[Federal Register Volume 79, Number 192 (Friday, October 3, 2014)]
[Notices]
[Pages 59776-59779]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2014-23596]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2011-D-0360]


Framework for Regulatory Oversight of Laboratory Developed Tests; 
Draft Guidance for Industry, Food and Drug Administration Staff, and 
Clinical Laboratories; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing the 
availability of the draft guidance entitled ``Framework for Regulatory 
Oversight of Laboratory Developed Tests (LDTs).'' This document 
describes a risk-based framework for addressing the regulatory 
oversight of a subset of in vitro diagnostic devices (IVDs) referred to 
as laboratory developed tests (LDTs), which are intended for clinical 
use and designed, manufactured and used within a single laboratory. 
This document describes FDA's priorities for enforcing pre- and post-
market requirements for LDTs, and the process by which FDA intends to 
phase in enforcement of FDA regulatory requirements for LDTs over time. 
This draft guidance is not final, nor is it in effect at this time.

DATES: Although you can comment on any guidance at any time (see 21 CFR 
10.115(g)(5)), to ensure that the Agency considers your comment on this 
draft guidance before it begins work on the final version of the 
guidance, submit either electronic or written comments on the draft 
guidance by February 2, 2015.

ADDRESSES: An electronic copy of the guidance document is available for 
download from the Internet. See the SUPPLEMENTARY INFORMATION section 
for information on electronic access to the guidance. Submit written 
requests for single hard copies of the draft guidance document entitled 
``Framework for Regulatory Oversight of Laboratory Developed Tests 
(LDTs)'' to the Office of the Center Director, Guidance and Policy 
Development, Center for Devices and Radiological Health (CDRH), Food 
and Drug Administration, 10903 New Hampshire Ave., Bldg. 66, Rm. 5431, 
Silver Spring, MD 20993-0002, or the Office of Communication, Outreach, 
and Development, Center for Biologics Evaluation and Research (CBER), 
Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 71, Rm. 
3128, Silver Spring, MD 20993-0002. Send one self-addressed adhesive 
label to assist that office in processing your request. The guidance 
may also be obtained by mail by calling CBER at 1-800-835-4709 or 240-
402-7800.
    Submit electronic comments on the draft guidance to http://www.regulations.gov. Submit written comments to the Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852. Identify comments with the docket number 
found in brackets in the heading of this document.

FOR FURTHER INFORMATION CONTACT: [email protected]; or Katherine 
Serrano, Center for Devices and Radiological Health, Food and Drug 
Administration, Bldg. 66, Rm. 5646, 10903 New Hampshire Ave., Silver 
Spring, MD 20993-0002, 240-402-4217; or Stephen Ripley, Center for 
Biologics Evaluation and Research Food and Drug Administration, 10903 
New Hampshire Ave., Bldg. 71, Rm. 7301, Silver Spring, MD 20993-0002, 
240-402-7911.

SUPPLEMENTARY INFORMATION:

I. Background

    In 1976, Congress enacted the Medical Device Amendments (MDA), 
which amended the Federal Food, Drug, and Cosmetic Act (the FD&C Act) 
to create a comprehensive system for the regulation of medical devices 
intended for use in humans. At that time, the definition of a device 
was amended to make explicit that it encompassed in vitro diagnostic 
devices (IVDs): ``The term `device'. . . means an instrument, 
apparatus, implement, machine, contrivance, implant, in vitro reagent, 
or

[[Page 59777]]

other similar or related article . . .'' (section 201(h) of the FD&C 
Act (21 U.S.C. 321(h)). The definition of device applies equally to 
IVDs manufactured by conventional device manufacturers and those 
manufactured by laboratories. An IVD, therefore, meets the device 
definition irrespective of where and by whom it is manufactured.
    Since the implementation of the MDA of 1976, FDA has exercised 
enforcement discretion so that the Agency has generally not enforced 
applicable provisions under the FD&C Act and FDA regulations with 
respect to laboratory developed tests (LDTs), a subset of in vitro 
diagnostic devices that are intended for clinical use and designed, 
manufactured, and used within a single laboratory.
    In 1976, LDTs were mostly manufactured in small volumes by local 
laboratories. Many laboratories manufactured LDTs that were similar to 
well-characterized, standard diagnostic devices, as well as other LDTs 
that were intended for use in diagnosing rare diseases or for other 
uses to meet the needs of a local patient population. LDTs at the time 
tended to rely on the manual techniques used by laboratory personnel. 
LDTs were typically used and interpreted directly by physicians and 
pathologists working within a single institution that was responsible 
for the patient. In addition, historically, LDTs were manufactured 
using components that were legally marketed for clinical use (i.e., 
general purpose reagents, immunohistochemical stains, and other 
components marketed in compliance with FDA regulatory requirements).
    Although some laboratories today still manufacture LDTs in this 
``traditional'' manner, the landscape for laboratory testing in 
general, and LDTs along with it, has changed dramatically since 1976. 
Today, LDTs are often used in laboratories that are independent of the 
healthcare delivery entity. Additionally, LDTs are frequently 
manufactured with components and instruments that are not legally 
marketed for clinical use and also rely more heavily on complex, high-
tech instrumentation and software to generate results and clinical 
interpretations. Moreover, technological advances have increased the 
use of diagnostic devices in guiding critical clinical management 
decisions for high-risk diseases and conditions, particularly in the 
context of personalized medicine.
    Business models for laboratories have also changed since 1976. With 
the advent of overnight shipping and electronic delivery of information 
(e.g., device results), a single laboratory can now easily provide 
device results nationally and internationally. Today, many new LDT 
manufacturers are large corporations that nationally market a limited 
number of complex, high-risk devices, in contrast to 1976 when hospital 
or public health laboratories used a wide range of devices that were 
generally either well characterized and similar to standard devices; 
used to diagnose rare diseases; or designed specifically to meet the 
needs of their local patients. Together, these changes have resulted in 
a significant shift in the types of LDTs developed, the business model 
for developing them, and the potential risks they pose to patients.
    Because of changes in the complexity and use of LDTs and the 
associated increased risks, as described earlier, FDA believes the 
policy of general enforcement discretion towards LDTs is no longer 
appropriate. To initiate this step toward greater oversight, FDA held a 
two-day public meeting on July 19 and 20, 2010, to provide a forum for 
stakeholders to discuss issues and concerns surrounding greater 
oversight of LDTs. Comments submitted to the public docket for the July 
public meeting have been addressed, as appropriate, in the draft 
guidance document.
    Once finalized and implemented, this guidance document is intended 
to provide a risk-based oversight framework that will assure that 
devices used in the provision of health care, whether developed by a 
laboratory or a conventional IVD manufacturer, comply with the 
appropriate levels of regulatory controls needed to assure that they 
are safe and effective. Under the framework outlined in this guidance 
document, FDA intends to continue to exercise enforcement discretion 
for all applicable regulatory requirements for LDTs used solely for 
forensic (law enforcement) purposes as well as certain LDTs for 
transplantation when used in certified, high-complexity 
histocompatibility laboratories. Additionally, FDA intends to exercise 
enforcement discretion for applicable premarket review requirements and 
quality systems requirements, but enforce other applicable regulatory 
requirements, including registration and listing (with the option to 
provide notification instead) and adverse event reporting, for low risk 
LDTs (class I devices), LDTs for rare diseases, Traditional LDTs and 
LDTs for Unmet Needs, as described in the draft guidance document. For 
other high and moderate risk LDTs, FDA intends to enforce applicable 
regulatory requirements, including registration and listing (with the 
option to provide notification instead) and adverse event reporting, 
and phase in enforcement of premarket and quality system requirements 
in a risk-based manner.
    On July 31, 2014, as required by Section 1143 of the Food and Drug 
Administration Safety and Innovation Act, FDA provided notification to 
Congress of its intent to issue this draft guidance and the 
accompanying draft guidance entitled ``FDA Notification and Medical 
Device Reporting for Laboratory Developed Test (LDTs)'' (the 
availability of the accompanying draft guidance is announced elsewhere 
in this issue of the Federal Register). The anticipated details of 
these draft guidance documents were included in the notification to 
Congress.
    Although FDA was not accepting formal comments on its notification 
to Congress, the Agency has received informal comments and questions 
regarding the anticipated details of this draft guidance provided in 
the notification to Congress. To give everyone an opportunity to 
provide formal comments on the anticipated details as part of the 
administrative record, the details of the draft guidance are identical 
to that which were included in FDA's July 31, 2014, notification to 
Congress with the exception of the following technical amendments: The 
definition of companion diagnostic has been updated for consistency 
with the final guidance on ``In Vitro Companion Diagnostic Devices'' 
issued on August 6, 2014, and the ``Traditional LDT'' factor regarding 
whether the LDT is comprised only of components and instruments that 
are legally marketed has been clarified to more accurately reflect 
FDA's intent of considering whether the LDT is comprised of only 
components and instruments that are legally marketed for clinical use.
    To provide greater transparency on certain questions and issues 
that have been raised and to allow for broad public input, in addition 
to welcoming comments on all aspects of this draft guidance, FDA seeks 
feedback on the following specific issues:
     Traditional LDTs: In Section D.5.(a) of the draft 
guidance, FDA has proposed continued enforcement discretion for 
premarket review and quality system requirements for a category of LDTs 
called ``Traditional LDTs'' based on whether the device is: (1) an LDT 
(designed, manufactured and used within a single laboratory); (2) 
manufactured and used by a health care facility laboratory (such as one 
located in a hospital or clinic) for a patient that is being diagnosed 
and/or treated at that same health care facility or within the 
facility's healthcare system; (3)

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comprised only of components and instruments that are legally marketed 
for clinical use; and (4) interpreted by qualified laboratory 
professionals without the use of automated instrumentation or software 
for interpretation. FDA believes that these factors appropriately 
mitigate risks associated with Traditional LDTs being used on patients 
so that continued enforcement discretion with respect to premarket 
review and quality system requirements is appropriate. However, FDA is 
seeking public feedback as to whether the following three factors may 
be sufficient to appropriately mitigate risk for this category of tests 
and whether they may also be sufficient to support continued 
enforcement discretion in full (i.e., for all regulatory requirements 
rather than just for premarket review and quality system requirements): 
(1) the test is an LDT (designed, manufactured and used within a single 
laboratory); (2) the test makes use of only components and instruments 
that are legally marketed for clinical use, which have a number of 
regulatory controls in place, including reporting of adverse events; 
and (3) the test is interpreted by laboratory professionals who are 
appropriately qualified and trained as required by the Clinical 
Laboratory Improvement Amendments regulations (e.g., 42 CFR 493.1449), 
without the use of automated instrumentation or software for 
interpretation.
     LDTs Used for Rare Diseases: In Section D.5.(a) of the 
draft guidance, FDA has proposed continued enforcement discretion for 
premarket review and quality system requirements for LDTs used for rare 
diseases, which are those tests that meet the definition of LDT in the 
guidance (designed, manufactured and used within a single laboratory) 
and meet the definition of a Humanitarian Use Device (HUD) under 21 CFR 
814.102(a)(5). With these factors, FDA has attempted to balance the 
need to mitigate the risks associated with these tests with their 
potential benefit for patients. FDA invites stakeholders to provide 
feedback on the suitability of these factors for LDTs for rare 
diseases. Further, FDA is seeking feedback on whether a factor other 
than the HUD definition should be considered, such as a factor based on 
the number of tests for a rare disease or condition that would likely 
(based on the prevalence of the condition) be conducted annually in the 
United States, and if so what the annual number of tests should be for 
the purpose of defining an LDT as an LDT for a rare disease. FDA also 
seeks feedback on whether enforcement discretion should be limited to 
tests that are designed, manufactured and used within a single 
laboratory.
     Healthcare System: In Section D.5. of the draft guidance, 
for the categories of tests called ``Traditional LDTs'' and ``LDTs for 
Unmet Needs,'' FDA has identified factors it intends to consider in 
continuing to exercise enforcement discretion for premarket review and 
quality system requirements. One such factor is whether the LDT is both 
manufactured and used by a healthcare facility laboratory (such as one 
located in a hospital or clinic) for a patient that is being diagnosed 
and/or treated at that same healthcare facility or within that 
facility's healthcare system. To further clarify this factor, the 
guidance document explains that ``healthcare system'' refers to a 
collection of hospitals that are owned and operated by the same entity 
and that share access to patient care information for their patients, 
such as, but not limited to, drug order information, treatment and 
diagnosis information, and patient outcomes. While FDA invites feedback 
on all factors described in Section D.5. of the draft guidance, FDA 
specifically requests feedback on whether enforcement discretion should 
be limited, as proposed, to those LDTs that are both manufactured and 
used by a healthcare facility laboratory. FDA also invites the public 
to provide feedback to the Agency on which types of facilities would or 
would not be considered within a healthcare system, or to offer an 
alternative description of healthcare system for Agency consideration.
     Quality System (QS) Phase-in: In Section D.6. of the draft 
guidance, FDA has proposed to continue to exercise enforcement 
discretion with respect to QS regulation requirements, codified in 21 
CFR Part 820, until a manufacturer of a given LDT submits a Premarket 
Approval (PMA) or FDA issues a 510(k) clearance order for the LDT. 
Under this enforcement policy, the clinical laboratory manufacturing 
and using the LDT will be responsible for having a quality system in 
place that meets the minimum requirements codified in 21 CFR Part 820, 
either at the time of PMA submission (the facility that makes the 
device must pass an inspection as a condition of PMA approval as a 
matter of law (21 CFR 814.45(a)(3)), or prior to market launch for 
cleared devices, as applicable. FDA invites feedback on the timeframe 
for phase-in enforcement of QS regulation requirements. Specifically, 
FDA is considering whether those LDTs in the highest-risk category of 
devices (described in section D.5.(c) of the draft guidance), which FDA 
intends to generally enforce premarket review requirements 12 months 
following publication of the final Framework guidance, should remain 
under enforcement discretion for the design control requirements (21 
CFR 820.30(a-h) and (j)) of the QS regulation for up to 24 months after 
publication of the final guidance.
     Notification: FDA notes that some laboratory networks 
(i.e., more than one laboratory under the control of the same parent 
entity) offer the same test in multiple laboratories throughout their 
network. Although devices in this scenario do not meet FDA's definition 
of an LDT (i.e., they are not designed, manufactured and used within a 
single laboratory), FDA would like feedback on whether a single 
notification from the laboratory network for that test is sufficient, 
provided that the laboratory network indicates in the notification to 
FDA that the test is offered at multiple sites. In addition, FDA seeks 
comment on whether there are certain types of LDTs for which the Agency 
should neither enforce requirements for registration and listing nor 
request notification in lieu of registration and listing.
     FDA understands that members of the public may want more 
clarity around specific issues; such as how laboratory sponsors could 
interpret what elements make up a medical device, what might constitute 
the label or labeling for their device, whether or not unique device 
identifier requirements apply to LDTs, and how laboratory-physician 
communication about a test and its result would be viewed by FDA, among 
others. We invite public comment on these issues and any other issues 
or questions that should be addressed in the guidance, including how 
that issue or question should be addressed.
    Additionally, FDA intends to hold a public webinar in late October, 
2014 to summarize the proposed oversight framework and answer 
clarification questions from stakeholders. The webinar will not require 
registration and will be announced at least one week in advance on 
FDA's Web site. It will be recorded and made available on FDA's Web 
site shortly thereafter.

II. Significance of Guidance

    This draft guidance is being issued consistent with FDA's good 
guidance practices regulation (21 CFR 10.115). The draft guidance, when 
finalized, will represent the Agency's current thinking on oversight of 
laboratory developed tests. It does not create or confer any rights for 
or on any person and does not operate to bind FDA or the public. An

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alternative approach may be used if such approach satisfies the 
requirements of the applicable statute and regulations.

III. Electronic Access

    Persons interested in obtaining a copy of the draft guidance may do 
so by downloading an electronic copy from the Internet. A search 
capability for all CDRH guidance documents is available at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/default.htm. Guidance documents are also available at 
http://www.regulations.gov or the CBER Internet at http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/default.htm.
    Persons unable to download an electronic copy of ``Framework for 
Regulatory Oversight of Laboratory Developed Tests (LDTs)'' may send an 
email request to [email protected] to receive an electronic 
copy of the document. Please use the document number 1739 to identify 
the guidance you are requesting.

IV. Paperwork Reduction Act of 1995

    This draft guidance refers to previously approved collections of 
information found in FDA regulations. These collections of information 
are subject to review by the Office of Management and Budget (OMB) 
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). The 
collections of information in 21 CFR part 807 Subpart E have been 
approved under OMB control number 0910-0120; the collections of 
information in 21 CFR part 807 Subpart B and C have been approved under 
OMB control number 0910-0625; the collections of information in 21 CFR 
part 601 have been approved under OMB control number 0910-0338; the 
collections of information in 21 CFR part 814, subparts B and E, have 
been approved under OMB control number 0910-0231; the collections of 
information in 21 CFR part 814, subpart H, have been approved under OMB 
control number 0910-0332; the collections of information in 21 CFR part 
820 have been approved under OMB control number 0910-0073; the 
collections of information in 21 CFR part 812 have been approved under 
OMB control number 0910-0078; the collections of information in 21 CFR 
part 806 have been approved under OMB control number 0910-0359; the 
collections of information in 21 CFR 801 and 21 CFR 809.10 have been 
approved under OMB control number 0910-0485; and the collections of 
information in 21 CFR part 803 have been approved under OMB control 
numbers 0910-0291 and 0910-0437.

V. Comments

    Interested persons may submit either electronic comments regarding 
this document to http://www.regulations.gov or written comments to the 
Division of Dockets Management (see ADDRESSES). It is only necessary to 
send one set of comments. Identify comments with the docket number 
found in brackets in the heading of this document. Received comments 
may be seen in the Division of Dockets Management between 9 a.m. and 4 
p.m., Monday through Friday, and will be posted to the docket at http://www.regulations.gov.
    Comments will also be accepted at a public meeting, which will be 
held prior to finalizing this draft guidance. A 2-day meeting is 
tentatively scheduled for early January, 2015 and will be announced 
separately in the Federal Register.

    Dated: September 30, 2014.
Peter Lurie,
Associate Commissioner for Policy and Planning.
[FR Doc. 2014-23596 Filed 9-30-14; 11:15 am]
BILLING CODE 4164-01-P