboratory manufacturers to develop fewer tests, 
hindering the timely development and deployment of cutting-edge 
therapies and diagnostic tools and ultimately harming patients. 
Comments noted that LDTs are an area of rapid advancement, with some 
being in use only for short periods of time, and some comments 
expressed concern that enforcing premarket review requirements for each 
individual assay or slight modification would not be adequate to keep 
up with the progress of testing. One comment stated that the phaseout 
policy would force laboratories to focus efforts on developing 
premarket applications for current tests instead of innovating to 
improve patient care. Some comments stated that the phaseout policy 
would cause delays in the development of new diagnostics, impacting the 
``competitive edge of U.S. medical research and development.''
    (Response 214) FDA does not agree that the phaseout policy will 
hinder the timely development and deployment of innovative IVDs offered 
as LDTs. In fact, as discussed in response to comment 218, applying the 
same general oversight approach to laboratories and non-laboratories 
that manufacture IVDs may facilitate the development of innovative IVDs 
from non-laboratory manufacturers.
    Even when premarket review is required for an IVD offered as an 
LDT, FDA does not agree that such review generally impairs innovation. 
The evidentiary requirements of premarket review spur innovation based 
on reliable scientific evidence that enables an informed determination 
of the safety and effectiveness of medical devices for each intended 
use and product labeling that provides information for using the 
product safely and effectively for such use. The generation of 
scientific evidence that is independently reviewed by FDA supports 
physicians in making sound clinical decisions. See January 2017 
Discussion Paper at 3 (Ref. 57).
    We note that sponsors have sought and obtained FDA authorization 
for innovative IVDs offered as LDTs. For example, a list of authorized 
CDx IVDs, which include innovative IVDs offered as LDTs, is available 
on FDA's website (Ref. 206). Furthermore, FDA's Breakthrough Devices 
program is intended to help expedite the development and review of 
certain devices that provide for more effective treatment or diagnosis 
of life-threatening or irreversibly debilitating diseases or conditions 
(21 U.S.C. 360e-3).
    We agree that test innovation and development is important for 
patients and the public health, and we recognize the concern that 
expecting currently marketed IVDs offered as LDTs to come into 
compliance may cause laboratories to divert resources from the 
development of new IVDs, due to the time and resources that would be 
needed to comply with the regulatory requirements for their existing 
IVDs offered as LDTs. Based on these considerations along with concerns 
about reliance, and as discussed further in section V.B.3, FDA intends 
to exercise enforcement discretion and generally not enforce premarket 
review and QS requirements (except for requirements under part 820, 
subpart M (Records)) for currently marketed IVDs offered as LDTs that 
were first marketed prior to the date of issuance of this final rule. 
This enforcement discretion policy will improve patient access by 
allowing laboratories to focus resources on submissions for new, 
innovative tests based on reliable scientific evidence, rather than 
expend such resources in support of tests already on the market.
    In addition, FDA intends to continue exercising enforcement 
discretion and generally not enforce premarket review and most QS 
requirements for such currently marketed IVDs offered as LDTs when they 
are modified in certain limited ways as described in section V.B.3. 
This aspect of the enforcement discretion policy will help to 
facilitate patient access to these tests by permitting certain 
modifications to be made within the scope of the enforcement discretion 
policy.
    To further facilitate access going forward, FDA intends to exercise 
enforcement discretion and generally not enforce premarket review 
requirements for LDTs manufactured and performed by a laboratory 
integrated within a healthcare system to meet an unmet need of patients 
receiving care within the same healthcare system.\89\ In the context of 
tests for unmet needs, there may be less opportunity to recoup costs of 
premarket review. This policy is intended to reduce the risk that 
premarket review costs would dissuade development of and access to such 
tests, taking into account the mitigations described in section V.B.3.
---------------------------------------------------------------------------

    \89\ FDA recognizes that innovation often takes place in AMCs. 
See e.g., Refs. 207-210.
---------------------------------------------------------------------------

    Moreover, although we acknowledge that the preparation and 
submission of PMAs and 510(k)s impose the majority of costs estimated 
for laboratories under the final phaseout policy, we also note that as 
explained in the NPRM, under FDA's device authorities, FDA premarket 
review is required only for certain tests (88 FR 68006 at 68009). FDA 
estimates that approximately 50 percent of IVDs newly offered each year 
as LDTs will not require premarket review.
    For these reasons, FDA does not anticipate that the phaseout policy 
will hinder the timely development and deployment of cutting-edge 
diagnostic tools, impair the competitiveness of U.S. medical research 
and development, or ultimately harm patients, as suggested by the 
comments. See also our response to comment 218 for discussion regarding 
how applying the same general oversight approach to laboratories and 
non-laboratories that manufacture IVDs may facilitate the development 
of innovative IVDs.
    (Comment 215) Several comments noted that laboratories must be able 
to modify existing tests quickly to diagnose new conditions and monitor 
the impact of new therapies. Some comments stated that stifling 
modifications of currently marketed IVDs offered as LDTs would force 
pathologists and other healthcare providers to use older, less optimal 
tests, and noted that many patients do not have the time to wait for 
diagnostic development and rely on laboratories to be nimble and adapt 
to changing diagnostic criteria. One comment noted the ``redundancy and 
inability to update markers in flow cytometry panels based on new 
evidence'' as a longstanding issue and recommended FDA address the 
barriers that prevent laboratories from readily adapting tests in 
response to evolving scientific knowledge.
    (Response 215) FDA appreciates the need for improvements to 
existing tests to better serve patients and providers, and notes that a 
manufacturer's modifications to its tests that have already been 
cleared, approved, licensed, or had a De Novo request granted by FDA 
require FDA review only in certain circumstances (see Sec. Sec.  
814.39, 807.81(a)(3), and 601.12 (21 CFR 601.12)). FDA has published 
several resources to help stakeholders determine whether a certain 
change or modification to a test may require a regulatory submission, 
including: (1) FDA's final guidance document entitled ``Modifications 
to Devices Subject to Premarket Approval (PMA)--The PMA Supplement 
Decision-Making Process'' (Ref. 185), (2) FDA's final guidance document 
entitled ``Deciding When to Submit a 510(k) for a Change to an Existing 
Device'' (Ref. 61), and (3) FDA's

[[Page 37403]]

final guidance document entitled ``Deciding When to Submit a 510(k) for 
a Software Change to an Existing Device'' (Ref. 211).
    FDA recognizes that tests evolve in response to new scientific 
information, and FDA wants to avoid disincentivizing minor improvements 
to existing tests. As detailed in section V.B.3, for currently marketed 
IVDs offered as LDTs that were first marketed prior to the date of 
issuance of this rule, FDA intends to exercise enforcement discretion 
and generally not enforce premarket review and QS requirements (except 
for requirements under part 820, subpart M (Records)) even if the IVD 
is modified in certain limited ways as described in section V.B.3. FDA 
intends to issue a draft guidance with additional details and examples 
and will seek public comment on such draft guidance.
    (Comment 216) Some comments expressed concern regarding the 
potential impact of the phaseout policy on innovative academic research 
and clinical trials, suggesting that researchers will have little 
incentive or ability to develop new LDTs due to the costs associated 
with compliance with statutory and regulatory requirements. Several 
comments noted that non-profit AMCs are often the nexus for innovation 
in medicine and that LDTs developed by AMCs play a critical role in 
education, development, and quality monitoring for rare disease tests 
and other conditions that do not have a viable market for commercial 
test development. One comment stated that the phaseout policy may 
result in LDTs that are very expensive or limited to common health 
conditions with established demand.
    (Response 216) As discussed above, FDA anticipates that the 
enforcement discretion policy for currently marketed IVDs offered as 
LDTs that were first marketed prior to the date of issuance of this 
rule and that are not modified, or that are modified in certain limited 
ways as described in section V.B.3, will address concerns that patient 
access to new tests would be reduced due to laboratories' focus on 
premarket submissions, as well as concerns that LDTs will become more 
expensive due to the cost of resources that would be needed to prepare 
and submit premarket submissions for currently marketed tests under the 
phaseout policy as proposed in the NPRM. The Agency believes that the 
policies described herein will help avoid undue disruption to the 
testing market, specifically for healthcare providers and patients that 
are relying on continued access to currently offered tests, and will 
encourage genuine innovation.
    To facilitate access going forward, FDA intends to exercise 
enforcement discretion and generally not enforce premarket review 
requirements for LDTs manufactured and performed by a laboratory 
integrated within a healthcare system to meet an unmet need of patients 
receiving care within the same healthcare system. This policy carefully 
balances the risk of not having a test available with the risk of not 
having assurances of premarket review in the context of the mitigations 
described in section V.B.3.
    For additional discussion regarding the application of the phaseout 
policy in the clinical trial context, see our response to comment 175.
    (Comment 217) FDA received some comments disagreeing with the view 
that increased oversight of LDTs may lead to increased innovation in 
the IVD space. These comments stated that LDTs and the laboratories 
that develop them are the catalysts for innovation, as they are 
typically developed when no ``commercial'' option is available and 
later acquired by manufacturers after technology and market 
development. On the other hand, one comment stated that the investment 
community and some LDT manufacturers have indicated that FDA's proposal 
``will not significantly impede the ability of LDTs to reach the 
market.''
    (Response 217) FDA recognizes the concerns regarding potential 
impact on innovation, but for the reasons discussed in our response to 
comment 214, FDA disagrees with the statement that the phaseout policy 
will not foster innovation and access to IVDs that have appropriate 
assurance of safety and effectiveness. While continued patient and 
provider access to certain tests is important, FDA also recognizes that 
an uneven oversight approach for laboratory and non-laboratory 
manufacturers of IVDs may discourage test development and innovation, 
as further discussed in response to comment 218 (see also Ref. 88). By 
applying the same general oversight approach to laboratories and non-
laboratories that manufacture IVDs, FDA will give stakeholders greater 
clarity regarding regulatory expectations, and may facilitate 
investment in the development of innovative IVDs. Additionally, as 
recently noted in a joint statement issued by CMS and FDA regarding the 
oversight of LDTs, FDA's phaseout approach will remove a disincentive 
for non-laboratory manufacturers to develop novel tests (Ref. 71). We 
anticipate that phasing out the general enforcement discretion approach 
for LDTs will spur genuine innovation for IVDs for which there is a 
reasonable assurance of safety and effectiveness.

J. Level Playing Field

    (Comment 218) FDA received a few comments discussing the impact of 
applying the same oversight approach to laboratories and non-
laboratories that manufacture IVDs. One comment expressed support for a 
consistent framework for LDT risk assessment and the enforcement of FDA 
review requirements according to a test's intended use and stated that 
``[a] level playing field is critical to maintaining the integrity of 
FDA review, fostering innovation, and providing patients with high-
quality care.'' Another comment asserted that FDA's statements that 
application of the same oversight approach to laboratory and non-
laboratory manufacturers may remove a disincentive for non-laboratory 
manufacturers to innovate and thus spur innovation is speculative as 
FDA has not surveyed manufacturers. The comment added that ``market 
forces, financial considerations, and challenges with patient 
enrollment in clinical trials for low prevalence pathogens are more 
likely the disincentivizing factors.''
    (Response 218) FDA agrees that it is appropriate to apply the same 
general oversight approach to both laboratories and non-laboratories 
that manufacture IVDs. The general enforcement discretion approach for 
LDTs has led to an oversight scheme that does not best serve the public 
health, and there is no longer a sound basis to have a bifurcated 
enforcement approach for LDTs and other IVDs. As discussed in section 
III.B and our responses to comments in section VI.C, most IVDs offered 
as LDTs are functionally the same as those made by other manufacturers 
of IVDs, and evidence has exposed problems associated with certain IVDs 
offered as LDTs.
    In addition, FDA agrees that applying the same general oversight 
approach will result in more stability to the testing market overall, 
which could help to encourage the manufacture of IVDs for which there 
is a reasonable assurance of safety and effectiveness. FDA is also 
aware that some firms have claimed a superficial connection to 
laboratories and then offered IVDs as LDTs (see Refs. 212 to 215). 
Given FDA's general enforcement discretion approach for LDTs, firms 
that use this business model have offered tests to patients in the 
absence of FDA oversight, with the potential for inaccurate or 
incomplete results that may impact patients' healthcare decisions. In 
addition, FDA is aware of concerns that the use of this type of

[[Page 37404]]

business model unfairly disadvantages non-laboratory IVD manufacturers 
that manufacture and market similar tests that comply with applicable 
FDA requirements. The increase in firms using these business models 
underscores the need for more oversight.
    FDA is also aware of concerns that non-laboratory IVD manufacturers 
may currently be discouraged from investing time and resources into 
developing novel tests due to the concern that once the manufacturer 
receives marketing authorization for its test, laboratories will 
develop similar tests and market them without complying with FDA 
requirements, thereby disincentivizing innovation (see response to 
comment 217).\90\ We anticipate that applying the same general 
oversight approach to laboratories and non-laboratories that 
manufacture IVDs will address these business strategies that take 
advantage of the current bifurcated system.
---------------------------------------------------------------------------

    \90\ FDA also recognizes that challenges in conducting clinical 
trials for low prevalence pathogens may disincentivize the 
development of certain novel tests. As noted in section V.B.3 and in 
response to comment 142, FDA intends to consider whether issuing 
additional guidance regarding validation of tests, including those 
for rare diseases that takes into consideration the challenges in 
obtaining a robust number of samples for validation, would be 
helpful. In the event FDA were to issue any such guidance, FDA would 
do so in accordance with good guidance practices (see Sec.  10.115).
---------------------------------------------------------------------------

    However, FDA also recognizes the effect that its longstanding 
enforcement discretion approach has had on the market, the role that 
laboratory-manufactured tests play in modern healthcare, and the 
presence of other expert regulatory bodies. Many comments emphasized 
these considerations and FDA agrees with certain comments' concern, for 
example, that the proposed phaseout policy could lead to the widespread 
loss of access to safe and effective IVDs on which patients currently 
rely and certain LDTs for unmet needs. As such, and as further 
discussed in section V.B, while FDA believes it is appropriate to apply 
the same general oversight approach to both laboratories and non-
laboratories that manufacture IVDs, the Agency has determined that 
targeted enforcement discretion policies for certain categories of IVDs 
manufactured by laboratories is appropriate and in the best interest of 
the public health.
    (Comment 219) One comment disagreed with the statement that the 
phaseout of the general enforcement discretion approach would advance 
innovation by both laboratory and non-laboratory manufacturers, stating 
that under the general enforcement discretion approach, laboratory 
manufacturers, especially AMCs, provide innovative, personalized LDTs 
to fill gaps in test offerings, which then allow conventional 
manufacturers to assess the market impact of these LDTs and make 
business decisions based on the LDT experience.
    (Response 219) FDA believes that the phaseout of the general 
enforcement discretion approach for LDTs is necessary to better assure 
the safety and effectiveness of IVDs offered as LDTs and that the same 
general oversight approach for LDTs and other IVDs will bring more 
stability to the market overall. FDA recognizes that laboratory 
manufacturers of LDTs, including AMCs, may manufacture LDTs that are in 
lower demand and currently fill gaps in test offerings. As discussed 
further in section V.B.3, FDA intends to exercise enforcement 
discretion and generally not enforce premarket review and most QS 
requirements for LDTs manufactured and performed by a laboratory 
integrated within a healthcare system to meet an unmet need of patients 
receiving care within the same healthcare system. FDA believes that 
this policy will address concerns that laboratories integrated within a 
system and that manufacture LDTs for unmet needs will stop doing so in 
light of the limited market for such LDTs and the perceived costs of 
compliance with premarket review and QS requirements.
    (Comment 220) One comment noted that FDA's proposal could lead to 
an unfair playing field between AMCs and for-profit laboratories. The 
comment indicated that IVDs offered as LDTs by AMCs are typically tests 
for rare diseases that are not profitable, and suggested that the 
phaseout policy should perhaps distinguish between for-profit and non-
profit laboratories.
    (Response 220) As discussed in section V.B.3, FDA intends to 
exercise enforcement discretion and generally not enforce premarket 
review and most QS requirements for LDTs manufactured and performed by 
a laboratory integrated within a healthcare system to meet an unmet 
need of patients receiving care within the same healthcare system. FDA 
anticipates that this approach will help to reduce the possibility that 
laboratories in AMCs, or other healthcare systems, may stop 
manufacturing LDTs for unmet needs.

K. Impact to Specific Patient Populations

    (Comment 221) FDA received several comments expressing concern that 
ending the general enforcement discretion approach for LDTs will 
negatively impact patient access to necessary tests and thus worsen 
disparities in healthcare, particularly for racial and ethnic 
minorities that rely on IVDs offered as LDTs for diagnosis and to 
inform treatment.
    (Response 221) FDA disagrees with the comments stating that phasing 
out the general enforcement discretion approach for LDTs will 
exacerbate health inequities for underrepresented patient populations. 
As detailed in the NPRM, there are concerns that in the absence of 
greater FDA oversight, IVDs offered as LDTs may be exacerbating health 
inequities due to higher rates of inaccurate results among 
underrepresented patient populations, particularly racial and ethnic 
minorities undergoing genetic testing (88 FR 68006 at 68013; Refs. 21 
and 216 to 219). Some IVDs offered as LDTs have not been validated for 
use across patient populations within a disease state, which may result 
in decreased accuracy for underrepresented patient populations and 
further contribute to health disparities (Ref. 220). With increased 
oversight, FDA will be able to help promote adequate representation of 
the intended use population in validation studies, and transparency 
regarding potential differential performance and unknown performance in 
certain patient populations, which will ultimately help advance health 
equity.
    FDA also recognizes that IVDs offered as LDTs might serve 
communities in rural, medically underserved areas with disparities in 
access to diagnostic tests. However, the benefits of test access depend 
on the ability of tests to work as intended, and the harms of unsafe or 
ineffective IVDs offered as LDTs might disproportionately occur among 
medically underserved patient populations that such tests might aim to 
reach. Without appropriate oversight, IVDs offered as LDTs might 
exacerbate health disparities.
    Nevertheless, FDA recognizes the concerns articulated in these 
comments regarding potential access issues resulting from the proposed 
phaseout policy and has adopted several targeted enforcement discretion 
policies to address those issues, among other things. For example, FDA 
acknowledges the importance of avoiding widespread loss of access to 
IVDs on which patients and the healthcare community currently rely, 
which ultimately could be more harmful than helpful to the public. As 
such, and for the reasons further discussed in section V.B.3, FDA 
intends to exercise enforcement discretion and generally not enforce 
premarket review and QS requirements (except for requirements under 
part 820, subpart M

[[Page 37405]]

(Records)) for currently marketed IVDs offered as LDTs that were first 
marketed prior to the date of issuance of this rule and that are not 
modified, or that are modified as described in section V.B.3.
    FDA is also adopting a targeted enforcement discretion policy for 
certain unmet need LDTs to help avoid patients being deprived of 
critically needed LDTs where certain risk mitigations exist (see 
further discussion in section V.B.3).
    (Comment 222) One comment stated that ending the general 
enforcement discretion approach for LDTs will limit access to necessary 
tests and make it more difficult to enroll underrepresented patients in 
clinical trials, which will reduce clinical trial diversity.
    (Response 222) As discussed above, FDA is adopting enforcement 
discretion policies for currently marketed IVDs offered as LDTs and 
unmet needs LDTs, as described in section V.B.3. These policies will 
help to address concerns regarding limiting access to such IVDs and 
resulting difficulties in enrolling diverse populations in clinical 
trials.
    (Comment 223) FDA received one comment that stated that FDA had 
ignored the special needs of the Native American population, as LDTs 
are used to analyze mutations with high prevalence in this population, 
and the population may be ``disenfranchised by the loss of LDTs 
diagnosing their genetic disorders'' as a result of phasing out the 
general enforcement discretion approach for LDTs. The comment suggested 
that FDA's tentative determination that ``the rule does not contain 
policies that would have a substantial direct effect on one or more 
Indian Tribes, on the relationship between the Federal Government and 
Indian Tribes, or on the distribution of power and responsibilities 
between the Federal Government and Indian Tribes,'' as stated in 
section XII of the NPRM, was incorrect. The comment also suggested that 
other populations, specifically ``immigrant populations,'' would be 
similarly, negatively affected by the phaseout policy. Another comment 
stated that there could be legal implications if patients or groups 
argue that FDA's actions disproportionately affect certain populations' 
access to healthcare.
    (Response 223) FDA appreciates the need to consider potential 
impacts on the Native American population and other specific patient 
populations. The Agency recognizes that some IVDs offered as LDTs may 
be currently used to diagnose genetic disorders common in the Native 
American population. In light of the enforcement discretion policy for 
currently marketed IVDs offered as LDTs that FDA is adopting, FDA does 
not anticipate that the Native American population will lose access to 
such IVDs. In addition, we believe the unmet needs policy described in 
this preamble, see further discussion at section V.B.3, will help to 
avoid laboratories integrated in healthcare systems from no longer 
manufacturing LDTs that meet the unique needs of the Native American 
population due to the limited market for such tests and perceived costs 
of compliance with premarket review and QS requirements. As such, FDA 
does not believe that the Native American population will be 
disenfranchised as a result of the phaseout policy. For additional 
discussion regarding FDA's analysis of the rule in accordance with the 
principles set forth in E.O. 13175, please see section XII.
    The concepts described above with respect to the Native American 
population are also applicable to other groups, such as ``immigrant 
populations,'' mentioned in the comments.
    (Comment 224) FDA received comments regarding the impact of the 
phaseout policy on medically underserved patient populations. Some 
comments stated that the phaseout is likely to exacerbate health 
inequities by further limiting access to testing in rural areas and 
disproportionately impacting vulnerable patient populations such as 
pediatric, low-income, lesbian, gay, bisexual, transgender, queer, 
intersex, and asexual (LGBTQIA+), and minority communities. A few 
comments stated that the phaseout will further disadvantage underserved 
populations from both medical and financial perspectives, as AMC 
laboratories and other laboratories serving these populations will not 
have the resources to complete FDA submissions for their tests and will 
need to outsource testing. One comment voiced concern that FDA has not 
adequately or accurately assessed the impact of the phaseout on the 
practice of medicine and patient care, specifically for patients in 
underserved geographies and those with possible rare diseases. 
Additionally, a few comments stated that the phaseout will have a 
detrimental impact on the affordability and speed of testing, which 
will hinder the ability of some laboratories (particularly public 
health laboratories) to serve marginalized groups including 
incarcerated, elderly, and homeless populations.
    (Response 224) FDA disagrees that phasing out the general 
enforcement discretion approach for LDTs will negatively impact 
medically underserved populations' access to IVDs. FDA recognizes that 
IVDs offered as LDTs may serve rural communities and other patient 
populations with disparities in access to diagnostic tests, and 
recognizes the concern regarding potential disruption of access to IVDs 
offered as LDTs, particularly for underserved and vulnerable patient 
populations. However, FDA anticipates that the targeted enforcement 
discretion policies described in this preamble will help to address the 
concerns raised in the comments. For example, with respect to AMCs that 
serve medically underserved populations, as discussed further in 
section V.B.3, FDA intends to exercise enforcement discretion and 
generally not enforce premarket review and QS requirements (except for 
requirements under part 820, subpart M (Records)) for LDTs manufactured 
and performed by a laboratory integrated within a healthcare system 
(including an AMC) to meet an unmet need of patients receiving care 
within the same healthcare system. We believe this policy addresses the 
concerns raised in the comment regarding AMCs.
    FDA disagrees with the comment that the Agency has not adequately 
or accurately assessed the impact of the phaseout policy on patients in 
underserved geographies. As indicated in the PRIA, and again in section 
II.K of the FRIA (Ref. 10), FDA has considered the potential effects of 
the phaseout on health inequities to the extent we are able to do so 
based on available information. FDA recognizes that IVDs offered as 
LDTs might serve communities in underserved geographies with 
disparities in access to diagnostic tests, and the harms of unsafe or 
ineffective IVDs offered as LDTs might therefore disproportionately 
occur among individuals in such geographies. As noted in response to 
comment 221, the benefits of test access depend on the ability of tests 
to work as intended, and without appropriate oversight, IVDs offered as 
LDTs might exacerbate health disparities.
    FDA has carefully assessed information about IVDs offered as LDTs 
in scientific literature, news articles, submissions to FDA, and 
allegations and adverse event reports submitted to the Agency, among 
other sources, and this information supports a phaseout of FDA's 
general enforcement discretion approach for LDTs. By phasing out the 
general enforcement discretion approach, FDA seeks to better prevent 
and mitigate harm to patients, including those in underserved 
populations, that may result from inaccurate and unreliable tests, 
while also accounting for other important public health

[[Page 37406]]

considerations such as patient access and reliance.
    For discussion of the impact of the phaseout policy on the 
affordability and speed of testing, see our responses to comments 207 
and 209 in sections VI.H and VI.I of this preamble.
    (Comment 225) FDA received comments expressing concern that ending 
the general enforcement discretion approach for LDTs will negatively 
impact Medicare beneficiaries. One comment stated that increased costs 
for tests will lead to increased Medicare and Medicaid costs, and some 
comments inquired whether Medicare reimbursements will be adjusted to 
support the increased costs resulting from the phaseout of the general 
enforcement discretion approach for LDTs.
    (Response 225) As discussed in response to comments in section 
VI.H, and as noted in section II.F.6 of the PRIA and in the FRIA (Refs. 
60 and 10), the exact effect of the phaseout policy on the price of 
IVDs offered as LDTs is unknown. However, FDA's decision to include 
certain enforcement discretion policies in the final phaseout policy is 
predicted to significantly reduce the costs of compliance under the 
final phaseout policy, thus reducing the number of laboratories that 
scale back operations or exit the market, which may in turn reduce any 
impact of the phaseout policy on pricing. In addition, as noted in 
response to comment 207, phasing out the general enforcement discretion 
approach for LDTs will help to reduce other healthcare costs. While 
certain costs may be passed on to individuals and insurers, we expect 
some of these costs will be offset by the associated benefits.
    In terms of coverage and reimbursement, Medicare is administrated 
by CMS under different statutory authorities than those governing FDA 
regulation of IVDs, and future decisions regarding reimbursement are 
outside the scope of this rulemaking and phaseout policy.
    (Comment 226) Other comments articulated concerns regarding the 
impact of the phaseout policy on laboratory testing for hospitals and 
providers that serve Medicare and Medicaid patients. These comments 
expressed concern regarding the potential for the phaseout policy to 
increase costs for such providers and decrease access to testing for 
vulnerable patients, particularly children. One comment noted that 
Medicaid has limited coverage policies for certain laboratory tests and 
large reference laboratories often do not provide services to Medicaid 
patients unless the services are covered.
    (Response 226) As discussed above, the exact effect of the phaseout 
policy on the price of IVDs offered as LDTs is unknown, but the 
enforcement discretion policies described in this preamble are 
predicted to significantly reduce the costs of compliance associated 
with the final phaseout policy, thus reducing the number of 
laboratories that scale back operations or exit the market, which may 
in turn reduce any impact of the phaseout policy on pricing.
    In terms of the comments regarding Medicaid coverage policies, as 
Medicaid is administrated by CMS and the States under different 
statutory authorities than those governing FDA's regulation of IVDs, 
such comments are outside the scope of this rulemaking and phaseout 
policy.
    (Comment 227) FDA received comments stating that the phaseout 
policy will disproportionately impact pediatric patients. Several 
comments noted that tests for pediatric patients often do not have any 
FDA-authorized or ``commercial'' equivalents, and that tests must be 
modified to serve the pediatric patient population. As an example, some 
comments pointed to the lack of FDA-authorized tests to detect sexually 
transmitted infections (STIs) in children, which must be used in cases 
of sexual abuse and assault against children. Other comments noted that 
pediatric patients and their healthcare providers are highly reliant on 
LDTs because many conventional manufacturers do not seek FDA approval 
for all age groups and often choose not to develop tests for pediatric 
diseases, due to the challenges in studying pediatric populations and 
the relatively slim financial margins for such tests. These comments 
stated that any action that leads to LDTs not being offered for 
pediatric patients will result in delayed diagnosis and care for such 
patients.
    (Response 227) FDA understands that laboratories have been using 
IVDs offered as LDTs to test pediatric patients, and we recognize 
concerns that phasing out the general enforcement discretion approach 
for LDTs may lead to a higher chance that laboratories stop offering 
these tests. FDA believes that the enforcement discretion policies 
discussed further in section V.B.3, specifically the policies for 
currently marketed IVDs offered as LDTs and for LDTs for unmet needs, 
will help to avoid access issues to currently marketed IVDs for 
pediatric patients as well as LDTs for pediatric patients that meet the 
unique needs of the patient (see response to comment 228).
    (Comment 228) Some comments noted that specialized IVDs offered as 
LDTs are often vital to medical management for patients with complex 
medical needs. Comments asserted that the phaseout policy would leave 
gaps in detection and treatment for these and other vulnerable 
patients. One comment provided as an example the modification of FDA-
authorized assays for more rapid assessment of tuberculosis.
    (Response 228) FDA recognizes the need for specialized testing for 
patients with complex medical needs and for vulnerable populations, 
like children, who may not have access to FDA-authorized tests. As 
noted above, FDA intends to exercise enforcement discretion and 
generally not enforce premarket review and most QS requirements for 
currently marketed IVDs offered as LDTs as described in section V.B.3. 
FDA believes this policy will help to address concerns regarding 
continued access to currently marketed IVDs for patients with complex 
medical needs and vulnerable populations. FDA also intends to exercise 
enforcement discretion and generally not enforce premarket review and 
most QS requirements for LDTs manufactured and performed by a 
laboratory integrated within a healthcare system to meet an unmet need 
of patients receiving care within the same healthcare system. FDA 
believes that as a result of this policy, laboratories integrated 
within healthcare systems will be less likely to not manufacture LDTs 
for unmet needs due to the limited market for such tests and the 
perceived costs of compliance with premarket review and QS 
requirements. Additionally, FDA intends to exercise enforcement 
discretion and generally not enforce premarket review requirements when 
a laboratory certified under CLIA and meeting the regulatory 
requirements under CLIA to perform high complexity testing modifies 
another manufacturer's lawfully marketed test that is not a PMA-
approved or BLA-licensed test, in a manner that could not significantly 
affect the safety or effectiveness of the test or its intended use, as 
described in sections V.C.4 and V.C.5.

L. Specific Types of IVDs

1. Direct-to-Consumer IVDs
    (Comment 229) FDA received comments stating that regulation of 
direct-to-consumer tests should be prioritized because, unlike in AMCs 
and hospitals, they are provided to

[[Page 37407]]

consumers outside of a regulated environment. Comments noted that the 
direct-to-consumer market is where much of the public concern currently 
lies regarding unreliable results, as they are not subject to the same 
controls as LDTs in clinical laboratory settings (i.e., CLIA 
requirements). Other comments further stated that direct-to-consumer 
tests are often provided without accompanying healthcare counseling, 
which puts users at risk for misinterpretation or patient harm and 
therefore ``should be regulated by FDA.''
    (Response 229) FDA agrees with comments that direct-to-consumer 
tests present risks that are unique and different from some of those 
posed by IVDs offered as LDTs used in clinical laboratory settings. 
Indeed, FDA's general enforcement discretion approach for LDTs has not 
applied to direct-to-consumer tests, including for this reason. FDA's 
general enforcement discretion approach was originally premised, in 
part, on the participation of medical professionals who, among other 
things, help determine whether a particular test is appropriate, 
counsel patients, assist in interpreting results, and assess how the 
results fit in the overall clinical picture. FDA believes there is a 
heightened need for oversight of tests where test results are used by 
consumers to make potentially significant healthcare decisions without 
the involvement of a learned intermediary in a legitimate healthcare 
practitioner-patient relationship.
    (Comment 230) Some comments stated that the phaseout policy would 
make it harder for consumers to obtain and use at-home tests, 
particularly for STIs and human immunodeficiency virus (HIV). Comments 
noted that this would especially impact those in the LGBTQIA+ community 
who benefit from at-home tests that can be done discreetly and 
requested FDA consider ``exemptions'' for direct-to-consumer tests that 
further ``public health initiatives.''
    (Response 230) FDA disagrees that the phaseout policy would make it 
more difficult for consumers to obtain necessary at-home tests, and 
notes that FDA has approved a home use test for HIV (Ref. 221) and has 
authorized an STI test with at-home sample collection for chlamydia and 
gonorrhea (Ref. 222). As noted in the NPRM and this preamble, FDA's 
general enforcement discretion approach for LDTs has not applied to 
direct-to-consumer tests given the greater risks to consumers presented 
by these tests (88 FR 68006 at 68022). In situations where consumers 
may be relying on direct-to-consumer tests to rule out, or otherwise 
diagnose, a disease or condition, there is a heightened need for FDA 
oversight. For these tests, FDA has generally expected compliance with 
applicable requirements, and the Agency is not changing that approach 
with the phaseout policy.
    (Comment 231) One comment stated that the NPRM ``specifies [an] 
exemption for direct-to-consumer testing,'' the danger of which cannot 
be understated and noted that direct-to-consumer testing ``is the exact 
type of testing the FDA should be focusing on.''
    (Response 231) FDA agrees that direct-to-consumer tests should be a 
focus of FDA oversight due to the risks they present. This comment 
appears to reflect a misunderstanding of FDA's proposal. The NPRM 
indicated that direct-to-consumer tests would not be included in the 
phaseout policy and, as a result, FDA would continue to expect 
compliance with applicable regulatory requirements for direct-to-
consumer tests. As discussed above and in the NPRM, FDA's general 
enforcement discretion approach for LDTs has not applied to direct-to-
consumer tests (88 FR 68006 at 68022). FDA has generally expected 
compliance with applicable requirements for direct-to-consumer tests 
and the phaseout policy does not change that approach.
2. Forensic Tests
    (Comment 231) FDA received several comments regarding the Agency's 
proposal to continue its general enforcement discretion approach for 
tests intended solely for forensic (law enforcement) purposes. The 
majority of these comments supported FDA's proposed approach, including 
one comment which expressed that it was appropriate for FDA to focus on 
``clinical uses'' and to exercise enforcement discretion for tests 
intended solely for forensic purposes.
    (Response 232) FDA agrees with the comments supporting continued 
enforcement discretion for tests intended solely for forensic (law 
enforcement) purposes. We described an enforcement discretion approach 
for tests intended solely for forensic (law enforcement) purposes more 
than 20 years ago (see, e.g., 65 FR 18230, April 7, 2000). This policy 
recognized that protections within the judicial process could mitigate 
risk related to test accuracy and sample collection. Additionally, FDA 
agrees that it should focus its limited resources on tests that present 
risks to patients, where sufficient mitigations for test accuracy and 
sample collection do not otherwise exist. FDA did not receive any data 
to justify changing its longstanding policy. FDA, therefore, intends to 
continue to exercise enforcement discretion for tests intended solely 
for forensic (law enforcement) purposes. In addition, since the policy 
on tests for forensic (law enforcement) purposes applies to all tests 
for forensic (law enforcement) purposes, including those manufactured 
by non-laboratory manufacturers, changing that policy would not be 
appropriate in the context of this rulemaking and related policies 
which are focused on IVDs that are manufactured by laboratories.
    (Comment 233) We received a few comments that advocated against 
FDA's proposal to continue its enforcement discretion approach for 
tests intended solely for forensic (law enforcement) purposes, 
primarily because, according to these comments, such tests should be 
``regulated'' the same as other IVDs, and FDA authorization would 
likely enhance fairness of the judicial system. Another comment 
indicated that forensic laboratories are not typically CLIA-certified 
and that NYS CLEP currently requires review of forensic tests. Some 
laboratories offering forensic tests are accredited by the Substance 
Abuse and Mental Health Services Administration (SAMHSA), but this 
level of accreditation is currently required only if a laboratory is 
testing for certain Federal programs. The comment went on to argue for 
broader Federal oversight of this test category.
    (Response 233) FDA disagrees that ceasing its longstanding 
enforcement discretion approach for tests intended solely for forensic 
(law enforcement) purposes is warranted. As FDA explained in the 
Federal Register (65 FR 18230), tests intended solely for forensic (law 
enforcement) purposes are subject to additional protections such as the 
use of rules of evidence in judicial proceedings and the representation 
of the accused (i.e., the person being tested) through the judicial 
process. The fairness of the judicial process is a separate issue that 
is not within the scope of this rulemaking.
    Further, because FDA's longstanding enforcement discretion approach 
for these tests is grounded in the sufficient mitigations in the 
judicial process, it is inapposite whether these laboratories or their 
tests are accredited or reviewed by/under CMS, NYS CLEP, or SAMHSA.
    (Comment 234) A comment requested that FDA clarify that the general 
enforcement discretion approach for tests intended solely for forensic 
purposes includes only tests within FDA's jurisdiction and that it does 
not capture tests performed by forensic DNA testing laboratories that 
fall

[[Page 37408]]

outside of FDA's purview. The comment explained that tests at forensic 
DNA testing laboratories are not ``intended for use in the diagnosis of 
disease or other conditions, or in the cure, mitigation, treatment, or 
prevention of disease,'' or ``intended to affect the structure or any 
function of the body.'' Rather, relationship testing (DNA) facilities 
use forensic tests exclusively for legal and immigration proceedings, 
criminal investigations, and identification of human remains. The 
comment explained that the National Institute of Justice within the 
Department of Justice is the lead Federal Government Agency supporting 
forensic laboratories, including relationship testing facilities 
accredited by AABB.
    (Response 234) A device is defined, in relevant part, as ``an 
instrument, apparatus, implement, machine, contrivance, implant, in 
vitro reagent, or other similar or related article, including any 
component, part, or accessory, which is . . . (B) intended for use in 
the diagnosis of disease or other conditions, or in the cure, 
mitigation, treatment, or prevention of disease, in man or other 
animals.'' Section 201(h)(1) of the FD&C Act. The determination of 
whether a product meets the definition of a device is a highly fact-
dependent analysis and the context of use may not be determinative of 
whether a product is intended for ``diagnosis.'' \91\ In any event, FDA 
intends to continue to exercise enforcement discretion for tests 
intended solely for forensic (law enforcement) purposes, meaning that 
it generally does not intend to enforce applicable device requirements 
for such tests. Moreover, FDA would not be able to enforce device 
requirements for any tests that do not meet the definition of a device.
---------------------------------------------------------------------------

    \91\ See, e.g., United States v. An Undetermined Number of 
Unlabeled Cases, 21 F.3d 1026, 1028-29 (10th Cir. 1994) (finding 
that containers used to collect urine and saliva specimens for HIV 
testing for insurance purposes were devices because ``[t]he plain 
meaning of `diagnosis' disregards context and bears no connection to 
medical treatment''; and ``the fact insurance companies rather than 
health professionals considered [the results] to make business 
rather than medical decisions does not erase the diagnostic 
character of . . . the containers' use.'').
---------------------------------------------------------------------------

3. 1976-Type LDTs
    (Comment 235) A number of comments supported FDA's proposal to 
continue to exercise enforcement discretion for 1976-Type LDTs. 
However, a few comments stated that while they agreed with the spirit 
of this proposal, they were concerned that FDA's focus on 1976-Type 
LDTs ignores perceived accuracy enhancements from basic automation 
techniques. Other similar comments stated that FDA's proposed 
enforcement discretion policy for 1976-Type LDTs should be expanded to 
include automated techniques using components legally marketed \92\ for 
clinical use and interpreted by a pathologist. Some comments pointed to 
immunohistochemistry automated staining process as an example of such 
automated techniques, and one comment stated that ``the technical 
aspect of immunohistochemistry is virtually always automated these 
days, while interpretation is manual.'' Another comment indicated that 
automation was associated with a reduction in human error rate in that 
particular laboratory.
---------------------------------------------------------------------------

    \92\ As used through this rulemaking, a ``lawfully marketed'' 
device means a device that is in compliance with FDA requirements, 
which may include premarket authorization.
---------------------------------------------------------------------------

    (Response 235) As described in section V.B.1, FDA intends to 
exercise enforcement discretion and generally not enforce applicable 
requirements for 1976-Type LDTs given that the characteristics of these 
tests--i.e., they involve manual techniques (without automation), are 
performed by laboratory personnel with specialized expertise, use 
components legally marketed for clinical use, and are designed, 
manufactured, and used within a single CLIA-certified laboratory that 
meets the requirements under CLIA for high complexity testing--mitigate 
the risks associated with these tests. In particular, and as explained 
in the NPRM, these characteristics provide the greatest risk mitigation 
among the characteristics that were commonly associated with LDTs 
offered in 1976, which resulted in the emergence of FDA's general 
enforcement discretion approach for LDTs (88 FR 68006 at 68022). 
Automation, including automated slide preparation used in 
immunohistochemistry, can enhance test performance, but automation also 
introduces new opportunities for error and other risks that, due to the 
nature of automation, are not easily identifiable. For these reasons, 
FDA does not believe that expanding the policy for 1976-Type LDTs 
beyond these characteristics that were commonly associated with LDTs 
offered in 1976 to include IVDs offered as LDTs with automation is 
appropriate.
    (Comment 236) We received comments requesting clarity on the type 
of tests that FDA would consider to be 1976-Type LDTs. These comments 
included requests that FDA define terms such as ``automation,'' 
``specialized expertise,'' or ``manual.'' Other comments asked for 
examples of 1976-Type LDTs.
    (Response 236) Examples of tests that might be considered 1976-Type 
LDTs when done manually and without automation (e.g., without use of 
software) include: various tests that use staining antibodies and 
general purpose reagents for cytology, hematology, and bacterial 
infections; cystic fibrosis sweat tests; certain colorimetric newborn 
screening tests; certain immunohistochemistry tests; karyotyping tests; 
and fluorescence in situ hybridization (FISH) tests. We reiterate that 
the purpose behind this category of continued enforcement discretion is 
to recognize the tests that have the sort of mitigations in place that 
resulted in the emergence of FDA's general enforcement discretion 
approach for LDTs, and to help focus FDA's oversight on more complex 
tests and tests posing higher risks.
    FDA understands that commenters requested more information about 
the terms ``automation,'' ``specialized expertise,'' and ``manual.'' We 
generally intend for these terms to have their ordinary meaning. To the 
extent that additional information and examples would be helpful, FDA 
will consider issuing guidance on this topic as appropriate and in 
accordance with good guidance practices (Sec.  10.115).
    (Comment 237) A few comments expressed concern that FDA's 
continuation of the general enforcement discretion approach for 1976-
Type LDTs will encourage laboratories to avoid automation and instead 
perform manual tests. The comments stated that this will disincentivize 
efficiency and improvement, cause laboratories to close, or increase 
risks to patients because the comments perceived that manual tests have 
more room for error.
    (Response 237) FDA disagrees with these comments. FDA does not 
anticipate that the final phaseout policy will cause laboratories to 
avoid automation and instead perform manual tests. Many comments from 
laboratories described the substantial benefits of automated 
approaches. These comments stated that automation improves efficiency, 
because, for example, fewer individuals are needed to perform a test 
and testing can occur more quickly. Therefore, FDA thinks it is 
unlikely that laboratories will stop offering automated tests and 
switch to manual processes so that their tests may be considered 1976-
Type LDTs in the future.
    FDA also does not believe that IVDs currently on the market are 
likely to change from an automated to manual methodology because FDA 
generally

[[Page 37409]]

intends to exercise enforcement discretion with respect to premarket 
review and QS requirements (except for requirements under part 820, 
subpart M (Records)) for currently marketed IVDs offered as LDTs that 
were first marketed prior to the date of issuance of this rule and that 
are not modified, or that are modified as described in section V.B.3. 
Although this enforcement discretion policy pertains only to premarket 
review and most QS requirements, whereas FDA intends to exercise 
enforcement discretion and generally not enforce any applicable 
requirements for 1976-Type LDTs, the costs of compliance with 
applicable requirements other than premarket review and QS requirements 
are only a small fraction of the costs of compliance with applicable 
requirements under the FD&C Act and FDA's regulations (see section II.F 
of the FRIA (Ref. 10)). Out of the total estimated costs to industry of 
$1.17 billion, the estimated costs of compliance with requirements 
other than premarket review and QS requirements are about $95.35 
million. Therefore, FDA anticipates that laboratories will not 
drastically change their current practices or cease to use automation 
for IVDs currently on the market.
    Finally, FDA does not agree that 1976-Type LDTs pose more risk to 
patients than other tests. As previously noted, features like 
automation can lead to improved performance and efficiency but can also 
introduce new opportunities for error and other risks.
    (Comment 238) A comment supported the concept of FDA continuing its 
general enforcement discretion approach for 1976-Type LDTs. This 
comment suggested, however, that FDA instead use certain other factors 
(instead of the 1976-Type LDT characteristics) such as the risk to the 
patient posed by incorrect results, availability of laboratory controls 
to mitigate these risks, qualification required of those performing or 
interpreting the test, CLIA certification level of the laboratory, the 
level of integration between the healthcare provider, test provider, 
and patient, and whether there is an IVD available, to determine if 
FDA's general enforcement discretion approach should continue to 
apply--noting that FDA should continue to exercise enforcement 
discretion only for an LDT where all of these elements are present.
    (Response 238) FDA appreciates the support for its approach to 
1976-Type LDTs; however FDA does not agree with expanding the policy 
for 1976-Type LDTs in the manner suggested by the comment. The purpose 
behind this policy is to recognize the tests that have the sort of 
mitigations in place that resulted in the emergence of FDA's general 
enforcement discretion approach for LDTs and to help focus FDA's 
regulatory oversight on more complex tests and tests posing higher 
risks. The factors proposed by the comment do not achieve the same 
purpose. FDA notes, however, that many of the factors identified by the 
comment have informed FDA's policy for LDTs manufactured and performed 
by a laboratory integrated within a healthcare system to meet an unmet 
need of patients (see section V.B.3).
    (Comment 239) Comments requested clarification regarding whether 
adsorption of warm-reactive autoantibodies using allogeneic or 
autologous red blood cells to prepare samples for further 
immunohematology testing would be considered a 1976-Type LDT.
    (Response 239) Adsorption of warm-reactive autoantibodies using 
allogeneic or autologous red blood cells to prepare samples for further 
immunohematology testing generally involves only manual techniques 
performed by laboratory personnel with specialized expertise, and 
therefore would generally be considered a 1976-Type LDT that would fall 
under the enforcement discretion policy for those tests provided it 
uses components legally marketed for clinical use and the design, 
manufacture, and use is all within a single CLIA-certified laboratory 
that meets the requirements under CLIA for high complexity testing.
4. Low-Risk IVDs Offered as LDTs
    (Comment 240) FDA received several comments recommending FDA adopt 
a different approach for lower risk tests. One comment suggested FDA 
provide a ``tiered risk-based approach and have streamlined submission 
and approval options for simpler, lower risk LDTs'' to help reduce any 
negative consequences stemming from the phaseout policy. Another 
comment recommended the Agency ``adopt a new premarket review pathway'' 
for laboratories seeking FDA authorization for low- or moderate-risk 
tests. One comment stated that there should be an enforcement 
discretion policy for low-risk LDTs so that clinical microbiology 
laboratories would continue offering infectious disease LDTs to serve 
vulnerable communities.
    (Response 240) FDA does not intend to have a separate policy for 
low-risk IVDs offered as LDTs. The statutory framework for device 
regulation is already risk-based and provides different premarket 
pathways for devices based on their risk, and FDA can neither change 
the review pathways established by statute nor create new review 
pathways not authorized by the statute. Most low-risk tests are exempt 
from premarket review, and moderate-risk tests are reviewed through the 
510(k) and De Novo pathways rather than being subject to premarket 
approval.
    With respect to infectious disease tests, FDA disagrees that all 
such tests are low-risk or that FDA should adopt an enforcement 
discretion policy for all clinical microbiology laboratories offering 
infectious disease LDTs. There are over 500 distinct product codes for 
infectious disease IVDs in FDA's classification database, and less than 
half of those are considered low-risk, or class I (most of which are 
exempt from premarket notification). Infectious disease IVDs pose risks 
that are not necessarily mitigated by other safeguards, and these tests 
have implications both for an individual patient and other members of 
the public. Therefore, FDA does not agree that it should continue the 
general enforcement discretion approach for all infectious disease LDTs 
offered by clinical microbiology laboratories. However, as described in 
section V.B, FDA generally intends to exercise enforcement discretion 
with respect to premarket review requirements for certain categories of 
tests, including currently marketed IVDs offered as LDTs that were 
first marketed prior to the date of issuance of this rule and that are 
not modified, or that are modified as described in section V.B.3, and 
LDTs that are approved by NYS CLEP. FDA anticipates that these policies 
will help patients, including those in vulnerable communities, have 
continued access to existing beneficial tests on which they rely, and 
minimize undue disruption to the provision of care, while providing FDA 
with information about test performance through labeling, MDR 
reporting, and other applicable requirements.
    (Comment 241) One comment expressed concern that the proposed 
phaseout policy could ``inadvertently result in millions of Americans 
abruptly losing access to much needed tests'' due to ``undue delay'' of 
FDA premarket review and recommended that FDA should continue the 
general enforcement discretion approach with respect to premarket 
review and QS requirements for low- and moderate-risk LDTs until FDA 
has demonstrated its ability to review and ``regulate'' high-risk LDTs.
    (Response 241) Although FDA does not agree that FDA premarket 
review itself will cause ``undue delay,'' FDA is concerned that 
laboratories may stop

[[Page 37410]]

offering IVDs on which patients are currently relying if FDA expects 
compliance with premarket review and all QS requirements for currently 
marketed IVDs offered as LDTs. Therefore, as discussed elsewhere in the 
preamble, to address concern regarding potential disruption of access 
to currently marketed IVDs offered as LDTs, FDA generally intends to 
exercise enforcement discretion with respect to premarket review and QS 
requirements (except for requirements under part 820, subpart M 
(Records)) for currently marketed IVDs offered as LDTs that were first 
marketed prior to the date of issuance of this rule and that are not 
modified, or that are modified as described in section V.B.3.
    FDA disagrees with the comment's suggested approach for low- and 
moderate-risk IVDs offered as LDTs as it relates to IVDs introduced on 
or after the date of issuance of this rule. In general, low-risk 
devices are not subject to premarket review or the QS design control 
requirements (the main source of QS costs under the FRIA), so FDA does 
not consider the proposed enforcement discretion policy fitting with 
respect to those IVDs. In addition, FDA expects that compliance with 
premarket review and QS requirements for moderate-risk IVDs offered as 
LDTs will have substantial public-health benefits going forward. For 
example, FDA anticipates that oversight will help ensure the safety and 
effectiveness of tests that predict a person's risk of cancer, are used 
in newborn screening, provide information on the risk of adverse events 
from a therapeutic product, aid in the diagnosis of heart disease, aid 
in the diagnosis of chlamydia and gonorrhea, and aid in the diagnosis 
of neurodegenerative disease such as Alzheimer's, among others. 
Overall, IVDs that may be considered low- or moderate-risk still inform 
decisions by patients and their healthcare providers, and uncertainty 
about whether IVDs offered as LDTs provide accurate and reliable 
results can significantly impact public health. To the extent they 
apply, premarket review and QS requirements are valuable tools that 
will help to better ensure the safety and effectiveness of IVDs offered 
as LDTs by laboratories. Therefore, under the final phaseout policy, 
the general enforcement discretion approach with respect to premarket 
review requirements for low- and moderate-risk IVDs introduced on or 
after the date of issuance of this rule will end 4 years after 
publication of this final rule.
    Further, to the extent this comment is suggesting FDA will lack 
sufficient resources or technical expertise to conduct premarket review 
of IVDs offered as LDTs in a timely manner, FDA disagrees as explained 
in sections VI.C.2, VI.C.3, and VI.N.
    (Comment 242) One comment from a laboratory stated that results 
from its ``drugs of abuse screening tests'' are not used to ``diagnose, 
treat, or prevent any illness'' but rather ``provide accountability of 
patient use of controlled substances and are used as a means to monitor 
patient progress,'' and false positives or negatives are unlikely to 
result in patient harm. The comment concluded that such tests are low 
risk, and that low-risk tests should remain under the general 
enforcement discretion approach.
    (Response 242) FDA disagrees with the blanket statement that 
``drugs of abuse screening tests'' are low-risk tests. ``Drugs of 
abuse'' tests are used to diagnose a clinical condition (drug 
intoxication), which informs a state of health, and to monitor patient 
use of controlled substances or track patient progress with respect to 
substance use, which FDA does not consider to be low-risk. FDA 
generally regulates clinical toxicology tests for drugs of abuse as 
class II devices with special controls. See, e.g., 21 CFR 862.3650 
(opiates), 21 CFR 862.3250 (cocaine and metabolites). For additional 
information about drugs of abuse tests that FDA has cleared for 
marketing, we recommend consulting decision summaries in FDA's 510(k) 
database by searching under the toxicology panel. Although FDA has 
determined that it is appropriate to exercise enforcement discretion 
and generally not enforce any applicable requirements for drugs of 
abuse tests used solely for law enforcement purposes (see comment 
response 247), FDA does not see a reason to adopt an enforcement 
discretion policy for other drugs of abuse tests (see comment responses 
248 and 249 for additional information).
    (Comment 243) One comment urged FDA to establish classification 
panels that can act quickly to down-classify IVDs to class I or class 
II based on a risk assessment before enforcing any regulatory 
requirements related to LDTs. The comment noted that this would 
decrease regulatory burden on the Agency and laboratories and provide 
clarity on the number of class III IVDs offered as LDTs that would 
require premarket approval. As an example, the comment discussed CDx 
devices, which are generally class III devices. The comment also stated 
that ``it is critical that decisions regarding IVD risk classification 
be reexamined and that LDT device types be unambiguously assigned well 
before marketing application submission deadlines.''
    (Response 243) Generally, FDA believes that IVDs offered as LDTs 
and other IVDs for the same indications should be under the same 
classification, so FDA intends to consider any reclassification efforts 
for IVDs holistically, rather than separating out IVDs offered as LDTs.
    On January 31, 2024, FDA announced its intent to initiate the 
reclassification process for most IVDs that are currently class III 
into class II (Ref. 66). The majority of these tests are infectious 
disease and CDx IVDs. Reclassification would allow manufacturers of 
certain types of IVDs to seek clearance through the less burdensome 
510(k) pathway rather than the PMA pathway, the most stringent type of 
FDA device review. The reclassification process will include 
opportunities for public comment and FDA aims to complete the process 
before stage 4 of the phaseout policy.
    For discussion of the use of classification panels in the context 
of other IVDs offered as LDTs, please see comment response 195. In 
addition, FDA intends to continue taking a risk-based approach in the 
initial classification of individual IVDs (including IVDs offered as 
LDTs) to determine the appropriate level of regulatory controls and 
whether a new IVD may be classified into class II or class I through De 
Novo classification (and special controls established), rather than 
being class III and subject to the PMA pathway. FDA also regularly 
considers whether there are class II IVDs that can be reclassified to 
class I and intends to continue to do so.
5. IVDs Offered as LDTs for Rare Diseases/Unmet Needs
    (Comment 244) Many comments reported that LDTs address unmet needs 
for which there are no FDA-authorized alternatives. For example, 
comments cited various tests for rare diseases, pediatric patients, 
infectious diseases including STIs, confirmation of drugs of abuse 
screening test results, candida auris, immunohistochemistry, and 
chimerism analysis for monitoring bone marrow transplants. Comments 
stated that in some cases, laboratories modify FDA-authorized IVDs to 
meet unmet needs, such as when an alternative specimen type must be 
used for a patient. One patient's parent wrote about their child's 
multiyear diagnostic journey that concluded when a whole genome 
sequencing LDT revealed a pathogenic genetic alteration. Several 
comments described challenges in rare disease test development, 
including the lack of potential profit due to low

[[Page 37411]]

volume use. Comments stated that most patients with rare diseases are 
treated at AMCs. Comments expressed concern that increased FDA 
oversight could further disincentivize rare disease test development, 
noting that the HDE program does not effectively address the issue, 
including because the 8,000 tests per year limit is too restrictive and 
the perceived burden of IRB and reporting requirements dissuade use of 
the program. Some comments recommended that FDA expand the HDE program. 
In addition, some comments claimed that the shorter turnaround time for 
results from certain LDTs (e.g., LDTs for inflammatory cytokines and NK 
cell killing LDTs) compared to sending a sample to a reference 
laboratory can impact a physician's ability to cure a patient with a 
rare disease or condition.
    (Response 244) FDA recognizes the challenges faced by patients with 
rare diseases, their families, and their treating physicians. FDA also 
recognizes that IVDs offered as LDTs play an important role in 
healthcare and may address various unmet needs including for rare 
diseases. We believe several of the enforcement discretion policies 
adopted in the final phaseout policy will help to address the concerns 
raised in the comments regarding the availability of IVDs for unmet 
needs and rare diseases. For example, for the reasons discussed in 
section V.B.3, FDA intends to exercise enforcement discretion and 
generally not enforce premarket review and QS requirements (except for 
requirements under part 820, subpart M (Records)) for currently 
marketed IVDs offered as LDTs, including IVDs for unmet needs and rare 
diseases, as long as they are not modified following the issuance of 
this final rule, or are modified as described in section V.B.3. In 
addition, for the reasons discussed in section V.B.3, FDA intends to 
exercise enforcement discretion and generally not enforce premarket 
review and QS requirements (except for requirements under part 820, 
subpart M (Records)) for LDTs manufactured and performed by a 
laboratory integrated within a healthcare system to meet an unmet need 
of patients receiving care within the same healthcare system. This 
policy is intended, among other things, to address situations described 
in comments where there is no available FDA-authorized IVD for the 
disease or condition, where a laboratory needs to modify an FDA-
authorized IVD to meet a specific patient need, or where the improved 
turnaround time of an LDT compared to an FDA-authorized IVD may be 
critical for the patient's care.
    Several comments suggested FDA expand the HDE program. It is not 
clear what the comments meant by such an expansion, but to the extent 
this was a suggestion to change the criteria necessary for HDE 
approval, we note that such criteria are established by statute and 
cannot be expanded by FDA (see 21 U.S.C. 360j(m)).
    FDA intends to consider whether issuing additional guidance 
regarding validation of tests, including those for rare diseases that 
takes into consideration the challenges in obtaining a robust number of 
samples for validation, would be helpful, as discussed in section 
V.B.3. In the event FDA were to issue any such guidance, FDA would do 
so in accordance with good guidance practices (see Sec.  10.115).
    (Comment 245) One comment expressed concern about applying the HUD 
program to IVDs offered as LDTs due to the program's complexity and 
constraints. This comment noted that tests for rare diseases are often 
developed and run at the request of clinicians, do not have an FDA-
authorized alternative, and do not have the volume to support an FDA 
authorization. This comment recommended that tests for rare diseases 
remain under an enforcement discretion approach if they serve a local 
community, use a well-characterized standard test, and are offered in 
small volumes.
    (Response 245) FDA acknowledges concerns regarding the constraints 
of the HUD program. For these and other reasons discussed in section 
V.B.3, FDA believes that an enforcement discretion policy for LDTs 
manufactured and performed by a laboratory integrated within a 
healthcare system to meet an unmet need of patients receiving care 
within the same healthcare system is appropriate. This policy should 
help avoid laboratories integrated within healthcare systems from no 
longer manufacturing LDTs to meet the unique needs of their patients, 
such as when there is no available FDA-authorized alternative (often 
the case for rare diseases).
    FDA disagrees that an enforcement discretion policy for tests for 
rare diseases that serve a local community, use a well-characterized 
standard test, and are offered in small volumes would be appropriate as 
FDA has concerns that there would not be sufficient risk mitigations in 
such circumstances. Further, limiting an enforcement discretion policy 
for rare diseases to ``well-characterized standard tests'' would 
exclude certain LDTs for rare diseases that are critical to patients 
and that may not be manufactured by laboratories due to the limited 
market for such LDTs and the perceived costs of compliance with 
premarket review requirements.
6. IVDs Offered as LDTs Intended Only for Public Health Surveillance
    (Comment 246) FDA received comments regarding our proposal that 
tests exclusively used for public health surveillance remain unaffected 
by the phaseout policy. Some comments supported this while others 
suggested oversight of such tests should be considered, regardless of 
whether results are returned to the patient or provider. One cited an 
example of a test that monitors for the presence or spread of a 
microorganism in a healthcare facility, which may not be used 
``explicitly'' for patient management but is ``actionable'' by the 
facility and results may be made available to healthcare providers. The 
comment encouraged FDA to consider whether the phaseout policy should 
apply to certain surveillance tests, like this example.
    (Response 246) FDA continues to believe that tests manufactured and 
offered for use exclusively for public health surveillance should 
remain unaffected by the phaseout policy. As described in the NPRM and 
this preamble, the scope of public health surveillance tests is limited 
to tests where results are not reported to patients or their healthcare 
providers (see section V.A.2, 88 FR 68006 at 68023). Where test results 
are not reported to patients or their healthcare providers, they are 
not informing the care of that patient, and increased FDA oversight is 
less critical. As to the comment's example of tests for microorganisms 
in a healthcare facility, if those tests are not on human specimens, 
they are not IVDs, and are therefore outside the scope of this 
rulemaking.
7. IVDs Offered as LDTs Intended To Detect the Presence of Drugs of 
Abuse
    (Comment 247) FDA received several comments on ``drugs of abuse'' 
tests. Some suggested that FDA continue the general enforcement 
discretion approach for drugs of abuse IVDs offered as LDTs used in 
employment and insurance testing as well as for law enforcement 
purposes.
    (Response 247) Drugs of abuse tests intended solely for employment 
and insurance testing and not for Federal drug testing programs are 
exempt from premarket review and would continue to be, regardless of 
whether they are

[[Page 37412]]

offered as an LDT (see 21 CFR 862.3100, 862.3150, 862.3170, 862.3250, 
862.3270, 862.3580, 862.3610, 862.3620, 862,3630, 862.3640, 862.3650, 
862.3700, 862.3870, 862.3910; see also 84 FR 71794 to 71819, December 
30, 2019). With respect to other requirements applicable to drugs of 
abuse tests used in employment or insurance testing, FDA does not see a 
reason to treat IVDs offered as LDTs differently from other IVDs going 
forward; FDA believes it is important, for example, for such IVDs to be 
listed in FDA's database, labeled as required under FDA regulations, 
and manufactured in compliance with QS requirements, given their risks. 
FDA has not identified any characteristics that are unique to IVDs 
offered as LDTs intended to detect the presence of drugs of abuse tests 
that would justify treating them differently from other drugs of abuse 
tests.
    With respect to drugs of abuse tests used solely for law 
enforcement purposes, FDA has explained elsewhere in this preamble that 
it is appropriate to exercise enforcement discretion and generally not 
enforce any applicable requirements for such tests. This reflects 
current policy, regardless of whether the tests are IVDs offered as 
LDTs (see sections V.B.1 and VI.L.2 for additional information).
    (Comment 248) One comment stated that the general enforcement 
discretion approach should continue for all IVDs offered as LDTs 
intended as drugs of abuse tests because laboratories need to be able 
to adapt to combat modifications made to illicit drugs to evade 
detection. The comments stated, for example, that the FDA-cleared test 
for fentanyl does not detect modified versions of the drug.
    (Response 248) FDA disagrees with the comment suggesting FDA 
continue the general enforcement discretion approach for all IVDs 
offered as LDTs to test for drugs of abuse. We acknowledge that such 
drugs may be modified and that tests for drugs of abuse may need to be 
modified in order to detect the new versions of these substances. 
However, FDA oversight does not preclude laboratory manufacturers from 
making such changes. FDA believes this oversight is important due to 
the risks to patients from false positive and false negative drugs of 
abuse test results. False positive results may delay treatment for the 
patient's true condition if that condition involves symptoms that 
overlap with drug intoxication (for example, missing a critical 
opportunity to treat cerebral hemorrhage or stroke). False negative 
results may put the patient at risk--for example, if they were to drive 
or were to need urgent treatment for overdose. Compliance with quality 
system requirements, such as design controls, will help assure that 
these drugs of abuse tests perform as intended, and compliance with 
premarket review, where applicable, will help assure that the drugs of 
abuse test's performance is suitable for the test's intended use.
    Where a manufacturer may anticipate the types of changes it intends 
to make, it may consider seeking clearance or approval of a PCCP. Under 
section 515C of the FD&C Act, a PMA supplement or new 510(k) is not 
required for a modification to a device that would otherwise be 
required if the change is consistent with a PCCP previously approved or 
cleared by FDA. To the extent a PCCP is approved or cleared by FDA for 
a particular IVD, any changes within the bounds of that PCCP would not 
necessitate a new submission to FDA.
    (Comment 249) Because the FDA-cleared drugs of abuse tests are only 
for screening, comments suggested that FDA continue the enforcement 
discretion approach for confirmatory LDTs intended as drugs of abuse 
tests, given that these tests are addressing an unmet need.
    (Response 249) FDA acknowledges that in drugs of abuse testing, 
most confirmatory diagnostic tests are currently offered as LDTs. 
However, as discussed in response to comment 248, FDA oversight of 
drugs of abuse tests is important, including when such tests are 
confirmatory.
    With respect to the comments' concerns, FDA notes that the final 
phaseout policy includes several new enforcement discretion policies 
that may help address those concerns. As explained in section V.B.3, 
FDA generally intends to exercise enforcement discretion with respect 
to premarket review and QS requirements (except for requirements under 
part 820, subpart M (Records)) for currently marketed IVDs offered as 
LDTs that were first marketed prior to the date of issuance of this 
rule, including drugs of abuse IVDs offered as LDTs, and that are not 
modified, or that are modified as described in section V.B.3. In 
addition, going forward, LDTs may fall within the enforcement 
discretion policy for unmet needs when they are manufactured and 
performed by a laboratory integrated within a healthcare system to meet 
an unmet need of patients receiving care within the same healthcare 
system (see section V.B.3).
8. Genetic IVDs Offered as LDTs/Next Generation Sequencing
    (Comment 250) Comments asserted that the phaseout policy is 
problematic for genetic tests because if such tests are expected to 
comply with FDA requirements, that will hamper innovation and 
compromise patient care. One comment claimed that FDA's validation 
requirements for each variant are unmanageable for LDTs that analyze 
tens of thousands of variants from multiple sample types. The comment 
asserted that FDA requires 20 unique wildtype samples and 3-20 unique 
positive samples per variant per sample type. Other comments asserted 
that oversight is needed for genetic tests. One comment suggested FDA 
hire genetic counselors to facilitate decision-making focused on the 
risk of harm for genetic tests. Another expressed particular concern 
with pharmacogenomic tests making false claims.
    (Response 250) FDA agrees with comments expressing the need for 
oversight of genetic tests. As illustrated by the pharmacogenomic 
example cited by comments, FDA is concerned that test offerings are 
outpacing the science that supports them. Technological advances have 
made it possible to sequence DNA in large volumes quickly, but there is 
not always evidence of clinical validity for the variants reported and 
used for clinical decision-making. FDA oversight will help ensure 
appropriate clinical validation. FDA's office that oversees in vitro 
diagnostics employs individuals with a wide range of expertise in 
genetics, currently including molecular pathologists, a genetic 
counselor, and Ph.D. trained scientists.
    With respect to NGS tests for the detection of human genetic 
variants, FDA does not agree that its premarket expectations are 
unmanageable, and we do not necessarily require 20 unique positive 
samples for each variant for each specimen type. During premarket 
review, FDA considers prevalence when considering the number of samples 
necessary to validate an NGS assay and generally considers a 
representative approach to validation across variant types. For 
example, such an approach is described in FDA's final guidance document 
entitled ``Considerations for Design, Development, and Analytical 
Validation of Next Generation Sequencing (NGS)-Based In Vitro 
Diagnostics (IVDs) Intended to Aid in the Diagnosis of Suspected 
Germline Diseases'' (Ref. 223). This is feasible to do as demonstrated 
by the many NGS tests, including IVDs manufactured by laboratories, 
that have received premarket authorization from FDA (see, e.g., 
information available in FDA's PMA database (Ref. 165) for PMA numbers 
P210011, P160018, P190032,

[[Page 37413]]

P200011, and P190014; information available in FDA's De Novo database 
(Ref. 166) for De Novo numbers DEN170058 and DEN200059; and information 
available in FDA's 510(k) database (Ref. 224) for 510(k) numbers 
K210017, K202304, K192063, and K190661).
9. Antimicrobial Susceptibility Tests (ASTs)
    (Comment 251) Comments asserted that susceptibility test panels for 
bacteria, fungi, Nocardia, and mycobacteria are mostly LDTs, as the few 
FDA-authorized panels have substantial limitations and there is a lack 
of FDA authorization for less common pathogens. Comments further 
asserted that there are no FDA breakpoints for susceptibility tests for 
many of the pathogens listed by CDC as urgent and serious antibiotic 
resistance threats, including, for example: Candida auris, drug 
resistant N. gonorrhoeae, and carbapenem-resistant Acinetobacter 
baumannii. Comments claimed that it would be unlikely that a laboratory 
would be able to get FDA authorization for a test that applies non-FDA 
interpretive breakpoints (CLSI or European Committee on Antimicrobial 
Susceptibility Testing (EUCAST)), which creates a ``catch-22'' 
situation given the Agency's role in breakpoint approval. The comment 
stated that laboratories will have to default to the breakpoints for 
which the assays received FDA approval, which are also out of sync with 
many of the CLSI updated breakpoints.
    (Response 251) FDA recognizes the importance of using updated 
susceptibility test interpretive criteria (STIC), also referred to as 
breakpoints, when using antimicrobial susceptibility test (AST) 
systems. FDA's Center for Drug Evaluation and Research (CDER) maintains 
a website with the most up-to-date STIC for antibacterial and 
antifungal drugs, including FDA's recognition of STIC established by 
standards development organizations (SDOs) (Ref. 225). FDA has cleared 
hundreds of ASTs (addressing hundreds of individual organism/drug 
combinations) and has worked to ensure that the most up to date STIC 
are used, including having cleared more than 60 ASTs with breakpoint 
change protocols, allowing for the rapid adoption of updated 
breakpoints without further FDA review. To help address the importance 
of adopting updated breakpoints quickly, FDA recently issued a final 
guidance entitled ``Antimicrobial Susceptibility Test (AST) System 
Devices--Updating Breakpoints in Device Labeling,'' which describes 
least burdensome approaches for AST manufacturers to update their 
device labeling with the updated breakpoints listed on the FDA's STIC 
website (see Refs. 225 and 226). This final guidance provides FDA's 
recommendations for submission of PCCPs for new AST systems, describes 
a policy regarding device manufacturers applying certain change 
protocols submitted to FDA in a separate 510(k) to implement breakpoint 
updates for the sponsor's legacy AST system device without a new 510(k) 
submission to FDA, and clarifies the process for incorporating by 
reference a cleared PCCP or breakpoint change protocol into a new 
submission. FDA believes these approaches will facilitate more timely 
adoption of updated breakpoints for numerous marketed devices with out-
of-date breakpoints and streamline the process for future updated 
breakpoints to be incorporated quickly on an ongoing basis.
    FDA disagrees that ``there are no FDA breakpoints for 
susceptibility tests for many of the pathogens listed as CDC urgent and 
serious antibiotic resistance threats (including Candida auris, drug 
resistant N. gonorrhoeae, carbapenem-resistant Acinetobacter baumannii, 
and more)'' as stated in the comment. The CDC list often includes 
qualifiers such as noting resistance to a particular drug. Generally, 
breakpoints are established for organism groups without resistance 
qualifiers, with notable exceptions like methicillin-resistant S. 
aureus and vancomycin-resistant Enterococci for which there is specific 
and significant data to support inclusion of the qualifiers. For other 
organisms, the same breakpoint is used regardless of the isolates. For 
example, there are FDA recognized breakpoints for Acinetobacter with 
many drugs; however, there are no separate breakpoints identified for 
drug-resistant Acinetobacter as the differentiation between drug-
resistant and non-drug resistant Acinetobacter isolates has not been 
established in terms of breakpoint determination. It is important to 
note that CLSI and EUCAST similarly do not often have different 
breakpoints identified for drug-resistant and non-drug resistant 
isolates.
    FDA also disagrees that ``[s]usceptibility test panels . . . are 
mostly LDTs'' and with the characterization that there are only a ``few 
FDA cleared panels.'' As noted, FDA has cleared ASTs addressing 
hundreds of organism/drug combinations and continues working towards 
assuring the breakpoints are updated expeditiously once recognized. In 
addition, referring to Table 2 in Simner et al, 2022, FDA notes that 
between 95.3 percent and 98.8 percent of surveyed CAP-accredited U.S. 
laboratories use automated AST devices (described in the paper as one 
of three commercial AST systems) (see Ref. 227). While some of these 
may be LDTs if the laboratory is modifying the original FDA-authorized 
AST device to use a different breakpoint or a non-cleared organism, the 
same study noted that between 37.9 percent and 70.5 percent of U.S. 
laboratories reported using out-of-date breakpoints for the 
antimicrobials that were queried. Therefore, this publication does not 
support the claim that the majority of ASTs are LDTs. This data 
supports the need for these tests to be updated with current 
breakpoints but does not support the claim that the majority of FDA-
authorized AST devices are being modified and offered as LDTs in order 
to use updated breakpoints.
    FDA notes in response to the statement that ``there is a lack of 
FDA clearance for less common pathogens,'' that there are FDA-
authorized tests and FDA-recognized breakpoints for organism groups 
corresponding to commonly encountered pathogens described in CLSI M100 
Table 1, ``Antimicrobial Agents That Should Be Considered for Testing 
and Reporting.'' While there are some drug/organism combinations that 
lack FDA-recognized breakpoints, this is due to the lack of adequate 
data (clinical, pharmacological, in vitro, etc.) to support the 
establishment of breakpoints. In most of these cases, as well as the 
above discussed cases of drug-resistant isolates, there are no 
breakpoints established by CLSI or EUCAST, either. It is important to 
note that any stakeholder, including a test manufacturer, also has the 
ability to submit a request to FDA requesting recognition of a 
particular breakpoint. This process is described in the docket to which 
these requests can be made (Ref. 228).
10. IVDs Offered as LDTs for Emergency Use
    (Comment 252) Some comments stated that enforcement of premarket 
review requirements for emergency use tests is not appropriate while 
others stated it is necessary. Those opposed to such enforcement cited 
concerns with the ability of public health and AMC laboratories to 
respond to an outbreak quickly and the corresponding impact on patient 
access. Some also expressed concern about the impact of the phaseout 
policy on the availability of tests for emergent situations that do not

[[Page 37414]]

rise to the level of a declared public health emergency.
    (Response 252) FDA agrees with comments that oversight of IVDs for 
emergency use is important. In this context, the potential for false 
results can have serious implications for disease transmission and 
public health decision-making, in addition to the individual patient's 
care. For these reasons, after all previous declarations under section 
564(b) of the FD&C Act, FDA's general enforcement discretion approach 
generally has not applied to LDTs, and FDA is not changing its existing 
approach to tests for emergency use in this final rule (see section 
V.A.2). FDA issued EUAs to 116 IVDs from laboratories for COVID-19 and 
1 IVD from a laboratory for Mpox.
    We note that after a declaration is made under section 564 of the 
FD&C Act, FDA may issue EUAs to products that fall within the 
declaration and that meet certain statutory criteria. Notably, the 
statutory standard for EUAs is different than traditional premarket 
authorization. As discussed in FDA's final guidance entitled 
``Emergency Use Authorization of Medical Products and Related 
Authorities'' (Ref. 229), ``the `may be effective' standard for EUAs 
provides for a lower level of evidence than the `effectiveness' 
standard that FDA uses for product approvals.'' This final guidance 
includes information on how to request an EUA.
    FDA appreciates the need for immediate response to emergent 
situations (e.g., harmful exposures or outbreaks) during the time 
between detection of the exposure or outbreak and either resolution of 
that exposure/outbreak or issuance of a declaration under section 564 
of the FD&C Act. Accordingly, in parallel to this rulemaking, FDA is 
issuing draft guidance for an ``Enforcement Policy for Certain In Vitro 
Diagnostic Devices for Immediate Public Health Response in the Absence 
of a Declaration under Section 564.'' This draft guidance includes an 
enforcement discretion policy that is limited to certain tests needed 
for immediate response and limited to certain laboratories, such as 
those that are USG laboratories, State or local public health 
laboratories, or other laboratories that have agreements with the USG.
    FDA also appreciates that different emergency situations may 
present unique circumstances for which additional enforcement 
discretion policies should be considered. FDA has issued a draft 
guidance document describing ``Consideration of Enforcement Policies 
for Tests During a Section 564 Declared Emergency,'' which describes 
factors FDA intends to consider in determining whether to issue an 
enforcement discretion policy during an emergency declared under 
section 564 for certain tests.
11. IVDs Offered as LDTs by Public Health Laboratories
    (Comment 253) We received several comments that expressed concerns 
regarding the phaseout of FDA's general enforcement discretion approach 
with respect to IVDs offered as LDTs by public health laboratories. 
Comments stated that public health laboratories develop tests for unmet 
needs for: infectious diseases (e.g., STIs, biological and chemical 
threat agents), foodborne diseases, newborn screening, toxicology 
(e.g., blood lead), drugs of abuse testing, and low volume tests for 
rare diseases. Multiple state public health laboratories expressed 
concern with increased oversight of IVDs offered as LDTs for newborn 
screening. They stated that they use LDTs because there is no FDA-
authorized IVD for some disorders on the Recommended Uniform Screening 
Panel and, in other cases, their LDTs are less costly or provide faster 
turnaround times compared to available FDA-authorized IVDs. Comments 
also discussed the significant financial burden associated with 
premarket submissions to FDA and expressed concern regarding the impact 
of the phaseout policy on public health laboratories that develop LDTs 
that are not for profit. Various proposals were provided, including 
continuing the general enforcement discretion approach for existing 
public health laboratories' LDTs, making the FDA review and 
authorization processes similar to that of NYS CLEP or relying on that 
program, streamlining the regulatory process when a public health 
laboratory modifies an FDA-authorized IVD, FDA offering fee waivers or 
exemptions, and FDA providing additional guidance, templates, or other 
resources to facilitate compliance.
    (Response 253) FDA appreciates the important role public health 
laboratories play in our healthcare system. As discussed further in 
section V.B, FDA is adopting various enforcement discretion policies 
that should address some of the concerns raised in these comments. For 
example, FDA intends to exercise enforcement discretion and generally 
not enforce premarket review and QS requirements (except for 
requirements under part 820, subpart M (Records)) for currently 
marketed IVDs offered as LDTs that are not modified or that are 
modified as described in section V.B.3 (including those manufactured by 
public health laboratories) and generally not enforce premarket review 
requirements for LDTs approved by NYS CLEP (including those 
manufactured by public health laboratories).
    We acknowledge that public health laboratories may manufacture LDTs 
for unmet needs and that compliance with premarket review and other 
requirements will impose compliance costs on those laboratories. As 
discussed further in section V.B.3, we are adopting a policy for unmet 
needs LDTs manufactured and performed by a laboratory integrated within 
a healthcare system to meet an unmet need of patients receiving care 
within the same healthcare system. We believe that in such 
circumstances there are important risk mitigations present, 
particularly in the case of unmet need LDTs. We understand that this 
policy does not apply to most public health laboratories (as they are 
not integrated into a healthcare system and their public health mandate 
is to serve patients beyond the hospital system). We think it would be 
inappropriate to extend the policy to unmet needs LDTs developed and 
performed by public health laboratories, or other laboratories that are 
not integrated within a healthcare system, as there are not the same 
risk mitigations present for such LDTs that would help address and 
avoid the use of problematic LDTs.
    FDA disagrees with comments suggesting a streamlined process for 
when a public health laboratory modifies an FDA-authorized IVD. FDA 
does not think modifications by a public health laboratory to an FDA-
authorized IVD merit a different approach or policy, and the comments 
did not explain why the considerations raised in the comments are 
unique to public health laboratories. We note, however, that FDA 
intends to exercise enforcement discretion and generally not enforce 
premarket review requirements when a laboratory, including a public 
health laboratory, certified under CLIA and meeting the regulatory 
requirements under CLIA to perform high complexity testing modifies 
another manufacturer's lawfully marketed test that is not a PMA-
approved or BLA-licensed test, in a manner that could not significantly 
affect the safety or effectiveness of the test or its intended use, as 
described in sections V.C.4 and V.C.5. Further, FDA intends to develop 
appropriately targeted enforcement discretion policies for certain 
common changes to IVDs (including those manufactured and offered by 
public health laboratories), such as extension of specimen stability

[[Page 37415]]

and certain alternative specimen types, following good guidance 
practices.
    Regarding comments about fee waivers or exemptions, please refer to 
the response to comment 190 describing when payment of a user fee is 
required under the current MDUFA authorization. Exceptions from the 
requirement to pay a user fee are established by statute (see sections 
738(a)(2)(B) and 738(a)(3)(B) of the FD&C Act). The statute also 
provides authority for FDA to waive some user fees for certain small 
businesses (see sections 738(a)(3)(B) and 738(d)(1) of the FD&C Act). 
More information about MDUFA fees, user fee exceptions, and how to 
request a fee waiver are available on FDA's website (Ref. 183).
    Finally, FDA intends to consider making additional resources 
available over the course of the phaseout period, which could 
potentially include guidance documents and templates to facilitate 
compliance.
12. IVDs Offered as LDTs for Research Use Only
    (Comment 254) FDA received multiple comments requesting that FDA 
establish reasonable requirements to incentivize companies to seek FDA 
authorization for RUO IVD reagents or test kits. One asserted that the 
majority of LDTs performed in clinical laboratories use test kits 
distributed by large companies and labeled for RUO. Another comment 
stated it is common practice for laboratories to modify FDA-authorized 
IVDs to use RUO instruments or reagents rather than the specified 
instruments or reagents in the FDA-authorized IVD instructions for use. 
This comment stated that, in the event a laboratory makes an LDT from 
RUO components, only the final LDT should be required to comply with 
regulatory requirements.
    (Response 254) FDA has issued a final guidance document that 
addresses RUO products (see Ref. 176). As explained in the final 
guidance, the RUO labeling is meant to serve as a warning to prevent 
such products from being used in clinical diagnosis, patient 
management, or an investigation that is not exempt from part 812. In 
general, IVD products that are intended for clinical diagnosis or 
patient management must be labeled ``For In Vitro Diagnostic Use'' 
(Sec.  809.10(a)(4)) and be in compliance with all applicable 
requirements for in vitro diagnostic devices. In other words, if an IVD 
is intended for clinical diagnostic use, it should not be labeled RUO. 
RUO products are generally not manufactured under the QS requirements, 
and therefore, are not expected to have the quality controls necessary 
for clinical use. A manufacturer that labels their product RUO but 
intends it for clinical diagnostic use would be in violation of the 
FD&C Act, including misbranding the product under section 502(a) of the 
FD&C Act due to the labeling being false or misleading.
    If a laboratory chooses to use one or more RUO components in its 
IVDs offered as LDTs, then the laboratory is responsible for qualifying 
such components in its IVDs. For those IVDs offered as LDTs for which 
the phaseout policy with respect to the QS requirements would apply, as 
long as the laboratory has implemented a quality system that meets the 
QS requirements, as applicable, and is able to appropriately manage the 
quality of these components under that quality system, then the 
components may be incorporated as part of an IVD offered as an LDT (see 
section V.C.3 for a discussion of when FDA generally expects compliance 
with the QS requirements for IVDs offered as LDTs). The RUO-labeled 
component(s) will be reviewed in the premarket submission for the IVD 
offered as an LDT, if applicable.
13. IVDs Offered as LDTs for Sexually Transmitted Infections
    (Comment 255) Comments expressed concern that FDA's proposed 
phaseout of enforcement discretion would negatively affect access to 
STI tests currently in use. Multiple comments asserted that LDTs are 
``the only or most appropriate, and most timely tests available'' for 
HIV and other STIs, and that the proposed phaseout policy would ``make 
it substantially more difficult to adopt new tests or modify existing 
tests to meet urgent and emerging public health needs.'' A comment also 
expressed that home-testing programs implemented by public health 
departments and community-based organizations ``provide critical access 
to HIV, viral hepatitis, and STI testing'' that includes testing 
associated with pre-exposure prophylaxis (PrEP).
    (Response 255) FDA disagrees with comments predicting that phasing 
out the general enforcement discretion approach for LDTs will have 
negative impact on access to STI tests to meet ``urgent and emerging 
public health needs.'' As discussed in section VI.L.10 (IVDs Offered as 
LDTs for Emergency Use) and VI.L.11 (IVDs Offered as LDTs by Public 
Health Laboratories), FDA anticipates that several of the enforcement 
discretion policies adopted in the final phaseout policy will help to 
address the specific concerns raised in the comments regarding the 
availability of IVDs for emerging public health threats by facilitating 
timely access to STI IVDs.
    FDA also disagrees with the comment that ``the most appropriate 
tests'' for HIV and other STIs are currently offered as LDTs. We 
acknowledge the critical importance of access to safe and effective HIV 
tests, including tests that may inform decisions about beginning or 
continuing use of antiretroviral medications for PrEP. However, FDA-
authorized HIV diagnostic and supplemental tests and HIV viral load 
monitoring tests are available to provide such access. We note that 
there is an FDA-approved OTC HIV test that individuals may use to test 
themselves at home or in a private location (Ref. 221). FDA also 
acknowledges the importance of access to safe and effective tests for 
other STIs, such as chlamydia, gonorrhea, mycoplasma genitalium, and 
syphilis, for which FDA-authorized tests are also widely available 
(see, e.g., Refs. 230 to 233). This includes STI tests for use with 
self-collected samples in clinical settings and one STI test with at-
home sample collection for chlamydia and gonorrhea (see, e.g., Ref. 
222). As described in section V.B.3, FDA intends to exercise 
enforcement discretion and generally not enforce premarket review and 
QS requirements (except for requirements under part 820, subpart M 
(Records)) for currently marketed IVDs offered as LDTs, including STI 
tests, that were first marketed prior to the date of issuance of this 
rule. FDA anticipates that this policy will help address the concerns 
expressed in the comments regarding the impact of the proposed phaseout 
policy on access to STI tests currently in use. However, for the 
reasons described in the NPRM and in section V.A.2, we note that FDA's 
general enforcement discretion approach for LDTs has not applied to 
direct-to-consumer tests, including direct-to-consumer HIV and other 
STI tests, and they are not included in this enforcement discretion 
policy (88 FR 68006 at 68022).
14. IVDs Offered as LDTs Conducted by and Within Blood Establishments, 
Transfusion Services, and Cell and Gene Therapy Laboratories
    (Comment 256) Several comments requested that FDA ``exempt'' all 
tests conducted by and within blood establishments, hospitals' 
transfusion services, and accredited cell and gene therapy laboratories 
and services from FDA's proposed phaseout of the general enforcement 
discretion approach. In support of this request, a comment asserted 
that ``the existing regulatory

[[Page 37416]]

framework ensures that [these entities] provide high quality, safe, and 
effective care,'' noting that these entities offer LDTs in CLIA 
certified laboratories that are part of Federal, State, or locally 
licensed facilities. The comment also noted that ``[e]xtensive FDA 
regulatory requirements'' apply to such laboratories such as 
registration, licensure of donor screening tests, and premarket review 
(PMA, 510(k), or New Drug Application (NDA)) requirements for certain 
products, and that some of these laboratories are also subject to 
heightened State regulation, such as the NYS CLEP. Some comments 
expressed concerns that FDA's proposal could negatively affect 
laboratories' abilities to perform compatibility testing for patients 
in need of blood or testing that supports safe use of cell and gene 
therapies. Some comments also requested that FDA exclude 
immunohematology reference laboratories from the scope of the final 
phaseout policy as their LDTs involve ``highly educated and highly 
trained technologists perform[ing] specialized testing using manual 
techniques on select, complex samples'' and without which accurate and 
complete antibody identification would not be possible, resulting in 
``missed antibodies leading to increased transfusion reactions, strains 
to the blood supply due to unnecessary phenomatching of Red Cells and 
many other issues.''
    (Response 256) FDA disagrees with adopting an enforcement 
discretion policy for all tests used in blood establishments, 
transfusion services, and accredited cell and gene therapy (CGT) 
laboratories, and for all immunohematology reference laboratories. In 
the NPRM, FDA identified categories of tests that have not been part of 
the general enforcement discretion approach for LDTs. These categories 
of tests include those that are intended to screen donors of blood and 
HCT/Ps for infectious diseases under Sec. Sec.  610.40 and 1271.80(c), 
or for determination of blood group and Rh factors required under Sec.  
640.5 (88 FR 68006 at 68021-22). Such tests may be conducted in blood 
establishments, transfusion services and/or CGT laboratories. Under the 
cited regulations, a blood or HCT/P establishment must not use a test 
for the purposes described in the regulation unless the test is 
authorized by FDA for such use, and in our experience, establishments 
have been generally complying with these requirements. Therefore, for 
these tests, we would not expect the phaseout policy to negatively 
affect the ability to perform blood compatibility testing or testing to 
determine HCT/P donor eligibility that supports safe use of HCT/Ps, 
such as cellular therapies. As described in section V.A.2, these tests 
are not subject to any enforcement discretion policies included in the 
phaseout policy.
    For other tests conducted by blood establishments, transfusion 
services, or CGT laboratories (i.e., those not subject to the 
requirements under Sec. Sec.  610.40, 640.5, or 1271.80(c)), we 
disagree with the comment's assertion that enforcement discretion is 
appropriate because such tests are developed by laboratories that are 
CLIA certified and part of Federal, State, or locally licensed 
facilities. For discussion of why CLIA does not provide sufficient 
assurances of safety and effectiveness for IVDs offered as LDTs, see 
our responses to comments in section VI.C.2. While the comment did not 
provide details regarding which Federal, State, and local facility 
licensure requirements would be relevant, as a general matter, we note 
that the requirements against which a facility is assessed do not 
necessarily address the analytical and clinical validity of (or other 
issues affecting the safety and effectiveness of) IVDs offered as LDTs 
by a laboratory within that facility.
    With respect to the argument that FDA should exercise enforcement 
discretion for all LDTs conducted by blood establishments, transfusion 
services, or CGT laboratories because these entities already comply 
with FDA requirements for certain other products, such entities should 
already have familiarity with FDA's requirements and thus be better 
positioned to transition to compliance in accordance with the phaseout 
policy. Regarding the comment that some blood establishment and CGT 
laboratories are subject to State requirements like NYS CLEP, FDA 
considered comments received regarding NYS CLEP and intends to exercise 
enforcement discretion and generally not enforce premarket review 
requirements (but intends to phase out enforcement discretion with 
respect to other requirements) for LDTs that are approved by NYS CLEP. 
For further discussion of this policy and other comments received 
related to NYS CLEP see sections V.B.2 and VI.F.5. The comment did not 
mention other, specific state programs.
    Although we disagree with the comments' request for a broad 
enforcement discretion policy for all LDTs conducted by or within blood 
establishments or CGT laboratories and for all immunohematology 
reference laboratories' LDTs, we note that several of the targeted 
enforcement discretion policies described in section V may encompass 
some of these tests and help address the concerns raised in the 
comments. For example, as proposed in the NPRM and described in section 
V.B.1 of this preamble, FDA intends to exercise enforcement discretion 
and generally not enforce any applicable requirements for 1976-Type 
LDTs (88 FR 68006 at 68022). This includes some tests cited in the 
comments that are used in blood establishments and immunohematology 
laboratories such as adsorbing warm-reactive autoantibodies using 
allogeneic or autologous red blood cells, the Donath-Landsteiner test 
for aiding in the diagnosis of paroxysmal cold hemoglobinuria, Ham's 
test to aid in the diagnosis of paroxysmal nocturnal hemoglobinuria, 
tests to evaluate drug-induced hemolysis or interference in 
compatibility testing, monocyte-monolayer test to assess possible 
clinical significance of RBC alloantibodies, modified Kleihauer-Bethke, 
and SDa antigen neutralization with urine.
    In addition, FDA intends to exercise enforcement discretion and 
generally not enforce premarket review and QS requirements (except for 
requirements under part 820, subpart M (Records)) for currently 
marketed IVDs offered as LDTs that were first marketed prior to the 
date of issuance of this rule and that are not modified, or that are 
modified as described in section V.B.3. As noted above, FDA also 
intends to exercise enforcement discretion and generally not enforce 
premarket review requirements for LDTs approved by NYS CLEP, and to 
exercise enforcement discretion with respect to premarket review 
requirements and QS requirements (except for requirements under part 
820, subpart M (Records)) for LDTs manufactured and performed by a 
laboratory integrated within a healthcare system to meet an unmet need 
of patients receiving care within the same healthcare system.
    Finally, FDA intends to exercise enforcement discretion and 
generally not enforce premarket review and QS requirements (except for 
requirements under part 820, subpart M (Records)) for non-molecular 
antisera LDTs for rare RBC antigens when such tests are manufactured 
and performed in blood establishments, including transfusion services 
and immunohematology laboratories, and when there is no alternative 
available to meet the patient's need for a compatible blood transfusion 
as described in section V.B.3. This enforcement policy is based, in 
part, on FDA's recognition that there are occasions where licensed IVDs 
are not available for rare RBC antigens but

[[Page 37417]]

testing for such rare antigens is necessary to help ensure that 
patients receive a compatible blood transfusion and avoid potentially 
life-threatening reactions. We believe that this policy, in addition to 
some of the other enforcement discretion policies described above, 
helps mitigate the concern raised by one comment that a phaseout of 
enforcement discretion for immunohematology laboratories' LDTs will 
result in ``missed antibodies leading to increased transfusion 
reactions.''
15. IVDs Offered as LDTs Used in Manufacturing and Development of Cell 
or Gene Therapy Products
    (Comment 257) One comment recommended enforcement discretion for 
tests used as part of cell therapy product manufacturing. Another 
comment recommended enforcement discretion for tests on banked cord 
blood.
    (Response 257) We do not agree that it is appropriate to exercise 
enforcement discretion for all tests used as part of cell therapy 
product manufacturing or tests on banked cord blood. For example, as 
discussed in the NPRM, the general enforcement discretion approach for 
LDTs has not applied to HCT/P donor screening tests required for 
infectious disease testing under Sec.  1271.80(c), including screening 
tests for banked cord blood (88 FR 68006 at 68021-22); FDA is not 
changing this approach in the final phaseout policy. Under the cited 
regulation, HCT/P establishments must not use a test for the purposes 
listed in that regulation unless the test is authorized by FDA for such 
use. With respect to other tests used as part of cell therapy product 
manufacturing or performed on banked cord blood, we note that this 
would span a wide variety of tests depending on the particular product 
and nature of the manufacturing process, including tests that do not 
meet the definition of an IVD under Sec.  809.3 and are therefore 
outside the scope of this rulemaking and the phaseout policy. We note 
that FDA has mechanisms in place, such as ``Section 513(g) Requests for 
Information,'' for manufacturers to obtain information regarding the 
regulatory requirements applicable to a specific product under the FD&C 
Act (Ref. 65).
    To the extent tests about which the comments are concerned would 
fall within the definition of an IVD, we note that several targeted 
enforcement discretion policies are included in the final phaseout 
policy, as described in section V.B. These policies may help address 
the comments' concerns. For example, to help address harms that could 
result from widespread loss of access to IVDs currently on the market, 
FDA intends to exercise enforcement discretion and generally not 
enforce premarket review and QS requirements (except for requirements 
under part 820, subpart M (Records)) for currently marketed IVDs 
offered as LDTs that were first marketed prior to the date of issuance 
of this rule and that are not modified, or that are modified as 
described in section V.B.3.
    (Comment 258) A comment suggested we should continue the general 
enforcement discretion approach for premarket review and QS 
requirements for tests used in cell and gene therapy product 
development, particularly when screening for clinical trial eligibility 
and monitoring participant response to investigational treatments, 
since these tests are typically conducted in low volumes and reviewed 
in connection with therapeutic product sponsor INDs and NDAs. The 
comment stated that additional regulatory requirements would create 
additional burdens without countervailing benefits to trial 
participants and patients.
    (Response 258) FDA recognizes that some clinical investigations of 
therapeutic products (including cell and gene therapy products) use 
investigational IVDs to guide the management of participants, such as 
to determine eligibility or monitor response of participants to the 
investigational therapeutic product. However, the comment appears to 
suggest that because of the phaseout policy described in the NPRM, 
premarket review requirements would apply to and be enforced for all 
such IVDs when used in clinical investigations. Devices intended for 
use in clinical investigations, including IVDs offered as LDTs, are 
exempt from most regulatory requirements applicable to devices, 
including premarket review, as long as the investigation complies with 
applicable requirements under part 812. As discussed in more detail in 
response to comment 175, FDA's regulations do not necessarily require 
submission of an IDE application to FDA for use of a device in a 
clinical investigation. To the extent submission of an IDE application 
is required for use of an investigational IVD in a clinical 
investigation of a drug or biological product, there are steps that 
sponsors can take to help simplify the process. For example, IDE and 
IND applications may cross-reference each other through a letter of 
authorization. While we disagree that it is appropriate to exercise 
enforcement discretion with respect to applicable QS requirements for 
all IVDs used in CGT product development, we note that an 
investigational device with an approved IDE application (or deemed to 
have an approved IDE under Sec.  812.2(b)) is generally exempt from 
most QS requirements issued under section 520(f) of the FD&C Act (see 
Sec.  812.1). As described in section V.C, FDA intends to phase out the 
general enforcement discretion approach with respect to QS requirements 
during stage 3, including, as applicable, QS requirements for 
investigational devices.
    In all cases, FDA is committed to advancing CGT product development 
while protecting the safety of trial participants. Compliance with 
applicable investigational use requirements is important for the 
protection of participants. Under the phaseout policy described in 
section V.C, FDA expects compliance with applicable IDE requirements 
and other applicable requirements, such as parts 50 and 56, for 
investigations that involve investigational IVDs offered as LDTs 2 
years after publication of this final rule. The Agency has resources 
available that may help sponsors designing trials of therapeutic 
products that involve the use of investigational IVDs, which are 
discussed further in our response to comment 175. Sponsors can also 
engage with FDA under the Q-Submission Program to address questions 
related to IVD risk, study design, and regulatory requirements.
16. Histocompatibility
    (Comment 259) FDA received multiple comments regarding HLA tests. 
Many comments supported FDA's proposed approach to HLA tests for 
transplantation. Multiple comments that supported this approach 
indicated that the extensive and multilayer national system of 
regulatory oversight provided through United Network for Organ Sharing, 
OPTN, the Scientific Registry of Transplant Recipients, NMDP, FACT, and 
the Center for International Blood and Marrow Transplant Research for 
histocompatibility laboratories has ensured analytical and clinical 
validity and patient safety for decades. One comment noted that these 
tests often need to be ``customized'' to the needs of the patient, and 
that requiring premarket approval, or even notification, could prevent 
testing that is critical for patient care. One comment requested that 
FDA include HLA tests used for blood transfusion in its enforcement 
discretion approach. Another comment proposed that FDA broaden the 
scope of its continued enforcement discretion for HLA tests for 
transplantation to all histocompatibility tests. Another comment 
suggested that

[[Page 37418]]

other tests beyond HLA tests are ``generally performed in urgent, life-
saving situations for the patient'' and therefore should be treated 
similarly.
    (Response 259) FDA agrees with the comments to the extent that they 
support the Agency's proposed approach related to HLA tests for 
transplantation. As discussed in the NPRM, and consistent with the 2014 
draft guidance document on oversight of LDTs (Ref. 38), FDA intends to 
exercise enforcement discretion and generally not enforce any 
applicable requirements for HLA tests for transplantation used in 
histocompatibility laboratories that meet the regulatory requirements 
under CLIA to perform high complexity histocompatibility testing, when 
used in connection with organ, stem cell, and tissue transplantation to 
perform HLA allele typing, for HLA antibody screening and monitoring, 
or for conducting real and ``virtual'' HLA crossmatch tests (88 FR 
68006 at 68022). While other tests may be performed in urgent and life-
threatening situations, we note that HLA tests for transplantation are 
often modified rapidly in response to urgent situations and 
individualized within each medical facility based on local HLA 
polymorphisms and patient demographics. Further, we do not agree to 
exercise enforcement discretion with respect to all applicable 
requirements for HLA tests for blood transfusion. As described in the 
NPRM, and in contrast to HLA tests for transplantation, HLA tests for 
blood transfusion are highly standardized across institutions (88 FR 
68006 at 68022). In addition, as noted by some of the comments and 
explained in more detail in section V.B.1, in the context of HLA tests 
for transplantation, there are other Federal oversight mechanisms (such 
as OPTN and NMDP requirements for histocompatibility laboratories and 
HLA testing) that help mitigate risks of inaccurate results.
17. Antisera Used To Test for Rare Red Blood Cell Antigens
    (Comment 260) Several comments recommended FDA continue to exercise 
enforcement discretion for unlicensed antisera that are used to test 
for rare RBC antigens. A comment also asserted that FDA's guidance 
document entitled ``Labeling of Red Blood Cell Units with Historical 
Antigen Typing Results'' recognizes that blood establishments use 
unlicensed reagents or unapproved molecular tests for RBC antigen 
typing and that such tests did not appear to be included in the 
categories of tests for which FDA proposed to continue to apply its 
current general enforcement discretion approach going forward.
    (Response 260) FDA recognizes there are occasions where licensed 
IVDs are not available for rare RBC antigens but testing for such rare 
antigens is necessary to help ensure that patients receive a compatible 
blood transfusion. While there are molecular tests approved for use in 
genotyping RBC antigens, there may not be an available approved 
molecular test to use as an alternative for all rare antigens. After 
considering the comments on this issue, as discussed in section V.B.3, 
FDA intends to exercise enforcement discretion and generally not 
enforce premarket review and QS requirements (except for requirements 
under part 820, subpart M (Records)) for non-molecular antisera LDTs 
for rare RBC antigens when such tests are manufactured and performed in 
blood establishments, including transfusion services and 
immunohematology laboratories, and when there is no alternative 
available to meet the patient's need for a compatible blood 
transfusion. However, for the reasons discussed in section V.B.3, FDA 
does not intend to extend this enforcement discretion policy to 
molecular tests used for genotyping red blood cell antigens.

M. IVD Modifications

    (Comment 261) FDA received comments about modifications to IVDs in 
different scenarios. Some referred to modifications laboratories make 
to their own IVDs offered as LDTs for various reasons, including to 
improve their IVDs. Some stated that laboratories often make 
modifications to other manufacturers' FDA-authorized tests to 
accommodate different specimen types, different patient populations, 
various storage conditions, additional variants for genetic tests, and 
many other factors. Comments stated that laboratories cannot afford the 
expense or significant administrative burden associated with seeking 
FDA review for each such modification. One comment detailed the 
flexibilities under the VALID Act for CLIA-certified high-complexity 
laboratories to make certain modifications to approved in vitro 
clinical tests without seeking independent premarket review and 
suggested FDA adopt a similarly flexible policy for modifications 
through amendments to the FD&C Act and CLIA regulations or through 
continued enforcement discretion. The comment noted that a flexible 
modifications policy should extend to ``grandfathered tests'' because 
failure to do so would make a ``grandfathering'' policy ``obsolete as 
modifications are routinely made to improve performance and adjust to 
changing circumstances.''
    (Response 261) As discussed below, we believe the existing 
requirements and policies and the enforcement discretion policies 
described in section V above generally address laboratory modifications 
of IVDs.
    FDA's regulations describe when manufacturers must submit a 
premarket submission for a modification to their own device. 
Specifically, premarket review is required when: an approved device is 
modified in a way that changes the safety or effectiveness of the 
device, with certain exceptions (pursuant to Sec.  814.39(a)); a 
cleared device, or a device classified through the De Novo process and 
subject to 510(k) requirements, is modified in a way that could 
significantly affect the safety or effectiveness of the device 
(pursuant to Sec.  807.81(a)(3)); \93\ or a 510(k)-exempt device is 
modified outside the scope of the 510(k) exemption. In the context of 
IVDs, these standards have generally been interpreted to include 
changes to the operating principle, intended use and other changes that 
impact performance (see, e.g., Refs. 224 and 61). Post-approval changes 
to a licensed device must be submitted in accordance with Sec.  601.12. 
Where the manufacturer may anticipate the types of changes they intend 
to make, they may consider seeking clearance or approval of a PCCP. 
Under section 515C of the FD&C Act, a PMA supplement or new 510(k) is 
not required for a modification to a device that would otherwise 
require such a submission if the change is consistent with a PCCP 
previously approved or cleared by FDA. To the extent a PCCP is approved 
or cleared by FDA for a particular IVD, any changes within the bounds 
of that PCCP would not necessitate a new submission to FDA.
---------------------------------------------------------------------------

    \93\ FDA has published several guidance documents to help 
stakeholders navigate this process, including ``Deciding When to 
Submit a 510(k) for a Change to an Existing Device'' and ``Deciding 
When to Submit a 510(k) for a Software Change to an Existing 
Device'' (Refs. 61 and 211).
---------------------------------------------------------------------------

    In the final phaseout policy described in this preamble, FDA is 
also including several policies under which FDA generally does not 
intend to enforce the premarket review requirements for certain 
modified IVDs offered as LDTs. For example, if an IVD offered as an LDT 
was first marketed prior to the date of issuance of this rule, FDA 
intends to exercise enforcement discretion and generally not enforce 
premarket review requirements when the IVD is modified in certain 
limited ways as described in section V.B.3. As described in response to 
comment 124, this policy is intended to preserve access to beneficial 
IVDs on which patients and the healthcare community currently rely, 
including

[[Page 37419]]

versions of that IVD with minor changes. In addition, the final 
phaseout policy described in this preamble includes an enforcement 
discretion policy under which FDA generally does not intend to enforce 
premarket review requirements for certain LDTs for unmet needs, which 
may consist of a laboratory modification to an LDT or to another 
manufacturer's legally marketed test to meet an unmet need for use by a 
laboratory integrated within a healthcare system (see section V.B.3). 
Third, as described in sections V.C.4 and V.C.5, FDA intends to 
exercise enforcement discretion and generally not enforce premarket 
review requirements when a laboratory makes certain changes to another 
manufacturer's lawfully marketed 510(k) cleared or De Novo authorized 
test.
    FDA also intends to develop appropriately targeted enforcement 
discretion policies for certain common changes, such as extension of 
specimen stability and certain alternative specimen types, following 
good guidance practices. Although FDA does not anticipate that such 
enforcement discretion policies will be analogous to certain provisions 
in the VALID Act, FDA nonetheless anticipates that such enforcement 
discretion policies will further help to address concerns regarding 
modifications as described in comments submitted to the docket. 
Moreover, the custom device exemption in the FD&C Act (21 U.S.C. 
360j(b)), or enforcement discretion decisions for individual 
manufacturers, IVDs, or IVD modifications, may be appropriate to 
address unique patient needs or unforeseen circumstances.
    (Comment 262) FDA received comments discussing the use of PCCPs as 
an option in complying with FDA requirements addressed in the phaseout 
policy. One comment inquired as to whether the PCCP process would 
extend to all assays or if it would be specific to sequencing assays, 
and whether FDA would issue a document explaining the PCCP process, 
including the type of change that would still require submission to 
FDA.
    (Response 262) The use of PCCPs is not limited to certain types of 
devices, such as sequencing assays. FDA intends to issue draft guidance 
for stakeholders on Predetermined Change Control Plans for Medical 
Devices, as noted in the list of proposed guidances for fiscal year 
2024 prepared by CDRH (Ref. 234).
    (Comment 263) Another comment stated that PCCPs would not alleviate 
the need for new 510(k)s and PMA supplements for modifications because 
it would apply only to changes that a manufacturer makes to its own 
device and would not allow laboratories to adapt cleared or approved 
tests from other manufacturers to meet evolving clinical needs; and 
further, it would apply only to changes that the manufacturer can 
anticipate at the time of submission and does not enable laboratories 
to modify tests in response to other changing circumstances like 
reagent shortages or unique patient needs.
    (Response 263) FDA agrees that the use of a PCCP would not be 
applicable in all circumstances in which a laboratory modifies an IVD. 
Inclusion of a PCCP in the clearance or approval of a device is based 
on FDA's review of the manufacturer's approach for validating certain 
types of modifications and associated acceptance criteria. While PCCPs 
are necessarily limited to the types of modifications the manufacturer 
can anticipate for a device that is under premarket review, use of the 
PCCP is just one approach to support the iterative improvement of a 
manufacturer's own devices. In addition, FDA has adopted or intends to 
adopt other enforcement discretion policies that may be relevant to the 
modifications described by the comments, which are described in the 
previous comment response. Otherwise, FDA believes premarket review of 
modifications as described in response to comment 261 is appropriate, 
consistent with the overall goal of this rulemaking to better assure 
the safety and effectiveness of IVDs offered as LDTs.
    (Comment 264) FDA received a few comments that questioned the 
extent to which PCCPs would alleviate regulatory burdens for industry 
and how well they would function. One comment stated that, from 
experience with the current PCCP process, reaching agreement has been 
burdensome and lengthy, which limits the utility of PCCPs. Other 
comments stated that it is premature for FDA to assume that PCCPs will 
help laboratories as the program is still very new and it is unclear 
how well it will work for various categories of devices; and further, 
that it is unreasonable to expect laboratories that previously were 
generally not expected to comply with FDA requirements to leverage 
tools that still challenge more seasoned manufacturers.
    (Response 264) FDA recognizes that efforts around PCCPs are 
relatively new and not all manufacturers may utilize PCCPs when making 
IVD modifications. In order to provide additional information to 
stakeholders on this topic, FDA has announced that it intends to issue 
draft guidance on PCCPs in fiscal year 2024 (Ref. 234). In addition, by 
the time of stages 4 and 5 of the final phaseout policy, FDA 
anticipates that it will have more experience with PCCPs, including in 
the context of IVDs, in order to facilitate manufacturer use of this 
tool. FDA may also provide additional guidance and educational 
opportunities for stakeholders, as appropriate. In any event, whether 
laboratories choose to use the PCCP process does not affect the public-
health need for this rulemaking.
    (Comment 265) FDA received comments expressing concern that 
premarket review requirements will cause disruption in access to tests 
and requesting the Agency take a more flexible approach or provide 
simplified submission requirements for specific types of assay 
modifications. Some comments suggested that FDA create a new submission 
pathway whereby low-risk modifications are reviewed on an expedited 45-
day timeline and use this pathway when a PCCP may not be possible or 
available for low-risk modifications (i.e., those that do not change 
the intended use, indications for use, or adversely affect the approved 
analytical or clinical performance) so that test manufacturers may 
implement low-risk modifications more expeditiously and ensure patient 
access to cutting-edge technology.
    (Response 265) At the outset, FDA notes that compliance with 
premarket review requirements protects and promotes public health by 
helping assure that devices are safe and effective. In addition, not 
all modifications require premarket review. For modifications requiring 
premarket review, FDA will use the well-established premarket pathways 
set forth in the statute and regulations. With respect to the 45-day 
review period proposed by the comments, FDA declines to adopt a new 
policy expediting review of these modifications, which would divert 
resources from other priorities. However, for certain modifications 
that require premarket submission, FDA anticipates that the established 
expedited premarket pathways, such as the Special 510(k) program for 
moderate-risk devices with a 30-day timeline and the Real Time PMA 
program for high-risk devices with a 90-day timeline (see Refs. 235 and 
236), will help laboratories implement these modifications in a timely 
manner. In addition, FDA has adopted or intends to adopt other 
enforcement discretion policies that may be relevant to such 
modifications. See the discussion in comment response 261.

[[Page 37420]]

    (Comment 266) One comment proposed a continued enforcement 
discretion approach for modifications of certain FDA-approved (third-
party) IVDs by appropriately trained and ``certified'' clinical 
scientists/pathologists at certain clinical laboratories, such as 
laboratories with high sample volume, reference laboratories, and 
laboratories serving ethnically diverse patient populations. This 
comment further proposed that qualified laboratory personnel would 
develop, review, and validate the modifications and submit a final 
report to FDA ``for information only,'' which would be used to 
facilitate FDA's review of the test characteristics when a submission 
for the modified IVD is submitted by the initial third-party 
manufacturer. The comment proposed that this approach should be limited 
to modifications of an FDA approved assay adapted for the local 
clinical need.
    (Response 266) FDA does not agree that it should adopt the approach 
proposed in the comment. By ``FDA-approved'' IVD, we assume that the 
comment is referring to an IVD that is approved under a PMA. Such IVDs 
are class III devices that are considered high risk. When an IVD is 
high risk, changes to that IVD pose corresponding increased risks. 
Therefore, although FDA has adopted an enforcement discretion policy 
for certain laboratory changes to another manufacturer's lawfully 
marketed 510(k) cleared or De Novo authorized test (see sections V.C.4 
and V.C.5), this policy does not apply to IVDs approved under a PMA.
    However, FDA is adopting several other enforcement discretion 
policies that may be relevant to the comment's concern. As described in 
section V.B.3, FDA intends to exercise enforcement discretion and 
generally not enforce premarket review and QS requirements (except for 
requirements under part 820, subpart M (Records)), for: (1) IVDs 
offered as LDTs that were first marketed prior to the date of issuance 
of this rule, including versions of those IVDs with minor changes and 
(2) LDTs manufactured and performed by a laboratory integrated within a 
healthcare system to address an unmet need of patients receiving care 
within the same healthcare system.
    (Comment 267) With respect to laboratory modifications to another 
manufacturer's FDA-authorized test, another comment suggested that FDA 
``clarify through special controls what laboratories are expected to do 
when performing such validations and the extent to which the modified 
test's performance can change from the originally authorized version.'' 
The comment stated that it would be more practical for FDA to expect a 
premarket submission from a laboratory only when the modification is to 
another manufacturer's already cleared or approved device and a 
``significant change'' has been made, as defined in FDA's guidance 
document entitled ``Deciding When to Submit a 510(k) for a Change to an 
Existing Device'' (Ref. 61).
    (Response 267) FDA agrees with this comment in that FDA intends to 
exercise enforcement discretion with respect to the premarket review 
requirements for certain modifications to certain lawfully marketed 
tests. Specifically, as described in sections V.C.4 and V.C.5, FDA 
intends to exercise enforcement discretion and generally not enforce 
premarket review requirements when a laboratory certified under CLIA 
and meeting the regulatory requirements under CLIA to perform high 
complexity testing modifies another manufacturer's lawfully marketed 
510(k) cleared or De Novo authorized test, following design controls 
and other quality system requirements for which FDA expects compliance 
as described in section V.C.3, in a manner that could not significantly 
affect the safety or effectiveness of the test and does not constitute 
a major change or modification in intended use, and where the modified 
test is performed only in the laboratory making the modification. The 
guidance document mentioned in the comment applies to a manufacturer's 
modification of its own legally marketed device that is subject to 
510(k) requirements. However, its description of changes that could 
significantly affect the safety or effectiveness of a test or 
constitute a major change or modification in intended use would be 
helpful and relevant for purposes of the enforcement discretion policy 
described in this paragraph.
    Further, FDA intends to develop appropriately targeted enforcement 
discretion policies for certain common changes, such as extension of 
specimen stability and certain alternative specimen types, following 
good guidance practices.
    In addition, to the extent the comment suggested that FDA should 
not expect premarket submissions from laboratories when a modification 
is made to a laboratory's own IVD, we disagree. Even if a laboratory is 
making a change to its own IVD, certain of those changes warrant 
premarket review in order to protect and promote public health. For 
example, for a 510(k)-cleared device, premarket review is expected when 
a change could significantly affect the safety or effectiveness of the 
device.
    If a manufacturer needs assistance in understanding FDA's 
expectations for validation for a particular test, whether the test is 
designed initially by the laboratory manufacturer or whether the 
laboratory manufacturer is modifying another manufacturer's test, it 
may seek information through FDA's Pre-Submission program, which is 
further explained in FDA's guidance document entitled ``Requests for 
Feedback and Meetings for Medical Device Submissions: The Q-Submission 
Program'' (Ref. 65). Validation expectations may also be included in 
device-specific special controls, guidance documents, decision 
summaries, and recognized standards, all of which can be found on FDA's 
website. Further, FDA plans to consider what other resources may be 
helpful for laboratory manufacturers that modify another manufacturer's 
FDA-authorized test. Any future such resources will also be made 
available on FDA's website.
    (Comment 268) FDA received several comments regarding test 
modifications in various areas of medicine, such as genetic testing, 
STI tests, and others that would be impacted by the phaseout policy. 
One comment asserted that the ability to rapidly update tests has 
improved the accuracy of genetic testing and provides improved 
sensitivity and specificity of testing across diverse populations in 
the United States. Another comment stated that increased oversight of 
LDTs would have significant implications for ongoing improvements using 
real-world evidence and continuous feedback loops, which allows for 
iterative enhancements to tests that greatly benefit patients. Another 
comment discussed the modifications to another manufacturer's FDA-
authorized tests that are used in the pediatric population, where 
information in the labeling, such as intended use statements, are 
restrictive regarding patient population and specimen collection.
    (Response 268) FDA agrees that test modifications, including those 
implemented based on real-world evidence information and to expand the 
indications for use of another manufacturer's FDA-authorized test to 
include pediatrics, can greatly benefit patients when the modified test 
remains safe and effective. FDA has seen modifications to tests that 
were intended to improve the test but did not actually do so; once the 
modified test underwent validation testing, the performance of the test 
was worse than the unmodified test and the test was no

[[Page 37421]]

longer safe and effective for its intended purpose. FDA has also seen 
modifications to tests that have not been supported by valid scientific 
evidence--for example, when there has been a lack of valid scientific 
evidence demonstrating the clinical validity of the modified test. FDA 
does not agree with the underlying implication of these comments that 
being able to modify IVDs without premarket review, regardless of the 
type of modification, best serves public health. FDA premarket review 
of modifications that could affect a test's safety and effectiveness 
helps ensure that modified IVDs are safe and effective. For example, 
FDA premarket review helps ensure appropriate clinical validation for 
modifications, among other things, including for genetic and STI tests, 
which were specifically raised by one comment.
    (Comment 269) One comment expressed concern regarding the 
``potential rigidity'' of the device regulatory scheme and its impact 
on the ability to ``routinely adjust DNA/RNA extraction processes to 
obtain more quality material for testing based on improving 
technology.'' The comment went on to propose FDA adopt an ``improved 
technology verification protocol'' that will allow a party to submit 
the reasons for modifications with a justification of improvements and 
demonstration that QC measures are being maintained.
    (Response 269) The comment proposed a new regulatory approach to 
device modifications based on an ``improved technology verification 
protocol.'' Even assuming such an approach were within FDA's statutory 
authority, creating a new regulatory approach for all device or IVD 
modifications is not within the scope of this rulemaking, which is 
focused on phasing out the general enforcement discretion approach for 
LDTs. FDA notes that it may be appropriate to include certain changes, 
such as the modification to DNA/RNA extraction methods mentioned in the 
comment, in a PCCP in a premarket submission to FDA. For a more 
detailed discussion of PCCPs, see comment responses 262-264.
    (Comment 270) Several comments discussed antimicrobial breakpoints 
and whether updates to breakpoints of ASTs should fall within the 
phaseout policy. One comment asserted that FDA's policy for requiring 
manufacturers of automated AST devices to wait for FDA to recognize 
updated breakpoints forces laboratories ``to choose between FDA's 
outdated breakpoints . . . or performing internal validation of CLSI's 
updated breakpoints.'' Another comment asserted that manufacturers of 
``FDA-cleared or approved automated devices are not required to update 
breakpoints, and therefore modified FDA-cleared/approved (LDT) testing 
must be used'' and further asserted that their laboratory would not 
have the necessary staffing and financial resources to submit premarket 
submissions for revised breakpoints.
    (Response 270) FDA disagrees with the premise that FDA's recognized 
breakpoints are outdated. Section 3044 of the Cures Act created a 
system to expedite the recognition of breakpoints, referred to in the 
Act as antimicrobial STIC (section 511A of the FD&C Act, 21 U.S.C. 
360a-2). Since implementation of this statutory provision, FDA posts 
information online about FDA's recognition, or withdrawal from 
recognition, in whole or in part, of STIC established by an SDO and 
lists of exceptions or additions to the recognized STIC that the SDO 
established (Ref. 225). These online references are updated regularly. 
This approach allows FDA to more quickly communicate updated STIC than 
would be possible through updating and re-updating drug labeling. FDA 
has also created corresponding processes for rapid updates of 
breakpoints in AST devices. For example, FDA works with manufacturers 
to include PCCPs in their premarket submissions so that they can update 
their devices to address updated breakpoints without premarket review. 
In 2023, FDA issued a final guidance document, ``Antimicrobial 
Susceptibility Test (AST) System Devices--Updating Breakpoints in 
Device Labeling'' (Ref. 226), in which FDA describes least burdensome 
approaches for AST system device manufacturers to update their device 
labeling with the updated breakpoints listed on FDA's STIC website 
(Refs. 225 and 226). Generally, updating the STIC could significantly 
affect the safety and effectiveness of the AST system device and would 
therefore require a 510(k) submission prior to updating the device 
labeling. However, the final guidance provides recommendations on the 
marketing submission content for PCCPs for new AST system devices, 
describes an enforcement policy regarding applying such updates to 
``legacy'' AST system devices (AST system devices that were reviewed 
and cleared by FDA and did not include a breakpoint change protocol), 
and clarifies the process for incorporating by reference a cleared PCCP 
or breakpoint change protocol into a new 510(k) submission for an AST 
system device. FDA anticipates that this final guidance will facilitate 
timely adoption of updated breakpoints in AST system devices, which 
helps to maintain device safety and effectiveness. This should also 
reduce the burden on laboratories regarding the need to modify 
automated devices or submit premarket submissions where the 
manufacturers of the automated devices are using these streamlined 
approaches to quickly adopt updated breakpoints.
    Additionally, for laboratories that are already offering AST 
devices as LDTs, as discussed in section V.B.3, FDA intends to exercise 
enforcement discretion and generally not enforce premarket review and 
QS requirements (except for requirements under part 820, subpart M 
(Records)) for currently marketed IVDs offered as LDTs that were first 
marketed prior to the date of issuance of this rule, and for certain 
modifications to such currently marketed IVDs offered as LDTs. In 
general, future updates to breakpoints of currently marketed ASTs 
offered as LDTs are within the scope of this enforcement policy, 
provided that such update is validated, does not change the indications 
for use of the AST, does not alter the operating principle of the AST, 
does not include significantly different technology, and does not 
adversely change the performance or safety specifications of the AST. 
For a modification to the breakpoint to an IVD currently offered as an 
LDT to be considered clinically validated, FDA expects the updated 
breakpoint to reflect that identified on the STIC website.
    (Comment 271) Some comments stated that enforcing premarket review 
requirements for manufacturing changes will hamper process innovation, 
which will disincentivize changes that may improve laboratory 
operations and costs to patients, such as updating software, adding 
automation, and adjusting workflow to accommodate throughput needs of 
the institution.
    (Response 271) As an initial matter, FDA notes that updating 
software, adding automation, and adjusting workflow to accommodate 
throughput could be examples of manufacturing process changes or 
changes to the design of an IVD, depending on how the change applies. 
For example, an update to the software used by a test would generally 
be considered a design change. For additional information regarding 
modifications to IVDs offered as LDTs, including design modifications, 
see the responses to comments 261 through 270. To the extent the 
comments are specific to changes made to the manufacturing

[[Page 37422]]

process, FDA requirements for premarket review of manufacturing process 
changes are calibrated to the significance of the change and risk of 
the device, such that premarket review (to the extent required) of 
minor changes is more streamlined than for major manufacturing changes. 
We believe this framework helps address some of the comments' concerns.
    For example, for devices approved under a PMA or licensed under a 
BLA, FDA regulations require the submission of a supplement or a 30-day 
notice for certain manufacturing changes (see Sec. Sec.  814.39 and 
601.12). The appropriate type of submission varies with the nature of 
the change, as discussed in FDA's final guidance, ``Modifications to 
Devices Subject to Premarket Approval (PMA)--The PMA Supplement 
Decision-Making Process'' (Ref. 185) (see also Sec.  601.12(b)-(c)). In 
some cases, which generally involve minor changes, manufacturing 
changes may be noted in a PMA or BLA annual report after they have been 
implemented (see Sec. Sec.  814.39(b) and (e) and 601.12(e)). We also 
note that FDA estimates that premarket approval or licensure 
requirements will apply to only a small percentage of IVDs offered as 
LDTs (see Appendix A of the FRIA (Ref. 10)).
    For devices subject to premarket notification, which are generally 
lower risk than those subject to PMA or BLA requirements, a change in 
the device manufacturing process would require a new 510(k) only if the 
change was one that could significantly affect the safety or 
effectiveness of the device (see Sec.  807.81(a)(3)). Although, the 
need for premarket review of a manufacturing process change for an IVD 
is typically a case-specific evaluation, many changes implemented to 
improve laboratory operations may not trigger the requirement for a new 
510(k) submission under FDA regulations. As discussed in FDA final 
guidance, manufacturers should consider the impact of manufacturing 
changes on device labeling, technology, engineering, performance, and/
or materials to determine if a new 510(k) submission is required (Ref. 
61).
    In our experience, FDA premarket review of certain manufacturing 
changes is important to prevent adverse effects on device safety and 
effectiveness. For example, if a new manufacturing line is introduced 
that significantly alters the specificity of an antibody used for colon 
cancer screening, hundreds of individuals may receive false negative 
cancer screening results and miss critical early detection of colon 
cancer. In this example, even if introduction of the new manufacturing 
line was intended to improve operations, the change could have a 
significant, unintended adverse impact on the device's safety and 
effectiveness and, ultimately, on patients.
    Moreover, as discussed in response to comment 261, FDA is issuing 
several policies under which FDA generally does not intend to enforce 
the premarket review requirements for certain modifications to IVDs 
offered as LDTs. The Agency anticipates these enforcement discretion 
policies will also help alleviate some of the concerns expressed in 
these comments.
    (Comment 272) One comment stated that FDA should ``differentiate 
permitted off-label use from actions that create a `new' or `modified' 
test such that FDA would have jurisdiction'' and that FDA should 
``ensure that it protects the legitimate (and statutorily protected) 
right of a healthcare professional to utilize a legally marketed test 
for an unapproved use.''
    (Response 272) Section 1006 of the FD&C Act sets forth what conduct 
falls outside FDA's statutory authority as the ``practice of 
medicine,'' 21 U.S.C. 396, meaning Congress has already 
``differentiate[d]'' in the manner suggested by the comment. For 
further discussion of the practice of medicine, see sections VI.D.6 and 
VI.D.7 of this preamble.
    (Comment 273) One comment requested guidance ``on the use of 
specific IVD Cleared reagents and the conditions under which an LDT 
status is assigned.''
    (Response 273) To the extent this comment is requesting 
clarification on whether the use of 510(k)-cleared reagents to develop 
a new test system would be considered manufacture of an IVD offered as 
an LDT, the answer is that it would. A test system is itself a device 
subject to applicable device requirements, regardless of whether the 
components of the system comply with FDA requirements.

N. FDA Resources

    (Comment 274) Some comments expressed concerns that FDA would not 
have sufficient resources to conduct timely premarket review of IVDs 
offered as LDTs to meet the public health needs. Some recommended that 
FDA modify the phaseout policy to prolong the period of time prior to 
phasing out the general enforcement discretion approach with respect to 
premarket review requirements, and/or continue to apply the general 
enforcement discretion approach with respect to premarket review 
requirements for certain LDTs, to reduce the FDA resource needs.
    (Response 274) FDA has considered Agency resources in developing 
the final phaseout policy (see section II.G of the FRIA (Ref. 10)). FDA 
disagrees that the Agency will lack sufficient resources to conduct 
premarket review of IVDs offered as LDTs in a timely manner.
    First, FDA does not intend to phase out the general enforcement 
discretion approach with respect to premarket review requirements for 
high-risk IVDs offered as LDTs until 3\1/2\ years after publication of 
this final rule (stage 4 of the phaseout policy), and for moderate- and 
low-risk IVDs offered as LDTs (that require premarket submissions), 
until 4 years after publication of this final rule (stage 5 of the 
phaseout policy). This timeline aligns with the next reauthorization of 
MDUFA. This alignment will provide an opportunity for FDA and industry 
to negotiate regarding user fees and performance goals with the 
knowledge that laboratory manufacturers will be expected to comply with 
applicable premarket review requirements. Additional discussion 
regarding FDA's implementation of the phaseout policy is provided in 
response to comment 291. As discussed further in that response and in 
section V.C, for IVDs offered as LDTs for which a complete PMA, HDE 
application, 510(k) submission, BLA, or De Novo request has been 
received by the beginning of stage 4 or stage 5 of the phaseout policy 
(as applicable), FDA generally does not intend to enforce premarket 
review requirements until FDA completes its review of the application/
submission. Thus, the timeliness of review of these submissions 
generally should not impact patient access.
    Second, FDA intends to exercise enforcement discretion and 
generally not enforce premarket review and QS requirements (except for 
requirements under part 820, subpart M (Records)) for currently 
marketed IVDs offered as LDTs that were first marketed prior to the 
date of issuance of this rule and that are not modified, or that are 
modified as described in section V.B.3. FDA also intends to exercise 
enforcement discretion and generally not enforce premarket review 
requirements for LDTs approved by NYS CLEP, and to exercise enforcement 
discretion and generally not enforce premarket review requirements and 
QS requirements (except for requirements under part 820, subpart M 
(Records)) for LDTs manufactured and performed by a laboratory 
integrated within a healthcare system to meet an unmet need of patients 
receiving care within the same healthcare system. These aspects of the 
phaseout policy are

[[Page 37423]]

discussed further in section V.B of this preamble, and collectively 
will significantly reduce the number of premarket submissions for IVDs 
offered as LDTs, as compared to the estimates in the PRIA. In 
particular, the total estimated number of affected tests has been 
reduced from 88,176 (see Ref. 60) to 7,606 (Ref. 10).
    Third, FDA will gain more visibility into the universe of IVDs 
offered as LDTs through registration and listing in stage 2, which 
should help the Agency facilitate the efficient allocation of premarket 
review resources for those IVDs. As explained in the NPRM and discussed 
in the FRIA, FDA's device authorities require premarket review only for 
certain IVDs (88 FR 68006 at 68013). FDA estimates that approximately 
50 percent of IVDs offered as LDTs will not require premarket review 
(see section II.F.2 of the FRIA (Ref. 10)). However, there are 
uncertainties surrounding the estimate of total numbers of IVDs offered 
as LDTs on the market because FDA generally has not enforced the 
registration and listing requirements for LDTs under section 510 of the 
FD&C Act and parts 607 and 807 (excluding subpart E). By 2 years after 
publication of this final rule, during stage 2 of the phaseout policy, 
FDA will obtain registration and listing information from laboratory 
manufacturers offering IVDs as LDTs. This information will help FDA 
assess and plan for the resources needed for premarket review of those 
IVDs before stages 4 and 5 of the phaseout policy. In addition, on 
January 31, 2024, FDA announced its intent to initiate the 
reclassification process for most IVDs that are currently class III 
into class II (Ref. 66). The majority of these tests are infectious 
disease and CDx IVDs. FDA aims to complete this reclassification 
process before stage 4 of the phaseout policy. Reclassification would 
allow manufacturers of certain types of tests to seek marketing 
clearance through the less burdensome 510(k) pathway rather than the 
PMA pathway, the most stringent type of FDA medical device review. FDA 
also intends to continue taking a risk-based approach in the initial 
classification of individual IVDs to determine the appropriate level of 
regulatory controls and whether a new test may be classified into class 
II through De Novo classification (and special controls established), 
rather than being class III and subject to the PMA pathway. Based on 
our experience, we believe that special controls could be developed, 
along with general controls, that could provide a reasonable assurance 
of safety and effectiveness for most future CDx and infectious disease 
IVDs. We therefore anticipate the percent of IVDs, including LDTs, 
eligible for 510(k) review to increase.
    Fourth, other aspects of FDA's phaseout policy and related FDA 
actions will help to reduce premarket review resource needs. For 
example, FDA is currently working to enhance its Third Party review 
program to handle the review of low- and moderate-risk devices by 
3P510k Review Organizations. This will free up Agency staff time to 
review more complex, innovative, high-risk devices. FDA estimates that 
half of the IVDs offered as LDTs subject to 510(k) requirements will be 
reviewed under the Third Party review program.
    Fifth, FDA anticipates that laboratories may utilize PCCPs, and as 
discussed in response to comment 261, for certain common changes (like 
extension of reagent stability and certain alternative specimen types), 
FDA intends to develop appropriately targeted enforcement discretion 
policies, following good guidance practices. See additional discussion 
regarding test modifications in our responses to comments in section 
VI.M. FDA believes that PCCPs and targeted enforcement discretion 
policies will minimize the number of premarket submissions for 
modifications to IVDs offered as LDTs.
    (Comment 275) Some comments questioned whether FDA would have 
adequate capacity to provide timely review of LDT applications/
submissions because many EUA requests were not reviewed due to resource 
limitations during the COVID-19 pandemic. At least one comment cited 
FDA's review of a particular EUA request for an LDT during the COVID-19 
pandemic, in which FDA's review of the request did not conclude until 
after the subject LDT had been removed from the market, as proof that 
FDA does not have adequate resources to conduct premarket review of 
LDTs.
    (Response 275) FDA disagrees that its review of any one particular 
EUA request submitted for an LDT during the COVID-19 pandemic is 
indicative of how FDA will review premarket applications/submissions 
for IVDs offered as LDTs generally. FDA also disagrees that decision 
timelines on EUA requests, in general, are a good indicator to predict 
FDA's timelines for review of premarket applications/submissions for 
IVDs offered as LDTs.
    First, EUAs differ substantially from standard premarket review 
pathways. FDA's authority to issue EUAs for LDTs is under a different 
statutory provision (section 564 of the FD&C Act) than traditional 
premarket reviews. Moreover, FDA is not required to review individual 
EUA requests submitted to FDA or review them on a specific timeline, or 
to authorize the emergency use of a medical product even if it meets 
the relevant criteria for an EUA, giving FDA flexibility to determine 
how to prioritize its efforts in emergencies to protect and promote 
public health. Second, during the COVID-19 pandemic, FDA received a 
large influx of submissions that had not been anticipated. In the 
context of the phaseout policy, FDA has estimated the number and type 
of premarket submissions we can expect in stages 4 and 5, and annually 
thereafter, and can prepare for those submissions.
    Third, as noted in an FDA memorandum to file that was part of the 
record for this rulemaking (Ref. 18), FDA identified many issues with 
EUA requests from laboratories. When data are not presented clearly or 
data are inadequate to support authorization, FDA works with the 
submitter to address these issues and, in most cases, achieve 
authorization. This process extends review times. FDA anticipates that 
phasing out the general enforcement discretion approach for LDTs, 
combined with additional education or guidance, will ultimately lead to 
better submissions from laboratory manufacturers once they become 
familiar with FDA's expectations.
    (Comment 276) Some comments referenced FDA's MDUFA IV performance 
report from FY2020 to 2022 (during the COVID-19 pandemic) and predicted 
that the increased volume of submissions from laboratory manufacturers 
that would result from the phaseout policy would affect FDA's overall 
ability to review premarket submission for all IVDs, meet its MDUFA 
performance goals, and conduct other essential work, including policy 
and post-market activities.
    (Response 276) MDUFA performance goals include shared outcome goals 
agreed to by both FDA and representatives of the industry. FDA and 
applicants share the responsibility for achieving the Total Time to 
Decision objectives. Since premarket review of IVDs offered as LDTs is 
based on significant interaction between the Agency and applicants, 
high quality submissions will generally help reduce FDA's review time. 
FDA anticipates providing more targeted guidance on various topics, 
such as validation, and making additional resources available on the 
topic of premarket review of IVDs offered as LDTs over the course of 
the phaseout period. Further, as noted in

[[Page 37424]]

response to comment 274, the phaseout of enforcement discretion for 
premarket review requirements aligns with the next reauthorization of 
MDUFA, providing an opportunity for FDA and industry to negotiate 
regarding user fees and performance goals with the knowledge that 
laboratory manufacturers will be expected to comply with applicable 
premarket review requirements.
    (Comment 277) Another comment referenced FDA's ``prolonged review'' 
of a particular consensus standard and suggested that ``such an 
extended review period raises concerns about the FDA's capacity to 
regulate and approve essential LDTs in a timely manner.''
    (Response 277) FDA disagrees that our standards recognition process 
has any bearing on our ability to conduct timely premarket reviews, 
including reviews of LDTs. The premarket review process and the 
standards recognition process are independent and have different 
timelines and prioritization. Further, FDA's participation in standards 
writing committees does not automatically signal that FDA intends to 
recognize the standard. As these are consensus standards with many 
participants, FDA may or may not agree with the final published content 
and has a formal process for considering recognition.
    (Comment 278) Some comments expressed concerns that a substantial 
increase in FDA staff and review capacity will be required to implement 
the phaseout policy, and workforce shortages will make it difficult to 
recruit and retain adequate numbers of qualified reviewers who are 
trained in laboratory diagnostics. Some comments stated that FDA lacks 
the personnel with relevant knowledge and expertise in laboratory 
medicine to effectively oversee molecular genetic IVDs offered as LDTs. 
One comment concluded that FDA had not kept up with the state-of-the-
art methods for evaluating whole genome sequences, based on the fact 
that FDA declined to accept the Average Nucleotide Identity (ANI) 
results offered to correct the FDA-ARGOS database because the ANI 
results had not yet been standardized through the National Center for 
Biotechnology Information (NCBI).
    (Response 278) FDA disagrees that the Agency lacks the knowledge 
and expertise to oversee IVDs offered as LDTs in the field of molecular 
genetics or in other fields. FDA has regulated IVDs under the 
comprehensive device authorities of the FD&C Act for almost 50 years, 
and it has the expertise and experience to regulate these tests, as 
discussed in response to comments 10 and 92. Specifically, OHT7 is 
staffed with scientific and medical experts who specialize in IVDs. 
OHT7 is responsible for overseeing total product lifecycle activities 
for IVDs. As noted previously, FDA also plans to utilize resources 
outside the Agency to support the implementation of the phaseout policy 
via the Third Party review program, and intends to exercise enforcement 
discretion and generally not enforce certain requirements for currently 
marketed IVDs offered as LDTs that were first marketed prior to the 
date of issuance of this rule and that are not modified, or that are 
modified as described in section V.B.3; LDTs approved by NYS CLEP; LDTs 
manufactured and performed by a laboratory integrated within a 
healthcare system to meet an unmet need of patients receiving care 
within the same healthcare system; and LDTs manufactured and performed 
within VHA and DoD. Additional discussion can be found in response to 
comments in sections VI.F.5, VI.O, and VI.P of this preamble.
    FDA also disagrees that its decision to follow the established 
quality control procedures for inclusion of genome sequences in the 
FDA-ARGOS database suggests that FDA's regulatory science in this area 
is outdated. Rather, the ongoing FDA-ARGOS project demonstrates FDA's 
investment in tools to support innovation of emerging technologies and 
commitment to regulatory science. The public FDA dAtabase for Reference 
Grade MicrObial Sequences (FDA-ARGOS) was established in 2014 and is a 
collaboration between FDA and DoD, the Institute for Genome Sciences at 
the University of Maryland, and NCBI (Ref. 237). FDA-ARGOS contains 
quality controlled and curated genomic sequence data to support 
research and regulatory decisions (Ref. 238). This is an evolving 
database that can be used as a tool for in-silico (computer simulation) 
performance validation and potentially reduce the testing burden on 
manufacturers of infectious disease NGS devices. There are ongoing 
projects focused on expanding the FDA-ARGOS database (Ref. 239). To 
maintain quality control of FDA-ARGOS as a reliable genome reference 
database, established quality metrics must be met and any updates to 
the quality control process are appropriately considered and vetted.
    (Comment 279) Some comments expressed concerns related to whether 
FDA has sufficient resources to enforce compliance with requirements 
during stages 1 through 3 of the phaseout policy, which will occur 
before the next MDUFA reauthorization. Some of these comments stated 
that FDA would require additional resources before the next MDUFA 
reauthorization to support a significant increase in Pre-Submissions 
from laboratory manufacturers in anticipation of the phaseout of 
premarket review requirements for new and modified IVDs offered as 
LDTs. The comments suggested that FDA would need to hire more staff to 
review Pre-Submissions seeking FDA's input on the potential risk 
classification of many IVDs offered as LDTs for which there are no 
predicate devices. According to the comments, this increase in Pre-
Submissions would not be addressed by issuing guidance documents, 
unless FDA issued those guidance documents expeditiously.
    (Response 279) FDA believes that there will be adequate resources 
available from user fees (as permissible) and budget authority in 
stages 1 through 3 of the phaseout policy to provide advice, guidance, 
and education on premarket review and other regulatory requirements 
applicable to IVDs offered as LDTs. Also, during stages 1 through 3, 
FDA is phasing out the general enforcement discretion approach with 
respect to various requirements (e.g., MDR requirements, correction and 
removal reporting requirements, and QS requirements under Sec.  820.198 
(complaint files) in stage 1; registration and listing, labeling, and 
investigational use requirements in stage 2; and QS requirements in 
stage 3 (other than requirements under Sec.  820.198 (complaint files), 
which are already addressed in stage 1)) and we believe information FDA 
receives as a result of compliance with those requirements will help 
FDA's allocation of anticipated available resources. FDA's estimate of 
the resources associated with stages 1 through 3 can be found in 
section II.G of the FRIA (Ref. 10).
    FDA's projections do not presume a disproportionate increase in 
Pre-Submissions for IVDs offered as LDTs during stages 1 through 3 of 
the phaseout period in light of the enforcement discretion policies 
relating to premarket review described in section V.B, including for 
currently marketed IVDs offered as LDTs; LDTs approved by NYS CLEP; and 
LDTs manufactured and performed by a laboratory integrated within a 
healthcare system to meet an unmet need of patients receiving care 
within the same healthcare system.
    For all of the foregoing reasons, FDA believes that the resources 
authorized under MDUFA V, combined with budget authority, are 
sufficient to fund the activities necessary for the review of voluntary 
Pre-Submissions received

[[Page 37425]]

during stages 1 through 3 of the phaseout policy.
    (Comment 280) Some comments predicted that FDA's phaseout of the 
general enforcement discretion approach for LDTs will face challenges 
similar to those experienced in Europe in connection with the 
implementation of the In Vitro Diagnostic Medical Device Regulation, 
2017/746 (IVDR). The IVDR was reported to cause significant delays in 
drug clinical trials by creating a bottleneck with respect to IVD 
approvals, as well as the discontinuation of certain rare disease 
diagnostics.
    (Response 280) FDA disagrees that the phaseout policy will likely 
result in significant delays in clinical trials or disruption in 
patient access to LDTs for unmet needs, including tests for rare 
diseases, akin to what the comment claims has been observed during the 
implementation of the IVDR in Europe.
    First, FDA intends to exercise enforcement discretion and generally 
not enforce premarket review and most QS requirements for currently 
marketed IVDs offered as LDTs, and thus does not anticipate disruption 
of patient access to such tests, including those for certain rare 
diseases, due to the phaseout policy. Going forward, FDA also intends 
to exercise enforcement discretion and generally not enforce premarket 
review and most QS requirements for LDTs manufactured and performed by 
a laboratory integrated within a healthcare system to meet an unmet 
need of patients receiving care within the same healthcare system. FDA 
anticipates this policy will support continued innovation of new tests 
for rare diseases. For additional discussion regarding IVDs for unmet 
needs and IVDs for rare diseases, see our responses to comments in 
section VI.L.5.
    With respect to use of IVDs offered as LDTs in clinical 
investigations of drugs, FDA does not anticipate that compliance with 
IDE requirements will meaningfully delay drug or IVD development 
activities, as described in response to comment 175. To the extent the 
comments are concerned about a potential review bottleneck due to 
resources, FDA disagrees that this will be the case for implementation 
of this rule, as described in response to comment 274.

O. 510(k) Third Party Review Program

    (Comment 281) FDA received several comments supporting the use of 
FDA's Third Party review program to review 510(k) submissions for IVDs 
offered as LDTs. These comments stated that Third Party review will 
help to avoid strains on FDA's review capacity, streamline the timeline 
for review, limit redundancy with CLIA accreditation, and/or avoid 
detracting from other components of FDA's mission.
    (Response 281) FDA agrees that use of the Third Party review 
program to review IVDs offered as LDTs could provide significant 
benefits to both industry and FDA, including by potentially reducing 
demand on FDA resources and facilitating timely review of 510(k) 
submissions. Under the MDUFA V commitment letter, FDA is currently 
working to enhance the Third Party review program, and the Agency 
anticipates interest in the Third Party review program among 
laboratories that manufacture IVDs offered as LDTs. As discussed in 
section II.G of the FRIA, FDA estimates that half of the IVDs offered 
as LDTs being submitted for 510(k) review will be reviewed under the 
Third Party review program. FDA also recognizes that if CLIA 
accreditation organizations seek accreditation under FDA's Third Party 
review program, there may be certain efficiencies or other advantages 
because the two programs are complementary, as described in response to 
comment 7.
    (Comment 282) Some comments questioned the likelihood that a 
significant percentage of laboratories that manufacture IVDs offered as 
LDTs that require a 510(k) submission will use FDA's Third Party review 
program, based on historical utilization of the program. Comments 
suggested that the Third Party review program currently includes only a 
small number of Third Party reviewers, who review only a small subset 
of types of IVDs that require a 510(k) submission, and that 
laboratories may choose not to utilize the Third Party review program 
given that use of the program is voluntary.
    (Response 282) Under the MDUFA V agreement, FDA committed to 
undertake several activities intended to enhance the Third Party review 
program with the objective of eliminating FDA's routine re-review of 
Third Party reviews. These activities include providing training to 
Third Parties seeking accreditation, auditing 3P510k Review 
Organizations, providing tailored retraining to 3P510k Review 
Organizations (based on the results of audits), and other activities 
(Ref. 240).
    In addition, FDA has heard from entities interested in potentially 
serving as 3P510k Review Organizations for 510(k)s submitted for IVDs. 
Some of these entities are CLIA accreditation organizations with whom 
laboratories may already be familiar. We anticipate that when a 
laboratory already has a relationship with an organization, the 
laboratory may be inclined to work with that organization through the 
Third Party review program.
    FDA anticipates that improving the Third Party review program, 
including through continued efforts to eliminate routine re-review of 
510(k)s that have already been reviewed by a 3P510k Review 
Organization, as well as potential accreditation of organizations with 
whom laboratories may already be familiar, will increase use of the 
Third Party review program (as noted in response to comment 281 and 
discussed in section II.G of the FRIA, FDA estimates that half of the 
IVDs offered as LDTs being submitted for 510(k) review will be reviewed 
under the Third Party review program). FDA intends to continue efforts 
to enhance and facilitate greater use of the Third Party review program 
during implementation of the phaseout policy, including in advance of 
stage 5 of the phaseout policy.
    FDA nonetheless acknowledges that participation in the Third Party 
review program is voluntary. Although FDA anticipates increased 
participation in the Third Party review program, as discussed in FDA's 
response to comment 284, FDA also anticipates that it will have 
sufficient resources to review 510(k) submissions for IVDs offered as 
LDTs even if participation in the Third Party review program is lower 
than estimated.
    We also note that, as stated in FDA's final guidance document 
regarding the Third Party review program, ``[m]ost in vitro diagnostic 
(IVD) devices are eligible for [Third Party] review,'' provided they 
meet certain factors described in the final guidance (Ref. 56). About 
75 percent of product codes for IVDs that are subject to 510(k) 
requirements (i.e., ~750 out of 1,000 product codes) are currently 
eligible for submission to a 3P510k Review Organization, and FDA 
anticipates that this list may continue to grow as more IVDs are 
classified into class II (i.e., through reclassification or De Novo 
classification) and as FDA gains experience with newer types of class 
II devices that are subject to 510(k) requirements.
    (Comment 283) One comment noted that many devices do not qualify 
for Third Party review. Another comment noted that the Third Party 
review program does not extend to PMAs or De Novo submissions. These 
comments asserted that based in part on these factors, the Third Party 
review program does not sufficiently address concerns regarding the 
potential high volume of premarket submissions that may be submitted by 
laboratories as a result of the phaseout policy.

[[Page 37426]]

    (Response 283) FDA agrees that PMA and De Novo submissions are not 
eligible for Third Party review under the Third Party review program as 
currently authorized under section 523 of the FD&C Act (21 U.S.C. 
360m). In the FRIA, FDA has estimated the potential impact of the Third 
Party review program on costs and transfers associated with 510(k) 
submissions, but has not anticipated any impact from the program on 
costs or transfers associated with PMA or De Novo submissions (see 
sections II.G and II.H of the FRIA (Ref. 10)). FDA also recognizes that 
some devices that require a 510(k) submission are not eligible for 
Third Party review (see 21 U.S.C. 360m(a)(3)). However, as discussed in 
response to comment 282, about 75 percent of product codes for IVDs 
that are subject to 510(k) requirements (i.e., ~ 750 out of 1,000 
product codes) are currently eligible for submission to a 3P510k Review 
Organization, and FDA anticipates that this list may continue to grow 
as more IVDs are classified into class II (i.e., through 
reclassification or De Novo classification) and as FDA gains experience 
with newer types of class II devices that are subject to 510(k) 
requirements. In addition, as discussed in response to comment 274, the 
Agency anticipates that certain enforcement discretion policies with 
respect to premarket review requirements, among other requirements, 
described in section V.B will also help to address concerns regarding 
the potential high volume of premarket submissions that may be 
submitted by laboratories as a result of the phaseout policy.
    Further, as previously announced, FDA intends to initiate the 
reclassification process for most IVDs that have been previously 
classified in class III to class II (Ref. 66). FDA aims to complete 
this reclassification process before stage 4 of the phaseout policy. In 
addition, FDA intends to continue taking a risk-based approach in the 
initial classification of IVDs to determine the appropriate level of 
regulatory controls and whether a new test may be classified into class 
II through De Novo classification (and special controls established), 
rather than being class III and subject to the PMA pathway. Based on 
our experience, we believe that special controls could be developed 
that, along with general controls, could provide a reasonable assurance 
of safety and effectiveness for most future CDx and infectious disease 
IVDs, such that they could be regulated as class II devices. We 
therefore anticipate the percent of IVDs, including IVDs offered as 
LDTs, reviewed in a 510(k) submission to increase, and that the number 
of IVDs eligible for review by a 3P510k Review Organization may also 
increase. As shown in Table A.5 of the FRIA, the estimated numbers of 
PMAs and PMA supplements are lower after potential reclassification, 
while the estimated numbers of 510(k) submissions and De Novo requests 
are higher after potential reclassification.
    (Comment 284) FDA received comments stating that a high rate of re-
review of 510(k)s that have already been reviewed by a 3P510k Review 
Organization may extend premarket review times, and one comment stated 
that Third Party review should not be a substantial part of FDA's plans 
for managing the anticipated workload associated with premarket 
submissions for IVDs offered as LDTs until FDA has eliminated routine 
re-review of 510(k)s that have already been reviewed by a 3P510k Review 
Organization. One comment stated that if FDA intends to utilize the 
Third Party review program as a critical part of FDA's plans to manage 
the Agency's anticipated workload, FDA should not phase out the general 
enforcement discretion approach with respect to premarket submissions 
until FDA has demonstrated in a pilot program that 3P510k Review 
Organizations can apply FDA's requirements in a least burdensome 
manner. In addition, one comment suggested that FDA conduct a study to 
better understand the historical lack of utilization of the Third Party 
review program before making the program a core part of FDA's plans for 
managing the Agency's anticipated workload associated with premarket 
submissions for IVDs offered as LDTs.
    (Response 284) FDA disagrees with the comments indicating that it 
is premature for the Agency to incorporate use of the Third Party 
review program into its plans for managing review of 510(k)s for IVDs 
offered as LDTs. FDA also disagrees that it should delay the phase out 
of enforcement discretion with respect to premarket review requirements 
prior to conducting a pilot to demonstrate application of least 
burdensome principles in the Third Party review program. As discussed 
in response to comment 282, under the MDUFA V agreement, FDA committed 
to undertake several activities intended to enhance the Third Party 
review program with the objective of eliminating FDA's routine re-
review of Third Party reviews. These activities include providing 
training to Third Parties seeking accreditation, auditing 3P510k Review 
Organizations, and providing tailored re-training to 3P510k Review 
Organizations. FDA anticipates that these activities will advance FDA's 
efforts to eliminate routine re-review of 510(k)s that have already 
been reviewed by a 3P510k Review Organization and does not expect that 
there will be a ``high rate of re-review'' of 510(k)s submitted for 
IVDs offered as LDTs as some comments suggest. We also expect that 
these activities will facilitate 3P510k Review Organizations' 
consistent application of FDA's requirements for 510(k) review in a 
least burdensome manner. Further, we note that FDA provides training 
materials on its ``least burdensome'' approach to medical device 
regulation as part of its training curriculum for 3P510k Review 
Organizations (Ref. 241).
    As discussed in response to comment 282, FDA anticipates that 
improving the Third Party review program will increase the program's 
use and estimates that approximately half of IVDs offered as LDTs being 
submitted for 510(k) review will be reviewed under the Third Party 
review program (see section II.G of the FRIA (Ref. 10)). However, even 
if the majority of submitters do not choose to use the Third Party 
review program, FDA anticipates that the Agency will be able to 
effectively manage review of 510(k) submissions for IVDs offered as 
LDTs. As described in section V.B.3, FDA intends to exercise 
enforcement discretion and generally not enforce premarket review and 
QS requirements (except for requirements under part 820, subpart M 
(Records)) for currently marketed IVDs offered as LDTs. FDA also 
intends to exercise enforcement discretion and generally not enforce 
premarket review requirements for LDTs that are approved by NYS CLEP, 
and to exercise enforcement discretion and generally not enforce 
premarket review requirements and QS requirements (except for 
requirements under part 820, subpart M (Records)) for LDTs manufactured 
and performed by a laboratory integrated within a healthcare system to 
meet an unmet need of patients receiving care within the same 
healthcare system. Collectively, these policies significantly reduce 
the estimated number of premarket submissions for IVDs offered as LDTs, 
as compared to the preliminary estimates in the PRIA (see sections II.F 
and II.G of the FRIA (Ref. 10)). In addition, as noted in our response 
to comment 274, FDA does not intend to phase out enforcement discretion 
with respect to premarket review requirements for moderate- and low-
risk IVDs offered as LDTs that require 510(k) submissions until after 
the next reauthorization of MDUFA. This will

[[Page 37427]]

provide an opportunity for FDA and industry to negotiate regarding user 
fees taking into consideration FDA's anticipated resource needs to 
review 510(k) and other submissions for IVDs offered as LDTs.
    (Comment 285) Some comments stated that the Third Party review 
program should utilize 3P510k Review Organizations that are accustomed 
to CLIA, or that FDA should encourage laboratory accreditation bodies 
to become 3P510k Review Organizations, to facilitate integration of the 
two programs, ensure the involvement of expert reviewers, and be less 
burdensome for laboratories.
    (Response 285) As discussed in section V.C, FDA recognizes that a 
laboratory may be particularly inclined to use the Third Party review 
program when the laboratory is already familiar with a 3P510K Review 
Organization. FDA is aware of certain CLIA accreditation organizations 
that may be interested in becoming 3P510k Review Organizations, and the 
Agency encourages such organizations to continue exploring potential 
participation in the Third Party review program. To the extent the 
comments advocating for ``integration'' of CLIA accreditation and FDA's 
Third Party review programs were suggesting that CLIA accreditation and 
review of a 510(k) overlap, we note that, while there may be certain 
efficiencies or other advantages associated with CLIA accreditation 
organizations also serving as 3P510k Review Organizations, these are 
separate programs with complementary but distinct purposes (see, e.g., 
response to comment 7).
    (Comment 286) Several comments raised concerns about potential 
conflicts of interest among 3P510k Review Organizations, given that 
3P510k Review Organizations are paid by the laboratories whose 
submissions they review. One comment asserted that the potential 
conflicts of interest among 3P510k Review Organizations may be 
particularly significant when the 3P510k Review Organization is also a 
CLIA accrediting organization.
    (Response 286) FDA recognizes that avoiding conflicts of interest 
among 3P510k Review Organizations is critical to the success of the 
Third Party review program. With respect to the fact that laboratories 
would pay 3P510k Review Organizations to review 510(k)s for their IVDs 
offered as LDTs, we note that section 523(b)(5) of the FD&C Act (21 
U.S.C. 360m(b)(5)) specifically provides that compensation for 3P510k 
Review Organizations to review a 510(k) ``shall be paid by the person 
who engages such services.'' However, the FD&C Act also contains 
provisions related to conflicts of interest for 3P510k Review 
Organizations, including provisions concerning the minimum 
qualifications for 3P510k Review Organizations and certain 
recordkeeping requirements (see sections 523 and 704(f) of the FD&C 
Act). In addition, FDA's final guidance document entitled ``510(k) 
Third Party Review Program'' addresses safeguards against potential 
conflicts of interest among 3P510k Review Organizations. As explained 
in FDA's final guidance document, ``FDA expects 3P510k Review 
Organizations to be impartial and free from any commercial, financial, 
and other pressures that might present a conflict of interest or an 
appearance of a conflict of interest. Therefore, FDA will consider 
whether the potential 3P510k Review Organization has established, 
documented, and executed policies and procedures to prevent any 
individual or organizational conflict of interest or the appearance of 
a conflict of interest, including conflicts of interests pertaining to 
their external Technical Experts'' (Ref. 56). FDA's final guidance 
document also explains, among other things, that ``conflict of interest 
policies for a 3P510k Review Organization should be fully implemented 
and there should be an attestation that those policies have been 
implemented that is signed by the most responsible individual at the 
organization before any 510(k) is accepted for review.'' While FDA 
appreciates that concerns regarding potential conflicts of interest may 
be heightened when a 3P510k Review Organization is also a CLIA 
accreditation organization, the statutory provisions regarding the 
Third Party review program and FDA's implementation thereof already 
take potential conflicts of interest into account.
    (Comment 287) One comment stated that FDA's discussion in the NPRM 
regarding use of the Third Party review program was vague. Another 
comment stated that with respect to Third Party review, FDA should 
provide ``better clarity and more information as to the participating 
entities, their capacities, throughput and turnaround time to review 
submissions by such entities.'' A third comment stated that FDA should 
``formally withdraw inconsistent and outdated guidance,'' in particular 
FDA's draft guidance document regarding in vitro diagnostic 
multivariate index assays (IVDMIAs), as such guidance documents will 
create confusion among 3P510k Review Organizations and others if not 
withdrawn.
    (Response 287) In the NPRM, FDA's discussion of the Third Party 
review program: (1) provided a general description of the program; (2) 
stated that FDA anticipated interest in the Third Party review program 
among test manufacturers and new 3P510k Review Organizations; and (3) 
explained the basis for anticipating that interest (see 88 FR 68006 at 
68027). FDA does not agree that these statements were vague. However, 
to the extent stakeholders seek additional information regarding the 
Third Party review program, stakeholders may consult FDA's ``510(k) 
Third Party Review Program'' final guidance document (Ref. 56), which 
was cited as a reference in the NPRM (see 88 FR 68006 at 68027), as 
well as information available on FDA's website regarding the Third 
Party review program (Ref. 67). This includes information regarding 
current 3P510k Review Organizations and the devices they may review 
(Ref. 242). FDA publishes quarterly reports on the performance of 
3P510k Review Organizations (Ref. 243). These reports include, among 
other things, data on the total number of submissions, review times, 
and decisions. FDA notes that 3P510k Review Organizations are best 
situated to address specific questions from potential submitters 
regarding their capacity and turnaround time for review of 510(k) 
submissions.
    FDA agrees that inconsistent or outdated guidance documents may 
cause confusion among stakeholders. The Agency strives to maintain 
consistency across its final guidance documents and to update those 
documents when appropriate, consistent with good guidance practices 
(Sec.  10.115). We note that the specific guidance mentioned in the 
comment is a draft guidance. Draft guidance documents are not for 
implementation and explicitly state (on their title pages) that they 
are distributed for comment purposes only. Thus, the draft guidance 
mentioned in the comment should not cause confusion among stakeholders. 
With respect to final guidance documents, the Agency undertakes 
retrospective review of previously issued final guidance documents (21 
CFR 10.115(k)) and is interested in receiving external feedback about 
final guidance documents that should be revised or withdrawn (see Sec.  
10.115(f)(4)). Stakeholders can submit comments on any guidance 
document at any time (Sec.  10.115(g)(5)).
    (Comment 288) One comment stated that the ISO 15189 standard should 
be considered a viable alternative for quality management system 
requirements for laboratories that manufacture IVDs, and suggested that 
for specific provisions of the ISO 13485

[[Page 37428]]

standard that may not be covered in ISO 15189, FDA should include the 
provisions as a requirement (or through guidance) as part of the Third 
Party review program.
    (Response 288) FDA does not agree that ISO 15189 is a viable 
alternative for quality management system requirements for laboratories 
that manufacture IVDs offered as LDTs, or that the Third Party review 
program is an appropriate mechanism to address any differences between 
the ISO 13485 \94\ and ISO 15189 standards. For additional discussion 
of the ISO 15189 standard, see our response to comment 183. Further, 
the Third Party review program addresses 510(k) premarket review by 
accredited persons (see section 523 of the FD&C Act). It is not a 
mechanism to add or change the requirements that apply to a device 
manufacturer's quality system.
---------------------------------------------------------------------------

    \94\ As noted elsewhere in this preamble, FDA recently finalized 
amendments to part 820, which take effect in February 2026. These 
amended QS requirements incorporate by reference the 2016 edition of 
ISO 13485 (see 89 FR 7496).
---------------------------------------------------------------------------

    (Comment 289) FDA received a comment stating that FDA ``should 
leverage device performance reviews or external quality assessments of 
LDTs conducted by certified and creditable third parties'' as an 
alternative to premarket review by FDA for LDTs offered by AMCs.
    (Response 289) The comment did not provide additional detail on 
what would constitute a ``certified and creditable'' third party that 
could provide such assessments. However, we note that FDA intends to 
continue supporting the use of its Third Party review program 
authorized under section 523 of the FD&C Act, as described in our 
responses to comments 281 through 288. The statute authorizes FDA to 
recognize Third Parties to review 510(k) submissions for certain types 
of devices and imposes various requirements on those organizations. We 
also note that FDA discusses comments received related to LDTs 
manufactured and performed by AMCs, including an enforcement discretion 
policy that may apply to certain LDTs manufactured and performed by AMC 
laboratories, in section VI.F.4 (see also section V.B.3).

P. Implementation

    (Comment 290) FDA received comments suggesting that the Agency 
provide additional information regarding how FDA will be implementing 
the final phaseout policy. One comment recommended that the phaseout 
policy include timelines and ``criteria'' for transitioning from the 
general enforcement discretion approach for LDTs.
    (Response 290) FDA agrees with the comment suggesting that FDA 
include timelines for transitioning from the general enforcement 
discretion approach for LDTs, and notes that section V.C of this 
preamble addresses this issue. As set forth more fully in that section:
     Stage 1: beginning 1 year after the publication date of 
this final rule, FDA will expect compliance with MDR requirements, 
correction and removal reporting requirements, and QS requirements 
under Sec.  820.198 (complaint files) for IVDs offered as LDTs;
     Stage 2: beginning 2 years after the publication date of 
this final rule, FDA will expect compliance with requirements not 
covered during other stages of the phaseout policy, including 
registration and listing requirements, labeling requirements, and 
investigational use requirements, for IVDs offered as LDTs;
     Stage 3: beginning 3 years after the publication date of 
this final rule, FDA will expect compliance with QS requirements (other 
than requirements under Sec.  820.198 (complaint files), which are 
already addressed in stage 1) for IVDs offered as LDTs;
     Stage 4: beginning 3\1/2\ years after the publication date 
of this final rule, FDA will expect compliance with premarket review 
requirements for high-risk IVDs offered as LDTs, unless a premarket 
submission has been received by the beginning of this stage in which 
case FDA intends to continue to exercise enforcement discretion for the 
pendency of its review; and
     Stage 5: beginning 4 years after the publication date of 
this final rule, FDA will expect compliance with premarket review 
requirements for moderate-risk and low-risk IVDs offered as LDTs (that 
require premarket submissions), unless a premarket submission has been 
received by the beginning of this stage in which case FDA intends to 
continue to exercise enforcement discretion for the pendency of its 
review.
    (Comment 291) Comments requested that FDA publish clear guidance 
document(s), including regarding: practical instructions, examples, and 
case studies; definitions of and other information regarding LDT risk 
categories; guidance on how laboratories can tailor their validation 
processes based on the complexity and potential impact of their LDTs; 
scenarios addressing how the phaseout policy affects specialized LDTs, 
such as those for rare diseases; and other topics. Comments requested 
that stakeholders be offered the opportunity to participate in guidance 
document development. FDA also received questions regarding the content 
and format for premarket submissions.
    (Response 291) FDA agrees with comments that recommended that FDA 
provide additional resources on specific topics that may be useful as 
laboratories come into compliance with applicable requirements. FDA 
anticipates issuing a small entity compliance guide and/or making 
additional resources available on topics such as applicable labeling 
requirements over the course of the phaseout period. FDA also 
anticipates offering robust educational resources, potentially 
including but not limited to a webinar, a Town Hall meeting, Frequently 
Asked Questions web pages, and other materials designed to guide 
laboratories and other stakeholders. FDA also intends to consider 
issuing additional guidance during the phaseout period as appropriate, 
and would do so in accordance with good guidance practice regulations, 
which set forth the processes for participating in the development and 
issuance of guidance documents (Sec.  10.115).
    In response to the comments seeking information regarding how 
laboratories can determine the risk categories of their IVDs offered as 
LDTs, we note that this rule does not change the statutory framework 
under which FDA regulates medical devices, including the risk-based 
classification of devices. FDA has previously provided multiple 
resources intended to help manufacturers determine the classification 
of their devices, including on FDA's web page entitled ``Classify Your 
Medical Device'' (Ref. 201), and in FDA's classification database (Ref. 
200). In addition, laboratory manufacturers may request feedback from 
FDA regarding the potential regulatory pathway for a device through a 
Pre-Submission, described in FDA's final guidance document entitled 
``Requests for Feedback and Meetings for Medical Device Submissions: 
The Q-Submission Program'' (Ref. 65). Laboratory manufacturers may also 
consider submitting a request for information regarding the class in 
which a device is classified or the requirements applicable to a device 
under section 513(g) of the FD&C Act, the process for which is further 
described in FDA's final guidance document entitled ``FDA and Industry 
Procedures for Section 513(g) Requests for Information under the 
Federal Food, Drug, and Cosmetic Act'' (Ref. 244). For further 
information, you may view the training module available on FDA's 
website, entitled ``513(g) Requests for Information'' (Ref. 245).

[[Page 37429]]

    In response to comments seeking information regarding the content 
and format for premarket submissions, FDA offers Device Advice on 
Premarket Submissions: Selecting and Preparing the Correct Submission 
on FDA's web page (Ref. 246).
    As discussed in section V.C, for IVDs offered as LDTs for which a 
complete PMA, HDE application, 510(k), BLA, or De Novo request has been 
received by the beginning of stage 4 or stage 5 of the phaseout policy 
(as applicable), FDA generally does not intend to enforce premarket 
review requirements until FDA completes its review of the submission.
    (Comment 292) A comment stated that hospital and health system 
laboratories cannot currently assess how each part of the device 
regulations would apply to their LDTs under the phaseout policy. The 
comment noted that the uncertainty is problematic and underscores the 
need for continued enforcement discretion, most particularly in certain 
areas, such as for low- and moderate-risk tests.
    (Response 292) As discussed further in the response to comment 162, 
FDA believes the information included in the phaseout policy, including 
the timeline for the various stages in the phaseout policy and 
information regarding enforcement discretion policies described in this 
preamble, provides clear expectations for laboratories that offer IVDs 
as LDTs. FDA appreciates that additional guidance regarding 
implementation of the phaseout policy may facilitate efforts by 
laboratories to comply with applicable requirements.
    We note that FDA intends to exercise enforcement discretion and 
generally not enforce premarket review requirements and QS requirements 
(except for requirements under part 820, subpart M (Records)) for LDTs 
manufactured and performed by a laboratory integrated within a 
healthcare system to meet an unmet need of patients receiving care 
within the same healthcare system. For further discussion of this 
policy, refer to section V.B.3. As discussed further in the responses 
to comments in section VI.L.4, FDA is not adopting an enforcement 
discretion policy in the final phaseout policy for low- and moderate-
risk tests.
    Notably, and as set forth more fully in response to comment 291, 
FDA is not changing the statutory framework under which FDA regulates 
medical devices. In this rule, FDA has made explicit that IVDs are 
devices under the FD&C Act including when the manufacturer of the IVD 
is a laboratory. IVDs, as defined in Sec.  809.3, are devices intended 
for human use and are subject to the FD&C Act. They include class I, 
class II, and class III devices, as well as both preamendments and 
postamendments devices. Like other devices, IVDs are subject to general 
controls, including premarket notification, reporting requirements 
regarding adverse events and corrections and removals, IDE requirements 
(though some investigations of IVDs are exempt from most provisions of 
the IDE regulation), and other applicable requirements under the FD&C 
Act and FDA's regulations. IVDs are also subject to specific labeling 
requirements in part 809. FDA has made numerous resources available to 
assist device manufacturers, including laboratories, in understanding 
device requirements.
    (Comment 293) A comment stated that the phaseout policy does not 
provide enough guidance for laboratories to determine what data 
laboratories must submit for premarket review of existing or new LDTs.
    (Response 293) Where premarket review is expected, the particular 
data required may vary based on the type of test at issue. There are 
multiple resources available to help IVD manufacturers, including 
laboratories, understand the type of data and information that is 
included in support of premarket submissions for IVDs. For example, FDA 
posts on its website the decision summaries for each IVD authorized 
(see Refs. 66, 166, 224, 247, and 248). These decision summaries 
describe the data and information that was provided to support the 
authorization and can be used as a model for manufacturers of the same 
types of tests. FDA also has issued general and device specific final 
guidance documents that describe recommendations for the data and 
information to be submitted in premarket submissions (see, e.g., Refs. 
234, 165, 190, and 249 to 253)), and has partially or fully recognized 
110 CLSI consensus standards for In Vitro Diagnostics (Ref. 254). Many 
of these FDA recognized consensus standards describe recommendations 
for validation study designs. Manufacturers may also submit a Pre-
Submission for specific feedback on individual tests (Ref. 65).
    We note that FDA intends to exercise enforcement discretion and 
generally not enforce premarket review and most QS requirements for 
currently marketed IVDs offered as LDTs that were first marketed as of 
the date of issuance of this rule and that are not modified, or that 
are modified as described in section V.B.3. Thus, FDA generally does 
not expect laboratories to submit data for existing LDTs in a premarket 
review submission. FDA has also included several other enforcement 
discretion policies with respect to premarket review for certain LDTs 
as described in section V.B.
    Further, we note that as more fully described elsewhere in this 
preamble, under FDA's device authorities, FDA premarket review is 
required only for certain IVDs (generally those classified into class 
II or class III), and FDA estimates that approximately 50 percent of 
IVDs offered as LDTs would not require premarket review.
    In addition, when tests are modified, premarket review is required 
only in certain circumstances, as discussed elsewhere in this preamble 
(see response to comments 215 and 261).
    (Comment 294) A number of comments suggested that FDA should assess 
the LDT marketplace to determine which LDTs present the ``highest 
risk,'' and implement the phaseout policy by risk category.
    (Response 294) As described in section V.C, FDA's phaseout policy 
prioritizes the review of applications for high-risk IVDs offered as 
LDTs (stage 4) over those for moderate- and low-risk IVDs offered as 
LDTs that require premarket review (stage 5). For the reasons set forth 
in our response to comment 155, we do not believe the other stages of 
the phaseout should be ordered or dictated by the level of risk of an 
IVD offered as an LDT.
    (Comment 295) FDA received a comment inquiring whether facilities 
that manufacture LDTs will be inspected in the same manner as other 
devices.
    (Response 295) All domestic and foreign device establishments, 
including those that manufacture IVDs offered as LDTs, are subject to 
inspection. Section 704(a) of the FD&C Act provides FDA authority for 
inspections, specifically providing authority for duly designated 
officers or employees of FDA to enter, at reasonable times, and 
inspect, at reasonable times and within reasonable limits and in a 
reasonable manner, facilities subject to regulation under the FD&C Act.
    FDA uses a risk-based evaluation to select device manufacturing 
facilities for inspection. See section 510(h)(2) of the FD&C Act 
(stating that the Secretary ``shall inspect establishments . . . that 
are engaged in the manufacture, propagation, compounding, or processing 
of a device or devices . . . in accordance with a risk-based schedule 
established by the Secretary.''). The Agency prioritizes device 
surveillance inspections deemed high-risk based on a variety of 
specific criteria, such as: (1)

[[Page 37430]]

facility type, such as manufacturer, control laboratory; (2) the 
facility's compliance history, including whether it has been inspected 
in the last 4 years; (3) hazard signals, including the record of 
signals, history and nature of product recalls linked to the facility; 
and (4) inherent risks of the device manufactured at a facility (Ref. 
255). FDA does not intend to have a different approach for selecting 
laboratory manufacturing facilities for inspection.
    (Comment 296) We received several comments that FDA should include 
industry experts and solicit outside expertise at various points during 
the implementation of the phaseout policy and in the regulation of IVDs 
offered as LDTs going forward. Comments suggested FDA solicit input on 
test classifications on an ongoing basis, convene expert panels to 
recommend risk categories and advise on specific types of technology 
and tests, and allow experts to participate in reviewing and approving 
premarket submissions in the areas of their expertise, and to ``have a 
seat at the table during the implementation of the FDA regulations, as 
well as long-term monitoring/approval'' of IVDs offered as LDTs.
    (Response 296) To the extent the comments recommended that FDA seek 
input from stakeholders and outside experts, we agree that such input 
is important, and in fact required, in certain circumstances. For 
device classification, FDA follows the procedures required under 
section 513 of the FD&C Act and outlined in part 860. When classifying 
a preamendments device for the first time, for example, FDA provides a 
public process as required under section 513(d) of the FD&C Act. This 
process involves a public meeting of the appropriate advisory committee 
panel and notice and comment rulemaking.
    More generally, FDA uses panels of the Medical Devices Advisory 
Committee (MDAC) to provide advice and recommendations to FDA on 
various regulatory issues. This may include advice on particular 
submissions, general issues, and device type classifications, among 
other things. The MDAC consists of 18 panels, including the following 
panels with established rosters reflecting expertise regarding IVDs, 
including LDTs: Clinical Chemistry and Clinical Toxicology Devices 
Panel (Ref. 256), Hematology and Pathology Devices Panel (Ref. 257), 
Immunology Devices Panel (Ref. 258), Microbiology Devices Panel (Ref. 
259), and Molecular and Clinical Genetics Panel (Ref. 260). The 
rosters, calendars, and materials from past meetings are available on 
FDA's website as noted in the references above. For example, in 
September 2023, FDA convened the Microbiology Devices Panel to seek 
preliminary input on potential reclassification of certain types of 
IVDs for hepatitis B virus, human parvovirus B19, and M. tuberculosis 
from class III to class II with special controls (Ref. 261). In another 
recent example, FDA convened the Molecular and Clinical Genetics Panel 
in November 2023 to discuss and make recommendations on the design of 
multicancer detection in vitro diagnostic devices (tests) as well as 
potential study designs and study outcomes of interest that could 
inform the assessment of the probable benefits and risks of such tests 
(Ref. 262). The committee's discussion and recommendations from these 
meetings will help inform future Agency regulatory efforts for these 
tests.
    FDA can also seek external expertise through its Network of Experts 
program, which is a vetted network of partner organizations and their 
members, scientists, clinicians, and engineers who can provide FDA 
rapid access to expertise when it is needed to supplement existing 
knowledge and expertise within CDRH (Ref. 263). There are multiple 
organizations within the Network of Experts with expertise relevant to 
IVDs. As has been FDA's practice, and when appropriate, FDA will 
continue to engage with experts and stakeholders through conferences, 
meetings, industry roundtables, town halls, and through collaborative 
communities in which we participate.
    We note that FDA has long solicited and considered input from 
stakeholders regarding the Agency's oversight of LDTs. In 2010, FDA 
held a public meeting and requested comments on the ``Oversight of 
Laboratory Developed Tests'' (75 FR 34463, June 17, 2010). In 2014, FDA 
issued and requested comments on two draft guidance documents entitled 
``Framework for Regulatory Oversight of Laboratory Developed Tests 
(LDTs)'' (Ref. 38) and ``FDA Notification and Medical Device Reporting 
for Laboratory Developed Tests (LDTs)'' (Ref. 112), and subsequently 
held and requested comments on a 2015 Public Meeting regarding the 
Agency's proposed oversight framework (Ref. 116). In 2017 we issued the 
2017 Discussion Paper synthesizing the feedback that had been provided 
to the Agency (Ref. 57).
    Furthermore, our Q-Submission program, in addition to providing IVD 
manufacturers with an opportunity to provide input to and request 
feedback from FDA on specific devices or submissions, also includes an 
opportunity to request an Informational Meeting to share with FDA 
information, among other purposes, to familiarize the FDA review team 
with new device(s) with significant differences in technology from 
currently available devices and provide an overview of ongoing or 
upcoming device development (see FDA's final guidance document entitled 
``Requests for Feedback and Meetings for Medical Device Submissions: 
The Q-Submission Program'' (Ref. 65)).
    We note, however, that industry participation in certain activities 
referenced in the comments, such as the review and authorization of 
premarket submissions, would raise issues related to confidentiality 
and conflicts of interest (e.g., if IVD manufacturers, including those 
who may be developing similar or competitor products, review or 
influence the outcome of other IVD manufacturers' premarket 
submissions). FDA has obligations to maintain confidentiality of 
certain aspects of premarket submissions and to make decisions about 
whether to authorize devices without undue influence.

Q. Interplay With Oncology Drug Products Used With Certain In Vitro 
Diagnostic Tests Pilot Program

    (Comment 297) Several comments addressed FDA's ongoing pilot 
described in the final guidance document entitled ``Oncology Drug 
Products Used with Certain In Vitro Diagnostic Tests: Pilot Program'' 
(Ref. 264). Most comments indicated support for the pilot; one did not. 
Supporters thought the model described in the pilot is valuable and 
should be considered in other disease areas, including rare diseases. 
Another comment suggested that the pilot's model should be used for 
tests used as part of cell and gene therapy product development. One 
suggested that FDA delay finalizing the rule until the pilot is 
completed and expanded.
    (Response 297) FDA agrees that the concept of establishing 
performance expectations is valuable for test development generally, 
including for tests for rare disease. Such goals could be developed by 
the community and used to support premarket review submissions.
    We note that the pilot program was initiated as one step that may 
be helpful in reducing the risks associated with LDTs used for oncology 
drug treatment decisions (then under the general enforcement discretion 
approach for LDTs), while the Agency continued to work on a broader 
approach for LDTs, including moving forward with this rulemaking. As 
discussed further in the

[[Page 37431]]

response to comment 298, the phasing out of the general enforcement 
discretion approach for LDTs means that FDA generally will expect 
compliance with applicable requirements for IVDs offered as LDTs, 
including those IVDs described in the oncology pilot program.
    (Comment 298) Some comments asked for clarification regarding the 
impact of the phaseout policy on the pilot. One comment suggested pilot 
participants should be ``exempt'' from the phaseout. One comment asked 
if an unapproved clinical trial assay could be used upon approval of 
the therapeutic with a postmarket commitment to obtain approval of a 
CDx.
    (Response 298) FDA disagrees with the suggestion to ``exempt'' 
unapproved assays used in the pilot from the phaseout policy. The types 
of LDTs discussed in the pilot program may provide information that is 
essential for the safe and effective use of a corresponding therapeutic 
product. As described in the NPRM, we have seen variability in 
performance among LDTs offered for a use that is the same as a CDx such 
that, in some cases, selection of a treatment for a given patient can 
be impacted by which test is used (see 88 FR 68006 at 680209-10). For 
example, the same patient may receive a particular therapeutic if they 
are tested with one LDT and not receive the therapeutic if they are 
tested with another LDT due to differences in test performance. For 
these reasons, the phaseout of the general enforcement discretion 
approach generally applies to LDTs offered for a use that is the same 
as a CDx, including the types of LDTs discussed in the pilot program.
    (Comment 299) One comment asserted that the pilot program will 
amplify risks to patients by encouraging the use of tests that are not 
clinically validated.
    (Response 299) The pilot program was initiated as one step that may 
be helpful in reducing the risks associated with using LDTs for 
oncology drug treatment decisions while the Agency continued to work on 
a broader approach for LDTs, including moving forward with this 
rulemaking. For the reasons in this preamble, FDA is phasing out the 
general enforcement discretion approach for LDTs, including the types 
of LDTs discussed in the pilot program final guidance.
    (Comment 300) One comment suggested that FDA's general approach to 
CDx approvals is a barrier to innovation in that it requires clinical 
concordance studies to other PMA-approved devices or clinical trials in 
partnership with drug companies. The comment explained that there is no 
incentive for a drug company to conduct additional clinical trials to 
support diagnostic approvals and no incentive for the laboratory with 
the approved CDx to conduct clinical concordance studies with 
additional laboratories to support other diagnostic approvals. This 
comment expressed concern that increased oversight of LDTs is likely to 
put significant constraints on CDx availability, where doctors and 
patients would be forced to send samples to specific laboratories.
    (Response 300) As discussed in response to comment 298, FDA has 
seen variability in performance among LDTs offered for a use that is 
the same as a CDx such that, in some cases, selection of a treatment 
for a given patient can be impacted by which test is used. For this 
reason, and for the reasons further discussed throughout this preamble, 
FDA believes that increased oversight for these and others IVDs offered 
as LDTs is generally necessary and appropriate. FDA understands the 
current system presents challenges for development of additional tests 
to select patients for a drug once one CDx is authorized. FDA seeks to 
engage with the community on additional efforts to create 
standardization, such as through reference materials, so that clinical 
validity can be extrapolated to other tests of the same type in more 
cases.

R. Miscellaneous

    (Comment 301) We received many comments regarding the impacts that 
FDA's proposal would have on the medical education of those training in 
pathology. Comments noted that the increased financial and regulatory 
burdens on smaller teaching laboratories would reduce the number of 
tests available at those laboratories, which would eliminate, 
significantly delay, or make less attractive the opportunities for 
training clinical pathologists and additionally fewer laboratories 
would be able to meet the criteria for training programs prescribed by 
ACGME. Comments additionally stated that without robust opportunities 
to learn pathology principles and the skills needed to pass the 
pathology board certification exam, fewer trainees may be able to pass.
    Comments stated that fewer learning opportunities would, in turn, 
exacerbate existing pathologist workforce burnout and shortages, and 
lead to fewer and less qualified and competent pathologists, which 
would lead to a decline in the practice of pathology that would reduce 
the quality and timeliness of patient care, and potentially the ability 
for healthcare to address advanced or new disease altogether. 
Additional comments noted that for-profit reference laboratories are 
not obligated to train pathology residents and fellows and that the 
pipeline of medical students who train at small laboratories is also an 
important pool of talent for IVD manufacturers, other clinical 
laboratory affiliated industries, and regulatory agencies, which will 
be similarly negatively affected.
    Some comments stated that reduced medical training opportunities 
would particularly affect genetic and genomic medicine, an area of 
increasing demand and worsening workforce shortages, because it relies 
so heavily on LDTs. Another comment noted that if data available from 
LDTs was limited, then genomics and genetics biomedical research 
training at the Ph.D. graduate and postgraduate levels that depend on 
that data would also suffer and ultimately affect the health of the 
U.S. population and the competitiveness of the U.S. research 
enterprise.
    (Response 301) As set forth in section V.B, FDA is adopting several 
enforcement discretion policies in the phaseout policy that reflects a 
balancing of the important public health considerations at issue in the 
rule (see further discussion of these considerations in section III.B). 
We anticipate the impact of these policies will address some of the 
concerns expressed in comments related to the impact on medical 
education, insofar as the financial burdens on laboratories will be 
reduced, resulting in fewer laboratories scaling back operations, 
exiting the market, or otherwise limiting educational opportunities. As 
a result of these policies and other adjustments, the FRIA estimates a 
78 percent reduction in cost to industry compared to the PRIA. 
Specifically, the FRIA estimates a $1,166M 20-year annualized cost to 
industry--a reduction of $4,170M.
    (Comment 302) A comment requested clarity about how FDA considers 
its potential enforcement actions or remedies when the Agency 
identifies a violation of the law. In particular, the comment was 
interested in whether enforcement actions apply to the laboratory 
activity, revenue, and operations or only the manufacturing of the 
test.
    (Response 302) This comment was not entirely clear; we have 
interpreted this comment as seeking more information about FDA's 
approach to device enforcement. Such enforcement by FDA is taken on a 
case-by-case basis and the specifics of each enforcement action depend 
on the specific facts at issue. FDA generally seeks to work with

[[Page 37432]]

device manufacturers to address issues where the manufacturer or device 
is in noncompliance with requirements. FDA may issue a warning letter 
or take other advisory actions where appropriate. Administrative and 
enforcement actions authorized under the FD&C Act include: seizure of 
adulterated or misbranded devices (see section 304 of the FD&C Act); 
injunction against a manufacturer (see section 302 of the FD&C Act); 
and civil monetary penalties (see section 303 of the FD&C Act).
    (Comment 303) One comment stated that FDA's characterization of 
LDTs as simple devices was incorrect, because all tests require 
professional interpretation given that test results should be 
interpreted in the context of a patient's overall clinical status and 
the specifics of a particular test. The comment stated that two tests 
assessing the same parameter may measure different things (i.e., hot 
spot testing vs. sequencing of the entire coding region of a gene), 
while the same result may mean different things in different patients.
    (Response 303) FDA is not clear what the comment is referencing 
when it states that FDA characterized LDTs as ``simple.'' FDA did not 
include such a description in the NPRM. Rather, FDA noted in the NPRM 
that many LDTs rely on high-tech or complex instrumentation and 
software to generate results and clinical interpretations (88 FR 68006 
at 68008). Nevertheless, FDA agrees that test results should be 
interpreted in the context of overall clinical status and the specifics 
of a particular test. This is one reason why it is important that IVDs 
have appropriate assurance of safety and effective for their specific 
intended uses.
    (Comment 304) FDA received comments discussing part 11 (21 CFR part 
11). One comment asked whether IVDs offered as LDTs would be subject to 
part 11 and, if so, what type of documentation would be required for 
software associated with an IVD offered as an LDT, and requested 
guidance on how to treat software that analyzes results for automatic 
release or that analyzes sequencing data to identify mutations or other 
targets of interest.
    (Response 304) This rule does not change the framework under which 
FDA regulates devices, including the scope and application of 
electronic records and electronic signatures regulations found at part 
11.
    The comment that asked about the applicability of part 11 and 
requested guidance does not appear to be speaking for or against any 
aspect of this rulemaking, or presenting any matter which is relevant 
to this rulemaking. FDA notes nevertheless that it has issued final 
guidance on part 11. For example, FDA's final guidance document 
entitled ``Part 11, Electronic Records; Electronic Signatures--Scope 
and Application'' (Ref. 265) provides guidance to persons who, in 
fulfillment of a requirement in a statute or another part of FDA's 
regulations to maintain records or submit information to FDA, have 
chosen to maintain the records or submit designated information 
electronically and, as a result, have become subject to part 11. People 
can comment on that final guidance document or any other at any time, 
and FDA will revise guidance documents in response to comments when 
appropriate (Sec.  10.115(g)(5)). FDA also periodically reviews 
existing final guidance documents to determine among other things 
whether they need to be changed (Sec.  10.115(k)(1)).
    (Comment 305) One comment stated that it could be overly burdensome 
to meet the requirements of part 11 for systems that were designed to 
be used for clinical care but would now be used as the system of record 
for data that is included in a premarket submission.
    (Response 305) It is not clear what particular submission 
requirements are being referred to by the comment that said it could be 
overly burdensome to comply, or what legal or policy changes, if any, 
this comment would recommend. While this comment talked about the 
requirements of part 11, FDA notes that submission requirements might 
arise under the FD&C Act, the PHS Act, and FDA regulations other than 
part 11, and that FDA's policies regarding part 11 would not affect 
such requirements. And, of course, this rulemaking does not change part 
11.
    In any event, in the ``Part 11, Electronic Records; Electronic 
Signatures--Scope and Application'' final guidance, FDA observed that 
some broad interpretations of the scope of part 11 ``could lead to 
unnecessary controls and costs and could discourage innovation and 
technological advances without providing added benefit to the public 
health.'' Accordingly, in that final guidance document, FDA stated that 
it ``intends to interpret the scope of part 11 narrowly.'' Moreover, 
FDA currently exercises enforcement discretion with respect to certain 
part 11 requirements. In particular, and as described in that final 
guidance, FDA currently does ``not intend to take enforcement action to 
enforce compliance with the validation, audit trail, record retention, 
and record copying requirements of part 11 as explained in this 
guidance'' and does ``not intend to take (or recommend) action to 
enforce any part 11 requirements with regard to systems that were 
operational before August 20, 1997, the effective date of part 11 
(commonly known as legacy systems) under the circumstances described in 
section III.C.3 of this guidance.'' FDA believes that its 
interpretation of and enforcement policies regarding part 11 strike an 
appropriate balance between public health and innovation, without being 
overly burdensome. Nevertheless, and consistent with the ``Part 11, 
Electronic Records; Electronic Signatures--Scope and Application'' 
final guidance, as a result of its re-examination of part 11, FDA 
anticipates initiating rulemaking to change part 11 as appropriate.
    (Comment 306) One comment asked if FDA will establish a fund to 
compensate physicians who face malpractice lawsuits that may result 
from misdiagnoses as a result of phasing out the general enforcement 
discretion approach for LDTs.
    (Response 306) Malpractice lawsuits are outside the scope of this 
rulemaking.
    (Comment 307) Some comments stated that FDA should work with 
Congress to advance new legislation regarding the regulation of IVDs 
more broadly, such as the VALID Act. These comments generally 
acknowledged that FDA has a role to play in the oversight of LDTs, but 
suggested that legislation could better balance a variety of 
considerations and objectives--such as promoting patient safety, 
ensuring flexibilities, facilitating innovation, and supporting patient 
access--as compared to what is possible with FDA's existing 
authorities. One comment suggested that legislation could better take 
into consideration unique characteristics of the diagnostics industry 
and the ``multitude of stakeholders'' affected by the regulation 
thereof, while other comments stated that new legislation could provide 
``unequivocal'' statutory authority, as well as the resources necessary 
to effectively oversee diagnostics.
    (Response 307) These comments are outside the scope of this 
rulemaking. The ability to enact new legislation rests with Congress. 
This rulemaking is focused on FDA's oversight of devices under the 
current statutory authorities set forth in the FD&C Act. Based on the 
evidence currently available to the Agency, FDA has determined that 
there is a public health need to better assure the safety and 
effectiveness of IVDs offered as LDTs, and FDA has determined to 
address that need consistent with our existing authorities by amending 
our regulations to make explicit that IVDs are devices under the

[[Page 37433]]

FD&C Act including when the manufacturer of the IVD is a laboratory, 
and by phasing out the general enforcement discretion approach for 
LDTs.
    FDA recognizes that the Agency's current statutory authorities 
could be amended or supplemented to establish a different regulatory 
framework for IVDs than the one that currently exists. FDA notes that 
this rulemaking does not prevent Congress from enacting new 
legislation.

VII. Effective Date

    This rule is effective July 5, 2024.

VIII. Economic Analysis of Impacts

    We have examined the impacts of the final rule under E.O. 12866, 
E.O. 13563, E.O. 14094, the Regulatory Flexibility Act (5 U.S.C. 601-
612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 104-4).
    E.O.s 12866, 13563, and 14094 direct us to assess all benefits, 
costs, and transfers of available regulatory alternatives and to select 
regulatory approaches that maximize net benefits (including potential 
economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). Rules are 
``significant'' under E.O. 12866 Section 3(f)(1) (as amended by E.O. 
14094) if they ``have an annual effect on the economy of $200 million 
or more (adjusted every 3 years by the Administrator of OIRA for 
changes in gross domestic product); or adversely affect in a material 
way the economy, a sector of the economy, productivity, competition, 
jobs, the environment, public health or safety, or State, local, 
territorial, or tribal governments or communities.'' OIRA has 
determined that this final rule is a significant regulatory action 
under E.O. 12866 Section 3(f)(1).
    Because this rule is likely to result in an annual effect on the 
economy of $100 million or more or meets other criteria specified in 
the Congressional Review Act/Small Business Regulatory Enforcement 
Fairness Act, OIRA has determined that this rule falls within the scope 
of 5 U.S.C. 804(2).
    The Regulatory Flexibility Act requires Agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because most facilities that will be affected by 
this rule are defined as small businesses and the final rule is likely 
to impose a substantial burden on the affected small entities, we find 
that the rule will have a significant economic impact on a substantial 
number of small entities.
    We prepared an analysis consistent with the Unfunded Mandates 
Reform Act of 1995 (section 202(a)), which requires the preparation of 
a written statement that includes estimates of anticipated impacts 
before issuing ``any rule that includes any Federal mandate that may 
result in the expenditure by State, local, and tribal governments, in 
the aggregate, or by the private sector, of $100,000,000 or more 
(adjusted annually for inflation) in any one year.'' The current 
threshold after adjustment for inflation is $177 million, using the 
most current (2022) Implicit Price Deflator for the Gross Domestic 
Product. This final rule will result in an expenditure in at least one 
year that meets or exceeds this amount.
    This final rule amends FDA's regulations to make explicit that IVDs 
are devices under the FD&C Act including when the manufacturer of the 
IVD is a laboratory. As discussed in section V of the preamble to the 
final rule, FDA is phasing out its general enforcement discretion 
approach for LDTs so that IVDs manufactured by a laboratory will 
generally fall under the same enforcement approach as other IVDs.
    We anticipate that the benefits of phasing out FDA's general 
enforcement discretion approach for LDTs includes a reduction in 
healthcare costs associated with unsafe or ineffective IVDs offered as 
LDTs (generally referred to in this document as ``problematic IVDs''), 
including IVDs offered as LDTs that are promoted with false or 
misleading claims, and from therapeutic decisions based on unreliable 
results of those tests. Quantified benefits are the annualized sum of 
both health and non-health benefits. Unquantified benefits include the 
reduction in costs from lawsuits. We discuss the benefits of the 
phaseout of FDA's general enforcement discretion approach for IVDs 
offered as LDTs in section II.E of the FRIA.
    This phaseout policy will result in compliance costs for 
laboratories that are ensuring their IVDs offered as LDTs are compliant 
with statutory and regulatory requirements, as described in section V. 
We discuss the costs of the phaseout policy in section II.F of the 
FRIA. These costs overlap somewhat with effects associated with this 
phaseout policy in the form of user fees, including annual registration 
fees, fees for premarket applications/submissions, and annual fees for 
periodic reporting concerning PMA-approved devices, which are paid from 
laboratories to FDA. These fees are paid by laboratories but are 
revenue for FDA; the approach to estimating fee effects is distinct 
from the approaches for either benefits or costs, so they will be 
presented as transfers. We discuss transfers in section II.H of the 
FRIA.
    Table 1 summarizes the annualized benefits, costs, and transfers of 
the phaseout policy. At a 7 percent discount rate, 20-year annualized 
benefits range from about $0.99 billion to $11.1 billion, with a 
primary estimate of $3.51 billion per year. At a 3 percent discount 
rate, 20-year annualized benefits range from $1.24 billion to $13.62 
billion, with a primary estimate of $4.34 billion per year. At a 7 
percent discount rate, 20-year annualized costs range from about $566 
million to $3.56 billion, with a primary estimate of $1.29 billion per 
year. At a 3 percent discount rate, annualized costs range from about 
$603 million to $3.79 billion, with a primary estimate of $1.37 billion 
per year. At a 7 percent discount rate, 20-year annualized transfers 
range from $20 million to $81 million, with a primary estimate of $41 
million per year. At a 3 percent discount rate, 20-year annualized 
transfers range from $29 million to $115 million, with a primary 
estimate of $58 million per year. These estimates do not include 
anticipated offsets from user fees. At a 7 percent discount rate, 20-
year annualized costs to FDA range from $61 million to $243 million, 
with a primary estimate of $121 million per year. At a 3 percent 
discount rate, 20-year annualized costs to FDA range from $65 million 
to $259 million, with a primary estimate of $129 million per year. 
Factoring in offsets from user fees at current levels, estimated costs 
to FDA are reduced to $40 million to $162 million at a 7 percent 
discount rate, with a primary estimate of $81 million, and to $36 
million to $144 million at a 3 percent discount rate, with a primary 
estimate of $72 million, covering approximately 30 to 40 percent of the 
estimated costs to FDA.
BILLING CODE 4164-01-P

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[GRAPHIC] [TIFF OMITTED] TR06MY24.086

BILLING CODE 4164-01-C
    We have developed a comprehensive Economic Analysis of Impacts that 
assesses the impacts of the phaseout policy. The full analysis of 
economic impacts is available in the docket for this phaseout policy 
(Ref. 10) and at https://www.fda.gov/about-fda/economics-staff/regulatory-impact-analyses-ria.

IX. Analysis of Environmental Impact

    We have determined under 21 CFR 25.30(h) that this action is of a 
type that does not individually or cumulatively have a significant 
effect on the human

[[Page 37435]]

environment. Therefore, neither an environmental assessment nor an 
environmental impact statement is required.

X. Paperwork Reduction Act of 1995

    FDA concludes that this rule contains no new collections of 
information. However, we expect that the phaseout of our general 
enforcement discretion approach for LDTs will necessitate adjustment to 
the burden estimates for several approved information collections, 
before the relevant phaseout stage begins. Such adjustments will 
account for an anticipated increase in the number of responses due to 
the expected compliance of laboratory manufacturers with applicable 
requirements for which FDA previously exercised enforcement discretion 
under the general enforcement discretion approach. Such adjustments 
will be submitted for review and clearance by OMB under the Paperwork 
Reduction Act of 1995 (PRA) (44 U.S.C. 3501-3521).
    In section II.D.1 of the FRIA for this rulemaking, we estimate a 
range of 590 to 2,362 affected laboratories and 47 to 189 new affected 
laboratories entering the market per year. We intend to adjust the 
applicable information collection burden estimates to reflect 
additional responses to correspond with the phaseout policy.
    As discussed in section V.C of this preamble, FDA has determined to 
gradually phase out its current general enforcement discretion approach 
for LDTs so that IVDs manufactured by a laboratory will generally fall 
under the same enforcement approach as other IVDs. This phaseout policy 
includes targeted enforcement discretion policies for specific 
categories of IVDs manufactured by a laboratory, including currently 
marketed IVDs offered as LDTs and LDTs for unmet needs, as described in 
section V.B of this preamble. FDA has structured the phaseout policy to 
contain five key stages. In the following paragraphs, we include a 
brief description of the stages and the OMB control numbers under which 
the related information collections (corresponding to the requirements 
for which FDA will expect compliance in each stage) are approved.
    In stage 1, beginning 1 year after the publication date of this 
final rule, FDA generally will expect compliance with MDR requirements, 
correction and removal reporting requirements, and QS requirements 
under Sec.  820.198 (complaint files). Information collections 
associated with the MDR requirements under 21 U.S.C. 360i(a) through 
(c) and part 803 are approved under OMB control number 0910-0437. 
Information collections associated with correction and removal 
reporting requirements under 21 U.S.C. 360i(g) and part 806 are 
approved under OMB control number 0910-0359. Information collections 
associated with QS requirements under part 820, including Sec.  820.198 
(complaint files), are approved under OMB control number 0910-0073. 
Costs associated with stage 1 are discussed in section II.F.1 of the 
FRIA.
    In stage 2, beginning 2 years after the publication date of this 
final rule, FDA generally will expect compliance with requirements not 
covered during other stages of the phaseout policy. These other 
requirements include registration and listing requirements under 21 
U.S.C. 360 and parts 607 and 807 (excluding subpart E) (related 
information collections are approved under OMB control numbers 0910-
0052, and 0910-0625, respectively); labeling requirements under 21 
U.S.C. 352 and parts 801 and 809, subpart B (related information 
collections are approved under OMB control number 0910-0485); 
investigational use requirements under 21 U.S.C. 360j(g) and part 812 
(related information collections are approved under OMB control number 
0910-0078); and, for certain devices that are biological products, 
investigational use requirements under 42 U.S.C. 262 and 21 CFR part 
312 (related information collections are approved under OMB control 
number 0910-0014). Costs associated with stage 2 are discussed in 
section II.F.2 of the FRIA.
    Additionally, for questions that are specific to a particular IVD, 
laboratory manufacturers may request feedback from FDA through a Pre-
Submission, which is further explained in FDA's final guidance document 
entitled ``Requests for Feedback and Meetings for Medical Device 
Submissions: The Q-Submission Program'' (Ref. 65) (related information 
collections are approved under OMB control number 0910-0756).
    In stage 3, beginning 3 years after the publication date of this 
final rule, FDA generally will expect compliance with QS requirements 
under part 820 (other than requirements under Sec.  820.198 (complaint 
files), which are already addressed in stage 1). Information 
collections associated with QS requirements under part 820 are approved 
under OMB control number 0910-0073. Costs associated with stage 3 are 
discussed in section II.F.3 of the FRIA.
    In stage 4, beginning 3\1/2\ years after the publication date of 
this final rule, FDA generally will expect compliance with premarket 
review requirements for high-risk IVDs. The premarket review 
requirements for PMAs are set forth in 21 U.S.C. 360e and part 814 
(related information collections are approved under OMB control number 
0910-0231). Premarket review requirements specific to HDE applications 
are set forth in 21 U.S.C. 360j(m) and part 814, subpart H (related 
information collections are approved under OMB control number 0910-
0332). Licensure requirements are set forth in 42 U.S.C. 262 and 21 CFR 
part 601 (related information collections are approved under OMB 
control number 0910-0338). Costs associated with stage 4 are discussed 
in section II.F.4 of the FRIA.
    In stage 5, beginning 4 years after the publication date of this 
final rule, FDA generally will expect compliance with premarket review 
requirements for moderate-risk and low-risk IVDs offered as LDTs (that 
require premarket submissions). These premarket submissions include 
510(k) submissions, the requirements for which are set forth at 21 
U.S.C. 360(k), 360c(i), and part 807, subpart E (related information 
collections are approved under OMB control number 0910-0120). These 
submissions also include De Novo requests, which laboratories may 
submit for IVDs offered as LDTs for which there is no legally marketed 
device upon which to base a determination of substantial equivalence, 
and for which the laboratory seeks classification into class I or class 
II. These requirements are set forth at 21 U.S.C. 360c(f)(2) and part 
860, subpart D (related information collections are approved under OMB 
control number 0910-0844). Costs associated with stage 5 are discussed 
in section II.F.4 of the FRIA.
    FDA also anticipates that laboratories may seek to utilize FDA's 
Third Party review program. FDA currently operates a Third Party review 
program for medical devices, and multiple organizations are accredited 
to conduct reviews of 510(k) submissions for certain IVDs (see Ref. 
67). We anticipate interest in the Third Party review program among 
laboratory manufacturers, as well as potential new 3P510k Review 
Organizations. Information collections associated with the Third Party 
review program are approved under OMB control number 0910-0375.

XI. Federalism

    We have analyzed this final rule in accordance with the principles 
set forth in E.O. 13132. We have determined that the rule does not 
contain policies that have substantial direct effects on the

[[Page 37436]]

States, on the relationship between the National Government and the 
States, or on the distribution of power and responsibilities among the 
various levels of government. Accordingly, we conclude that the rule 
does not contain policies that have federalism implications as defined 
in the E.O. and, consequently, a federalism summary impact statement is 
not required.
    One comment stated that FDA failed to conduct the required 
federalism analysis under E.O. 13132 and that the Agency erroneously 
stated in the NPRM that the proposed rule does not contain policies 
that have substantial direct effects on the States, on the relationship 
between the National Government and the States, or on the distribution 
of power and responsibilities among the various levels of government. 
Another comment stated that the conclusions in the NPRM regarding 
federalism ``do not reflect the impact on practice of medicine'' given 
that, in the comment's view, FDA's proposal conflicts with certain 
state medical practice acts as well as NYS CLEP, which currently 
permits the review, approval, and use of LDTs.
    As discussed in response to comment 101, the requirement for a 
federalism summary impact statement applies to the proposed amendment 
to Sec.  809.3 (and not the phaseout policy), and because the proposed 
regulation would not establish any new requirements, it would not have 
any federalism implications under E.O. 13132. Moreover, even if the 
requirement for a federalism summary impact statement were to apply to 
the phaseout policy, the policy does not have federalism implications 
because it is not establishing any new requirements. For further 
discussion on the relationship between this rule and state medical 
practice acts and NYS CLEP, as raised in the comments summarized above, 
see comments 76 and 101 and the responses to those comments.

XII. Consultation and Coordination With Indian Tribal Governments

    We have analyzed this rule in accordance with the principles set 
forth in E.O. 13175. We have determined that the rule does not contain 
policies that have substantial direct effects on one or more Indian 
Tribes, on the relationship between the Federal Government and Indian 
Tribes, or on the distribution of power and responsibilities between 
the Federal Government and Indian Tribes. FDA received one comment on 
the NPRM that expressed concern that the rule, if implemented, would 
have significant tribal implications, resulting from loss of access to 
IVDs offered as LDTs that address special needs of the Native American 
population. As discussed in response to comment 223 (section VI.K), FDA 
does not anticipate that the Native American population will lose 
access to such IVDs offered as LDTs based on the final phaseout policy. 
We conclude that the rule does not contain policies that have tribal 
implications as defined in the E.O. and, consequently, a tribal summary 
impact statement is not required.

XIII. References

    The following references marked with an asterisk (*) are on display 
at the Dockets Management Staff (see ADDRESSES) and are available for 
viewing by interested persons between 9 a.m. and 4 p.m., Monday through 
Friday; they also are available electronically at https://www.regulations.gov. References without asterisks are not on public 
display at https://www.regulations.gov because they have copyright 
restriction. Some may be available at the website address, if listed. 
References without asterisks are available for viewing only at the 
Dockets Management Staff. Although FDA verified the website addresses 
in this document, please note that websites are subject to change over 
time.

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Announcement.'' Available at https://www.fda.gov/advisory-committees/advisory-committee-calendar/november-29-2023-molecular-and-clinical-genetics-panel-medical-devices-advisory-committee-meeting (last accessed on March 21, 2024).
*263. FDA, ``Network of Experts Program: Connecting the FDA with 
External Expertise.'' Available at https://www.fda.gov/about-fda/center-devices-and-radiological-health/network-experts-program-connecting-fda-external-expertise (last accessed on March 21, 2024).
*264. FDA, ``Oncology Drug Products Used with Certain In Vitro 
Diagnostics Pilot Program.'' Available at https://www.fda.gov/medical-devices/in-vitro-diagnostics/oncology-drug-products-used-certain-in-vitro-diagnostics-pilot-program (last accessed on January 
30, 2024).
*265. FDA, ``Part 11, Electronic Records; Electronic Signatures--
Scope and Application; Guidance for Industry,'' September 2003. 
Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/part-11-electronic-records-electronic-signatures-scope-and-application.

List of Subjects in 21 CFR Part 809

    Labeling, Medical devices.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
809 is amended as follows:

PART 809--IN VITRO DIAGNOSTIC PRODUCTS FOR HUMAN USE

0
1. The authority citation for part 809 is revised to read as follows:


[[Page 37445]]


    Authority: 21 U.S.C. 321(h)(1), 331, 351, 352, 360, 360c, 360d, 
360e, 360h, 360i, 360j, 371, 372, 374, 381, and 42 U.S.C. 262.


0
2. In Sec.  809.3, revise the last sentence of paragraph (a) to read as 
follows:


Sec.  809.3   Definitions.

(a) * * * These products are devices as defined in section 201(h)(1) of 
the Federal Food, Drug, and Cosmetic Act (the act) and may also be 
biological products subject to section 351 of the Public Health Service 
Act, including when the manufacturer of these products is a laboratory.
* * * * *

    Dated: April 22, 2024.
Robert M. Califf,
Commissioner of Food and Drugs.
[FR Doc. 2024-08935 Filed 4-29-24; 8:45 am]
 BILLING CODE 4164-01-P