[Federal Register Volume 88, Number 190 (Tuesday, October 3, 2023)]
[Proposed Rules]
[Pages 68006-68031]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2023-21662]


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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: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is 
proposing 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, FDA is proposing a 
policy under which FDA intends to phase out its general enforcement 
discretion approach for laboratory developed tests

[[Page 68007]]

(LDTs) so that IVDs manufactured by a laboratory would generally fall 
under the same enforcement approach as other IVDs. FDA is proposing 
this phaseout to better protect the public health by helping to assure 
the safety and effectiveness of LDTs. If finalized, this phaseout may 
also foster the manufacturing of innovative IVDs for which FDA has 
determined there is a reasonable assurance of safety and effectiveness.

DATES: Either electronic or written comments on the proposed rule must 
be submitted by December 4, 2023.

ADDRESSES: You may submit comments as follows. Please note that late, 
untimely filed comments will not be considered. The https://www.regulations.gov electronic filing system will accept comments until 
11:59 p.m. Eastern Time at the end of December 4, 2023. Comments 
received by mail/hand delivery/courier (for written/paper submissions) 
will be considered timely if they are received on or before that date.

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to https://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2023-N-2177 for ``Medical Devices; Laboratory Developed Tests.'' 
Received comments, those filed in a timely manner (see ADDRESSES), will 
be placed in the docket and, except for those submitted as 
``Confidential Submissions,'' publicly viewable at https://www.regulations.gov or at the Dockets Management Staff between 9 a.m. 
and 4 p.m., Monday through Friday, 240-402-7500.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, 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 Proposed Rule
    B. Summary of the Major Provisions of the Proposed Rule
    C. Legal Authority
    D. Costs and Benefits
II. Table of Abbreviations/Commonly Used Acronyms in This Document
III. Background
    A. Introduction
    B. Need for the Rule
    C. FDA's Current Regulatory Framework
    D. History of the Rulemaking
IV. Legal Authority
V. Description of the Proposed Amendment to the Definition of In 
Vitro Diagnostic Products
    A. Proposed Amendment
    B. Legal Basis for the Proposed Amendment
VI. Description of the Proposed Enforcement Policy
    A. Scope
    B. Stages
VII. Proposed Effective Date
VIII. Preliminary 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. Other Issues for Consideration
XIV. References

I. Executive Summary

A. Purpose of the Proposed Rule

    FDA is proposing to amend 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 would reflect that the device 
definition in the FD&C Act does not differentiate between entities 
manufacturing the device, and would provide further clarity, including 
for stakeholders affected by the accompanying changes to FDA's general 
enforcement discretion approach for LDTs. In connection with amending 
the regulation, FDA intends to phase out its general enforcement 
discretion approach for LDTs so that IVDs manufactured by a laboratory 
would generally fall under the same enforcement approach as other IVDs. 
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,

[[Page 68008]]

preparation, propagation, assembly, and processing).
    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 
generally 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 general 
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 section III.B, today's LDTs are generally, 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 been 
under this general enforcement discretion approach. Given these 
changes, and for the additional reasons discussed in section III.B, 
phasing out the general enforcement discretion approach for LDTs is 
important to protect the public health. The phaseout of FDA's general 
enforcement discretion approach for LDTs is intended to help assure the 
safety and effectiveness of LDTs, and may also foster the manufacturing 
of innovative IVDs for which FDA has determined there is a reasonable 
assurance of safety and effectiveness.

B. Summary of the Major Provisions of the Proposed Rule

    This rulemaking would amend the definition of ``in vitro diagnostic 
products'' in FDA regulations to state that IVDs are devices under the 
FD&C Act ``including when the manufacturer of these products is a 
laboratory.'' In conjunction with this amendment, FDA is also proposing 
a policy under which FDA intends to phase out its general enforcement 
discretion approach for LDTs so that IVDs manufactured by a laboratory 
would generally fall under the same enforcement approach as other IVDs. 
Additional details regarding the proposed phaseout policy are discussed 
further in section VI.

C. Legal Authority

    FDA is proposing to issue 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).

D. Costs and Benefits

    We quantify benefits to patients from averted health losses due to 
problematic IVDs offered as LDTs.\1\ Due to limitations in the data, we 
quantify health benefits only with respect to IVDs for certain diseases 
and conditions; however, we would expect additional health benefits 
associated with averted health losses for other diseases and 
conditions. We estimate that the annualized benefits over 20 years 
would range from $2.67 billion to $86.01 billion at a 7 percent 
discount rate, with a primary estimate of $31.41 billion, and from 
$1.81 billion to $61.41 billion at a 3 percent discount rate, with a 
primary estimate of $22.33 billion. Additional benefits would include 
averted non-health losses from the quantified reduction in costs of 
problematic IVDs offered as LDTs and unquantified reduction in costs 
from lawsuits and costs to healthcare systems. We quantify costs to 
affected laboratories for complying with applicable statutory and 
regulatory requirements. Additional costs would include some costs to 
FDA, which we include in our estimates. The annualized costs would 
range from $2.52 billion to $19.45 billion at a 7 percent discount 
rate, with a primary estimate of $5.87 billion, and from $2.39 billion 
to $18.55 billion at a 3 percent discount rate, with a primary estimate 
of $5.60 billion. The annualized transfers \2\ would range from $100 
million to $452 million at a 7 percent discount rate, with a primary 
estimate of $226 million, and from $121 million to $538 million at a 3 
percent discount rate, with a primary estimate of $269 million. The 
annualized costs to FDA would range from $265 million to $1.06 billion 
at a 7 percent discount rate, with a primary estimate of $530 million, 
and from $251 million to $1.00 billion at a 3 percent discount rate, 
with a primary estimate of $501 million. These estimates do not include 
anticipated offsets from user fees. Factoring in offsets from user fees 
at current levels, estimated costs to FDA are reduced to $165 million 
to $607 million at a 7 percent discount rate, with a primary estimate 
of $304 million, and to $103 million to $465 million at a 7 percent 
discount rate, with a primary estimate of $233 million, covering 
approximately half of the estimated costs to FDA.
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    \1\ See discussion of ``IVDs offered as LDTs'' in section VI.A 
below.
    \2\ This proposed rule would result in compliance costs for 
laboratories that are ensuring their IVDs offered as LDTs are 
compliant with applicable statutory and regulatory requirements. 
These costs overlap somewhat with effects associated with this rule 
in the form of user fees including annual registration fees, fees 
for premarket submissions, and annual fees for periodic PMA 
reporting, which are paid from laboratories to FDA. These fees are 
paid by laboratories but are considered 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.
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II. Table of Abbreviations/Commonly Used Acronyms in This Document

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     Abbreviation/acronym                    What it means
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510(k).......................  Premarket Notification.
AMC..........................  Academic Medical Center.
ASR..........................  Analyte Specific Reagent.
CFR..........................  Code of Federal Regulations.
CGMP.........................  Current Good Manufacturing Practice.
CLIA.........................  Clinical Laboratory Improvement
                                Amendments of 1988.
CMS..........................  Centers for Medicare & Medicaid Services.
EUA..........................  Emergency Use Authorization.
FDA..........................  Food and Drug Administration.
FD&C Act.....................  Federal Food, Drug, and Cosmetic Act.
HCT/Ps.......................  Human Cells, Tissues, and Cellular and
                                Tissue-Based Products.
HLA..........................  Human Leukocyte Antigen.
IDE..........................  Investigational Device Exemption.
IVD..........................  In Vitro Diagnostic Product.
IVDMIA.......................  In Vitro Diagnostic Multivariate Index
                                Assay.
LDT..........................  Laboratory Developed Test.

[[Page 68009]]

 
MDA..........................  Medical Device Amendments of 1976.
MDR..........................  Medical Device Report.
MDUFA........................  Medical Device User Fee Amendments.
NIPS.........................  Non-Invasive Prenatal Screening.
PMA..........................  Premarket Approval Application.
QS...........................  Quality System.
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III. Background

A. Introduction

    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 performed on samples taken from 
the human body, such as blood or tissue, for the purpose of detecting 
diseases or other conditions, monitoring 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 
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. 
Section V.B sets forth the legal reasoning for FDA's position that IVDs 
manufactured by laboratories, including LDTs, are devices.
    However, in implementing the MDA, FDA generally has exercised 
enforcement discretion such that it generally has not enforced 
applicable requirements with respect to most LDTs. 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 tests. They also tended to employ manual 
techniques (and did not use automation) 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 regulatory requirements. Due to these and other 
factors, FDA generally exercised enforcement discretion such that it 
generally has not enforced applicable requirements for most LDTs.\3\
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    \3\ Although FDA's general enforcement discretion approach 
continues today, it does not apply to LDTs in all contexts; for 
example, it does not apply 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 rely on high-tech or complex instrumentation and 
software to generate results and clinical interpretations. They are 
often used in laboratories outside of the patient's healthcare setting 
and are often manufactured in high volume for large and diverse 
populations. Many LDTs are manufactured by laboratory corporations that 
market the tests 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 modern LDTs are therefore much greater today 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, 
because they are not actually designed, manufactured, and used within a 
single laboratory (see, e.g., Refs. 4 and 5).
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    \4\ See, e.g., Refs. 1 to 3. 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 developing and running LDTs.
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    As a result of this evolution 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 set forth in the ``History of the Rulemaking'' 
section below (section III.D). Over the past few years, FDA has 
accumulated even more information supporting the need for a change, as 
discussed below. In light of these developments, FDA is proposing to 
amend 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 proposing a policy under which FDA intends to phase out FDA's 
general enforcement discretion approach for LDTs so that IVDs 
manufactured by a laboratory would generally fall under the same 
enforcement approach as other IVDs.
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    \5\ As discussed further in section V, FDA is also proposing to 
amend 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 (21 U.S.C. 321(h)(1)).
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B. Need for the Rule

    FDA is proposing a policy under which FDA intends to phase out the 
general enforcement discretion approach for LDTs because that approach 
has led to an oversight scheme that does not best serve the public 
health. LDTs that are under the general enforcement discretion approach 
are treated differently from other IVDs. However, there is no longer a 
sound basis for this distinction. In FDA's experience, including with 
COVID-19 tests and IVDs that are offered as LDTs after FDA's approval 
of a comparable companion diagnostic, many test systems made by 
laboratories today are functionally the same as those made by other 
manufacturers of IVDs. They

[[Page 68010]]

involve the same materials and technologies, are intended for the same 
or similar purposes, are developed by and for individuals with similar 
expertise, and are marketed to the same patients, sometimes on a 
national scale. For these reasons, tests made by laboratories are often 
used interchangeably by healthcare providers and patients with tests 
made by other manufacturers. In fact, today, the testing industry has 
come to view FDA's general enforcement discretion approach as an 
alternative pathway to market for test systems, such that test systems 
are often ``launched as LDTs'' with no assurance that they meet 
requirements under the FD&C Act and its implementing regulations (see, 
e.g., Refs. 6 and 7).\6\ These tests lack the characteristics and 
institutional safeguards that originally justified FDA's general 
enforcement discretion approach, as discussed above, and may directly 
compete with FDA-authorized kit-based test systems. FDA views this 
bifurcated system of oversight as untenable and inconsistent with FDA's 
public health mission.
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    \6\ The references cited are examples of the described practice. 
Their inclusion does not represent FDA support for or approval of 
the activities described.
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    The proposed phaseout of FDA's general enforcement discretion 
approach is designed to redress the imbalance in oversight and protect 
the public health. Diagnostic testing is a cornerstone of modern 
medicine; CDC estimates that 70 percent of medical decisions are based 
on laboratory test results (Ref. 8). IVDs offered as LDTs are a growing 
sector of that market (Ref. 1). Moreover, these tests are proliferating 
in some of the most complicated and sensitive areas of medical 
practice, where the presence of a valid test can be most important.
    As the testing landscape has evolved, information about these tests 
in the scientific literature, news articles, and anecdotal reports 
submitted to the Agency, among other sources, has exposed evidence of 
problems associated with these tests. This evidence is discussed in 
more detail below. Particularly over the last few years, this evidence 
has been growing and likely does not reflect the full scale of the 
problems. (Until FDA systematically collects information on these 
tests, such as adverse event reports, it will not be able to assess 
more fully the extent of the risks to patients in the manner it does 
for other devices.) Based on current safety signals, FDA is proposing 
to phase out the general enforcement discretion approach to help assure 
that patients are receiving accurate and reliable diagnostic test 
results regardless of where the tests are made.
1. IVDs Offered as LDTs Have a Significant Impact on Modern Medical 
Care
    Today, IVDs offered as LDTs are ubiquitous, and are intended to 
diagnose a broad range of diseases and conditions (see Ref. 2). In many 
cases, these IVDs are meant for use in complex areas of medicine 
involving life-threatening diseases, such as cancer, neurological 
diseases, cardiovascular illness, infectious diseases, and rare 
diseases. They can proliferate in areas where diagnosis is difficult, 
and the healthcare community has few points of reference for 
determining test validity. Sometimes, they use complex algorithms to 
calculate ``scores'' for diagnosis with little transparency to the user 
about the basis for these algorithms. Increasingly, these IVDs are 
intended to inform drug treatment, directing physicians to choose 
certain drugs based on a patient's genetic or other information. FDA 
has witnessed an explosion in the volume, complexity, and scope of IVDs 
offered as LDTs for use in determining cancer treatments,\7\ and as 
discussed below, news coverage, including as recently as this year, has 
drawn attention to the use of IVDs offered as LDTs for non-invasive 
prenatal screening (NIPS), which evaluate fetal DNA circulating in a 
pregnant individual's blood. In general, IVDs offered as LDTs are 
occupying a growing share of the testing market and are used in some of 
the most complex areas of medicine (see, e.g., Refs. 1 and 2).
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    \7\ FDA has initiated a pilot program for certain oncology 
diagnostics as one step that may be helpful in reducing the risks 
associated with using certain LDTs to identify cancer biomarkers 
(see 88 FR 40273 (June 21, 2023)).
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    Given the role these IVDs play in modern medical care, their 
validity has a significant impact on the public health. False positive 
test results, which erroneously indicate that a patient has a certain 
disease or condition, can delay diagnosis and treatment of the true 
disease or condition, lead to unwarranted interventions, and cause 
needless distress. Interventions may involve medication with serious 
side effects or risky medical procedures. False negative results can 
lead to progression of disease, in some cases without the opportunity 
for life-saving treatment, and the spread of infectious disease. The 
harms to patients from false positive and negative results can be 
significant. For example, the application of an ineffective oncology 
treatment due to a false positive for a patient already weakened from 
disease, or the failure to receive a life-saving medication due to a 
false negative, can be fatal. These false results 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. 
Flaws in a test's algorithm can mean the difference in whether a 
patient with cancer receives a beneficial immunotherapy. Pregnant 
people may use screening tests to make decisions without obtaining 
appropriate confirmatory testing. In 2016, FDA learned of a false 
positive result from a genetic test for long QT syndrome (a heart 
signaling disorder) that led to the erroneous implantation of a 
defibrillator in a healthy individual. In addition to the risks 
associated with the implantation procedure, the defibrillator delivered 
inappropriate shocks to the patient, which posed the risk of sudden 
cardiac death (Refs. 9 and 10). These are just a few examples of how 
diagnostic tests can and do have significant long-term consequences for 
patients.
2. Current Information Raises Serious Questions About Whether Patients 
Can Rely on IVDs Offered as LDTs
    FDA has highlighted the risks associated with IVDs offered as LDTs 
for decades, and our concerns have grown in recent years. As described 
in the ``History of the Rulemaking'' section, we first took steps to 
address the issue in the late 1990s, followed by a series of different 
proposed strategies for increasing oversight. In 2015, the Agency 
published a report of 20 case studies involving inaccurate, unsafe, 
ineffective, or poor quality LDTs that caused or may have caused 
patient harm (``2015 Report'') (Ref. 11). More recent evidence suggests 
that the situation is getting worse. This evidence 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. 
Overall, the evidence points to fundamental uncertainty in the 
marketplace about whether IVDs offered as LDTs provide accurate and 
reliable results.
    Scientific literature is one source of evidence. Over time, FDA has 
become aware of various publications that describe problems with IVDs 
offered as LDTs. In the past 3 years, four different studies have 
documented high variability in performance among these IVDs (Refs. 12 
to 15). In one study, the

[[Page 68011]]

same samples were sent to 19 laboratories for testing using their own 
manufactured test and only 7 of those laboratories correctly reported 
all results (Ref. 12). For almost half of the tests studied, analytical 
accuracy was significantly lower than that of the parallel test 
approved by FDA. In another study, researchers sent identical samples 
to two different laboratories to detect tumor mutations and found over 
70 percent discordance in the results from their tests (Ref. 13). A 
study by Friends of Cancer Research found substantial variability among 
tumor mutational burden (TMB) tests manufactured by laboratories and 
used to identify patients with cancer most likely to benefit from 
immunotherapy (Ref. 14). A fourth study highlighted validity concerns 
specific to early cancer detection tests, including one IVD offered as 
an LDT that delivered nine false positive results for every true cancer 
diagnosis (Ref. 15). An article published earlier this year detailed an 
oncologist's experience with false results from an unapproved blood-
based multi-cancer early detection IVD offered as an LDT and intended 
to screen for more than 50 types of cancer (Ref. 16). A 2016 study 
published in the New England Journal of Medicine reported false 
positive results from genetic IVDs offered as LDTs for hypertrophic 
cardiomyopathy in multiple patients of African American descent (Ref. 
17). These studies do not mean that every laboratory is manufacturing 
bad tests or that no patient can rely on IVDs offered as LDTs. Instead, 
they reflect a level of variability, including the potential for 
inaccurate or incomplete results, that highlights the need for changes 
to the basic oversight scheme.
    FDA's own experience has reinforced concerns regarding IVDs offered 
as LDTs. FDA has gathered information about IVDs offered as LDTs 
through its review of submissions. Although the Agency generally has 
not enforced requirements for LDTs, it has received premarket 
submissions from some laboratories seeking authorization for their 
tests. We have received numerous submissions for such tests, including 
premarket review submissions,\8\ Q-submissions,\9\ and investigational 
use submissions for IVDs offered as LDTs, as well as many emergency use 
authorization (EUA) requests from laboratories (which are discussed 
further below). FDA's review of these submissions has provided insight 
into laboratory test development and, in some cases, revealed 
significant concerns. For example, FDA has observed that many 
laboratories fail to perform appropriate or adequate validation 
studies, have data demonstrating their test does not work as intended 
but offer the test anyway, or use instruments and other components that 
are not adequately controlled for clinical use. The tests described in 
these submissions have been intended for a range of diseases or 
conditions, some of which are very serious. FDA has received 
submissions for IVDs offered as LDTs to diagnose Alzheimer's disease, 
predict heart disease risk, diagnose Fabry disease (a rare neurological 
disorder), and inform treatment considerations for a rare blood cancer, 
all of which lacked adequate validation to support authorization.
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    \8\ These submissions have been for a wide variety of 
indications, including tests intended to detect nucleic acids from 
viruses associated with head and neck cancers; to identify patients 
with obesity due to rare genetic conditions to inform treatment 
eligibility; to aid in the management of therapy for patients taking 
certain anticoagulants; and tests for breast cancer prognosis, tumor 
profiling, and treatment selection, for patients with cancer.
    \9\ For discussion of FDA's Q-submission program, see FDA's 
guidance document issued on June 2, 2023, entitled ``Requests for 
Feedback and Meetings for Medical Device Submissions: The Q-
Submissions Program,'' available at https://www.fda.gov/media/114034/download.
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    In addition, given that FDA's general enforcement discretion 
approach for LDTs has not applied to IVDs for emergency use (though FDA 
has issued enforcement policies for such IVDs during specific 
emergencies, as explained elsewhere in this preamble), FDA has received 
EUA requests for tests from laboratories, including many for COVID-19 
diagnostics. Of the first 125 EUA requests for COVID-19 molecular 
diagnostic tests submitted from laboratories, 82 showed test design or 
validation problems (Ref. 18). In one case, the approach to validation 
was so poor that when redone correctly, there was a 400-fold difference 
in performance, leading the laboratory to take the test off the market. 
In another example, an academic medical center (AMC) laboratory 
purported to validate its test with only 12 positive samples, showing 
perfect performance. FDA requested evaluation of additional specimens 
to confirm. When an additional 12 samples were evaluated, the 
cumulative performance revealed an unacceptably high false negative 
rate, where the test identified only 71 percent of known positive 
specimens as positive and falsely identified 29 percent of known 
positive samples as negative, and the EUA request was withdrawn. In 
addition, multiple laboratories that offered their tests as described 
in FDA's COVID-19 test guidance (see discussion in Ref. 19) did not 
provide any analytical and/or clinical validation data in the EUA 
requests that they submitted after the tests were in use. This 
experience provided a window into the approach that many laboratories 
may take to test validation, and not only confirmed but increased FDA's 
concerns about the validation of IVDs offered as LDTs. The experience 
also showed that even tests involving relatively well-understood 
techniques (here, the polymerase chain reaction, or PCR, technique) may 
not perform well. In all, test performance seen in this subset of 
submissions from laboratories was far worse than we expected. To the 
extent that this sample represents larger trends in the performance of 
IVDs offered as LDTs, it underscores the need for greater FDA 
oversight.
    FDA has also received multiple complaints, adverse event reports, 
and other allegations identifying problems with IVDs offered as 
LDTs.\10\ One complaint alleged that an IVD offered as an LDT to 
diagnose autism had insufficient clinical validation to support this 
use. In another complaint, an informant alleged that a laboratory was 
forging results when its liquid biopsy test did not work. Additionally, 
FDA has received multiple voluntary medical device reports (primarily 
from patients) of inaccurate NIPS test results, as well as inaccurate 
results from an oncology IVD offered as an LDT that predicts risk of 
breast cancer recurrence and informs the decision to pursue 
chemotherapy, both of which can pose serious, irreversible harm to 
patients. Another report described a false negative result from a BRCA 
test marketed to predict one's risk of breast cancer. The patient was 
later diagnosed with breast cancer and found to be BRCA1 positive by 
another test. A separate report from a healthcare provider described a 
different patient that received discrepant results from testing with 
this BRCA test and with another IVD offered as an LDT for hereditary 
cancer risk prediction. In yet another report, a patient described a 
false positive breast cancer result from an oncology blood IVD offered 
as an LDT and that led to invasive followup procedures, emotional 
anguish, and unnecessary monetary expenses. FDA also received a report 
regarding a blood-based test for lung cancer that underestimated cancer 
in about 40 percent of patients. Additionally, FDA has received medical 
device reports

[[Page 68012]]

regarding infectious disease genetic IVDs offered as LDTs without 
validation, from which inaccurate results could lead to limb loss or 
women's health issues, and regarding inaccurate results from an IVD 
offered as an LDT to assess medication adherence. As noted above, 
collectively, this information, though anecdotal, points to potential 
problems among IVDs offered as LDTs, the scope and scale of which FDA 
cannot fully assess or address without phasing out the general 
enforcement discretion approach for applicable requirements (such as 
adverse event reporting).
---------------------------------------------------------------------------

    \10\ FDA has not confirmed the veracity of the allegations or 
facts in every complaint, report, and allegation. Nevertheless, 
collectively this information points to potential problems among 
IVDs offered as LDTs.
---------------------------------------------------------------------------

    Aside from the scientific community and FDA, the general public is 
coming to recognize concerns with the current scheme, in which most 
LDTs are generally not overseen by FDA. General news sources and other 
outlets have reported on such concerns (see, e.g., Refs. 20 to 26). For 
example, the New York Times recently conducted an indepth investigation 
into NIPS tests and found that positive results from the tests are 
incorrect about 85 percent of the time (Ref. 22). NIPS tests are 
screening tests, so they should be followed up with confirmatory 
diagnostic testing, but the New York Times article reported that 
patients and healthcare providers are making healthcare decisions based 
on results from these screening tests alone due to manufacturers' 
marketing claims. A device whose labeling is false or misleading in any 
particular manner is misbranded under the FD&C Act; however, under the 
general enforcement discretion approach, FDA generally has not enforced 
this proscription for IVDs offered as LDTs. As another example, 
ProPublica reported on a COVID-19 test offered by a laboratory under 
contract with a university without EUA authorization from FDA, which, 
according to the report, missed 96 percent of the positive cases from 
the university campus, and routinely sent people infected with COVID-19 
back into the community (Ref. 26). In addition, consumers, 
shareholders, and investors are filing lawsuits against laboratory 
manufacturers for false and misleading statements about test efficacy, 
including lawsuits related to pharmacogenetic tests (genetic tests 
intended to inform drug selection) and NIPS (see, e.g., Complaint, In 
re Myriad Genetics, Inc. Sec. Litig., No. 2:19-cv-00707-PMW (D. Utah 
2019); Complaint, Hickok v. Capone, No. 2021-0686 (Del. Ch. 2021); 
Complaint, Davis v. Natera, Inc., No. 3:22-cv-00985 (N.D. Cal. 2022); 
Complaint, Carroll v. Myriad Genetics Inc., No. 4:22-CV-00739 (N.D. 
Cal. 2022); Biesterfeld v. Ariosa Diagnostics, Inc., No. 1:21-CV-03085, 
2022 WL 972281 (N.D. Ill. 2022); and Complaint, Kogus v. Capone, No. 
2022-0047-SG (Del. Ch. 2022)). The overall picture presented by this 
evidence indicates that a change in oversight is needed to better 
assure the safety and effectiveness of IVDs offered as LDTs.
3. Greater FDA Oversight is Needed To Protect the Public Health
    As described above, the evidence FDA has collected points to flaws 
in laboratory manufacturing of tests that need to be addressed to 
protect the public. Greater oversight by FDA would help address these 
flaws.
    In the past, FDA has communicated with the public when it is 
particularly concerned about a type of IVD offered as an LDT. For 
example, in addition to the 2015 Report, FDA has issued safety 
communications about pharmacogenetic tests, NIPS tests, ovarian cancer 
screening tests, nipple aspirate tests, and instruments used in the 
design of many different LDTs (Refs. 27 to 31). FDA has also taken 
compliance action in some circumstances, such as issuing a warning 
letter to a laboratory manufacturing a pharmacogenetic test in April 
2019 (Ref. 32). However, more structural change is needed. FDA's 
general enforcement discretion approach emerged at a time when the 
typical IVD offered as an LDT looked very different from how it looks 
today. FDA has made a preliminary determination that this approach has 
become outdated, and the proposed steps to end this approach in this 
rulemaking would better protect the public health.
    Increased oversight would help to ensure the safety and 
effectiveness of IVDs offered as LDTs. More accurate diagnoses would 
lead to better care, which would advance public health overall. Through 
increased oversight, the public, including patients and healthcare 
professionals, could have more confidence that the test results they 
rely on are accurate. Greater FDA oversight of IVDs offered as LDTs has 
become particularly important as more and more novel treatments require 
use of a specialized test to identify patients likely to benefit from 
them. This, in turn, has led to increased development of tests used as 
the primary driver for therapeutic decisions. These include tests to 
determine whether to administer a therapeutic, which therapeutic to 
administer, and at what dose to administer the therapeutic. For 
example, recent approvals of drug products to treat diseases in their 
early stages, such as for early-stage Alzheimer's patients, make 
accurate and early diagnosis of these diseases more critical today than 
ever before. As another example, gene therapy is an emerging field with 
incredible potential to treat many diseases or conditions. Testing is 
required to identify patients with the defective gene targeted by the 
treatment and, in some cases, to assess whether the patient has 
antibodies to the vector delivering the treatment that would prevent it 
from working. In these and other cases, accurate and reliable test 
results are essential for safe and effective use of a therapeutic.
    Increased oversight would also address business strategies that 
take advantage of the current bifurcated system. For example, in a 
number of cases, laboratories that have submitted premarket submissions 
for their tests, but whose tests did not meet applicable requirements 
for authorization, have still offered these IVDs as ``LDTs.'' Some of 
these tests, such as a test intended to diagnose Alzheimer's disease, 
had inadequate validation data to support authorization (see Ref. 33). 
A genotyping test purported to predict heart disease risk, but FDA 
found that there was no association between the genetic information the 
test identified (KIF6) and heart disease. A third test, intended to 
diagnose Fabry disease, showed a high level of false negatives. The 
public health is not served by a scheme in which tests that have these 
types of problems are still offered to patients simply because the 
manufacturer is a laboratory. FDA is also aware that some industry 
players have created business models that claim a connection to 
laboratories and offer IVDs as LDTs. The increase in firms using these 
business models, as well as their substantial magnitude of reach, 
underscores the need for more oversight.
    In addition, FDA anticipates that consistent oversight would bring 
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 aware of arguments that 
better assuring the safety and effectiveness of LDTs would foster test 
innovation. FDA is also aware of arguments that IVD manufacturers that 
are not laboratories 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 their tests without 
complying with FDA requirements. We anticipate that applying the same 
oversight approach to

[[Page 68013]]

laboratories and non-laboratories that manufacture IVDs would better 
assure the safety and effectiveness of LDTs, and would remove a 
disincentive for non-laboratory manufacturers to develop novel tests, 
thereby spurring innovation and access to IVDs for which there is a 
reasonable assurance of safety and effectiveness. As a result, we 
anticipate that phasing out the general enforcement discretion approach 
for LDTs would advance responsible innovation by both laboratory and 
non-laboratory IVD manufacturers alike, rather than discouraging it.
    FDA is aware of other arguments that ending the general enforcement 
discretion approach for LDTs would interfere with test innovation and 
patient access due to the potential need for premarket review of new 
tests. However, under FDA's device authorities, FDA premarket review is 
only required for certain tests (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 (see section 
II.F.4 of the Preliminary Economic Analysis of Impacts (Ref. 34)). In 
addition, FDA review is only required for device modifications in 
certain circumstances. For devices that are subject to PMA 
requirements, a PMA supplement is required only for changes that affect 
the safety or effectiveness of the device, and in some cases the change 
may be made prior to FDA approval (see 21 CFR 814.39(d)); may be made 
30 days after a supplement has been filed, unless FDA takes certain 
action (see 21 CFR 814.39(e)); or may be made 30 days after FDA 
receives a notice describing the change (in lieu of a supplement), 
unless FDA takes certain action (see 21 CFR 814.39(f)). For devices 
that are subject to 510(k) requirements, a new 510(k) is only required 
for a significant change or modification in design, components, method 
of manufacture, or intended use, where a significant change or 
modification is one that could significantly affect the safety or 
effectiveness of the device or that is a major change or modification 
in the device's intended use (21 CFR 807.81(a)). FDA has published 
several guidance documents to help stakeholders determine whether a 
certain change or modification may require a PMA supplement, new 
510(k), or other submission to FDA, and FDA has several mechanisms 
available through which manufacturers may seek FDA assistance in making 
this determination. In addition, under section 515C of the FD&C Act (21 
U.S.C. 360e-4), a PMA supplement or new 510(k) is not required for a 
change to a device that would otherwise require a supplement or new 
510(k) if the change is consistent with a predetermined change control 
plan previously approved or cleared by FDA. We also note that as 
described in section VI.B, FDA is proposing to phase out the general 
enforcement discretion approach for LDTs with respect to premarket 
review requirements on a date that aligns with or follows the beginning 
of a new user fee cycle, such that FDA's review timelines and goals 
would be reflected in commitments newly negotiated with industry. For 
all of these reasons, FDA does not anticipate that ending the general 
enforcement discretion approach for LDTs would unduly impair test 
innovation and patient access.
    Furthermore, FDA's approach was never intended to selectively 
foster laboratory innovation at a cost to public health. Rather, the 
approach arose based on certain test characteristics and institutional 
safeguards that at the time adequately protected patients. In general, 
those characteristics and safeguards are no longer present, putting 
public health at risk. Further, FDA is aware that this scheme is in 
some cases fostering unfounded claims of innovation rather than 
responsible innovation. These claims are concerning to FDA because they 
can mislead the public, undermine legitimate competition, and 
disincentivize responsible, science-based innovation.
    Finally, increased oversight may help to advance health equity. FDA 
is aware of concerns that IVDs offered as LDTs may exacerbate health 
inequities due to higher rates of inaccurate results among 
underrepresented patient populations, particularly racial and ethnic 
minorities undergoing genetic testing (see, e.g., Refs. 17 and 35 to 
38). Some IVDs offered as LDTs have not been validated for use in all 
patient populations within a disease state, meaning that it is unknown 
how well the test may perform across diverse patient populations 
expected to use the test and the test may be less accurate in 
underrepresented patient populations, potentially contributing to 
health disparities (see, e.g., Ref. 39). Increased FDA oversight may 
help to ensure that information is available pertaining to device 
safety and effectiveness for specific demographic characteristics if 
performance differs within the target population, through the 
enforcement of applicable labeling requirements. In addition, when FDA 
conducts premarket review of a device, FDA may ask that sponsors 
provide data for different intended patient populations, and with new 
authorities under the Food and Drug Omnibus Reform Act of 2022 (FDORA), 
sponsors generally are required to submit diversity action plans to 
FDA, including the sponsor's goals for enrollment in device clinical 
studies. In contrast, with limited oversight over these tests, FDA does 
not know whether diverse patient populations are being included in 
validation studies for these IVDs. FDA has made a preliminary 
determination that increased oversight for these IVDs would help ensure 
adequate representation of the intended use population in validation 
studies and transparency regarding potential differential performance, 
helping to advance health equity. FDA also recognizes that IVDs offered 
as LDTs may serve communities in rural, medically underserved areas 
with disparities in access to diagnostic tests. However, the benefits 
of test access directly depend on the ability of tests to work as 
intended. Thus, to the extent that access to IVDs offered as LDTs may 
benefit patients in rural, medically underserved communities, the harms 
of unsafe or ineffective IVDs offered as LDTs may also be realized 
among these underserved patient populations. By increasing its 
oversight, FDA may better prevent and mitigate such harms, thereby 
better protecting the health of these underserved populations.
    We are aware of arguments that other mechanisms--such as the 
medical expertise of laboratorians or requirements under CLIA--already 
provide adequate oversight of IVDs offered as LDTs. However, our review 
of the evidence indicates otherwise. Evidence suggests that under the 
current scheme, the healthcare community lacks adequate assurances 
about the safety and effectiveness of IVDs offered as LDTs. Although 
laboratories that offer LDTs are also subject to CLIA, which is 
primarily administered by the Centers for Medicare & Medicaid Services 
(CMS), CLIA is not a substitute for FDA oversight. CLIA establishes 
requirements for laboratories and laboratory personnel pertaining to 
operations, inspections, and certification, with a focus on the 
proficiency with which laboratories perform clinical testing (see 42 
U.S.C. 263a and 42 CFR part 493). Among other requirements, clinical 
laboratories generally must have a CLIA certificate that corresponds to 
the complexity of tests performed prior to accepting human samples for 
testing. However, under CLIA, CMS does not regulate critical aspects of 
laboratory test

[[Page 68014]]

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 patients who participate in test 
clinical research trials; and does not require adverse event reporting. 
As such, CMS has described the FDA and CMS ``regulatory schemes'' as 
``different in focus, scope and purpose, but they are intended to be 
complementary'' (Ref. 40). Where CLIA does play a role (as discussed 
further below, compliance with CLIA may provide certain assurances 
relating to quality system (QS) requirements), FDA has tailored its 
proposed phaseout policy accordingly.\11\
---------------------------------------------------------------------------

    \11\ When ``QS'' requirements are discussed throughout this 
preamble, FDA is referring to the current good manufacturing 
practice (CGMP) requirements set forth in part 820 (21 CFR part 
820). Generally, the requirements are referred to as QS 
requirements, but that terminology may change when amendments to 
part 820 are finalized. See 87 FR 10119 (February 23, 2022) and 
section VI.B.3 for a further discussion of FDA's proposed amendments 
to part 820.
---------------------------------------------------------------------------

    We are also aware of arguments that any additional oversight of 
LDTs should be accomplished by granting new statutory authorities to 
CMS. However, this would cause a problematic split in oversight, with 
the same types of tests being reviewed by different Agencies depending 
on where the test was made. 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.
    FDA has both the authority and the expertise to perform the 
necessary oversight of IVDs offered as LDTs and is the only Agency for 
which that is the case. One of FDA's most basic and well-understood 
responsibilities is helping to ensure the safety and effectiveness of 
medical products. FDA employs staff across a wide range of disciplines, 
including physicians, statisticians, engineers, biologists, chemists, 
geneticists, and others, to evaluate the science behind medical 
products before they reach the market. Understanding the complex 
technical information in applications, such as clinical trial data, 
bench testing results, and product manufacturing and design 
characteristics--and putting that information in context to assess 
whether a product can be marketed--is within the unique expertise of 
FDA. This type of expertise is no less important for IVDs, which can 
have a wide variety of public-health consequences, as described 
elsewhere in this rule. During review of an application for an IVD, FDA 
reviewers closely examine data relevant to analytical validity, 
clinical validity, and safety, and draw on their expertise and 
experience to understand both the product and the science supporting 
the product.
    Review of the underlying science behind an IVD is based on what the 
IVD does and is in no way related to where the IVD is made. Thus, FDA's 
experience and expertise with respect to oversight of other IVDs is 
directly applicable to oversight of LDTs. In fact, FDA has already 
applied its expertise to the review of some IVDs offered as LDTs--for 
example, during public health emergencies. As stated above, FDA has 
reviewed many EUA requests for tests from laboratories during the 
public health response to COVID-19.
    Entities outside FDA have also recognized that FDA should oversee 
LDTs, and that greater oversight is needed. For example, the 
Secretary's Advisory Committee on Genetics, Health, and Society, in its 
April 2008 report entitled ``U.S. System of Oversight of Genetic 
Testing,'' stated that ``FDA should address all laboratory tests, 
regardless of how they are produced (i.e., as a commercial test kit or 
laboratory-developed test), in a manner that takes advantage of its 
current experience'' (Ref. 41). The American Cancer Society Cancer 
Action Network has taken a similar position, noting in a November 2016 
statement that ``[c]urrent oversight of LDTs falls short of ensuring 
these tests produce accurate and meaningful results . . . [t]he FDA is 
the most appropriate agency to evaluate the analytical and clinical 
validity of diagnostic tests, along with their safety, to help ensure 
that cancer patients and their doctors are able to make appropriate 
treatment decisions based on accurate information'' (Ref. 42). 
Likewise, the Advanced Medical Technology Association (AdvaMed) stated 
in November 2021 that the association has ``long supported the idea 
that all diagnostic test developers . . . should be subject to the same 
FDA standards and processes'' (Ref. 43).
4. FDA Should Increase Oversight in a Manner That Recognizes the 
Current State of the Testing Market
    As discussed throughout this section, increased oversight of IVDs 
offered as LDTs is needed. However, FDA has also made a preliminary 
determination that our general enforcement discretion approach should 
be phased out in a manner that accounts for the level of public health 
concern and the importance of avoiding undue disruption to the testing 
market, including undue disruption to the provision of care. Therefore, 
we are proposing a gradual phaseout to occur in stages over a total 
period of 4 years, as described in section VI.B. FDA anticipates that 
this phaseout policy should ultimately enable IVDs offered as LDTs that 
are supported by sound science to remain on the market. FDA also 
recognizes that some IVDs may need to 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 chooses not to 
invest resources to meet those requirements. To the extent that 
withdrawal from the market of these IVDs implicates any reliance 
interests, FDA has made a preliminary determination that the public-
health benefits associated with the reasonable assurance of safety and 
effectiveness of IVDs offered as LDTs outweigh any such interests. In 
addition, in the long run, it is possible that any reduction in the 
number of current IVDs offered as LDTs may be offset by the market 
entry of IVDs from other manufacturers who will have benefitted from a 
more consistent oversight approach and increased stability spurring 
innovation.

C. FDA's Current Regulatory Framework

    The FD&C Act, as amended by the MDA and subsequent statutes, 
establishes a comprehensive system for the regulation of devices, 
defined in section 201(h)(1) of the FD&C Act, that are intended for 
human use. 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

[[Page 68015]]

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 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; and current good 
manufacturing practice (CGMP) requirements. These controls apply to all 
devices unless an exemption applies.
    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).
    In addition, 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 investigational device exemption (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).
    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).
    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, including premarket notification, reporting 
requirements regarding adverse events and corrections and removals, IDE 
requirements (though most 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 of the regulations (21 CFR 
part 809).

D. History of the Rulemaking

1. FDA's Longstanding Recognition That IVDs Manufactured by 
Laboratories Are Devices
    FDA has made clear, on many occasions and over many years, that 
LDTs are devices under the FD&C Act (for the legal reasoning for this 
conclusion, see section V.B). Over 25 years ago, FDA explained that 
clinical laboratories that develop tests are acting as manufacturers of 
medical devices (62 FR 62243 at 62249 (November 21, 1997)). FDA 
reiterated that position in a citizen petition response a year later 
(Ref. 44), and in the preamble to a final rule 3 years after that (65 
FR 18230 at 18231 (April 7, 2000)). In 2006, FDA again cited its prior 
statement that clinical laboratories that develop tests are acting as 
manufacturers of medical devices (Ref. 45 (quoting 62 FR 62243 at 
62249)). In 2014, FDA expressly considered and rejected arguments that 
LDTs are not devices under the FD&C Act, stating in a citizen petition 
response that ``LDTs are devices within the plain language of the 
[statutory] definition'' (Ref. 46). Five years later, FDA issued a 
warning letter stating that ``FDA has not created a legal `carve-out' 
for LDTs such that they are not required to comply with the 
requirements under the Act that otherwise would apply. . . . Although 
FDA has generally exercised enforcement discretion for LDTs, the Agency 
always retains discretion to take action when appropriate, such as when 
it is appropriate to address significant public health concerns'' (Ref. 
47). A wide range of other FDA documents, including guidance documents, 
safety communications, compliance letters, and other public statements, 
have

[[Page 68016]]

indicated or otherwise taken as their premise that IVDs are devices 
even when the manufacturer is a laboratory (see, e.g., Refs. 11, 18, 
27, 28, and 48 to 56).
    FDA has also taken regulatory actions consistent with these 
statements and documents. Since 2017, the Agency has reviewed over 40 
PMAs, 510(k)s, and De Novo classification requests for tests identified 
by the manufacturer as LDTs, and has approved, cleared, or granted De 
Novo classification for roughly half of those tests under authorities 
in the FD&C Act specifically reserved for ``devices.'' FDA has also 
received many EUA requests from laboratories and has authorized over 
150 such tests for emergency use, an authority that is also limited to 
``devices'' or other FDA-regulated medical products.
2. Past FDA Initiatives To Address LDTs
    In light of FDA's recognition that LDTs are devices and our 
increasing concerns about IVDs offered as LDTs (as detailed in the 
``Need for the Rule'' section, section III.B of this document), over 
the years the Agency has considered various ways to address IVDs 
manufactured by laboratories that raise safety or effectiveness 
concerns. In 1997, FDA sought to address these concerns by establishing 
restrictions on the sale, distribution, and use of analyte specific 
reagents (ASRs), which the Agency described as the ``primary 
ingredients'' of most LDTs (62 FR 62243 at 62249). In 2006, FDA issued 
a draft guidance outlining a different enforcement approach for a type 
of LDT known as an in vitro diagnostic multivariate index assay 
(IVDMIA),\12\ which raised particular safety and effectiveness concerns 
(Ref. 45). FDA later determined that it should engage in a more 
comprehensive effort to oversee LDTs, in part due to stakeholder 
feedback.
---------------------------------------------------------------------------

    \12\ As defined in the draft guidance document, IVDMIAs are 
``test systems that employ data, derived in part from one or more in 
vitro assays, and an algorithm that usually, but not necessarily, 
runs on software to generate a result that diagnoses a disease or 
condition or is used in the cure, mitigation, treatment, or 
prevention of disease.'' The draft guidance document further 
characterized IVDMIAs as having the following three features: they 
use clinical data to empirically identify variables and derive 
weights/coefficients used in an algorithm; they employ that 
algorithm to calculate a patient-specific result, which cannot be 
independently derived and confirmed by another laboratory (absent 
access to proprietary information used in the development and 
derivation of the test); and they report that result, which cannot 
be interpreted by a well-trained healthcare practitioner using prior 
knowledge of medicine in the absence of information from the test 
developer regarding clinical performance and effectiveness.
---------------------------------------------------------------------------

    Consistent with this determination, in 2010, FDA announced plans to 
develop a broader approach to the oversight of LDTs. The Agency held a 
2-day public meeting and opened a docket for public comment (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) (Refs. 
48 and 49). In those draft guidance documents, FDA proposed to 
implement a risk-based oversight framework for IVDs offered as LDTs, 
with a phased enforcement strategy. 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 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.
    On January 13, 2017, FDA issued a discussion paper (2017 Discussion 
Paper) synthesizing the feedback that had been provided to the Agency, 
following a choice by FDA not to finalize the draft guidance documents 
to allow for further public discussion and to provide an opportunity 
for Congress to develop legislation for a new regulatory framework 
encompassing all IVDs that appropriately balances patient protection 
with continued access and innovation (Ref. 50).
    In August 2020, HHS posted a statement on its website entitled 
``Rescission of Guidances and Other Informal Issuances,'' which stated, 
among other things, that ``the department has determined that the Food 
and Drug Administration (`FDA') will not require premarket review of 
laboratory developed tests (`LDT') absent notice-and-comment 
rulemaking'' (Ref. 57).\13\ This statement was informed by advice in a 
legal memorandum from the HHS Office of General Counsel (see Ref. 59). 
In November 2021, based on new advice from the HHS Office of General 
Counsel, HHS leadership determined that the August 2020 statement no 
longer represented the Department's policy or legal views (Ref. 59). 
HHS Secretary Xavier Becerra publicly announced the withdrawal of the 
statement on November 15, 2021 (Ref. 60). Various news outlets have 
reported on these events (Refs. 61 to 64).
---------------------------------------------------------------------------

    \13\ HHS also posted an accompanying document entitled ``FAQs on 
Laboratory Developed Tests (LDTs)'' on its website (Ref. 58).
---------------------------------------------------------------------------

IV. Legal Authority

    FDA is proposing to issue 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 (21 U.S.C. 321(h)(1), 
331, 351, 352, 360, 360c, 360d, 360e, 360h, 360i, 360j, 371, 372, 374, 
and 381). 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 ``FDA's Current Regulatory Framework'' section (section 
III.C.). For additional discussion of how these legal authorities apply 
to LDTs, see ``Legal Basis for the Proposed Amendment'' section 
(section V.B.).

[[Page 68017]]

V. Description of the Proposed Amendment to the Definition of In Vitro 
Diagnostic Products

A. Proposed Amendment

    We are proposing to amend part 809, subpart A, specifically Sec.  
809.3, by updating the definition of ``in vitro diagnostic products'' 
to make explicit that IVDs are devices under the FD&C Act including 
when the manufacturer of the IVD is a laboratory. IVDs are defined 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'' (Sec.  809.3). This amendment would reflect FDA's 
longstanding view that LDTs are devices under the FD&C Act, and would 
reflect the fact that the device definition in the FD&C Act does not 
differentiate between entities manufacturing the device. In other 
words, whether an IVD is a device does not depend on where or by whom 
the IVD is manufactured.
    FDA is also proposing to amend 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, 134 Stat. 4915). 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).

B. Legal Basis for the Proposed Amendment

    If amended as proposed, Sec.  809.3 would express in plain terms 
that IVDs, including test systems, fall within the definition of a 
device in section 201(h)(1) of the FD&C Act when they have been 
manufactured by laboratories. In this subsection, FDA sets forth the 
legal reasoning for this position.
1. In Vitro Diagnostic Test Systems Are Devices
    The FD&C Act defines a device as, in relevant part, ``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'' (see 21 U.S.C. 321(h)(1); see 
also 21 U.S.C. 360j(o) (identifying circumstances under which software 
is and is not within the device definition)). This definition includes 
IVD test systems. Test systems are sets of IVDs--for example, reagents, 
instruments, specimen collection devices, software, and other related 
materials--that function together to produce a test result. See, e.g., 
Sec.  809.10(a)(9)(iii) (21 CFR 809.10(a)(9)(iii)) (discussing 
``multiple unit products which require the use of included units 
together as a system''); id. Sec.  809.10(b) (referring to reagents and 
instruments within a system). According to a straightforward reading of 
the statutory text, these systems are ``apparatus[es],'' 
``contrivance[s],'' and articles that are ``similar or related'' to 
``instrument[s]'' and ``in vitro reagent[s],'' that are intended for 
use in the diagnosis of disease or other conditions or in the cure, 
mitigation, treatment, or prevention of disease. They consist of 
individual parts that have their own regulatory identity, but, when 
combined, constitute a new device.
    The device definition expressly contemplates this scenario because 
it provides that both an overall article and each of its ``components'' 
and ``parts'' are devices subject to regulation. (21 U.S.C. 321(h)(1); 
cf. Shuker v. Smith & Nephew, PLC, 885 F.3d 760, 768 (3d Cir. 2018) 
(describing the distinct status of a ``system that is itself a `device' 
but that is comprised of Class II [device] components in addition to 
one or more Class III [device] components'').) The word ``apparatus,'' 
which is defined as ``a set of materials or equipment designed for a 
particular use,'' encompasses test systems by its plain terms. (See 
Apparatus, Merriam-Webster.com (last accessed June 28, 2023); 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'').) Consistent with this analysis, FDA's 
definition of an ``in vitro diagnostic product,'' which was first 
promulgated in 1973 and is still in effect today, identifies a 
``system'' as a type of IVD and a device under the FD&C Act. (Section 
809.3 (IVDs include ``reagents, instruments, and systems''); see 38 FR 
7096 at 7098 (March 15, 1973).)
    The regulation of test systems is important because test systems 
are generally the IVDs that produce a result--a ``positive'' or 
``negative'' (such as what patients receive in the context of COVID-19 
diagnostic tests), a quantitative value (such as a concentration of 
glucose), or perhaps a more detailed report of results. The quality of 
test results is generally what defines both the risks and benefits of 
IVDs: the risks stem from inaccurate, unreliable, incomplete, or 
misleading test results, and the benefits stem from accurate, reliable, 
and complete test results. For that reason, test systems and their 
results are a key focus of FDA's regulation of IVDs. FDA has issued 
over 350 regulations classifying different types of test systems (see 
generally 21 CFR parts 862, 864, 866) and has evaluated the performance 
and results of innumerable test systems over the course of decades. 
Patients and healthcare professionals rely on FDA to help ensure the 
validity of test systems, and conventional IVD manufacturers have built 
their business around this premise.
    The focus on test systems and their results is not new; it has been 
a consistent theme throughout the history of FDA's regulation of IVDs. 
Congress expressly granted FDA authority over diagnostic products in 
1938. (Federal Food, Drug and Cosmetic Act (June 25, 1938), Pub. L. 75-
717, 52 Stat. 1040 (defining ``drug'' and ``device'' with reference to 
an intended use in ``diagnosis,'' among other things).) Following the 
1938 Act, FDA took action against diagnostic products, including 
against a system intended to diagnose illness based on human blood 
samples. (See Drown v. United States, 198 F.2d 999, 1001 (9th Cir. 
1952).) And, in the early 1970s, FDA established a specific IVD 
regulatory program in response to ``rapid growth in development of in 
vitro diagnostic products combined with the increasing use and reliance 
on the results by physicians, hospital personnel, and clinical 
laboratories.'' (37 FR 819, January 19, 1972). This program addressed 
the ``need [for] closer scrutiny because of the possibility that 
inaccurate and unreliable results may be obtained.'' Id. FDA issued 
final regulations establishing controls over IVDs, including 
``systems,'' in 1973 (38 FR 7096 at 7098) (creating, among other 
things, ``product class standards'' to set ``performance requirements 
necessary to assure accuracy and reliability of results''). FDA's 
increasing concerns about these products was evident from the fact 
that--even before Congress expanded the Agency's device authorities in 
1976--it applied the drug authorities to certain IVDs. The Supreme 
Court upheld that application in Bacto-Unidisk, 394 U.S. at 800-01.
    In 1976, Congress enacted the MDA, sweeping legislation meant to 
broaden and strengthen FDA's authority over

[[Page 68018]]

devices. (See, e.g., H.R. Rep. 94-853 at 11 (February 29, 1976).) The 
MDA included revisions to the definition of ``device'' to clarify that 
IVDs should be regulated under the new, more robust device authorities. 
(Medical Device Amendments of 1976, Pub. L. 94-295, 90 Stat. 539 
(adding the term ``in vitro reagent'' to the definition of a device); 
S. Rep. No. 93-670 at 16 (January 29, 1974) (``The 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 
legislative history shows that Congress had serious concerns about test 
systems and sought to empower FDA to address them. (See, e.g., S. Rep. 
No. 93-670 at 3-4 (January 29, 1974) (describing with concern ``quack 
devices'' such as a ``diagnostic service'' in which ``[p]ractitioners . 
. . mailed in the blood spots taken from their patients,'' ``[t]he 
blood-spotted paper was put into a slot of the electrical device called 
the `Radioscope' while the operator stroked with a wand the abdomen of 
a person holding metal plates connected to the device,'' and ``the 
operator determined from this the identity, kind, location, and 
significance of any disease present'').) Congress also contemplated 
performance standards relevant to test systems, such as required 
labeling with ``ranges of accuracy of diagnosis.'' (H.R. Rep. 94-853 at 
27.) Thus, in the MDA, Congress endorsed FDA's focus on test systems 
and their results.
2. Test Systems Manufactured by Laboratories Are Devices
    The definition of ``device'' in the FD&C Act encompasses test 
systems regardless of where or by whom they are manufactured. (See 21 
U.S.C. 321(h)(1).) In particular, the definition contains no exception 
or limitation for devices manufactured by laboratories. ``Congress 
expresses its intentions through statutory text passed by both Houses 
and signed by the President (or passed over a Presidential veto).'' 
(Oklahoma v. Castro-Huerta, 142 S. Ct. 2486, 2496 (2022).) If Congress 
had intended such a limitation, it could have said so. Instead, 
Congress made clear that the definition does not turn on the type of 
entity manufacturing the device: for example, the statute expressly 
recognizes that even ``practitioners licensed by law to prescribe or 
administer . . . devices'' (the professionals most closely associated 
with traditional medical practice) can ``manufacture . . . devices,'' 
though they may be exempt from certain requirements when they do so 
``solely for use in the course of their professional practice.'' \14\ 
(See 21 U.S.C. 360(g)(2); see also 21 U.S.C. 360i(c)(1), 374(a)(2)(B).)
---------------------------------------------------------------------------

    \14\ These exemptions apply when a practitioner (1) is licensed 
by law to prescribe or administer a device such as an IVD, (2) 
manufactures that device, and (3) does so ``solely for use in the 
course of [his or her] professional practice.'' Thus, these 
exemptions apply to practitioners, not entities such as corporate or 
hospital laboratories that employ licensed practitioners. For 
example, FDA has long held that hospitals that reprocess single-use 
devices are subject to registration and other requirements under the 
FD&C Act because they are the owners/operators, manufacturers, etc. 
even though those hospitals employ licensed practitioners. See 
Frequently-Asked-Questions about the Reprocessing and Reuse of 
Single-Use Devices by Third-Party and Hospital Reprocessors; Final 
Guidance for Industry and FDA Staff (July 2001), available at 
https://www.fda.gov/media/71057/download (stating ``Third-party and 
hospital reprocessors of single-use devices (SUDs) are subject to 
all the regulatory requirements currently applicable to original 
equipment manufacturers, including premarket submission 
requirements'' and including a Q&A that provides instructions on how 
to register and list for such entities).
---------------------------------------------------------------------------

    Courts have repeatedly recognized that articles manufactured by 
medical professionals fall within FDA's jurisdiction (e.g., United 
States v. Regenerative Sciences, 741 F.3d 1314 (D.C. Cir. 2014) 
(holding that doctors ``producing, as part of their medical practice,'' 
a ``drug'' under the FD&C Act violated the FD&C Act); Drown v. United 
States, 198 F.2d 999, 1001 (9th Cir. 1952) (upholding FDA action 
against chiropractor who ``manufacture[d] certain photographic, 
therapeutic and diagnostic instruments of her own design which she 
use[d] in her practice'')). As the D.C. Circuit in Regenerative 
Sciences observed, an approach that rejects ``the [FD&C Act]'s 
regulation of doctors'' would ``create an enormous gap in the [FD&C 
Act]'s coverage.'' (741 F.3d at 1320.)
    The inclusion of articles in the FD&C Act's definition of a device 
without regard to the identity of their manufacturer makes particular 
sense in the context of test systems. Today, in FDA's experience, there 
is little distinction between the test systems manufactured by 
laboratories and other manufacturers. These systems generally consist 
of highly specialized components with complex functionality working in 
combination; they rarely resemble the ``1976-type'' tests discussed in 
this rule. For example, a modern-day next generation sequencing (NGS) 
test system for genetic testing typically consists of (among other 
things) a DNA extraction kit to extract nucleic acids from a human 
sample; an NGS instrument that analyzes the nucleic-acid output and 
(after days) generates gigabytes of sequencing raw data; and multiple 
pieces of computer software that translate that raw data into a test 
report. The systems look the same, and function the same way, 
regardless of who manufactures them. And although not all systems look 
exactly like an NGS system, they do typically involve sophisticated 
instruments with advanced software that, when used in conjunction with 
other test components, produce the system's results. Their manufacture 
generally requires knowledge of bioinformatics, software development, 
and an underlying specialty, such as medical genetics--knowledge that 
is neither traditionally associated with nor unique to laboratories. 
FDA understands that many test systems offered as LDTs are designed at 
Fortune 500 companies (see Ref. 65) by a ``development team,'' similar 
to how systems from conventional manufacturers are designed. And in 
FDA's experience, the individuals on these development teams generally 
have the same training and expertise regardless of whether they are 
employed by a ``laboratory'' organization or a conventional 
manufacturer. Even smaller laboratories use the same complex equipment 
for their systems, although they may purchase and use components that 
are labeled by other companies for ``research use only.'' In short, 
there is nothing inherent in the nature or design of laboratory 
developed test systems that would justify exclusion from FDA's 
jurisdiction.
    That is not to say that laboratories and conventional IVD 
manufacturers are identical. Laboratories do occupy a distinct role in 
diagnostic testing because they are the entities that generally perform 
the tests. Like many devices, such as a magnetic resonance imaging unit 
used by a trained technician, test systems are usually used by trained 
professionals. Laboratories that are certified under CLIA and that meet 
the regulatory requirements under CLIA to perform high complexity 
testing employ trained laboratorians to ``run'' test systems, and CLIA 
is the statutory scheme that governs that work, as discussed in more 
detail in section III.B. However, a laboratory's role in performing 
test systems does not change its obligations under the FD&C Act when it 
is manufacturing test systems. As previously noted, the FD&C Act does 
not exclude medical professionals who manufacture devices from its 
scope, and the mere fact that a device is manufactured in connection 
with a

[[Page 68019]]

medical service or procedure does not eliminate FDA's jurisdiction. 
(See United States v. Regenerative Sciences, 741 F.3d at 1319 
(``Notwithstanding appellants' attempt to characterize this case as an 
effort by the FDA to `restrict[ ] the use of an autologous stem cell 
procedure,' the focus of the FDA's regulation is on the Mixture [that 
is, the product that is created in connection with the procedure].'').)
    Although some commentators have argued that laboratory 
manufacturing is immune from regulation because it is within the 
``practice of medicine,'' that argument misconstrues the scope of the 
FD&C Act's ``practice of medicine'' provision. Section 1006 of the FD&C 
Act (21 U.S.C. 396) provides: ``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.'' Section 1006 carves out a specific 
zone of protected conduct that does not reach laboratory manufacturing 
of test systems. 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. (Judge Rotenberg 
Educ. Ctr., Inc. v. United States, 3 F.4th at 395 (emphases added); 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'').) The statutory 
provision 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.'' It does not apply to the manufacture of new test 
systems. The manufacture of a new device falls squarely within FDA's 
realm. Cf. United States v. Regenerative Sciences, 741 F.3d at 1320 
(``[W]hile the [FD&C Act] was not intended to regulate the practice of 
medicine, it was obviously intended to control the availability of 
drugs for prescribing by physicians.'') (quoting United States v. 
Evers, 643 F.2d 1043, 1048 (1981)). The fact that healthcare 
practitioners may prescribe a device, such as a test system, in the 
context of a healthcare practitioner-patient relationship does not mean 
that entities manufacturing that device can escape regulation. If that 
were the case, few devices would be regulated, because most are 
intended for use by healthcare practitioners in the context of a 
healthcare practitioner-patient relationship.
    Furthermore, contrary to what some commentators have suggested, 
CLIA did not repeal FDA's authority over IVDs manufactured by 
laboratories, which dates back to at least 1938. CLIA does not 
expressly repeal FDA's authority, nor was FDA's authority repealed by 
implication. ``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. 40). As explained in section 
III.B, CLIA puts a focus on the proficiency with which laboratories 
perform clinical testing, and the FD&C Act puts a focus on the 
manufacturing of test systems. 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. v. Sullivan, 791 
F. Supp. 1499, 1509 (D. Kan. 1992) (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).)
    In fact, Congress has affirmed that test systems manufactured by 
laboratories are devices under the FD&C Act. In the Protecting Access 
to Medicare Act of 2014 (PAMA) (Pub. L. 113-93), Congress listed 510(k) 
clearance or premarket approval under the FD&C Act as one of several 
bases for Medicare payment for an ``advanced diagnostic laboratory 
test,'' which is defined in part as a clinical diagnostic laboratory 
test ``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)'' (section 216(a) of PAMA). If such 
laboratory tests were not devices, the 510(k) clearance and premarket 
approval provisions would not apply to them and the inclusion of such 
provisions would be pointless and ineffectual. In addition, Congress 
indicated that clinical laboratory tests are devices in 2016 amendments 
to the FD&C Act. (21 U.S.C. 360j(o)(1)(D) (repeatedly referring to 
``clinical laboratory test or other device data'') (emphasis added).)
    The FD&C Act confers jurisdiction on FDA to regulate test systems, 
a point that has been codified in FDA's regulations for more than half 
a century. And nothing in the text, history, or purpose of the statute 
suggests that test systems manufactured by laboratories are excluded 
from that jurisdiction. This interpretation is not only the most 
straightforward reading of the statute, it is also the most reasonable: 
any other interpretation would create a bifurcated scheme in which 
systems that are functionally identical are treated differently under 
the law.
3. FDA's Jurisdiction Over IVDs Manufactured by Laboratories Is Not 
Altered by the FD&C Act's Provisions Related to Interstate Commerce and 
Commercial Distribution
    Modern Commerce Clause jurisprudence holds that Congress has 
``authority to regulate even purely local activities that are part of 
an economic `class of activities' that have a substantial effect on 
interstate commerce.'' (United States v. Regenerative Sciences, 741 
F.3d at 1320 (quoting Gonzales v. Raich, 545 U.S. 1, 17 (2005)).) Thus, 
few have disputed that Congress possesses the power to grant FDA 
authority to regulate even purely intrastate activities. However, some 
commentators have asserted that language in the FD&C Act referencing 
``interstate commerce'' and ``commercial distribution'' precludes FDA 
from regulating IVDs that are designed, manufactured, and used in a 
single laboratory. As discussed below, these assertions lack merit.
    a. Interstate commerce. There is no overarching requirement in the 
FD&C Act that FDA-regulated articles have a particular nexus with 
interstate commerce. Interstate commerce is not a prerequisite to FDA 
jurisdiction (beyond the constitutional minimum). Rather, under the 
FD&C Act, a limited number of provisions include specific interstate 
commerce ``elements,'' and thus require a particular connection with 
interstate commerce in order for those provisions to apply. For 
example, certain of the FD&C Act's ``prohibited acts'' contain an 
interstate commerce element that must be satisfied before the 
government can bring an enforcement action under those

[[Page 68020]]

provisions (e.g., 21 U.S.C. 331(a), (c), (d), and (k)). But relatively 
few of the FD&C Act's device provisions 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); id. 331(p) (prohibiting the failure to register a device 
establishment without reference to interstate commerce); id. 331(q)(1) 
(prohibiting the failure to comply with device investigational-use 
requirements without reference to interstate commerce); id. 331(fff)(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); see generally United States v. Walsh, 331 U.S. 432, 434-36 
(1947) (finding no interstate commerce element to 21 U.S.C. 331(h), 
which prohibits false guaranties) (``[21 U.S.C. 331(a)] is directed to 
illegal interstate shipments, while [21 U.S.C. 331(h)] is directed to 
the giving of false guaranties'').) 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. For 
devices, the FD&C Act imposes obligations even where there is no 
interstate commerce element and likewise gives FDA authority to take 
action when there is a violation of those obligations. Thus, FDA does 
not, for example, somehow lose jurisdiction if a particular device has 
not been ``introduced'' into interstate commerce.
    In fact, Congress intentionally revised a provision of the FD&C Act 
to ensure that FDA could take action against devices without satisfying 
any particular interstate commerce element. In the MDA, Congress 
revised the seizure provisions in section 304 of the FD&C Act to 
``permit seizure of devices without reference to interstate commerce'' 
because the previous interstate commerce requirement ``ha[d] been a 
burden to the effective enforcement of existing authorities'' and 
``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.'' (H.R. Rep. 94-853 at 15; 
see 21 U.S.C. 334(a)(2).) In other words, Congress recognized that the 
interstate commerce element in this provision did not advance the goals 
of the MDA. Consistent with that view, the FD&C Act grants FDA wide-
ranging authority over devices, including IVDs, and that general 
authority does not turn on a connection with interstate commerce above 
the constitutional minimum.
    In addition, 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 applies even when a problematic device 
has not been introduced in 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 is satisfied if the 
components used in manufacturing the product have traveled in 
interstate commerce. (See United States v. Regenerative Sciences, 741 
F.3d at 1320-21 (upholding FDA enforcement action under 331(k) because 
a drug component had traveled in interstate commerce); Baker v. United 
States, 932 F.2d 813, 815 (9th Cir. 1991); United States v. Dianovin 
Pharm., Inc., 475 F.2d 100, 102 (1st Cir. 1973).) At least some 
components of test systems, such as general purpose reagents, ASRs, 
instruments, and collection devices, are usually shipped in interstate 
commerce even if the system itself is designed, manufactured, and used 
solely in the laboratory (i.e., intrastate). And section 709 of the 
FD&C Act (21 U.S.C. 379a) establishes a presumption of interstate 
commerce in 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.'').
    Some commentators have cited the interstate commerce element in 
section 510(k) of the FD&C Act to raise questions about FDA's authority 
over LDTs. Section 510(k) provides 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. Under this line of argument, laboratories that 
design, manufacture, and use an IVD in a single laboratory are not 
proposing to introduce their IVD into interstate commerce, and 
therefore section 510(k) does not apply to them. That argument, 
however, does not lead to the conclusion that FDA lacks jurisdiction 
over LDTs or that none of the FD&C Act requirements apply to LDTs. It 
would mean only that section 510(k) does not apply. And if accepted, 
the only practical consequence of that assertion would be that affected 
laboratories are subject to more burdensome requirements under the FD&C 
Act.
    In particular, if section 510(k) is construed to mean that such 
IVDs are not eligible for the premarket notification pathway, that 
would only mean that those IVDs (unless they are 510(k)-exempt, in 
which case section 510(k) would not apply anyway, or are for 
investigational use) would be forced into the more rigorous review 
pathways of premarket approval or authorization through the De Novo 
pathway. That is because under section 513(f)(l) of the FD&C Act, a 
postamendments device, i.e., a device that was ``not introduced or 
delivered for introduction into interstate commerce for commercial 
distribution before [May 28, 1976],'' is a class III device by 
operation of law (21 U.S.C. 360c(f)(1)). If such a device cannot be 
found to be substantially equivalent through the premarket notification 
pathway, it must either have an approved PMA (21 U.S.C. 360e(a)), or be 
reclassified and gain authorization through a pathway such as the De 
Novo process (21 U.S.C. 360c(f)(2)(A)(ii)). Thus, under this theory, 
laboratories would not escape FDA regulation--they would face heavier 
regulation. However, because section 510(k) does not, in fact, preclude 
regulated entities from submitting premarket notifications even 
assuming their devices are not introduced into interstate commerce, and 
because laboratories have every incentive to take the less burdensome 
path to market of 510(k) notification, the 510(k) pathway should play 
the same role in device reclassification (21 U.S.C. 360c(f)) for IVDs 
offered as LDTs as for any other device. 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.
    b. Commercial distribution. The phrase ``for commercial 
distribution'' also appears in various device provisions of the FD&C 
Act, and some commentators have asserted that this phrase, too, signals 
that FDA lacks authority over LDTs. For example, they point to the 
510(k) premarket notification requirement, which is triggered when a 
person who is required to register ``proposes to begin the introduction 
or delivery for introduction into interstate commerce for commercial 
distribution of a device intended for

[[Page 68021]]

human use'' (21 U.S.C. 360(k)). As with ``interstate commerce,'' the 
presence of this phrase in that provision and certain other specific 
device provisions does not bear on the Agency's overall jurisdiction. 
Furthermore, LDTs are for commercial distribution, so the presence of 
the phrase does not change the operation of those provisions with 
respect to these IVDs.
    Under our longstanding, judicially endorsed interpretation, 
``commercial distribution'' does not require the physical transfer of 
an object, as some commentators have argued. Instead, the legislative 
history, FDA's near-contemporaneous regulation, and at least one 
judicial decision reflect that the phrase ``commercial distribution'' 
means ``on the market.'' A House Report issued 3 months before 
enactment of the MDA contains an unusually clear statement of the 
intended meaning of the phrase: ```Commercial distribution' is the 
functional equivalent of the popular phrase `on the market.' '' (H.R. 
Rep. No. 94-853 at 36) FDA's regulations implementing the registration, 
listing, and 510(k) provisions, which were finalized in 1977 (soon 
after enactment of the MDA), similarly define commercial distribution 
as ``any distribution of a device intended for human use which is held 
or offered for sale.'' (21 CFR 807.3(b)) In the preambles to the 
proposed and final rule, FDA equated the term with the phrase ``on the 
market'' (41 FR 37458 at 37459 (September 3, 1976); 42 FR 42520 at 
42524 (August 23, 1977)). A court has also endorsed this interpretation 
of the term (United States v. An Article of Device Consisting of 1,217 
Cardboard Boxes, 607 F. Supp. 990, 994-95 (W.D. Mich. 1985) (giving 
deference to FDA's reasonable interpretation of ``commercial 
distribution'' to mean, ``in its popular sense, `on the market' '')). 
These sources show that the term does not relate to physical movement, 
and because IVDs manufactured by laboratories (including LDTs) 
generally are ``on the market,'' they are for commercial distribution.

VI. Description of the Proposed Enforcement Policy

    Based on the considerations set forth in this preamble, FDA is 
proposing to end the general enforcement discretion approach for LDTs. 
However, FDA also recognizes that many IVDs manufactured by 
laboratories are currently being marketed as LDTs, and that a sudden 
change could negatively affect the public, including patients and 
industry. In particular, FDA understands that the healthcare community 
and patients have been using these IVDs, and that coming into 
compliance will take time for manufacturers. FDA also recognizes that 
we should consider Agency resources. For additional information 
regarding the estimated costs associated with this rulemaking, see the 
Preliminary Economic Analysis of Impacts (Ref. 34).
    To achieve greater oversight in a manner that accounts for the 
various considerations, FDA is proposing to gradually end its general 
enforcement discretion approach in stages, as described below 
(hereinafter ``the phaseout policy''). FDA's intent is that, following 
a 4-year phaseout period, IVDs offered as LDTs generally would be 
expected to meet applicable requirements.
    Although FDA is proposing to gradually end 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 continued enforcement discretion approach for 
certain IVDs discussed below, FDA retains discretion to pursue 
enforcement action at any time against violative IVDs when appropriate.
    Moreover, FDA has adopted and intends to continue adopting 
enforcement discretion policies for certain types of IVDs in certain 
circumstances, as appropriate. For example, FDA issued guidance 
documents with enforcement discretion policies for certain COVID-19 and 
Mpox tests at the beginning of each declared emergency (as described 
further below), and intends to issue a draft guidance with an 
enforcement policy for IVDs for emerging outbreaks offered prior to FDA 
review to address the immediate public health need. FDA will seek 
public comment on such draft guidance in accordance with good guidance 
practices (see 21 CFR 10.115).
    With this notice of proposed rulemaking, FDA seeks public comment 
on whether specific enforcement discretion policies would be 
appropriate for IVDs offered as LDTs for other public health scenarios. 
If so, please provide a description of those scenarios, an explanation 
of why enforcement discretion policies with respect to those scenarios 
would be appropriate, and any relevant evidence to support such 
policies. FDA would also appreciate public comment on what, if any, 
unintended consequences may result from the proposed phaseout policy to 
certain patient populations (for example, Medicare beneficiaries, rural 
populations, etc.) and what steps could be taken to mitigate those 
consequences.
    FDA's proposed phaseout policy, including the scope and phaseout 
timeline, is set forth below.

A. Scope

    While FDA's general enforcement discretion approach has been 
focused on LDTs, FDA is proposing a broader scope for the phaseout 
policy. Specifically, FDA is proposing to apply 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,\15\ 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.\16\ 
Throughout this preamble, these IVDs are referred to as ``IVDs offered 
as LDTs.'' FDA is proposing 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 they do not fit what FDA generally considers to 
be an LDT. As previously discussed, FDA has made a preliminary 
determination to structure the phaseout in a way that avoids undue 
disruption to the testing market. This is important even for certain 
IVDs currently on the market that do not fall within the scope of FDA's 
general enforcement discretion approach.
---------------------------------------------------------------------------

    \15\ 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. 32, 40, 
and 54).
    \16\ 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.
---------------------------------------------------------------------------

    Although FDA is proposing this broader scope for the phaseout 
policy, it does not intend to sweep in certain tests that were excluded 
from the general enforcement discretion approach, as reflected in 
compliance patterns, multiple public FDA actions and communications, or 
both. These tests are:
    1. Tests that are intended as blood donor screening or human cells, 
tissues, and cellular and tissue-based products (HCT/Ps) donor 
screening tests required for infectious disease testing under 21 CFR 
610.40 and 1271.80(c), respectively, or for determination of

[[Page 68022]]

blood group and Rh factors required under 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 licensed, approved, or cleared 
by FDA for such use. Blood and HCT/P establishments must register with 
FDA and are subject to FDA inspection (see 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. Based on FDA experience, establishments have been 
generally complying with these requirements (see, e.g., Refs. 66 and 
67).
    2. 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. 51 and 52). In addition, 
consistent with the Government Accountability Office's 2022 
recommendation that ``FDA should develop a policy for the use of 
enforcement discretion regarding unauthorized tests in future public 
health emergencies,'' FDA intends to issue guidance on factors to 
consider in adopting such enforcement discretion policies (Ref. 68). 
FDA has communicated its expectations regarding tests for emergency use 
in guidance and elsewhere, including ``It has come to our attention'' 
letters posted on FDA's website and other public communications (see, 
e.g., Refs. 51 to 54, 69, and 70).
    3. 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. 48, 55, and 71 to 75). 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, and make decisions (such as a decision to stop 
medication) without this expert intermediary, there is a heightened 
need for FDA oversight.
    For these categories of tests, FDA has generally expected 
applicable requirements to be met, and we are not proposing to change 
that approach.
    FDA notes that the manufacturing of test components outside of a 
laboratory--for example, when the same entity owns both the laboratory 
and a manufacturing facility separate from the laboratory--does not 
fall within FDA's general enforcement discretion approach. FDA's 
approach has long been specific to laboratory development (e.g., 61 FR 
10484 (``in-house developed tests have not been actively regulated by 
the Agency'') (emphasis added); Ref. 48 (describing an LDT as an IVD 
that is ``designed, manufactured, and used within a single 
laboratory''). The proposed phaseout policy would not change FDA's 
longstanding expectation that IVD manufacturing activities occurring 
outside of a CLIA-certified laboratory comply with applicable device 
requirements.
    In addition, for certain categories of tests manufactured by 
laboratories, FDA is proposing to continue to apply the current general 
enforcement discretion approach going forward. 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: 
use of manual techniques (without automation) performed by laboratory 
personnel with specialized expertise; use of components legally 
marketed for clinical use; and 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.A). 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 made a preliminary determination 
that the risks are sufficiently mitigated such that FDA's general 
enforcement discretion approach for LDTs should continue to apply. 
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.
    FDA is also proposing to continue to apply the general enforcement 
discretion approach to Human Leukocyte Antigen (HLA) tests that are 
designed, manufactured, and used in 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. FDA has made a preliminary 
determination that HLA LDTs for transplantation used in 
histocompatibility laboratories that meet the regulatory requirements 
under CLIA to perform high complexity testing, when used in connection 
with organ, stem cell, and tissue transplantation for certain purposes 
as described in this paragraph, are unique in that they are generally 
developed, and the testing is generally performed, in urgent, life-
saving situations for the patient. 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. 
Further, these tests are often individualized within each medical 
facility, for example, they include reagents that reflect local HLA 
polymorphisms and patient demographics. Note that the general 
enforcement discretion approach does not apply to HLA tests used for 
blood transfusion as such tests are highly standardized across 
institutions; FDA intends to continue to enforce applicable 
requirements for HLA tests used for blood transfusion.
    FDA also intends to maintain its longstanding enforcement 
discretion approach for tests intended solely for forensic (law 
enforcement) purposes. This approach has been in place for over 20 
years and 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

[[Page 68023]]

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. We seek comment on any implications of 
continued enforcement discretion with regard to LDTs used for law 
enforcement purposes and any factors that FDA should consider--
particularly as it relates to civil rights and equity--related to the 
scientific validity and accuracy of these tests.
    In addition, tests exclusively used 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. These tests would not be affected by the phaseout policy. 
The results of these tests are generally used for trending on a 
population basis. Public health authorities also have access to test 
results from non-surveillance tests that are FDA approved, cleared, or 
authorized and that are reported under State reporting laws for 
infectious and other diseases. In addition, during a public health 
emergency, if there was a 564 declaration (as there was for past public 
health emergencies), FDA could require test result reporting to public 
health authorities under emergency use authorizations, as appropriate.
    In 2017, FDA indicated support for less oversight of other 
categories of tests, such as low-risk tests (class I devices), tests 
currently on the market, and tests for rare diseases. However, FDA has 
accumulated information in the intervening years that suggests we 
should treat these categories of tests similarly to other FDA-regulated 
tests. For example, as discussed above in section III.B, FDA has gained 
additional information showing that there is a high variability in the 
performance of IVDs offered as LDTs that are currently on the market, 
including in circumstances where the test technology is relatively 
simple and well-understood, where the tests are for rare diseases, and 
where the tests are low risk. Among other things, FDA's recent 
experience with tests for COVID-19 suggests that many tests 
manufactured by laboratories are not appropriately validated. 
Compliance with premarket review requirements (when applicable), QS 
requirements, and registration and listing requirements would help 
assure that these IVDs work as intended, enable FDA to keep track of 
IVDs offered as LDTs (and, for example, help FDA locate IVDs that are 
raising concerns or independently evaluate the risk status of marketed 
IVDs), assist with FDA's inspection and planning efforts, and make 
information available to patients and healthcare providers that may 
inform the selection of particular IVDs for use. Therefore, FDA is now 
proposing to end the general enforcement discretion approach, via a 
phaseout approach, with respect to premarket review requirements (as 
applicable), QS requirements, and registration and listing requirements 
for these tests, in addition to medical device reporting (MDR) 
requirements (i.e., reporting of adverse events), correction and 
removal reporting requirements, and other requirements applicable to 
such tests. Based on the information available at this time, FDA has 
made a preliminary determination that this proposal appropriately 
balances the relevant considerations with respect to these tests, 
including currently marketed IVDs offered as LDTs.
    However, FDA expects that some stakeholders will suggest that FDA 
continue to maintain the current general enforcement discretion 
approach with respect to premarket review and some or all QS 
requirements for currently marketed LDTs or a subset of currently 
marketed LDTs (i.e., what some previously referred to as 
``grandfathering''). To the extent commenters suggest such an approach 
for FDA's consideration, FDA requests information to support such an 
approach, including the following:
     Given the information in the ``Need for the Rule'' section 
of this preamble in particular, what would be the public health 
rationale for generally exercising enforcement discretion with respect 
to premarket review and some or all QS requirements, for LDTs that are 
being offered as of the date of issuance of this proposed rule and are 
not changed with respect to indications for use or performance after 
that date? Please provide data to support such an approach. Also, if 
you think there are steps that might help support such an approach, 
including ideas that might help to address the public health concerns 
discussed in the ``Need for the Rule'' section, please describe them, 
and include a rationale and any supporting evidence.
     If commenters suggest maintaining the general enforcement 
discretion approach with respect to premarket review and QS 
requirements for a subset of LDTs (e.g., low and moderate risk LDTs) 
currently on the market that are being offered as of the date of 
issuance of this proposed rule and are not changed with respect to 
indications for use or performance after that date, what would be the 
public health rationale to support such an approach? Please provide any 
data supporting such an approach. Also, if you think there are steps 
that might help support such an approach, including ideas that might 
help to address the public health concerns discussed in the ``Need for 
the Rule'' section, please describe them and include a rationale and 
any supporting evidence.
    FDA recognizes that the phaseout of the general enforcement 
discretion approach described in this section may have a relatively 
greater impact on small laboratories. Therefore, FDA seeks comment on 
the following:
     Is there a public health rationale to have a longer 
phaseout period for IVDs offered as LDTs by laboratories with annual 
receipts below a certain threshold (e.g., $150,000) (see Table 43 in 
the Preliminary Economic Analysis of Impacts (Ref. 34))? If so, please 
provide relevant data and comment specifically on an alternative 
recommended timeline.
    In addition, FDA is aware that some AMCs have claimed that their 
laboratories operate under unique circumstances (such as being 
integrated into direct patient care) and therefore their tests should 
be treated differently than tests manufactured by other laboratories. 
Although FDA is not aware of an established definition of an AMC 
laboratory, one possible description is: a laboratory for which a 
certificate is in effect under CLIA and that meets the requirements 
under CLIA to perform tests of high-complexity; that is part of an 
accredited public or nonprofit private AMC that has a medical residency 
training program or fellowship program related to test development, 
application, and interpretation; and that is integrated into the direct 
medical care for a patient, including specimen collection, testing, 
interaction with the treating provider, and, as appropriate, patient 
treatment based on the test, all at the same physical location. FDA 
seeks comments on the following:
     What are the characteristics of AMC laboratories? Do the 
characteristics included above accurately describe

[[Page 68024]]

AMC laboratories and in fact distinguish them from other laboratories?
     Should FDA continue the general enforcement discretion 
approach with respect to any requirements, such as premarket review 
requirements, for tests manufactured by AMC laboratories?
     If FDA should continue the general enforcement discretion 
approach with respect to any requirements, such as premarket review 
requirements, for tests manufactured by AMC laboratories, are there any 
additional considerations that should be taken into account with 
respect to this approach, for example, whether an FDA cleared or 
approved test is available for the same intended use as the test 
manufactured by an AMC laboratory? Please provide a rationale and other 
information (e.g., data) to support any additional considerations.
     If FDA should have a different policy for AMC 
laboratories, what would be the public health rationale to support such 
a policy? For example, if integration of an AMC laboratory into direct 
patient care is included as a basis for a different policy, please 
include a public health rationale when explaining why and how such 
integration supports the different policy, and how integration could 
ensure that there is a reasonable assurance of IVD safety and 
effectiveness.
     If FDA should have a different policy for AMC 
laboratories, is there evidence to support such a policy?
    FDA also is interested in and seeks comment on leveraging programs 
such as the New York State Department of Health Clinical Laboratory 
Evaluation Program (NYSDOH CLEP) or those within the Veterans Health 
Administration (VHA), as appropriate. In particular, FDA requests 
comment on whether it may 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. If FDA should continue to exercise enforcement discretion 
under these circumstances:
     What specific characteristics of and activities within 
these programs justify such an approach?
     Should the scope of such a policy be more limited for each 
program in question? For example, should FDA continue enforcement 
discretion for premarket review requirements and intend to enforce 
other requirements, such as reporting adverse events?
     Are there any additional considerations that should be 
taken into account?
    Please provide a rationale and other information (e.g., data) to 
support any suggestions.

B. Stages

    As previously discussed, FDA is proposing to gradually phase out 
its current general enforcement discretion approach so that most IVDs 
offered as LDTs would generally fall under the same enforcement 
approach as other IVDs. In developing the proposed phaseout policy, FDA 
has considered a number of factors, including the public health 
importance of better assuring the safety and effectiveness of IVDs 
offered as LDTs, the desire to avoid undue disruption to the testing 
market, the time it may take for laboratories to come into compliance 
with FDA requirements, the need for adequate resources to implement the 
phaseout policy in a manner that does not undermine reasonable 
expectations with regards to premarket review timing (per the Medical 
Device User Fee Amendments (MDUFA) V agreement), and the benefits of a 
relatively simple policy that can be easily understood and implemented. 
Keeping these factors in mind, FDA has structured the phaseout policy 
to contain five key stages:
     Stage 1: End the general enforcement discretion approach 
with respect to MDR requirements and correction and removal reporting 
requirements 1 year after FDA publishes a final phaseout policy, which 
FDA intends to issue in the preamble of the final rule.
     Stage 2: End the general enforcement discretion approach 
with respect to requirements other than MDR, correction and removal 
reporting, QS, and premarket review requirements 2 years after FDA 
publishes a final phaseout policy.
     Stage 3: End the general enforcement discretion approach 
with respect to QS requirements 3 years after FDA publishes a final 
phaseout policy.
     Stage 4: End the general enforcement discretion approach 
with respect to premarket review requirements for high-risk IVDs 3\1/2\ 
years after FDA publishes a final phaseout policy, but not before 
October 1, 2027.
     Stage 5: End the general enforcement discretion approach 
with respect to premarket review requirements for moderate risk and low 
risk IVDs (that require premarket submissions) 4 years after FDA 
publishes a final phaseout policy, but not before April 1, 2028.
    Each of these stages is discussed in further detail below. For each 
stage, FDA is proposing a period of time for laboratories to come into 
compliance before FDA intends to end the general enforcement discretion 
approach. FDA encourages laboratory manufacturers to begin early and 
work toward compliance with requirements sooner than the end of the 
specified timeframes. 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.
    1. Stage 1: End the general enforcement discretion approach with 
respect to MDR requirements and correction and removal reporting 
requirements 1 year after FDA publishes a final phaseout policy.
    FDA has structured the phaseout policy to obtain information about 
potentially harmful IVDs offered as LDTs as soon as feasible. As 
detailed elsewhere in this preamble, FDA is concerned that some of the 
IVDs offered as LDTs may be posing risks to patients. Therefore, FDA is 
prioritizing the phaseout of the general enforcement discretion 
approach for requirements that would help FDA identify and monitor 
significant issues with IVDs offered as LDTs, consistent with other 
considerations described in this proposed policy.
    Enforcement of the MDR requirements under 21 U.S.C. 360i(a) through 
(c) and 21 CFR part 803, in particular, would 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 preliminary determination that 
gathering this information 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 analytical 
and clinical validity 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 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. Because FDA intends 
for the phaseout of the general enforcement discretion approach with 
respect to

[[Page 68025]]

correction and removal reporting requirements to occur before phaseout 
of the general enforcement discretion approach with respect to 
registration and listing requirements, FDA intends to exercise 
enforcement discretion, such that it generally does not intend to 
enforce, the requirement to use the establishment registration number 
on such reports (21 CFR 806.10) when laboratories use their CLIA 
certificate number instead prior to registering.
    FDA's proposal to phase out enforcement discretion for MDR 
requirements within 1 year after finalization of the policy is informed 
by comments FDA received in response to the draft guidance documents 
that FDA issued in 2014 proposing to implement an oversight framework 
for IVDs offered as LDTs. In 2014, FDA proposed a 6-month timeline for 
laboratory compliance with MDR requirements (Ref. 48), and we received 
comments suggesting that a longer period may be appropriate for the 
establishment of a system to identify, review, and report adverse 
events. Based in part on those comments, FDA is now proposing a 1-year 
time period for laboratories to come into compliance with the MDR 
requirements. In conjunction with the phaseout of the general 
enforcement discretion approach with respect to the MDR requirements, 
FDA is also proposing to end the general enforcement discretion 
approach with respect to the requirements of part 806, concerning 
reports of corrections and removals. Because MDRs frequently are a 
basis for corrections and removals, FDA views these requirements as 
working together to provide information to FDA about issues with device 
performance or quality. We anticipate that this 1-year time period is 
adequate, particularly given that laboratories should already have some 
processes in place for detecting problems with their IVDs to comply 
with CLIA regulations.
    2. Stage 2: End the general enforcement discretion approach with 
respect to requirements not covered during other stages of the phaseout 
policy 2 years after FDA publishes a final phaseout policy.
    FDA is proposing to end the general enforcement discretion approach 
for requirements besides MDR, correction and removal reporting, QS, and 
premarket review requirements 2 years after the final policy is 
published. These other requirements include registration and listing 
requirements under 21 U.S.C. 360 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. 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.\17\ We are 
therefore including these requirements in the phaseout policy.
---------------------------------------------------------------------------

    \17\ 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. 48).
---------------------------------------------------------------------------

    FDA recognizes that this proposal is different from FDA's prior 
statements in the 2017 Discussion Paper regarding oversight of IVDs 
manufactured by laboratories with respect to certain requirements, for 
which the timing of FDA's expectations for compliance generally 
depended on the type of premarket review applicable to the device. 
However, upon review, FDA anticipates that it would better serve the 
public health and be simpler to phase out the general enforcement 
discretion approach for these requirements at the 2-year mark. For 
example, under this timeline, laboratories could work toward compliance 
with the stage 2 requirements without necessarily determining the risk 
category of their IVDs until later stages of the proposed phaseout 
policy. Another advantage of this timeline is that FDA would obtain 
registration and listing information before the enforcement discretion 
phaseout date for premarket review requirements, which could give the 
Agency an initial understanding of the universe of IVDs offered as LDTs 
to facilitate premarket review of those IVDs. Based on its experience, 
FDA anticipates that 2 years is adequate time to come into compliance 
with the various requirements.
    3. Stage 3: End the general enforcement discretion approach with 
respect to QS requirements 3 years after FDA publishes a final phaseout 
policy.
    At the 3-year mark, FDA would expect compliance with the device 
CGMP requirements of the QS requirements under 21 U.S.C. 360j(f) and 
part 820 (21 CFR part 820). However, for IVDs for which all 
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, FDA would expect compliance at the 3-
year mark with some, but not all, of the QS requirements. 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 manufacturing activities 
regulated by FDA. For FDA to effectively leverage the CLIA assurances, 
this proposed approach would apply only when all manufacturing 
activities occur within a single laboratory and the IVD is not 
distributed outside that laboratory. However, even in the context of 
this approach, there are certain QS requirements for which CLIA 
regulations do not provide the assurances that FDA requirements would 
provide. These requirements include design controls under 21 CFR 
820.30; purchasing controls (including supplier controls) under 21 CFR 
820.50; acceptance activities (receiving, in-process, and finished 
device acceptance) under 21 CFR 820.80 and 21 CFR 820.86; corrective 
and preventative actions (CAPA) under 21 CFR 820.100; and records 
requirements under part 820, subpart M. Because CLIA does not provide 
assurances relevant to these requirements, FDA is proposing to end the 
general enforcement discretion approach for these specific requirements 
for IVDs for which all manufacturing activities occur within a single 
CLIA-certified laboratory that meets the regulatory requirements to 
perform high complexity testing, and which are not distributed outside 
that laboratory, 3 years after finalizing this policy. For all other 
IVDs offered as LDTs and subject to this phaseout policy, FDA is 
proposing to end the general enforcement discretion approach for all QS 
requirements 3 years after finalizing this policy.
    Based on its experience, FDA anticipates that 3 years is adequate 
time for laboratories to come into compliance with QS requirements. In 
addition, based on the discussion above regarding concerns with the 
quality and validation of IVDs offered as LDTs, FDA has made a 
preliminary determination that phasing out the general enforcement 
discretion approach for QS requirements later than 3 years would not be 
in the best interest of the public health. Compliance with QS 
requirements is critical to the quality and validity of IVDs offered as 
LDTs.

[[Page 68026]]

For example, under the design controls of the QS requirements, 
laboratories would, among other things, generally have better 
procedures for validating the design of their tests, which would help 
to ensure that they are analytically and clinically valid (see Ref. 
76).
    FDA also notes that on February 23, 2022, FDA proposed to amend the 
device QS regulation, part 820, to align more closely with 
international consensus standards for devices (87 FR 10119). As stated 
in that proposed rule, the requirements, if finalized, would be 
substantially similar to the requirements of the current part 820, 
providing a similar level of assurance in a firm's quality management 
system, and FDA intends for this phaseout policy to apply with respect 
to any regulations promulgated through that rulemaking.
    FDA intends to finalize amendments to the QS regulation 
expeditiously, such that the amended QS requirements would be in effect 
before the proposed beginning of stage 3. Upon the start of stage 3, or 
if the laboratory complies with QS requirements prior to the start of 
stage 3, FDA would expect compliance with the QS requirements that are 
in effect at that time. For further information on the QS requirements 
that would be established pursuant to the amendments to the QS 
regulation, if finalized as proposed, please refer to the proposed 
codified at 87 FR 10119 at 10133 and 10134. Notably, the requirements 
relating to design controls, purchasing controls, acceptance 
activities, CAPA, and records requirements are set forth in the 
following ISO 13485 clauses as modified by the proposed 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 8.2.5, Subclause 8.2.6, 
and Subclause 8.3.
    In addition, 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 21 CFR 820.1).
    4. Stage 4: End the general enforcement discretion approach with 
respect to premarket review requirements for high-risk IVDs 3\1/2\ 
years after FDA publishes a final phaseout policy, but not before 
October 1, 2027.
    FDA proposes that the phaseout date for the general enforcement 
discretion approach with respect to premarket review requirements for 
high-risk IVDs offered as LDTs (IVDs that may be eligible for 
classification into class III) should occur 3\1/2\ years from the time 
that FDA issues a final phaseout policy. The premarket review 
requirements are set forth in 21 U.S.C. 360e and 21 CFR part 814. FDA 
is proposing this time period because it is mindful that phasing out 
the general enforcement discretion approach on a timeline that is too 
short could cause undue disruption in the testing market. Among other 
things, we anticipate that 3\1/2\ years would provide sufficient notice 
and opportunity for laboratories manufacturing IVDs to plan for and 
prepare PMAs and would appropriately account for any reliance 
interests. We note that 3\1/2\ years is a longer time period than was 
discussed in either the 2014 draft guidance documents or the 2017 
Discussion Paper for the phaseout of the general enforcement discretion 
approach for premarket review requirements.
    This timeline is also intended to align the phaseout date 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 would provide an opportunity for industry 
participation in negotiations regarding the next user fee cycle with 
the knowledge that laboratory manufacturers would be expected to comply 
with premarket review requirements. (Although a trade association 
representing laboratories previously has participated in MDUFA 
negotiations, the prior negotiations have not incorporated similar 
expectations regarding laboratory compliance with premarket 
requirements.) Thus, we propose that this amount of time is appropriate 
to foster stability and consistency in the marketplace for the current 
MDUFA cycle, and would 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 would 
work with FDA to determine whether PMAs should be submitted for their 
IVDs.
    Under FDA's proposed policy, FDA generally would not intend to 
enforce against IVDs offered as LDTs after a PMA has been submitted 
(within the 3\1/2\-year timeframe) until FDA completes its review of 
the application. 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.
    Finally, FDA recognizes that the 2017 Discussion Paper described a 
possible premarket-review approach specific to LDTs for unmet needs. 
FDA has not included such an approach in this proposed policy because 
we anticipate that the 3\1/2\-year timeframe should be sufficient for 
laboratories to meet premarket review requirements for each of their 
marketed IVDs, as applicable, including IVDs for unmet needs. FDA also 
anticipates that programs currently in place may facilitate the 
development and premarket authorization of IVDs for unmet needs. These 
programs include the Humanitarian Use Devices (HUD)/Humanitarian Device 
Exemption (HDE) program,\18\ which, among other things, provides an 
exemption from the requirement to establish a reasonable assurance of 
effectiveness for devices intended for use in the treatment or 
diagnosis of rare diseases or conditions (21 U.S.C. 360j(m); 21 CFR 
part 814, subpart H), and the Breakthrough Devices program, which 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).
---------------------------------------------------------------------------

    \18\ Under the proposed phaseout policy, laboratories that 
intend to submit an HDE application should do so within the same 
3\1/2\-year timeframe provided for submission of PMAs. As in the 
case of PMAs, under FDA's proposed policy, FDA generally would not 
intend to enforce against IVDs after an HDE application has been 
submitted (within the 3\1/2\-year timeframe) until FDA completes its 
review of the application.

    5. Stage 5: End the general enforcement discretion approach with 
respect to premarket review requirements for moderate risk and low 
risk IVDs (that require premarket submissions) 4 years after FDA 
---------------------------------------------------------------------------
publishes a final phaseout policy, but not before April 1, 2028.

    FDA is proposing to end 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 after FDA publishes the final phaseout policy. These premarket 
submissions include 510(k) submissions, the requirements for which are 
set forth at 21 U.S.C. 360(k),

[[Page 68027]]

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 intends this stage to begin no earlier than April 1, 2028. 
FDA's reasons for proposing this time period to phase out the general 
enforcement discretion approach with respect to premarket review 
requirements for moderate risk and low risk IVDs offered as LDTs are 
similar to those for the ``stage 4'' time period, except that FDA has 
lengthened the time period by 6 months in order to prioritize the 
review of applications for high-risk IVDs offered as LDTs (subject to 
premarket approval requirements), so that FDA can focus first on IVDs 
for which the consequences of a false result are most significant. FDA 
also recognizes that a greater number of IVDs are subject to the 510(k) 
requirements, as compared with premarket approval requirements, so a 
longer period of time for laboratories to come into compliance with 
these requirements may be appropriate, particularly for laboratories 
with large test menus.
    FDA generally would not intend to enforce against IVDs offered as 
LDTs after a 510(k) or De Novo request has been submitted (within the 
4-year timeframe) until FDA completes its review of the submission.
    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. 
77). We anticipate interest in the Third Party review program among 
test manufacturers, as well as potential new Third Party review 
organizations. In particular, FDA is aware of certain CLIA 
accreditation organizations that may be interested in potentially 
becoming Third Party reviewers under FDA's program, and to the extent 
laboratories are already familiar with these organizations, 
laboratories may be 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.

VII. Proposed Effective Date

    The Agency proposes that any final rule based on this proposed rule 
will become effective 60 days after the date of publication of the 
final rule in the Federal Register.

VIII. Preliminary Economic Analysis of Impacts

    We have examined the impacts of the proposed rule under Executive 
Order 12866, Executive Order 13563, Executive Order 14094, the 
Regulatory Flexibility Act (5 U.S.C. 601-612), and the Unfunded 
Mandates Reform Act of 1995 (Pub. L. 104-4).
    Executive Orders 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 Executive Order 12866 Section 3(f)(1) (as amended 
by Executive Order 14094) if they ``have an annual effect on the 
economy of $200 million or more (adjusted every 3 years by the 
Administrator of [the Office of Information and Regulatory Affairs 
(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 proposed rule is a significant regulatory action 
under Executive Order 12866 Section 3(f)(1).
    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 proposed rule is 
likely to impose a substantial burden on the affected small entities, 
we find that the proposed 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 us to prepare a 
written statement that includes estimates of anticipated impacts, 
before proposing ``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 proposed rule would result in an expenditure in at least 
one year that meets or exceeds this amount.
    This proposed rule, if finalized, would amend 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 
VI, FDA intends to phase out its general enforcement discretion 
approach for LDTs so that IVDs manufactured by a laboratory would 
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 would include a reduction in 
healthcare costs associated with unsafe or ineffective tests, including 
tests promoted with false or misleading claims, and from therapeutic 
decisions based on the results of those tests. Quantified benefits are 
the annualized sum of both health and non-health benefits. Unquantified 
benefits would include the reduction in costs from lawsuits and 
reduction in costs to healthcare systems.
    Table 1 summarizes the annualized benefits, costs, and transfers of 
the proposed rule. At a 7 percent discount rate, 20-year annualized 
benefits range from $2.67 billion to $86.01 billion, with a primary 
estimate of $31.41 billion per year. At a 3 percent discount rate, 20-
year annualized benefits range from $1.81 billion to $61.41 billion, 
with a primary estimate of $22.33 billion per year. At a 7 percent 
discount rate, 20-year annualized costs range from about $2.52 billion 
to $19.45 billion, with a primary estimate of $5.87 billion per year. 
At a 3 percent discount rate, annualized costs range from about $2.39 
billion to $18.55 billion, with a primary estimate of $5.60 billion per 
year. At a 7 percent discount rate, 20-year annualized transfers range 
from $100 million to $452 million, with a primary estimate of $226 
million per year. At a 3 percent discount rate, 20-year annualized 
transfers range from $121 million to $538 million, with a primary 
estimate of $269 million per year.

[[Page 68028]]



                                         Table 1--Summary of Benefits, Costs and Transfers of the Proposed Rule
                                                             [Millions of 2022 U.S. dollars]
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                   Units
                                                                                   ------------------------------------
                   Category                       Primary       Low        High                               Period                  Notes
                                                 estimate    estimate    estimate      Year      Discount     covered
                                                                                      dollars    rate  (%)    (years)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits:
    Annualized Monetized ($m/year)............     $31,408      $2,670     $86,013        2022           7          20
                                                    22,332       1,810      61,413        2022           3          20
    Annualized Quantified.....................  ..........  ..........  ..........  ..........           7
                                                                                                         3
                                               ---------------------------------------------------------------------------------------------------------
    Qualitative...............................
--------------------------------------------------------------------------------------------------------------------------------------------------------
Costs:
    Annualized Monetized ($m/year)............       5,874       2,522      19,452        2022           7          20  A portion of foreign costs could
                                                     5,598       2,394      18,549        2022           3          20   be passed on to domestic
                                                                                                                         consumers. We estimate that up
                                                                                                                         to $30.73 million in annualized
                                                                                                                         costs (7%, 20 years) to foreign
                                                                                                                         facilities could be passed on
                                                                                                                         to domestic consumers.
    Annualized Quantified.....................  ..........  ..........  ..........  ..........           7
                                                                                                         3
                                               ---------------------------------------------------------------------------------------------------------
    Qualitative...............................
--------------------------------------------------------------------------------------------------------------------------------------------------------
Transfers:
    Federal Annualized Monetized ($m/year)....         226         100         452        2022           7          20
                                                       269         121         538        2022           3          20
                                               ------------------------------------------------------------------------
                                                From: Device Industry
                                                To: FDA
                                               ---------------------------------------------------------------------------------------------------------
    Other Annualized Monetized ($m/year)......  ..........  ..........  ..........  ..........           7
                                                                                                         3
                                               ------------------------------------------------------------------------
                                                From:
                                                To:
--------------------------------------------------------------------------------------------------------------------------------------------------------
Effects:
    State, Local, or Tribal Government:.................................................................................................................
    Small Business: The proposed rule is likely to have a significant economic impact on a substantial number of small laboratories that manufacture
     IVDs offered as LDTs..
    Wages:..............................................................................................................................................
    Growth:.............................................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------

    We have developed a comprehensive Preliminary Economic Analysis of 
Impacts that assesses the impacts of the proposed rule. The full 
preliminary analysis of economic impacts is available in the docket for 
this proposed rule (Ref. 34) 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 environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

X. Paperwork Reduction Act of 1995

    FDA tentatively concludes that this proposed rule contains no new 
collections of information. However, FDA does assume that there will 
need to be corresponding adjustments to the burden estimates for 
relevant approved collections of information before the relevant 
phaseout stage begins and any such collection of information would not 
be as a result of the implementation of the proposed rule. FDA 
tentatively concludes that the following information collections will 
need adjustment before the relevant phaseout stage begins: Office of 
Management and Budget (OMB) control number 0910-0437, Medical Device 
Reporting; OMB control number 0910-0359, Corrections and Removals; OMB 
control number 0910-0625, Device Registration and Listing; OMB control 
number 0910-0485, Labeling; OMB control number 0910-0078, 
Investigational Device Exemption; OMB control number 0910-0073, Quality 
Systems; OMB control number 0910-0231, Premarket Approval; OMB control 
number 0910-0332, Humanitarian Device Exemption; OMB control number 
0910-0756, Q-Submissions; OMB control number 0910-0120, Premarket 
Notification; and OMB control number 0910-0844 De Novo. 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).

XI. Federalism

    We have analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. We have determined 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. Accordingly, 
we conclude that the rule does not contain policies that have 
federalism implications as defined in the Executive order and, 
consequently, a federalism summary impact statement is not required. 
Through publication of this proposed rule, we are providing notice and 
an opportunity for State and local officials to comment on this 
rulemaking.

XII. Consultation and Coordination With Indian Tribal Governments

    We have analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13175. We have tentatively 
determined that the rule does not contain policies that would have a 
substantial direct effect on

[[Page 68029]]

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. The 
Agency solicits comments from tribal officials on any potential impact 
on Indian Tribes from this proposed action.

XIII. Other Issues for Consideration

    FDA anticipates that this proposed rule, if finalized, may require 
conforming amendments to other FDA regulations, including provisions 
regarding IVD labeling and ASRs in part 809. FDA intends to consider 
and propose conforming amendments, where appropriate, at a future date.
    In addition, we note that various bills have been introduced in 
Congress that would change the legal status of IVDs as devices (under 
these bills, IVDs would generally be regulated as ``in vitro clinical 
tests'' and would be subject to new statutory authorities).\19\ We 
recognize that the enactment of such legislation would directly impact 
this rule, given that it is being proposed under the statutory device 
authorities and other authorities under the FD&C Act.
---------------------------------------------------------------------------

    \19\ See, e.g. H.R.4128--117th Congress (2021-2022): VALID Act 
of 2021, H.R.4128, 117th Cong. (2021), https://www.congress.gov/bill/117th-congress/house-bill/4128/text; S.2209--117th Congress 
(2021-2022): VALID Act of 2021, S.2209, 117th Cong. (2021), https://www.congress.gov/bill/117th-congress/senate-bill/2209.
---------------------------------------------------------------------------

XIV. 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. FDA has verified the website addresses, as of 
the date this document publishes in the Federal Register, but websites 
are subject to change over time.

    1. Grand View Research, ``Laboratory Developed Tests Market 
Size, Share & Trends Analysis Report By Technology (Immunoassay, 
Molecular Diagnostics), By Application (Oncology, Nutritional & 
Metabolic Disease), By Region, and Segment Forecasts, 2023-2030: 
Report Summary,'' available at https://www.grandviewresearch.com/industry-analysis/laboratory-developed-tests-market-report (last 
accessed on April 28, 2023).
    2. The Pew Charitable Trusts, ``The Role of Lab-Developed Tests 
in the In Vitro Diagnostics Market,'' October 2021. Available at 
https://www.pewtrusts.org/en/research-and-analysis/reports/2021/10/the-role-of-lab-developed-tests-in-the-in-vitro-diagnostics-market.
    * 3. Congressional Research Service, ``FDA Regulation of 
Laboratory-Developed Tests (LDTs),'' December 7, 2022. Available at 
https://crsreports.congress.gov/product/pdf/IF/IF11389.
    * 4. Warning Letter to deCODE Genetics re: deCODEme Complete 
Scan (June 10, 2010). Available at https://www.fda.gov/media/79216/download.
    * 5. Warning Letter to 23andMe, Inc. re: 23andMe Personal Genome 
Service (June 10, 2010). Available at http://web.archive.org/web/20191214010336/https:/www.fda.gov/media/79205/download.
    6. ThermoFisher Scientific, ``Demystify Molecular Test 
Development and Implementation: How Do Labs Implement Molecular 
Tests To Meet Complex Clinical Needs?'' Available at https://www.thermofisher.com/us/en/home/clinical/clinical-genomics/molecular-diagnostics/molecular-diagnostic-education.html (last 
accessed on March 28, 2023).
    7. Lighthouse Lab Services, ``Industry Insights: Paths To 
Consider When Commercializing Your LDT,'' December 19, 2022; 
available at https://www.lighthouselabservices.com/paths-to-consider-when-commercializing-your-ldt/ (last accessed on March 31, 
2023).
    * 8. Centers for Disease Control and Prevention, Division of 
Laboratory Systems (DLS), ``Strengthening Clinical Laboratories,'' 
November 15, 2018, available at https://www.cdc.gov/csels/dls/strengthening-clinical-labs.html (last accessed on March 31, 2023).
    9. Ackerman, J.P., DC Bartos, J.D. Kapplinger, et al., ``The 
Promise and Peril of Precision Medicine: Phenotyping Still Matters 
Most,'' Mayo Clinic Proceedings, 91(11):1606-1616, 2016. Available 
at https://doi.org/10.1016/j.mayocp.2016.08.008.
    10. Begley, S., ``Genetic Testing Fumbles, Revealing `Dark Side' 
of Precision Medicine,'' STAT, October 31, 2016. Available at 
https://www.statnews.com/2016/10/31/genetic-testing-precision-medicine/.
    * 11. FDA, ``The Public Health Evidence for FDA Oversight of 
Laboratory Developed Tests: 20 Case Studies,'' November 16, 2015, 
available at http://web.archive.org/web/20151122235012/https://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Reports/UCM472777.pdf.
    12. Pfeifer, J.D., R. Loberg, C. Lofton-Day, et al., ``Reference 
Samples To Compare Next-Generation Sequencing Test Performance for 
Oncology Therapeutics and Diagnostics,'' American Journal of 
Clinical Pathology, 157(4):628-638, 2022. Available at https://doi.org/10.1093/ajcp/aqab164.
    13. Quy, P.N., K. Fukuyama, M. Kanai, et al., ``Inter-Assay 
Variability of Next-Generation Sequencing-Based Gene Panels,'' BMC 
Medical Genomics, 15: 86, 2022. Available at https://doi.org/10.1186/s12920-022-01230-y.
    14. Vega, D.M., L.M. Yee, L.M. McShane, et al., ``Aligning Tumor 
Mutational Burden (TMB) Quantification Across Diagnostic Platforms: 
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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, FDA proposes 
to amend 21 CFR part 809 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:

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

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: September 27, 2023.
Robert M. Califf,
Commissioner of Food and Drugs.
[FR Doc. 2023-21662 Filed 9-29-23; 8:45 am]
BILLING CODE 4164-01-P