Rule2024-08935
Medical Devices; Laboratory Developed Tests
Primary source
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Published
May 6, 2024
Effective
July 5, 2024
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
The Food and Drug Administration is issuing a final rule to amend its regulations to make explicit that in vitro diagnostic products (IVDs) are devices under the Federal Food, Drug, and Cosmetic Act (FD&C Act) including when the manufacturer of the IVD is a laboratory. In conjunction with this amendment, the Food and Drug Administration is phasing out its general enforcement discretion approach for laboratory developed tests (LDTs) so that IVDs manufactured by a laboratory will generally fall under the same enforcement approach as other IVDs. This phaseout policy includes enforcement discretion policies for specific categories of IVDs manufactured by a laboratory, including currently marketed IVDs offered as LDTs and LDTs for unmet needs. This phaseout policy is intended to better protect the public health by helping to assure the safety and effectiveness of IVDs offered as LDTs, while also accounting for other important public health considerations such as patient access and reliance.
Full Text
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[Federal Register Volume 89, Number 88 (Monday, May 6, 2024)]
[Rules and Regulations]
[Pages 37286-37445]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2024-08935]
[[Page 37285]]
Vol. 89
Monday,
No. 88
May 6, 2024
Part II
Department of Health and Human Services
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Food and Drug Administration
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21 CFR Part 809
Medical Devices; Laboratory Developed Tests; Final Rule
Federal Register / Vol. 89, No. 88 / Monday, May 6, 2024 / Rules and
Regulations
[[Page 37286]]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 809
[Docket No. FDA-2023-N-2177]
RIN 0910-AI85
Medical Devices; Laboratory Developed Tests
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration is issuing a final rule to
amend its regulations to make explicit that in vitro diagnostic
products (IVDs) are devices under the Federal Food, Drug, and Cosmetic
Act (FD&C Act) including when the manufacturer of the IVD is a
laboratory. In conjunction with this amendment, the Food and Drug
Administration is phasing out its general enforcement discretion
approach for laboratory developed tests (LDTs) so that IVDs
manufactured by a laboratory will generally fall under the same
enforcement approach as other IVDs. This phaseout policy includes
enforcement discretion policies for specific categories of IVDs
manufactured by a laboratory, including currently marketed IVDs offered
as LDTs and LDTs for unmet needs. This phaseout policy is intended to
better protect the public health by helping to assure the safety and
effectiveness of IVDs offered as LDTs, while also accounting for other
important public health considerations such as patient access and
reliance.
DATES: This rule is effective July 5, 2024.
ADDRESSES: For access to the docket to read background documents or
comments received, go to <a href="https://www.regulations.gov">https://www.regulations.gov</a> and insert the
docket number found in brackets in the heading of this final rule into
the ``Search'' box and follow the prompts, and/or go to the Dockets
Management Staff, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852,
240-402-7500.
FOR FURTHER INFORMATION CONTACT: Toby Lowe, Center for Devices and
Radiological Health, Food and Drug Administration, 10903 New Hampshire
Ave., Silver Spring, MD 20993, 301-796-6512, <a href="/cdn-cgi/l/email-protection#a7ebe3f3e1cec9c6cbf5d2cbc2e7c1c3c689cfcfd489c0c8d1"><span class="__cf_email__" data-cfemail="024e4656446b6c636e50776e67426466632c6a6a712c656d74">[email protected]</span></a>.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Executive Summary
A. Purpose of the Final Rule
B. Summary of Select Provisions of the Final Rule
C. Legal Authority
D. Costs and Benefits
II. Table of Abbreviations/Commonly Used Acronyms in This Document
III. Background
A. FDA's Current Regulatory Framework
B. Need for the Rule
C. Summary of Comments on the Notice of Proposed Rulemaking
D. General Overview of the Final Amendment to the Definition of
In Vitro Diagnostic Products
E. General Overview of the Final Phaseout Policy
IV. Legal Authority
V. Phaseout Policy
A. Scope
B. Enforcement Discretion Policies
C. Stages
VI. Comments on the Notice of Proposed Rulemaking and FDA Responses
A. General Comments on the Notice of Proposed Rulemaking
B. Definitions
C. Need for the Rule
D. FDA Authority To Regulate LDTs
E. Other Legal Comments
F. Phaseout Policy
G. Impact on Small Businesses
H. Impact on Pricing
I. Impact on Access and Innovation
J. Level Playing Field
K. Impact to Specific Patient Populations
L. Specific Types of IVDs
M. IVD Modifications
N. FDA Resources
O. 510(k) Third Party Review Program
P. Implementation
Q. Interplay With Oncology Drug Products Used With Certain In
Vitro Diagnostic Tests Pilot Program
R. Miscellaneous
VII. Effective Date
VIII. Economic Analysis of Impacts
IX. Analysis of Environmental Impact
X. Paperwork Reduction Act of 1995
XI. Federalism
XII. Consultation and Coordination With Indian Tribal Governments
XIII. References
I. Executive Summary
A. Purpose of the Final Rule
The Food and Drug Administration (FDA, the Agency, or we) is
amending its regulations to make explicit that IVDs are devices under
the FD&C Act including when the manufacturer of the IVD is a
laboratory. This amendment reflects that the device definition in the
FD&C Act does not differentiate between entities manufacturing the
device. In connection with amending the regulation, FDA is phasing out
its general enforcement discretion approach for LDTs so that IVDs
manufactured by a laboratory will generally fall under the same
enforcement approach as other IVDs (i.e., FDA's expectations for
compliance will generally be the same). This phaseout policy includes
enforcement discretion policies for specific categories of IVDs
manufactured by a laboratory, including currently marketed IVDs offered
as LDTs \1\ and LDTs for unmet needs. For purposes of this document, we
use ``manufacture'' and related terms as a shorthand for the various
activities that constitute manufacturing as described in FDA
regulations (e.g., design, preparation, propagation, assembly, and
processing).
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\1\ As discussed in section V.A.1, FDA uses the phrase ``IVDs
offered as LDTs'' throughout this preamble to refer to IVDs that are
manufactured and offered as LDTs by laboratories that are certified
under the Clinical Laboratory Improvement Amendments of 1988 (CLIA)
and that meet the regulatory requirements under CLIA to perform high
complexity testing, and used within such laboratories, even if those
IVDs do not fall within FDA's traditional understanding of an LDT
because they are not designed, manufactured, and used within a
single laboratory.
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In 1976, the Medical Device Amendments of 1976 (the MDA) amended
the FD&C Act to create a comprehensive system for the regulation of
devices intended for human use. In implementing the MDA, FDA has
exercised enforcement discretion such that it generally has not
enforced applicable requirements with respect to most LDTs. Enforcement
discretion for LDTs developed as a matter of practice. However, the
risks associated with LDTs are much greater today than they were at the
time of enactment of the MDA. As discussed more fully in the notice of
proposed rulemaking (NPRM) (88 FR 68006, October 3, 2023) and this
preamble, today's LDTs are, among other things, used more widely, by a
more diverse population, with an increasing reliance on high-tech
instrumentation and software, and more frequently for the purpose of
guiding critical healthcare decisions. In this regard, today's LDTs are
similar to other IVDs that have not come within FDA's general
enforcement discretion approach.
Given these changes, and for the additional reasons discussed in
the NPRM and this preamble, FDA is phasing out the general enforcement
discretion approach for LDTs. By phasing out this approach, FDA intends
to better protect the public health by helping to assure the safety and
effectiveness of IVDs offered as LDTs, while also accounting for other
important public health considerations such as patient access and
reliance.
B. Summary of Select Provisions of the Final Rule
FDA is amending the definition of ``in vitro diagnostic products''
in its regulations to state that IVDs are devices
[[Page 37287]]
under the FD&C Act ``including when the manufacturer of these products
is a laboratory.''
In conjunction with this amendment, FDA is phasing out the general
enforcement discretion approach for LDTs. As discussed further in this
preamble, however, FDA is adopting targeted enforcement discretion
policies for several categories of IVDs manufactured by a laboratory in
certain circumstances. As with any enforcement discretion policy, FDA
may update any of these enforcement discretion policies as
circumstances warrant or if the circumstances that inform these
policies change, consistent with FDA's good guidance practices (21
U.S.C. 371(h), Sec. 10.115 (21 CFR 10.115)).
Additional details regarding the phaseout policy are discussed
further in section V of this preamble.
C. Legal Authority
FDA is issuing this rule under the Agency's general rulemaking
authorities and statutory authorities relating to devices. These
authorities include sections 201(h)(1), 301, 501, 502, 510, 513, 514,
515, 518, 519, 520, 701, 702, 704, and 801 of the FD&C Act (21 U.S.C.
321(h)(1), 331, 351, 352, 360, 360c, 360d, 360e, 360h, 360i, 360j, 371,
372, 374, and 381) and section 351 of the Public Health Service Act
(PHS Act) (42 U.S.C. 262).
D. Costs and Benefits
We quantify benefits to patients from averted health losses due to
problematic IVDs offered as LDTs. We focus mainly on certain broad
disease categories associated with the majority of misdiagnosis-related
harms in the United States. Additional benefits include averted non-
health losses from reduced spending on problematic IVDs offered as LDTs
and unquantified reduction in costs from lawsuits. We quantify costs to
affected laboratories for complying with statutory and regulatory
requirements. Additional costs include costs to FDA, which we include
in our estimates. We estimate that the annualized benefits over 20
years range from $0.99 billion to $11.1 billion at a 7 percent discount
rate, with a primary estimate of $3.51 billion, and from $1.24 billion
to $13.62 billion at a 3 percent discount rate, with a primary estimate
of $4.34 billion. The annualized costs range from $566 million to $3.56
billion at a 7 percent discount rate, with a primary estimate of $1.29
billion, and from $603 million to $3.79 billion at a 3 percent discount
rate, with a primary estimate of $1.37 billion.
II. Table of Abbreviations/Commonly Used Acronyms in This Document
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Abbreviation/acronym What it means
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3P510k Review Organization... Third Party Review Organization
Accredited Under FDA's Third Party
Review Program
510(k)....................... Premarket Notification.
AABB......................... Association for the Advancement of Blood
and Biotherapies.
ACGME........................ Accreditation Council for Graduate
Medical Education.
ACLA......................... American Clinical Laboratory Association.
ADLT......................... Advanced Diagnostic Laboratory Test.
ACHC......................... Accreditation Commission for Health Care.
AMC.......................... Academic Medical Center.
AML.......................... Acute Myeloid Leukemia.
AMP.......................... Association for Molecular Pathology.
ANI.......................... Average Nucleotide Identity.
APA.......................... Administrative Procedure Act.
ASHI......................... American Society for Histocompatibility
and Immunogenetics.
ASR.......................... Analyte Specific Reagent.
AST.......................... Antimicrobial Susceptibility Test.
BLA.......................... Biologics License Application.
CAP.......................... College of American Pathologists.
CAPA......................... Corrective and Preventive Action.
CBRN......................... Chemical, Biological, Radiological, or
Nuclear.
CDER......................... Center for Drug Evaluation and Research.
CDRH......................... Center for Devices and Radiological
Health.
CDC.......................... Centers for Disease Control and
Prevention.
CDx.......................... Companion Diagnostic.
CFR.......................... Code of Federal Regulations.
CGMP......................... Current Good Manufacturing Practice.
CGT.......................... Cell and Gene Therapy.
CLIA......................... Clinical Laboratory Improvement
Amendments of 1988.
CLIAC........................ Clinical Laboratory Improvement Advisory
Committee.
CLSI......................... Clinical and Laboratory Standards
Institute.
CMS.......................... Centers for Medicare & Medicaid Services.
COLA......................... Commission on Office Laboratory
Accreditation.
CRO.......................... Clinical Research Organization.
Cures Act.................... 21st Century Cures Act.
DNA.......................... Deoxyribonucleic Acid.
DoD.......................... Department of Defense.
EGFR......................... Epidermal Growth Factor Receptor.
EMR.......................... Electronic Medical Record.
EO........................... Executive Order.
EUA.......................... Emergency Use Authorization.
EUCAST....................... European Committee on Antimicrobial
Susceptibility Testing.
FACT......................... Foundation for the Accreditation of
Cellular Therapy.
FCC.......................... Federal Communications Commission.
FDA.......................... Food and Drug Administration.
FDAAA........................ Food and Drug Administration Amendments
Act.
FDAMA........................ Food and Drug Administration
Modernization Act.
FDA-ARGOS.................... FDA dAtabase for Reference Grade
MicrObial Sequences.
FD&C Act..................... Federal Food, Drug, and Cosmetic Act.
[[Page 37288]]
FRIA......................... Final Regulatory Impact Analysis.
GAO.......................... Government Accountability Office.
HCFA......................... Health Care Financing Administration.
HCT/Ps....................... Human Cells, Tissues, and Cellular and
Tissue-Based Products.
HDE.......................... Humanitarian Device Exemption.
HHS.......................... Department of Health & Human Services.
HIV.......................... Human Immunodeficiency Virus.
HLA.......................... Human Leukocyte Antigen.
HUD.......................... Humanitarian Use Device.
ICCS......................... International Clinical Cytometry Society.
IDE.......................... Investigational Device Exemption.
IND.......................... Investigational New Drug Application.
ISO.......................... International Organization for
Standardization.
IVD.......................... In Vitro Diagnostic Product.
IVDR......................... In Vitro Diagnostic Medical Device
Regulation.
LDT.......................... Laboratory Developed Test.
LGBTQIA+..................... Lesbian, Gay, Bisexual, Transgender,
Queer, Intersex, and Asexual.
LoQ.......................... Limit of Quantitation.
MAF.......................... Master File.
MDA.......................... Medical Device Amendments of 1976.
MDAC......................... Medical Devices Advisory Committee.
MDR.......................... Medical Device Report.
MDUFA........................ Medical Device User Fee Amendments.
MolDx........................ Molecular Diagnostic Services.
NCBI......................... National Center for Biotechnology
Information.
NDA.......................... New Drug Application.
NGS.......................... Next Generation Sequencing.
NIFLA........................ National Institute of Family and Life
Advocates.
NIH.......................... National Institutes of Health.
NIPS......................... Non-Invasive Prenatal Screening.
NLRB......................... National Labor Relations Board.
NMDP......................... National Marrow Donor Program.
NOTA......................... National Organ Transplant Act.
NPRM......................... Notice of Proposed Rulemaking.
NSQAP........................ Newborn Screening Laboratory Quality
Assurance Program.
NYS CLEP..................... New York State Department of Health's
Clinical Laboratory Evaluation Program.
OED.......................... Oxford English Dictionary.
OHT7......................... Office of Health Technology 7.
OIRA......................... Office of Information and Regulatory
Affairs.
OMB.......................... Office of Management and Budget.
OPTN......................... Organ Procurement and Transplant Network.
OTC.......................... Over-the-Counter.
PAMA......................... Protecting Access to Medicare Act of
2014.
PCCP......................... Predetermined Change Control Plan.
PHS Act...................... Public Health Service Act.
PMA.......................... Premarket Approval Application.
PrEP......................... Pre-Exposure Prophylaxis.
PRIA......................... Preliminary Regulatory Impact Analysis.
QS........................... Quality System.
QSR.......................... Quality System Regulation.
RBC.......................... Red Blood Cell.
RNA.......................... Ribonucleic Acid.
RUO.......................... Research Use Only.
SAMHSA....................... Substance Abuse and Mental Health
Services Administration.
SDO.......................... Standards Development Organization.
Secretary.................... Secretary of HHS.
STI.......................... Sexually Transmitted Infection.
STIC......................... Susceptibility Test Interpretive
Criteria.
TMB.......................... Tumor Mutational Burden.
UDI.......................... Unique Device Identification.
UMRA......................... Unfunded Mandates Reform Act of 1995.
USG.......................... United States Government.
VALID Act.................... Verifying Accurate, Leading-Edge IVCT
Development Act of 2023.
VHA.......................... Veterans Health Administration.
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III. Background
FDA's regulations define IVDs as reagents, instruments, and systems
intended for use in the diagnosis of disease or other conditions,
including a determination of the state of health, in order to cure,
mitigate, treat, or prevent disease or its sequelae, and intended for
use in the collection, preparation, and examination of specimens taken
from the human body. IVDs include test systems (also referred to in
this preamble as ``tests'') that are intended for use in the
collection, preparation, and examination of samples taken from the
human body, such as blood or tissue, for the purpose of detecting
diseases or other conditions, monitoring
[[Page 37289]]
a person's overall health, identifying patients who are likely to
benefit from specific therapies, or otherwise helping to diagnose,
cure, mitigate, treat, or prevent disease or its sequelae. Some IVDs
are manufactured by conventional medical device manufacturers for use
by other entities such as laboratories, healthcare providers, or, in
some cases, patients. Such IVDs may include ``test kits,'' containing
packaged sets of components that are part of or comprise a test system.
Other IVDs are manufactured by laboratories for use by the same or
other laboratories. Such IVDs include LDTs. FDA has generally
considered an LDT to be an IVD that is intended for clinical use and
that is designed, manufactured, and used within a single laboratory
that is certified under the Clinical Laboratory Improvement Amendments
of 1988 (CLIA) and meets the regulatory requirements under CLIA to
perform high complexity testing.\2\
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\2\ Such laboratories may include those operating under State
licensure programs deemed exempt from CLIA. See CMS, ``Exempt States
Under the Clinical Laboratory Improvement Amendments'' (Ref. 1).
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However, in implementing the MDA since 1976, FDA has exercised
enforcement discretion such that it generally has not enforced
applicable legal requirements with respect to most LDTs. This means
that, for most LDTs, FDA generally has not enforced requirements
related to registration and listing, reporting adverse events to FDA,
current good manufacturing practices (CGMPs), or premarket review of an
IVD by FDA prior to use of the LDT in patient care, among other
requirements. The rationale for this approach was that, at the time of
passage of the MDA, LDTs were mostly manufactured in small volumes by
laboratories that served their local communities. They were typically
intended for use in diagnosing rare diseases or for other uses to meet
the needs of a local patient population, or were generally similar to
well-characterized, standard IVDs (Refs. 2 and 3). They also tended to
employ manual techniques (and did not use automation) and were
performed by laboratory personnel with specialized expertise; to be
used and interpreted by physicians or pathologists in a single
institution responsible for the patient (and who were actively involved
in patient care); and to be manufactured using components legally
marketed for clinical use, such as general purpose reagents or
immunohistochemical stains marketed in compliance with FDA
requirements. Due to these and other factors, FDA exercised enforcement
discretion such that it generally has not enforced applicable
requirements for most LDTs.\3\
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\3\ FDA's general enforcement discretion approach has not
applied to LDTs in all contexts; for example, it has not applied to,
among other LDTs, those used for declared emergencies/potential
emergencies/material threats under section 564 of the FD&C Act (21
U.S.C. 360bbb-3).
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However, the LDT landscape has evolved significantly since 1976.
Today, many LDTs increasingly rely on high-tech or complex
instrumentation and software to generate results and clinical
interpretations (Refs. 2 and 3). They are often used in laboratories
outside of the patient's healthcare setting and are often run in high
volume for large and diverse populations. Many LDTs are manufactured by
laboratory corporations that market the IVDs nationwide, as they accept
specimens from patients across the country and run their LDTs in very
large volumes in a single laboratory. Today's LDTs are also more
commonly manufactured with instruments or other components not legally
marketed for clinical use and are more often used to inform or direct
critical treatment decisions, to widely screen for common diseases, to
predict personal risk of developing certain diseases, and to diagnose
serious medical conditions such as cancer and heart disease.\4\ The
risks associated with most LDTs today are therefore much greater than
they were at the time FDA began implementing the MDA, and most LDTs
today are similar to other IVDs that have not been under FDA's general
enforcement discretion approach. In addition, FDA is concerned that
firms are offering IVDs as ``LDTs'' even when they are not LDTs as
defined on FDA's website, because they are not actually designed,
manufactured, and used within a single laboratory (see, e.g., Refs. 5
and 6).
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\4\ See, e.g., Refs. 2-4. These observations are also informed
by FDA's own experience, including the review of submissions and
site visits, and staff with prior experience in the laboratory
industry manufacturing and performing LDTs.
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As LDTs increasingly rely on high-tech instrumentation and
software, the potential for cybersecurity vulnerabilities is growing.
Many LDTs are connected to Laboratory Information Management Systems
and other IT infrastructure, making them a potential conduit for those
looking to access information in such systems. This may include patient
genetic information, among other things, which could have national
security implications. Further, it has been demonstrated that hackers
can modify medical test results (Ref. 7). Through premarket review, FDA
works with manufacturers to ensure cybersecurity is appropriately
considered, mitigating the potential for future problems. Through
medical device reporting (MDR) and correction and removal reporting
requirements, FDA helps to ensure that any problems are appropriately
addressed. In fact, FDA has seen cybersecurity problems with certain
instruments and issued two safety communications where laboratories may
not have otherwise been aware that the research use only (RUO) versions
of the instruments used as part of their LDTs had the same
vulnerabilities (Refs. 8 and 9).
As a result of these evolutions in the testing landscape, FDA has
long recognized the need for a change in the Agency's general
enforcement discretion approach for LDTs. The history of FDA's efforts
with respect to LDTs is described more fully in the NPRM. Over the past
few years, FDA has accumulated even more information supporting the
need for a change, as noted in the NPRM and discussed below. In light
of these developments, FDA is amending FDA's regulations to make
explicit that IVDs are devices under the FD&C Act including when the
manufacturer is a laboratory.\5\ FDA is also issuing a policy (see
section V) under which FDA is: (1) phasing out its general enforcement
discretion approach for LDTs so that IVDs manufactured by a laboratory
will generally fall under the same enforcement approach as other IVDs
and (2) adopting targeted enforcement discretion policies for specific
categories of IVDs manufactured by a laboratory. As reflected in FDA's
Final Regulatory Impact Analysis (FRIA), FDA estimates that the
benefits of the phaseout policy outweigh the costs (see Ref. 10).
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\5\ FDA is also amending the statutory citation for the device
definition included in Sec. 809.3 (21 CFR 809.3) to reflect that it
is now codified at section 201(h)(1) of the FD&C Act.
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A. FDA's Current Regulatory Framework
A comprehensive system for the regulation of devices is included in
the FD&C Act, as amended by the MDA. Section 513 of the FD&C Act (21
U.S.C. 360c) establishes three categories (classes) of devices
depending on the regulatory controls needed to provide reasonable
assurance of their safety and effectiveness. The three categories of
devices are class I (general controls), class II (special controls),
and class III (premarket approval).
Class I devices are those devices for which the general controls of
the FD&C Act (controls authorized by or under section 501, 502, 510,
516, 518, 519, or 520 (21 U.S.C. 351, 352, 360, 360f, 360h, 360i, or
360j) or any combination of
[[Page 37290]]
such sections) are sufficient to provide reasonable assurance of safety
and effectiveness of the device; or those devices for which
insufficient information exists to determine that general controls are
sufficient to provide reasonable assurance of safety and effectiveness
or to establish special controls to provide such assurance, but because
the devices are not purported or represented to be for a use in
supporting or sustaining human life or for a use which is of
substantial importance in preventing impairment of human health, and do
not present a potential unreasonable risk of illness or injury, are to
be regulated by general controls (section 513(a)(1)(A) of the FD&C
Act).
General controls include, but are not limited to, provisions that
relate to establishment registration and device listing; premarket
notification; prohibitions against adulteration and misbranding (e.g.,
labeling that fails to bear adequate directions for use); recordkeeping
and reporting, including adverse event reporting and reporting of
corrections and removals initiated to reduce a risk to health posed by
the device or to remedy a violation of the FD&C Act caused by the
device which may present a risk to health; investigational device
exemption (IDE) requirements; \6\ and CGMP requirements. These controls
apply to all devices unless an exemption applies.
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\6\ Under section 520(g) of the FD&C Act and part 812 of FDA's
regulations (21 CFR part 812), a clinical investigation to determine
the safety and effectiveness of certain devices must be the subject
of an approved IDE before such investigation may commence. If an IDE
has been granted, a failure to comply with a requirement under which
the device was exempted for investigational use renders the device
adulterated (see section 501(i) of the FD&C Act).
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Class II devices are those devices for which general controls by
themselves are insufficient to provide reasonable assurance of safety
and effectiveness, but for which there is sufficient information to
establish special controls to provide such assurance, including the
promulgation of performance standards, post-market surveillance,
patient registries, development and dissemination of guidelines,
recommendations, and other appropriate actions the Agency deems
necessary to provide such assurance (section 513(a)(1)(B) of the FD&C
Act).
Class III devices are those devices for which insufficient
information exists to determine that general controls and special
controls would provide a reasonable assurance of safety and
effectiveness, and are purported or represented for a use in supporting
or sustaining human life or for a use which is of substantial
importance in preventing impairment of human health, or present a
potential unreasonable risk of illness or injury (section 513(a)(1)(C)
of the FD&C Act).
Under section 513(d)(1) of the FD&C Act, devices that were
introduced or delivered for introduction into interstate commerce for
commercial distribution before the enactment of the MDA on May 28, 1976
(generally referred to as ``preamendments devices'') are classified
after FDA: (1) receives a recommendation from a device classification
panel (an FDA advisory committee); (2) publishes the panel's
recommendation, along with a proposed regulation classifying the
device, and provides an opportunity for interested persons to submit
comments; and (3) publishes a final regulation classifying the device.
A preamendments device for which a classification regulation has not
been promulgated is known as an ``unclassified device.'' Until an
unclassified device type has been formally classified by regulation,
the marketing of new devices within the device type requires FDA
premarket review through a premarket notification (510(k)) under
section 510(k) of the FD&C Act.
Devices that were not introduced or delivered for introduction into
interstate commerce for commercial distribution before May 28, 1976
(generally referred to as ``postamendments devices'') are classified
automatically by section 513(f) of the FD&C Act into class III without
any FDA rulemaking process. Those devices remain in class III and
require approval of a premarket approval application (PMA), unless and
until: (1) FDA classifies or reclassifies the device into class I or II
under section 513(f)(2) or (3) of the FD&C Act, or (2) FDA issues an
order finding the device to be substantially equivalent, in accordance
with section 513(i) of the FD&C Act, to a predicate device that does
not require premarket approval. The Agency determines whether new
devices are substantially equivalent to predicate devices by means of
premarket notification procedures in section 510(k) of the FD&C Act and
part 807 of the regulations (21 CFR part 807).
Failure to comply with applicable requirements of the FD&C Act and
FDA regulations may render the device adulterated and misbranded under
sections 501 and 502 of the FD&C Act and may constitute a prohibited
act under section 301 of the FD&C Act (21 U.S.C. 331). For a further
discussion of these regulatory measures, and specifically how they help
to ensure device safety and effectiveness, see section III.B.1 of this
preamble.
IVDs, as defined in Sec. 809.3 (21 CFR 809.3), are devices
intended for human use and are subject to the FD&C Act. They include
class I, class II, and class III devices, as well as both preamendments
and postamendments devices. Like other devices, IVDs are subject to
general controls, and other applicable requirements under the FD&C Act
and FDA's regulations. IVDs are also subject to specific labeling
requirements in part 809 of the regulations (21 CFR part 809).
For additional discussion of how FDA's legal authorities apply to
LDTs, see the ``Legal Basis for the Amendment'' section (section V.B)
of the NPRM (88 FR 68006 at 68017) and sections VI.D and VI.E of this
preamble.
B. Need for the Rule
This final rule is the culmination of years of study and
deliberation by FDA and represents a significant step forward for
public health. By phasing out the general enforcement discretion
approach for LDTs, FDA is correcting the imbalance in its oversight
between non-laboratory and laboratory IVD manufacturers--an imbalance
that harms American patients. As a result of the final phaseout policy,
the public will benefit from laboratory manufacturer compliance with
basic FDA requirements that protect and promote public health, such as
adverse event reporting, establishment registration and device listing,
labeling standards, investigational use requirements and, as new IVDs
enter the market or are significantly modified, CGMPs and premarket
review. Compliance with these time-tested regulatory measures will put
patients in a better position to understand and have confidence in IVDs
regardless of where they are manufactured. FDA believes that the
benefits of this rulemaking will become more and more pronounced over
time, as new IVDs come on the market and as the circumstances in which
we exercise enforcement discretion narrow correspondingly (as discussed
in section V.B of this preamble).
FDA has considered a wide array of input on this topic. In light of
that input, we have adapted our thinking and adjusted the phaseout
policy in a manner that we believe best serves the public health. The
final phaseout policy, as set forth in section V of this preamble,
fulfills the core goal of greater oversight of laboratory-manufactured
IVDs while also accounting for other key public health interests, such
as helping to maintain access to those beneficial IVDs on which
patients currently rely and access to certain IVDs for which
[[Page 37291]]
there is little financial incentive for development. This final
phaseout policy reflects a careful balancing of relevant factors and,
overall, will substantially promote and protect public health, both now
and in the future.
1. The Device Regulatory Scheme Advances Public Health, Including as
Applied to Laboratory Manufacturers
Since Congress first enacted the FD&C Act, over time and across a
wide range of product areas, Congress has empowered FDA with a standard
set of tools to manage the risks (and, as applicable, help assure the
effectiveness) of regulated products. See 21 U.S.C. 393(b). These
tools--such as adverse-event reporting, establishment registration and
product listing, labeling standards, investigational controls, CGMPs,
and premarket review--routinely appear in FDA statutory schemes because
they effectively serve the public. See section IV for a more complete
description of these authorities. As applied to devices, these
regulatory measures help ensure product safety and effectiveness and
facilitate greater information production and sharing, among other
things.\7\ FDA anticipates that compliance with these regulatory
measures will have equal benefit in the context of laboratory-
manufactured IVDs.\8\
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\7\ See, e.g., Ref. 11 (finding, for stents, that the testing
required under U.S. device premarket review standards improves
consumer welfare and reflects ``optimal policy in terms of trading
off testing versus access to innovation''--while also noting that
post-market surveillance or learning could theoretically yield the
same benefits as pre-market review at lower cost); Ref. 12 (noting
that one benefit of ``approval regulation'' is the collection of
``information useful to `downstream' product users,'' such as
physicians, who then ``exhibit higher consumption and will more
readily switch to superior products''); Ref. 13 (``The FDA is a
critical component to the industries' success because it (1)
provides appropriate reviews for safety and effectiveness, and (2)
helps provide consumers with confidence that these technologies are
safe and effective.'').
\8\ See, e.g., Ref. 14 (``Negative consequences of poorly
understood or weakly applied regulatory oversight processes for
laboratory developed tests have been vividly demonstrated . . . .
Failure to insist on good clinical and laboratory practices, apply
rigorous standards for the design, conduct, and analysis of
biomedical research, and implement safeguards to address conflicts
of interest poses threats to the integrity of biomedical research
and exposes patients to potential harms.''); Ref. 15 (``Increasing
regulatory responsibilities and requirements could encourage
laboratories seeking to introduce LDTs . . . to prioritize tests
with the greatest potential to positively affect patient care, which
could reduce the clutter of available assays with limited
utility.'').
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For example, FDA expects that laboratory compliance with MDR
requirements will yield significant public health benefits. Today,
clinical laboratories comply with CLIA, which means that complaints are
investigated and monitored generally only on a laboratory-by-laboratory
basis. That approach makes sense in light of CLIA's focus on individual
laboratory operations. However, FDA is focused on identifying problems
with an IVD itself--such as design or other manufacturing problems--so
FDA looks for different types of errors and applies a different
analysis to the MDRs it receives. Among other things, FDA aggregates
MDR information across IVD types for tracking and trending, enabling
the detection of issues that a single laboratory may never see. FDA has
identified and helped resolve a wide range of IVD issues using this
type of information (see the response to comment 165 for additional
information). For example, using MDRs submitted by multiple
manufacturers, FDA discovered that high dose biotin supplements were
interfering with certain immunoassays (biotin is commonly used in the
design of these assays), which caused inaccurate results among those
tests. FDA's investigation of the issue--an issue that could apply
equally to laboratory-manufactured tests--led to the redesign of
multiple tests on the market (see also comment response 122). In order
to maximize the value of medical device reporting, FDA's Office of
Health Technology 7 (OHT7): Office of In Vitro Diagnostics, within the
Office of Product Evaluation and Quality in FDA's Center for Devices
and Radiological Health (CDRH), employs trained staff dedicated to the
review of MDRs for each IVD product code. These efforts help ensure
that FDA catches and addresses potentially problematic IVDs to better
protect the public.
Compliance with registration and listing requirements will also
have substantial public health value. The collection of this
information provides FDA with the location of device establishments and
all devices manufactured at those establishments. Knowledge of the
location where devices are manufactured allows for effective planning,
coordinating, and scheduling of inspections, ensuring that FDA has
visibility into the operations and practices at different manufacturing
facilities. Through inspections, FDA has been able to determine when
manufacturers have deficient processes, such as failure to investigate
complaints and adverse events (which can signal larger problems, as
just described). Although CLIA inspections occur for laboratories, such
inspections do not have the same focus on design issues, for example,
such as design changes that fundamentally alter the IVD's safety or
effectiveness and present novel risks to patients. In addition,
compliance with listing requirements will give FDA better information
about the universe of IVDs on the market. With respect to the biotin
interference issue discussed earlier, for example, FDA's investigation
led to the redesign of affected tests in FDA's listing database, but
FDA did not have insight into laboratory developed tests on the market
that might have the same issue because they were not in the database.
It is possible that laboratories today are still manufacturing and
offering tests with inaccurate results due to biotin interference. With
greater listing information, FDA can better protect the public through
more comprehensive remediation efforts, among other things. FDA's
publicly accessible registration and listing database also gives the
public greater knowledge of IVD manufacturers and the range of IVDs on
the market, which will benefit patients and providers who seek to
better understand the different testing options that are available and
the source and location of those testing options. Right now, as noted
in the FRIA, there is no reliable inventory of IVDs on the market. More
comprehensive information will do a great service to the public and
improve patient care.
Laboratory compliance with FDA labeling requirements will also
materially advance public health, because it will provide for the
availability of a consistent set of information critical to
understanding the IVD, whether the IVD is manufactured by a laboratory
or another manufacturer. The labeling requirements in Sec. 809.10 (21
CFR 809.10) require IVD manufacturers to disclose basic facts about an
IVD that can inform a doctor or patient's selection decisions, such as
the intended use, limitations, and performance characteristics of the
test. Today, ordering physicians do not necessarily have access to this
standardized set of information for IVDs offered as LDTs, and therefore
may lack the information needed to understand the use and performance
of tests for their intended uses, make decisions in the context of an
individual patient's needs, and pass on relevant information to their
patients. Laboratory compliance with labeling requirements will mean
that laboratories both compile and provide access to this type of
information, which will facilitate knowledge transfer and,
consequently, more informed healthcare decisions. Labeling also
provides a frame of
[[Page 37292]]
reference for evaluating a manufacturer's promotional claims, helping
FDA determine, for example, whether manufacturers may be misleading the
public about the safety or effectiveness of their IVDs. Based on the
various lawsuits cited in the NPRM (88 FR 68006 at 68012), FDA is aware
that such promotion may be taking place and should be addressed.
FDA is also aware that, today, laboratories are conducting IVD
clinical investigations without complying with FDA requirements,
including the requirement to submit an IDE application for FDA review
before beginning studies involving ``significant risk'' IVDs. When this
occurs, subjects may be enrolled in studies that lack key human subject
protections. Among other things, such investigations may lack an
appropriate evaluation of whether, for example, the informed consent
documents that are provided to potential subjects contain adequate
information about the reasonably foreseeable risks or potential
benefits of participation in the study. Such investigations of
significant risk IVDs may also lack review by FDA to evaluate whether
there are sufficient data to justify use of a significant risk IVD in
the proposed study population. As explained in an FDA memorandum to
file that was part of the record for this rulemaking, FDA is aware of
circumstances in which laboratories have failed to conduct appropriate
analytical validation studies to support the use of tests in clinical
investigations (Ref. 16). In these instances, in the absence of FDA
review of these investigations, subjects may have been enrolled in
studies that exposed them to safety risks with little potential for
benefit or for generating useful information.
Laboratory compliance with CGMP requirements will benefit the
public as well. The Quality System Regulation (QSR) requires
manufacturers to establish procedures for the consistent, quality
manufacturing of devices. FDA recently issued comprehensive amendments
to harmonize the QSR with international quality management system
requirements (89 FR 7496, February 2, 2024). Under FDA's quality system
(QS) requirements, design controls are a key area of focus, and an area
that is distinct from CLIA (see the response to comment 188 for further
information). Design controls require manufacturers to have procedures
for generating IVD specifications, making sure their IVDs actually meet
those specifications, and confirming that those specifications conform
with user needs and intended use(s). By establishing and following a
set system of documentation, manufacturers approach device design and
modifications systemically, ensuring that the original design and any
changes have been properly evaluated and do not have unintended
consequences. In 1990, Congress specifically granted FDA authority to
issue design control requirements after the Agency found that 44
percent of the quality problems that had led to voluntary recall
actions between 1983 and 1989 were due to design errors or
deficiencies, and the Agency promulgated corresponding QS regulations
in 1996 (61 FR 52602, October 7, 1996). Design controls play such a key
role because, as FDA explained when it issued those regulations,
``[t]he intrinsic quality of devices, including their safety and
effectiveness, is established during the design phase'' (61 FR 52602 at
52615). Other QS requirements help ensure effective and appropriate
design, such as acceptance activities, corrective and preventive
actions, and records requirements. Although FDA recognizes that
compliance with the QS requirements is associated with relatively
higher costs for laboratories, and has taken that fact into account in
crafting the phaseout policy, FDA believes laboratory compliance with
the requirements generally will advance public health.
Finally, premarket review is one of FDA's most important tools for
protecting and promoting public health. Through premarket review, the
Agency evaluates the scientific information supporting the analytical
validity, clinical validity, and safety of high- and moderate-risk
IVDs, which helps ensure the IVD's safety and effectiveness before it
reaches a patient. In FDA's experience, premarket review serves an
important gatekeeping function regardless of whether an IVD is
manufactured by a laboratory or another manufacturer. For example, FDA
has received submissions for IVDs offered as LDTs showing that
laboratories do not always properly validate tests or have sound
clinical data to support a test's intended use (Ref. 16). If marketed
as originally presented to FDA, many of these tests could have led to
missed diagnoses or misdiagnoses, improper patient management
decisions, or missed opportunities for beneficial treatment. Through
premarket review, FDA works with applicants to obtain adequate data,
determine whether a device works as intended, and refine labeling to
reflect the intended use and limitations of an IVD. This process
motivates the development of robust scientific data on safety and
effectiveness \9\ and gives patients confidence that an independent,
expert third party has determined that patients can rely on these IVDs.
FDA has recognized circumstances in the final phaseout policy in which
the benefits of laboratory compliance with premarket review
requirements are outweighed by other public-health considerations. The
Agency will exercise enforcement discretion in those circumstances, as
described below. Apart from these circumstances, FDA expects that
laboratory compliance with premarket review requirements will have a
significant positive impact on public health.
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\9\ See Ref. 17.
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2. The Oversight Approach Set Forth in This Preamble Will Advance
Public Health
Those who object to this rulemaking appear to argue that the IVDs
manufactured by laboratories are so fundamentally different from, or
better than, other IVDs that these IVDs should not fall under the
oversight scheme outlined above. But these commenters are not able to
point to differences that logically sustain that position. Many
laboratory-manufactured tests use the same materials and technology,
are based on the same scientific principles, are intended for the same
or similar purposes, are developed by those with similar expertise,
require the same level of training to perform, and are marketed for the
same patients as tests from other manufacturers. Although some
activities of these laboratories are also subject to CLIA, CLIA is not
a substitute for FDA oversight, as detailed throughout this preamble
and as the Centers for Medicare & Medicaid Services (CMS) has
explained.
Furthermore, a review of the evidence does not bear out the
suggestion that laboratory-manufactured IVDs have higher quality or
perform better than other IVDs. FDA's memorandum to file describing
submissions for IVDs offered as LDTs detailed the many defects FDA has
seen with laboratory validation, among other things, and described the
submissions as raising ``significant concerns'' in some cases (Ref.
16). During the COVID-19 emergency, FDA's conversations with laboratory
manufacturers revealed that many were unfamiliar with what constitutes
appropriate analytical and clinical validation for an IVD generally
(see comment response 37 and Ref. 18). FDA's experience is corroborated
by new information in the record from New York State. New York State
submitted
[[Page 37293]]
data indicating that more than half of original applications from
laboratories could not be approved by the New York State Department of
Health Clinical Laboratory Evaluation Program (NYS CLEP) based on
deficiencies such as ``design flaws, inadequate validation data, and
process problems that call into question the reliability of the
results'' (Ref. 19). And in one of the only true head-to-head
comparisons between IVDs offered as LDTs and the parallel FDA-
authorized IVD,\10\ the IVDs offered as LDTs were less accurate than
the FDA-authorized IVD (Ref. 20). Although some commenters suggested
that a reanalysis of that data supports a different conclusion, even
under the reanalysis, the laboratory tests had worse performance, with
only 8 of 19 laboratories correctly reporting all variants (compared to
7 in the original analysis). For additional information about the
analysis and reanalysis, see comment responses 34 and 38.\11\
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\10\ For purposes of this preamble, ``FDA-authorized'' refers to
FDA permitting the marketing of a device via the premarket approval,
510(k), De Novo classification, Biologics License Application (BLA),
or Humanitarian Device Exemption (HDE) pathway and to devices that
are exempt from premarket notification. This term does not include
devices authorized for emergency use under section 564 of the FD&C
Act.
\11\ For additional discussion of evidence relevant to IVDs
offered as LDTs, see section III.B.2 of the NPRM (88 FR 68006 at
68010-12).
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In short, based on the information before us, we do not believe
that the general enforcement discretion approach for LDTs should
continue. Today, IVDs offered as LDTs do not have appropriate
assurances of safety and effectiveness. At least one survey suggests
that the public agrees.\12\ Therefore, FDA is phasing out the general
enforcement discretion approach for LDTs, as explained in more detail
in section V.
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\12\ Ref. 21 (``When presented with information on the
differences between FDA regulation and CMS oversight, most
participants supported FDA having oversight over all diagnostic
tests.'').
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However, FDA also recognizes the effect that its longstanding
enforcement discretion approach has had on the market, the role that
laboratory-manufactured tests play in modern healthcare, and the
presence of other expert regulatory bodies. Many comments emphasized
these considerations. FDA agrees with certain comments' concern, for
example, that expecting compliance with full QS and premarket review
requirements for all currently marketed IVDs offered as LDTs could lead
to the loss of access to safe and effective IVDs on which patients
currently rely, and we are issuing an enforcement discretion policy to
address that issue (see section V.B.3). FDA also agrees with the
concern that, for certain LDTs for unmet needs, expecting full
compliance with FDA requirements could lead to loss of access to tests
for unmet needs for which laboratories cannot recoup the costs of
compliance; we are issuing an enforcement discretion policy to address
that issue in circumstances in which certain risk mitigations apply
(see section V.B.3). FDA has also incorporated enforcement discretion
policies recognizing the regulatory role that other Federal and State
entities play (see sections V.B.1 and 2). In these and other ways, FDA
has crafted a tailored phaseout policy that balances the important
public health considerations at issue in this rule.
We anticipate that the final phaseout policy will provide
significant benefits to the public. As indicated in the FRIA, the
anticipated benefits significantly outweigh the anticipated costs.
Through this Agency action, patients will have greater assurance that
the IVDs used in their care are safe and effective, a significant step
forward for public health. In addition, by applying the same general
oversight approach to laboratories and non-laboratories that
manufacture IVDs, FDA will reduce regulatory uncertainty, which will
give stakeholders more stability, clarity, and confidence, and
facilitate investment in the development of innovative IVDs (Ref. 22).
FDA oversight will help to support coverage and reimbursement
determinations for IVDs offered as LDTs, which we anticipate will make
certain IVDs offered as LDTs for which there is a reasonable assurance
of safety and effectiveness more affordable for patients. And with
increased oversight, FDA will be able to help promote adequate
representation in validation studies, and transparency regarding
potential differential performance and unknown performance in certain
patient populations, which will ultimately help advance health equity
(see comment response 221 for additional information).
FDA expects the benefits of the phaseout policy to become more and
more pronounced over time, as new tests come on the market and as the
circumstances in which we exercise enforcement discretion narrow
correspondingly. Diagnostic testing is increasingly important; for
example, as time goes on, more novel treatments will require use of a
specialized test to identify patients likely to benefit from those
treatments.\13\ Furthermore, IVDs offered as LDTs are a growing sector
of the diagnostic testing market (Ref. 4). FDA anticipates that IVDs
will continue to become more complex and play a greater role in modern
healthcare (Ref. 3). The U.S. LDT market size is anticipated to grow 6
percent from 2023 to 2030 due to varying factors including increased
use in personalized medicine and rising prevalence of chronic diseases.
(Id.) FDA is therefore taking steps to help ensure that IVDs are safe
and effective regardless of where they are manufactured, so that both
now and in the future, patients can have confidence about the tests
used in their care.
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\13\ See, e.g., Ref. 23 (``Demand is increasing in the CDx
market, due to the paradigm shift to precision medicine.'').
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C. Summary of Comments on the Notice of Proposed Rulemaking
In the Federal Register of October 3, 2023, FDA published a rule
proposing an amendment to its regulations to make explicit that IVDs
are devices under the FD&C Act including when the manufacturer is a
laboratory, and proposing a policy under which FDA would phase out its
general enforcement discretion approach for LDTs. The comment period
for the NPRM closed on December 4, 2023. FDA received more than 6,500
comments on the NPRM from a variety of entities including medical
device associations, members of the medical device and pharmaceutical
industries, medical and healthcare professional associations, hospitals
and academic medical centers (AMCs), accreditation organizations, other
advocacy organizations, government agencies, and individuals.
Comments supporting FDA's proposal pointed to problems with LDTs,
concerns about the significant impact of problematic LDTs on patients
and the treatment decisions of healthcare providers, and the need for
increased oversight of LDTs by FDA. Some comments also emphasized the
importance of creating a ``level playing field'' between laboratory and
non-laboratory manufacturers of IVDs, and described how phasing out the
general enforcement discretion approach for LDTs would incentivize
innovation by non-laboratory IVD manufacturers.
Some comments raised concerns or requested clarification regarding
the following:
<bullet> the evidence related to the safety or effectiveness of IVDs
offered as LDTs,
<bullet> the sufficiency of regulation by CMS and other non-FDA
entities,
<bullet> FDA's legal authority to regulate LDTs,
<bullet> the impact of the phaseout policy on access to and the pricing
of IVDs offered as LDTs,
[[Page 37294]]
<bullet> the impact of the phaseout policy on test innovation,
<bullet> the impact of the phaseout policy on small laboratories,
<bullet> the impact of the phaseout policy on specific patient
populations, including underrepresented and underserved populations,
<bullet> the details of the phaseout policy,
<bullet> the types of IVDs offered as LDTs for which FDA intends to
continue the general enforcement discretion approach and generally not
enforce some or all applicable requirements, and
<bullet> FDA's implementation of the phaseout policy and the resources
needed for such implementation.
D. General Overview of the Final Amendment to the Definition of In
Vitro Diagnostic Products
FDA is amending its regulations to make explicit that IVDs are
devices under the FD&C Act including when the manufacturer of the IVD
is a laboratory. This amendment reflects that the device definition in
the FD&C Act does not differentiate between entities manufacturing the
device, and provides further clarity, including for stakeholders
affected by the accompanying changes to FDA's general enforcement
discretion approach for LDTs.
FDA is also amending the statutory citation for the device
definition included in Sec. 809.3 to reflect amendments to section
201(h) of the FD&C Act as a result of the enactment of the Safeguarding
Therapeutics Act (Pub. L. 116-304). For many years, the definition of
``device'' had been codified at section 201(h) of the FD&C Act. Upon
enactment of the Safeguarding Therapeutics Act, the definition of
``device'' was redesignated as paragraph (h)(1) and a new definition of
``counterfeit device'' was codified at paragraph (h)(2).
FDA considered comments received on the NPRM, as discussed in more
detail throughout this preamble, and has made no changes to the
amendment.
E. General Overview of the Final Phaseout Policy
FDA has had a general enforcement discretion approach for most
LDTs.\14\ FDA is phasing out this general enforcement discretion
approach so that IVDs manufactured by a laboratory will generally fall
under the same enforcement approach as other IVDs. The phaseout is
intended to help assure the safety and effectiveness of IVDs offered as
LDTs, while also accounting for other important public health
considerations such as patient access and reliance.
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\14\ As discussed further in section V.A.2, FDA's general
enforcement discretion approach has not applied to certain
categories of LDTs. For these categories of LDTs, FDA has generally
expected applicable requirements to be met, and in the NPRM we
proposed that this approach be maintained (88 FR 68006 at 68021).
After considering comments received on this topic we are not
changing that approach for these categories with the phaseout policy
described in this preamble.
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Following a 4-year phaseout period, FDA will no longer have a
general enforcement discretion approach for LDTs. The phaseout policy
includes the following five stages for IVDs offered as LDTs (a term
discussed further in section V.A.1):
<bullet> Stage 1: beginning 1 year after the publication date of
this final rule, FDA will expect compliance with MDR requirements,
correction and removal reporting requirements, and QS requirements
under Sec. 820.198 (21 CFR 820.198) (complaint files);
<bullet> Stage 2: beginning 2 years after the publication date of
this final rule, FDA will expect compliance with requirements not
covered during other stages of the phaseout policy, including
registration and listing requirements, labeling requirements, and
investigational use requirements;
<bullet> Stage 3: beginning 3 years after the publication date of
this final rule, FDA will expect compliance with QS requirements under
part 820 (21 CFR part 820) (other than requirements under Sec. 820.198
(complaint files), which are already addressed in stage 1);
<bullet> Stage 4: beginning 3\1/2\ years after the publication date
of this final rule, FDA will expect compliance with premarket review
requirements for high-risk IVDs offered as LDTs (IVDs that may be
classified into class III or that are subject to licensure under
section 351 of the Public Health Service Act), unless a premarket
submission has been received by the beginning of this stage in which
case FDA intends to continue to exercise enforcement discretion for the
pendency of its review; and
<bullet> Stage 5: beginning 4 years after the publication date of
this final rule, FDA will expect compliance with premarket review
requirements for moderate-risk and low-risk IVDs offered as LDTs (that
require premarket submissions), unless a premarket submission has been
received by the beginning of this stage in which case FDA intends to
continue to exercise enforcement discretion for the pendency of its
review.
The phaseout policy includes targeted enforcement discretion
policies for certain categories of IVDs manufactured by a laboratory,
as explained in more detail in sections V.B. and V.C. For example, as
proposed in the NPRM, FDA generally does not intend to enforce
requirements under the FD&C Act and FDA's regulations for ``1976-Type
LDTs'' (as described in section V.B.1); Human Leukocyte Antigen (HLA)
tests that are designed, manufactured, and used within a single
laboratory certified under CLIA that meets the requirements to perform
high-complexity histocompatibility testing when used in connection with
organ, stem cell, and tissue transplantation to perform HLA allele
typing, for HLA antibody screening and monitoring, or for conducting
real and ``virtual'' HLA crossmatch tests; and tests intended solely
for forensic (law enforcement) purposes (88 FR 68006 at 68022).
In addition, FDA considered comments received on the proposed
phaseout policy and, based in part on those comments, made various
changes to the phaseout policy, which include the addition of the
following enforcement discretion policies:
<bullet> FDA intends to exercise enforcement discretion and
generally not enforce requirements for LDTs manufactured and performed
within the Veterans Health Administration (VHA) or the Department of
Defense (DoD);
<bullet> FDA intends to exercise enforcement discretion and
generally not enforce premarket review requirements for LDTs approved
by NYS CLEP; \15\
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\15\ For purposes of this preamble, FDA uses the phrase ``LDTs
approved by NYS CLEP'' to refer to LDTs that are approved,
conditionally approved, or within an approved exemption from full
technical documentation, under NYS CLEP. These three categories of
LDTs are discussed further below in section V.B.2. Other LDTs,
including ``LDTs used in Clinical Trials'' and ``Tests Not Subject
to Evaluation'' which are described on NYS CLEP's website (Ref. 24),
are not considered ``LDTs approved by NYS CLEP'' and are not within
the enforcement discretion policy with respect to premarket review
requirements described in section V.B.2. For additional discussion
of the NYS CLEP premarket review program, see section V.B.2.
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<bullet> FDA intends to exercise enforcement discretion and
generally not enforce premarket review requirements and QS requirements
(except for requirements under part 820, subpart M
(Records))<SUP>16 17</SUP> for LDTs manufactured and performed by a
[[Page 37295]]
laboratory integrated within a healthcare system to meet an unmet need
of patients receiving care within the same healthcare system;
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\16\ When the final rule to amend part 820 takes effect in
February 2026, the comparable requirements can be found in
International Organization for Standardization (ISO) 13485 subclause
4.2 as modified by part 820.
\17\ FDA recognizes that part 820, subpart M (Records) includes
cross-references to Sec. Sec. 820.20, 820.22, 820.40, and 820.50
(21 CFR 820.20, 820.22, 820.40, and 820.50). For the categories of
IVDs discussed in section V.B.3 of this preamble, FDA generally
expects compliance with requirements under subpart M but not
Sec. Sec. 820.20, 820.22, 820.40, and 820.50, or comparable
provisions of ISO 13485 in accordance with the amendments to part
820 once that rule takes effect in February 2026.
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<bullet> FDA intends to exercise enforcement discretion and
generally not enforce premarket review and QS requirements (except for
requirements under part 820, subpart M (Records)) for currently
marketed IVDs offered as LDTs that were first marketed prior to the
date of issuance of this rule and that are not modified, or that are
modified in certain limited ways as described in section V.B.3; and
<bullet> FDA intends to exercise enforcement discretion and
generally not enforce premarket review and QS requirements (except for
requirements under part 820, subpart M (Records)) for non-molecular
antisera LDTs for rare red blood cell (RBC) antigens where such tests
are manufactured and performed in blood establishments, including
transfusion services and immunohematology laboratories and where there
is no alternative available to meet the patient's need for a compatible
blood transfusion.
These enforcement policies do not apply to any IVDs identified in
section V.A.2 as falling outside the scope of the phaseout policy or as
discussed in section V.B.
IV. Legal Authority
FDA is issuing this final rule under the Agency's general
rulemaking authorities and statutory authorities relating to devices.
These authorities include sections 201(h)(1), 301, 501, 502, 510, 513,
514, 515, 518, 519, 520, 701, 702, 704, and 801 of the FD&C Act and
section 351 of the PHS Act. In particular:
<bullet> 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.''
<bullet> Section 701(a) of the FD&C Act authorizes FDA to issue
regulations for the efficient enforcement of the FD&C Act.
For additional descriptions of some of the authorities referenced
above, see section III.A of this preamble. For additional discussion of
how these legal authorities apply to LDTs, see the ``Legal Basis for
the Amendment'' section (section V.B) of the NPRM (88 FR 68006 at
68017) and sections VI.D and VI.E of this preamble.
V. Phaseout Policy
Based on the considerations set forth in the NPRM and this
preamble, including the public comments discussed in section VI.F
below, FDA is phasing out the general enforcement discretion approach
for LDTs in stages, as described in more detail below. FDA's intent is
that following a 4-year phaseout period, IVDs offered as LDTs generally
will be expected to meet applicable requirements, with several
enforcement discretion policies for certain categories of IVDs
manufactured by a laboratory as discussed further below.
We note that these policies may not be the only enforcement
discretion policies applicable to these IVDs, and other enforcement
discretion policies not addressed in this phaseout policy may apply to
certain IVDs. As discussed in the NPRM, FDA has adopted and intends to
continue adopting enforcement discretion policies for certain types of
IVDs in certain circumstances, as appropriate (88 FR 68006 at 68021).
For example, FDA issued final guidance documents with enforcement
discretion policies for certain COVID-19 and mpox tests at the
beginning of each declared emergency and, concurrent with this final
rule, is issuing a draft guidance document with an enforcement policy
for certain IVDs for immediate response to a chemical, biological,
radiological, or nuclear (CBRN) agent in the absence of a declaration
under section 564 of the FD&C Act (21 U.S.C. 360bbb-3).
Although FDA is phasing out its current general enforcement
discretion approach over a period of years, the phaseout policy does
not in any way alter the fact that it is illegal to offer IVDs without
complying with applicable requirements. Regardless of the phaseout
timeline and enforcement discretion policies for certain IVDs discussed
below, FDA retains discretion to pursue enforcement action for
violations of the FD&C Act at any time, and intends to do so when
appropriate.
The details of FDA's final phaseout policy, including the scope,
subsidiary enforcement discretion policies, and stages, are set forth
below.
A. Scope
1. IVDs Within the Scope of the Phaseout Policy
While FDA's general enforcement discretion approach has been
focused on LDTs,\18\ FDA has determined to apply a broader scope for
the phaseout policy, consistent with FDA's proposal in the NPRM (88 FR
68006 at 68021).\19\ Specifically, the phaseout policy applies to IVDs
that are manufactured and offered as LDTs by laboratories that are
certified under CLIA and that meet the regulatory requirements under
CLIA to perform high complexity testing, and used within such
laboratories,\20\ even if those IVDs do not fall within FDA's
traditional understanding of an LDT because they are not designed,
manufactured, and used within a single laboratory. Throughout this
preamble, these IVDs are referred to as ``IVDs offered as LDTs.'' \21\
FDA is adopting this scope because it recognizes that not all
laboratories have understood the limited nature of FDA's general
enforcement discretion approach and have been offering IVDs based on
the approach even when those IVDs do not fit what FDA generally
considers to be an LDT. FDA has determined that this
[[Page 37296]]
approach will help facilitate uniform compliance going forward.
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\18\ As discussed elsewhere in this preamble, FDA has generally
considered the term ``laboratory developed test (LDT)'' to mean an
IVD that is intended for clinical use and that is designed,
manufactured, and used within a single CLIA-certified laboratory
that meets the regulatory requirements under CLIA to perform high
complexity testing.
\19\ However, certain enforcement discretion policies described
in sections V.B and V.C apply only to LDTs.
\20\ Other laboratories would be out of compliance with CLIA
regulations if they were developing and performing tests that are
not FDA authorized. Such tests have never fallen within FDA's
general enforcement discretion approach (see, e.g., Refs. 25-27).
\21\ We note that ``IVDs offered as LDTs'' does not include IVDs
manufactured or used outside of a laboratory, including collection
devices. FDA's statements and actions have shown that the Agency has
expected compliance where, for example, CLIA is inapplicable (e.g.,
manufacturing outside of a laboratory and collection devices). See,
e.g., 61 FR 10484 (``in-house developed tests have not been actively
regulated by the Agency'') (emphasis added); Ref. 23 (describing an
LDT as an IVD that is ``designed, manufactured, and used within a
single laboratory'') (emphasis added); United States v. Undetermined
No. of Unlabeled Cases, 21 F.3d 1026 (10th Cir. 1994) (FDA
enforcement action against a laboratory that ``purchased specimen
containers, repackaged them into kits which included instruction
sheets, and forwarded them along with consent forms to insurers to
collect specimens''); Ref. 28 (compliance action regarding a blood
lead testing system manufactured outside of a laboratory but for use
by a laboratory); Ref. 29 (compliance action involving a laboratory
and a sample collection kit).
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2. IVDs Outside the Scope of the Phaseout Policy
Although FDA is adopting a broader scope for the phaseout policy,
it does not intend to sweep in certain IVDs that were excluded from the
general enforcement discretion approach, as reflected in compliance
patterns, multiple public FDA actions and communications, or both. In
particular, the general enforcement discretion approach has never
applied to the following tests:
a. Tests that are intended as blood donor screening or human cells,
tissues, and cellular and tissue-based products (HCT/P) donor screening
tests required for infectious disease testing under Sec. 610.40 (21
CFR 610.40) and Sec. 1271.80(c) (21 CFR 1271.80(c)), respectively, or
required for determination of blood group and Rh factors under Sec.
640.5 (21 CFR 640.5). Under the cited regulations, a blood or HCT/P
establishment must not use a test for the purposes listed here unless
the test is authorized by FDA for such use. Blood and HCT/P
establishments must register with FDA and are subject to FDA inspection
(see parts 207, 607, 807, and 1271 (21 CFR parts 207, 607, 807, and
1271)). FDA's general enforcement discretion approach for LDTs has
never applied to these tests because these tests are a critical part of
the overall process of ensuring the safety of blood and blood
components and HCT/Ps by preventing infectious disease transmission and
incompatible blood transfusions which can have life-threatening
consequences (see, e.g., Refs. 30 and 31). Based on FDA experience,
establishments have been generally complying with the requirements to
use authorized tests under Sec. Sec. 1271.80(c), 610.40, and 640.5.
FDA addresses comments related, in part, to this category of tests in
sections VI.L.14 and VI.L.15.
b. Tests intended for emergencies, potential emergencies, or
material threats declared under section 564 of the FD&C Act. After all
previous declarations under section 564(b), FDA has generally expected
LDTs to comply with applicable requirements in the FD&C Act and FDA
regulations. FDA's general enforcement discretion approach has not
applied to these tests because of the significant risk posed by the
disease (as signified by the unusual step of issuing a declaration) and
because false results can have serious implications for disease
progression and public health decision-making, in addition to the
individual patient's care. As it has done in other areas, FDA has
adopted (and may continue to adopt) specific enforcement discretion
policies for such tests (see, e.g., Refs. 32 and 33). In addition,
consistent with the Government Accountability Office (GAO)'s 2022
recommendation that ``FDA should develop a policy for the use of
enforcement discretion regarding unauthorized tests in future public
health emergencies'' (Ref. 34), FDA is issuing a draft guidance
document, concurrent with this final rule, on factors to consider in
adopting such enforcement discretion policies. FDA has communicated its
expectations regarding tests for emergency use in final guidance and
elsewhere, including ``It has come to our attention'' letters posted on
FDA's website and other public communications (see, e.g., Refs. 27, 32
to 37). FDA addresses comments related, in part, to this category of
tests in section VI.L.10.
c. Direct-to-consumer tests. FDA's general enforcement discretion
approach has not applied to tests intended for consumer use (without
meaningful involvement by a licensed healthcare professional), given
the greater risks to patients presented by these tests (see, e.g.,
Refs. 28 and 39 to 44). FDA's enforcement discretion approach for LDTs
was originally premised, in part, on the participation of medical
professionals to help determine whether a particular test was
appropriate, counsel patients on the significance and limitations of a
test, assist in interpreting results, assess how the results fit in the
overall clinical picture, and consider next steps. When patients order
tests, receive results, or make decisions (such as a decision to stop
medication) without this expert intermediary, there is a heightened
need for FDA oversight. FDA addresses comments related, in part, to
this category of tests in section VI.L.1.
For these categories of tests, FDA has generally expected
applicable requirements to be met, and we are not changing that
approach with the phaseout policy. FDA intends to continue to enforce
all applicable requirements for these categories of tests. Neither the
phaseout policy nor any subsidiary enforcement discretion policies
described in sections V.B and V.C apply to these tests.
Finally, as further discussed in the NPRM, tests manufactured and
offered for use exclusively for public health surveillance are distinct
from other tests where: (1) they are intended solely for use on
systematically collected samples for analysis and interpretation of
health data in connection with disease prevention and control and (2)
test results are not reported to patients or their healthcare providers
(88 FR 68006 at 68023). The results of these tests are generally used
for trending on a population basis or public health outbreaks, where
the test results are not intended for clinical decision making. FDA
received several comments on these tests (see section VI.L.6), and for
the reasons discussed in the NPRM (88 FR 68006 at 68023) and in our
responses to those comments, we continue to believe that these tests
should not be affected by the phaseout policy.\22\
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\22\ Surveillance tests are not used for individual decision-
making. Screening tests are distinct from public health surveillance
tests and do fall within the phaseout policy.
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B. Enforcement Discretion Policies
FDA is phasing out the general enforcement discretion approach for
LDTs so that IVDs manufactured by laboratories will generally fall
under the same enforcement approach as other IVDs. For certain IVDs,
however, FDA intends to exercise enforcement discretion and generally
not enforce all or some applicable requirements, for the reasons
discussed further below. Specifically, and as described further in
section V.B.1, FDA intends to exercise enforcement discretion and
generally not enforce all applicable requirements for 1976-Type LDTs,
certain HLA tests, tests intended solely for forensic (law enforcement)
purposes, and LDTs manufactured and performed within DoD or VHA. As
described further in section V.B.2, FDA also intends to exercise
enforcement discretion and generally not enforce premarket review
requirements for LDTs that are approved by NYS CLEP. In addition, and
as described further in section V.B.3, FDA intends to exercise
enforcement discretion and generally not enforce premarket review and
QS requirements (except for requirements under part 820, subpart M
(Records)) for LDTs manufactured and performed by a laboratory
integrated within a healthcare system to meet an unmet need of patients
receiving care within the same healthcare system, currently marketed
IVDs offered as LDTs, and certain non-molecular antisera LDTs for rare
RBC antigens.
As noted above, these policies do not apply to the tests described
in section V.A.2. Moreover, in an emergent situation (see additional
discussion of this time period below), these policies do not apply to
tests that are: (1) intended to detect or diagnose a serious or life-
threatening disease or condition that may be attributed to a newly
identified, previously unknown, or
[[Page 37297]]
unusual CBRN agent or agents; or a known agent or agents that results
in a newly identified or unusual clinical presentation of such a
disease or condition; and (2) needed for immediate response to a
potential case or cases of such disease or condition for which there is
no adequate, authorized, and available alternative. FDA is proposing a
separate enforcement policy for some such tests in a concurrently
issued draft guidance entitled ``Enforcement Policy for Certain In
Vitro Diagnostic Devices for Immediate Public Health Response in the
Absence of a Declaration under Section 564.'' As discussed in that
draft guidance, that proposed enforcement policy would be for tests
that are intended to help ensure the government's coordinated and
effective public health response and so is limited to certain tests and
certain laboratories, such as those that are U.S. Government (USG)
laboratories, State or local public health laboratories, or other
laboratories that have agreements with the USG.\23\ FDA believes that
the proposed policy in that draft guidance (and not the enforcement
discretion policies described in section V.B of this preamble) would be
appropriate for such tests during the limited time period described in
the draft guidance--specifically, during an emergent situation.\24\ We
note that prior to an emergent situation and after an emergent
situation has been resolved, when there is not a critical need for a
coordinated and immediate public health response and where the
implications of false results may not have as serious implications for
public health decision-making, such tests may fall within the
enforcement discretion policies described in section V.B of this
preamble.
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\23\ For tests that meet the description included at the
beginning of this paragraph but that would not otherwise fall within
the proposed policy described in the draft guidance because, for
example, they are manufactured by entities that fall outside the
scope of the draft guidance, FDA is not proposing an enforcement
discretion policy in the draft guidance. For such tests, FDA
generally will expect compliance with applicable FDA requirements in
line with the phaseout policy during an emergent situation, and
outside of an emergent situation, these tests could potentially fall
within an enforcement discretion policy described in section V.B. of
this preamble.
\24\ Prior to finalization of that draft guidance, FDA intends
to act consistent with the relevant policies for LDTs included in
this final rule and will consider whether to update any policies
herein as a result of any changes to the proposed enforcement policy
described in the draft guidance, when finalized.
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As with any enforcement discretion policy, FDA may update any of
these policies as circumstances warrant or if the circumstances that
inform these policies change, consistent with FDA's good guidance
practices (21 U.S.C. 371(h), Sec. 10.115). Notably, these enforcement
discretion policies do not confer lawful marketing status on any IVD
being marketed as described in the policies. These policies do not in
any way alter the fact that it is illegal to market an IVD that lacks
required premarket authorization or is otherwise in violation of the
FD&C Act, the PHS Act, or FDA regulations. These policies set forth
FDA's general priorities and, consistent with FDA's public health
mission, FDA intends to take action to enforce applicable requirements
for IVDs (including IVDs described in these policies) as appropriate,
taking into account any public health concerns as evaluated on a case-
by-case basis.\25\ For example, if FDA receives reports, or otherwise
learns of information, that raise safety or effectiveness concerns with
an IVD that falls within an enforcement discretion policy, FDA
generally intends to take action with respect to requirements
applicable to that specific IVD.
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\25\ See Heckler v. Chaney, 470 U.S. 821, 835 (1985) (providing
that the FD&C Act's enforcement provisions commit broad discretion
to the Secretary to decide how and when they should be exercised).
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1. Enforcement Discretion Policies With Respect to All FDA Requirements
For several categories of tests, FDA intends to continue the
general enforcement discretion approach and generally not enforce any
applicable requirement because tests in these categories are, in our
experience, unlikely to pose significant risks or are conducted in
circumstances that themselves will mitigate the risks. One such
category of tests is referred to in this preamble as ``1976-Type
LDTs.'' Such tests have the following characteristics common among LDTs
offered in 1976: (1) use of manual techniques (without automation)
performed by laboratory personnel with specialized expertise; (2) use
of components legally marketed for clinical use; and (3) design,
manufacture, and use within a single CLIA-certified laboratory that
meets the requirements under CLIA for high complexity testing. The
characteristics associated with LDTs offered in 1976 resulted in the
emergence of FDA's general enforcement discretion approach for LDTs,
and the specific characteristics listed above provide the greatest risk
mitigation among the characteristics that were commonly associated with
LDTs offered in 1976 (discussed in section III). Based on changes to
the LDT landscape since 1976, the risks associated with most modern
LDTs are generally much greater today than they were in 1976; however,
for tests that share the characteristics listed above, FDA has
determined that the risks are sufficiently low such that FDA's general
enforcement discretion approach for LDTs should continue to apply (see
section VI.L.3 for a discussion of the comments on this topic and FDA's
responses to those comments). These tests might include, for example,
immunohistochemistry tests that involve no automated preparation or
interpretation, but would not include, for example, lateral flow tests,
as they do not generally rely on laboratory personnel expertise. This
enforcement discretion policy does not apply to any IVDs identified in
section V.A.2 as falling outside the scope of the phaseout policy or as
discussed in section V.B. FDA intends to consider whether guidance
containing additional discussion and examples of tests that may fall
within this category would be helpful, and would issue any such
guidance in accordance with good guidance practices (see Sec. 10.115).
Another category of such tests is HLA tests that are designed,
manufactured, and used within a single laboratory certified under CLIA
that meets the requirements to perform high-complexity
histocompatibility testing when used in connection with organ, stem
cell, and tissue transplantation to perform HLA allele typing, for HLA
antibody screening and monitoring, or for conducting real and
``virtual'' HLA crossmatch tests (hereinafter ``HLA tests for
transplantation''). Physicians must often make prompt decisions about
transplantation based on medical judgment regarding their patient's
condition and degree of mismatch between the donor and patient should
an organ, stem cells, or tissue become available. Because new alleles
are continuously identified, and the need for assessing degree of
crossmatch is generally urgent, modifications to HLA tests for
transplantation are often made rapidly in response to urgent
situations. Further, these tests are often individualized within each
medical facility; for example, they include reagents that reflect local
HLA polymorphisms and patient demographics.
In addition, oversight under certain Federal programs helps to
mitigate the risks of harm from inaccurate and unreliable HLA tests for
transplantation. For example, the National Organ Transplant Act (NOTA)
of 1984 created the Organ Procurement and Transplant Network (OPTN).
NOTA, as amended (42 U.S.C. 273 et seq.), and the OPTN
[[Page 37298]]
Final Rule, 42 CFR part 121, establish a comprehensive system for the
safe and equitable allocation, distribution, and transplantation of
donated organs. The OPTN Final Rule and OPTN bylaws and policies govern
operation of all member transplant hospitals, organ procurement
organizations, and histocompatibility laboratories in the United
States. The Stem Cell Therapeutic and Research Act of 2005 (Pub. L.
109-129), as amended, authorizes a national registry (``Be the Match
Registry'') to support patients in need of bone marrow or umbilical
cord blood transplants, which is operated under Federal contracts by
the National Marrow Donor Program[supreg] (NMDP) (Ref. 45). NMDP sets
forth minimum requirements for organizations working through the NMDP
to facilitate stem cell transplants (Refs. 46 and 47).
OPTN has requirements for performance of HLA typing, antibody
screening, and crossmatching tests, and NMDP requires HLA typing for
donors and potential recipients for stem cell transplants facilitated
by the Be the Match Registry, as well as reporting of test results to
NMDP (Refs. 47 and 48). Both OPTN and NMDP have procedures in place for
identifying, investigating, and reporting discrepant tests results
(Refs. 48 and 49).
In addition to these safeguards designed to identify and resolve
potentially inaccurate results, each OPTN member histocompatibility
laboratory must, among other things, meet specified American Society
for Histocompatibility and Immunogenetics (ASHI) and/or College of
American Pathologists (CAP) standards as a condition of OPTN membership
(Ref. 50). NMDP similarly requires histocompatibility laboratories used
by U.S. transplant centers and donor centers to be accredited by CAP
and/or ASHI (Refs. 46, 51 and 52). Both ASHI and CAP standards have
provisions that specifically address OPTN and/or NMDP requirements for
histocompatibility laboratories that perform tests for those programs.
Importantly, as discussed below, FDA does not believe that a CAP or
ASHI accreditation of a laboratory, on its own, is sufficient to
mitigate risk and provide assurance of the safety and effectiveness for
all IVDs offered as LDTs by the accredited laboratory. However, we
consider the fact that OPTN and NMDP require adherence to CAP and/or
ASHI standards, including provisions specific to OPTN and NMDP
requirements, to be one factor that helps mitigate risk of inaccurate
results or unreliable HLA tests for transplantation. After considering
this factor in combination with the protections provided through the
programs described above and the urgent circumstances in which HLA
tests for transplantation may be modified and performed, as well as the
comments received on our proposed approach to HLA tests for
transplantation, FDA intends to continue the general enforcement
discretion approach for these tests. We note that this enforcement
discretion policy does not apply to HLA tests used for blood
transfusion, which are highly standardized across institutions, nor
does it apply to any IVDs identified in section V.A.2 as falling
outside the scope of the phaseout policy or as discussed in section
V.B.
An additional category of such tests is tests intended solely for
forensic (law enforcement) purposes. FDA has had an enforcement
discretion approach for such tests for over 20 years and that approach
applies to such tests regardless of whether they are offered as an LDT.
See, e.g., 65 FR 18230, April 7, 2000. Tests used in the law
enforcement setting are subject to protections and requirements
associated with the judicial process that mitigate risk related to test
accuracy and sample collection and that generally are not available in
the home, workplace, insurance, and sports settings. These protections
include the use of rules of evidence in judicial proceedings and legal
representation of the accused (i.e., the person being tested) through
the judicial process during which the accuracy of the test may be
raised during the adjudication. This enforcement discretion policy does
not apply to any IVDs identified in section V.A.2 as falling outside
the scope of the phaseout policy or as discussed in section V.B.
A final category of such tests is LDTs \26\ manufactured and
performed within DoD or VHA. This policy applies only to LDTs used for
patients that are being tested and treated within the DoD or VHA. In
the NPRM, FDA sought comment on whether it would be appropriate to
continue the general enforcement discretion approach, such that FDA
generally would not enforce any applicable device requirements, ``where
outside programs can be leveraged'' (88 FR 68006 at 68024). FDA
mentioned programs within VHA as an example, and we received several
comments stating that FDA should continue the general enforcement
discretion approach for LDTs manufactured and performed by VHA,
generally on the grounds that it would avoid ``duplicating regulatory
oversight regimes'' and promote the efficient use of resources. Two
comments suggested that FDA should not continue the general enforcement
discretion approach for LDTs manufactured and performed by VHA because
VHA's program is not in alignment with FDA regulation (though one of
these comments supported ``leveraging'' outside programs ``in
principle''). FDA received one comment, submitted by DoD, which stated
that FDA should maintain an enforcement discretion approach for LDTs
``utilized by DoD for our service members.'' Among other things, DoD
emphasized ``the importance of LDTs to DoD's operational readiness and
mission success,'' and referenced DoD's internal programs, including
``the authority, oversight, and responsibilities vested in the
Assistant Secretary of Defense (Health Affairs).''
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\26\ Consistent with what FDA has generally considered to be an
LDT (as discussed elsewhere in this preamble), this enforcement
discretion policy applies only to tests that are designed,
manufactured, and used within a single CLIA-certified laboratory
that meets the requirements under CLIA for high complexity testing.
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FDA recognizes that DoD and VHA have statutory mandates under 10
U.S.C. chapter 55 and 38 U.S.C. chapter 73 to provide for the care of
specific populations in their systems and have existing oversight and
enforcement groups within their respective systems. Based on
consultation with DoD and VHA, FDA understands that both departments
use and will continue to use FDA-authorized IVDs wherever available.
However, to meet the needs of their patient populations (i.e., military
personnel, veterans, and their families) and fulfill their mandates,
DoD and VHA often manufacture unique LDTs, such as tests for diseases
or chemicals to which their patients may be exposed while serving
abroad but which do not exist at home. DoD and VHA have developed
expertise for evaluating these unique tests, and are taking steps in
consultation with FDA to track all LDTs in their systems and to ensure
the analytical and clinical validity of their LDTs, the quality
manufacturing of their LDTs, and the central reporting of adverse
events.\27\ Additional oversight by FDA would not be an efficient use
of government resources in these circumstances.
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\27\ To the extent that VHA and DoD anticipate the need for
additional resources, FDA understands that such matters will be
addressed through the management of those departments.
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This enforcement discretion policy does not apply to any IVDs
identified in section V.A.2 as falling outside the scope of the
phaseout policy or as discussed in section V.B.
[[Page 37299]]
2. Enforcement Discretion Policies With Respect to Premarket Review
Requirements
FDA also generally intends to exercise enforcement discretion with
respect to premarket review requirements for LDTs \28\ that are
approved by NYS CLEP.\29\ For these LDTs, FDA intends to exercise
enforcement discretion and generally not enforce premarket review
requirements given certain risk mitigations under NYS CLEP as discussed
further below. This policy applies only to the approved version of the
test (FDA is aware that some laboratories may offer different versions
of an LDT depending on whether a patient specimen comes from NYS or
from elsewhere). This enforcement discretion policy does not apply to
any IVDs identified in section V.A.2 as falling outside the scope of
the phaseout policy or as discussed in section V.B.
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\28\ Consistent with what FDA has generally considered to be an
LDT (as discussed elsewhere in this preamble), this enforcement
discretion policy applies only to tests that are designed,
manufactured, and used within a single laboratory that is certified
under CLIA and meets the regulatory requirements under CLIA to
perform high complexity testing.
\29\ As noted elsewhere in this preamble, for purposes of this
preamble FDA uses the phrase ``LDTs approved by NYS CLEP'' to refer
to LDTs that are approved, conditionally approved, or within an
approved exemption from full technical documentation, under NYS
CLEP. These three categories of LDTs are discussed further below in
this section (section V.B.2). Other LDTs, including ``LDTs used in
Clinical Trials'' and ``Tests Not Subject to Evaluation'' which are
described on NYS CLEP's website (Ref. 24), are not considered ``LDTs
approved by NYS CLEP'' and are not within the enforcement discretion
policy with respect to premarket review requirements described in
this section.
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FDA intends to phase out the general enforcement discretion
approach with respect to other applicable requirements for these tests
consistent with the stages described in section V.C below. In brief,
for these tests, FDA intends at stage 1 to phase out the general
enforcement discretion approach with respect to MDR requirements,
correction and removal reporting requirements, and QS requirements
under Sec. 820.198 (complaint files) 1 year after publication of this
final rule; at stage 2 to phase out the general enforcement discretion
approach with respect to requirements not addressed in the other stages
(these requirements include, e.g., registration and listing
requirements and labeling requirements) 2 years after publication of
this final rule; and at stage 3 to phase out the general enforcement
discretion approach with respect to certain QS requirements (see below
for further discussion) 3 years after publication of this final rule.
See section V.C for further information.
As noted above, in the NPRM, FDA sought comment on whether it would
be appropriate to continue the general enforcement discretion approach
with respect to LDTs that are under NYS CLEP or certain other programs
(88 FR 68006 at 68024), and we received several comments in response
(see discussion in section VI.F.5 of this preamble). This policy
reflects consideration of those comments. Should experience with this
policy indicate that changes are warranted, FDA would consider
appropriate policy changes through guidance in accordance with good
guidance practices (see Sec. 10.115).
FDA believes that NYS CLEP has a program that provides for certain
mitigations that help reduce the risk of harm from inaccurate and
unreliable LDTs. Specifically, as discussed further below, NYS CLEP has
a program under which high risk and moderate risk LDTs generally are
evaluated for analytical and clinical validity. Based on the available
information, FDA believes that generally NYS CLEP's review of
analytical and clinical validity of LDTs helps to mitigate the risk of
harm from inaccurate and unreliable LDTs and that, rather than
enforcing premarket review requirements by FDA, it would be more
efficient and effective to use our resources for other oversight
activities regarding IVDs offered as LDTs.
Under NYS CLEP's program, high risk LDTs require full technical
review and approval prior to testing on specimens from NYS (Ref. 53).
Moderate risk LDTs require full technical review but may receive
conditional approval if the laboratory holds a permit in the
appropriate category (Ref. 53). For classification as a moderate risk
LDT under NYS CLEP, certain criteria must be met, e.g., the LDT uses
well-established methodology (as defined by NYS CLEP, this includes,
among other things, the laboratory having demonstrated competence for
development of LDTs of the same or similar technology through multiple
prior high-quality submissions) (Ref. 53). Upon notification of a
moderate risk classification and conditional approval, the laboratory
may offer the test (Ref. 53). Once the full technical review has been
completed, the moderate risk LDT may receive approval (Ref. 53). For
additional information, see NYS CLEP's Tiered Evaluation of Laboratory
Developed Tests Policy (Ref. 53).
In its enforcement discretion policy with respect to premarket
review requirements, FDA is including not just those moderate risk LDTs
that receive full approval by NYS CLEP but also those that receive
conditional approval by that agency. For LDTs receiving conditional
approval, full technical review is pending and these tests may receive
approval by NYS CLEP once their review has been completed. FDA does not
intend to use its resources to enforce premarket review requirements
for these LDTs that are under review by NYS CLEP and may eventually
receive approval. However, if an LDT has its conditional approval
withdrawn by NYS (e.g., because approval is denied after NYS CLEP
completes the full technical review), the LDT would no longer be under
this enforcement discretion policy as it would neither have conditional
approval nor full approval.\30\
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\30\ Although not relevant to our decision-making with respect
to our policy regarding LDTs approved by NYS CLEP, it is our
understanding, based on consultation with NYS CLEP, that withdrawal
of conditional approval due to approval being denied after NYS CLEP
completes the full technical review is a rare occurrence.
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For purposes of full technical review (as mentioned above, this
applies to high risk and moderate risk LDTs), NYS CLEP requires the
submission of detailed information as specified in the applicable
checklist (either the general checklist or test-specific checklist)
(Ref. 24). For example, under the general checklist, laboratories must
submit, among other things, a description of the test target, data
supporting analytical validity, data supporting clinical validity,
sample test reports, standard operating procedures, and other
information regarding the subject test (Ref. 54). Additionally,
laboratories must submit a ``Risk Attestation Form for Laboratory
Developed Tests'' containing additional information about the test,
including a summary of intended use (including target population,
methodology and technology, specimen types, and whether the intend use
makes claims or direct reference to recognized diseases/conditions),
whether the laboratory has full approval of other LDTs using the same
test method that is used for the proposed new test, whether the
methodology is well-established in the laboratory and generally
accepted by the field, evidence of clinical validity, and information
regarding the potential impact of an inaccurate test result (Ref. 55).
NYS CLEP also has a process for laboratories to request an
exemption from full technical documentation. As described on NYS CLEP's
website, ``[o]nce acceptable method validation performance has been
demonstrated by the NYS approval of a representative sampling of tests
that utilize a
[[Page 37300]]
methodology that is common across many analytes/targets, the laboratory
may request an exemption from the requirement to submit full method
validation documentation for future test/assays that utilize the same
methodology'' (Ref. 24). An application for an exemption from full
technical documentation must include: a written request for an
exemption that identifies ``the previously submitted tests to be used
as the predicate submissions for the exemption''; ``a standardized
protocol for method validation to include a description of the
laboratory's principles and practices for assay development and initial
validation''; and ``laboratory-specific protocols for on-going
validation, including quality control procedures and quality assurance
indicators'' (Ref. 24). If an exemption is approved, then a streamlined
process applies to new LDTs with the same methodology under the
exemption. For such new LDTs, certain information must be provided,
including data on analytical and clinical validity, but this can be
provided in summary form (see the Add Under Exemption Form available on
NYS CLEP's website, Ref. 24). The summary of the validation studies
performed must address how analytical and clinical performance
characteristics were established (see the Add Under Exemption Form
available on NYS CLEP's website, Ref. 24). Additionally, for such new
LDTs, laboratories must submit sample reports for all applicable
findings (see the Add Under Exemption Form available on NYS CLEP's
website, Ref. 24), a ``Risk Attestation Form for Laboratory Developed
Tests'' containing additional information about the test, including
information regarding the potential impact of an inaccurate test result
(Ref. 55), and certain other information if applicable (Ref. 24).
Although specific approval of new LDTs added under an approved
exemption is not required, it is our understanding that NYS CLEP
reviews the information submitted for these LDTs. Further, NYS CLEP
reserves the right to rescind an exemption at any time (Ref. 24).
Because NYS CLEP reviews the analytical and clinical validity of LDTs
that are added under an approved exemption and may rescind an exemption
at any time, FDA is including such LDTs within the enforcement
discretion policy with respect to LDTs approved by NYS CLEP.
Based on the available information as discussed above, FDA believes
that generally NYS CLEP's review of analytical and clinical validity of
LDTs helps to mitigate the risk of harm from inaccurate and unreliable
LDTs. First, NYS CLEP reviews much of the same information that FDA
reviews in assessing analytical and clinical validity (e.g., data
supporting analytical validity, data supporting clinical validity,
sample test reports, and standard operating procedures). For example,
in comments submitted to the docket for this rulemaking, NYS CLEP
explained, ``Applications must include validation data throughout the
reportable range, particularly at or near the limit of detection, and
for intended specimen types, specimen stability range, clinical
indications, and target populations (pediatric vs adult, symptomatic vs
asymptomatic, varied ethnicities, etc.).'' Second, NYS CLEP is
identifying many of the same types of issues that FDA has identified
with LDTs. In their comments, NYS CLEP provided a detailed description
of the issues they have identified when reviewing LDT applications. For
example, NYS CLEP noted that more than half of the LDTs submitted for
their review cannot be approved based on the original application. For
such applications, NYS CLEP requests additional information, sometimes
multiple times, to address a range of issues, including ``design flaws,
inadequate validation data, and process problems that call into the
question the reliability of the results.'' These are the same types of
issues FDA has observed in the review of emergency use authorization
(EUA) requests from laboratories for molecular tests for COVID-19 (see
Ref. 18) and in other premarket submissions for LDTs (see Ref. 16).
Additionally, FDA collaborated with NYS CLEP in the review of the first
authorized tumor profiling test and found substantial alignment in
FDA's and NYS CLEP's assessments of the analytical and clinical
validity of this LDT for tumor profiling. FDA has also accredited NYS
CLEP as a Third Party Review Organization accredited under FDA's Third
Party review program (3P510K Review Organization) qualified to conduct
reviews of 510(k)s for certain IVDs. Accreditation of 3P510K Review
Organizations is based on many factors, including qualification of
staff in the scientific disciplines relevant to the review of the
specific device types that the 3P510K Review Organization intends to
review (Ref. 56). In the case of IVDs, the 3P510K Review Organization
must be qualified to assess the analytical and clinical validity of
tests which NYS CLEP was able to demonstrate.
Exercising enforcement discretion with respect to the premarket
review requirements for LDTs approved by NYS CLEP will facilitate more
efficient use of FDA resources. The resources that FDA would otherwise
spend on premarket review of such LDTs can instead be focused on
premarket review of other IVDs offered as LDTs and enforcement of other
applicable requirements. FDA estimates that 12.1 percent of IVDs
offered as LDTs would not experience new costs associated with
submission preparation and review as a result of the enforcement
discretion policy with respect to LDTs approved by NYS CLEP, as
discussed in appendix A of the FRIA (Ref. 10).
As mentioned above, FDA intends to phase out the general
enforcement discretion approach with respect to other applicable
requirements for LDTs approved by NYS CLEP, consistent with the stages
described below in section V.C. Enforcement of other requirements will
help to protect and promote the public health, e.g., by providing FDA
and the public with important information about these tests. For
example, compliance with registration and listing requirements will
provide FDA and the public with basic information on these LDTs, and
compliance with MDR requirements will provide FDA and the public with
adverse event information about these LDTs. Further, under Sec.
807.26(e) (21 CFR 807.26(e)) (additional device listing information),
FDA intends to request the labeling for these LDTs, which will provide
information on test performance and a summary of the supporting
validation, among other things.\31\ Additionally, compliance with
labeling requirements, including those in Sec. 809.10(b)(12), will
help to ensure that healthcare providers and patients have information
on test performance, among other things, and thus enable more informed
decision making. The labeling information and adverse event reports
will help FDA identify LDTs that raise concerns, e.g., concerns
regarding insufficient validation or inaccurate
[[Page 37301]]
results. Compliance with the QS requirements that FDA intends to
enforce for these LDTs will help provide for quality manufacturing of
these tests. As discussed in section V.C, for LDTs, FDA generally will
expect compliance at the 3-year mark with some, but not all, of the QS
requirements (specifically, design controls, purchasing controls,
acceptance activities, corrective and preventive actions (CAPA), and
records requirements). This includes for LDTs approved by NYS CLEP.
However, it is our understanding, based on consultation with NYS CLEP,
that compliance with NYS CLEP's clinical laboratory standards (which
exceed CLIA requirements in certain respects) and its premarket review
requirements collectively could generally satisfy these subparts of the
QSR except as to certain aspects of design control documentation.
Therefore, although not relevant to our decision-making with respect to
our policy regarding LDTs approved by NYS CLEP, FDA does not anticipate
significant additional burden with respect to compliance with these QS
requirements for laboratories offering LDTs approved by NYS CLEP.
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\31\ Devices licensed under section 351 of the PHS Act register
and list pursuant to part 607 (21 CFR 607.1 and 807.20(e)), which
does not contain a provision identical to 21 CFR 807.26(e). Most
licensed IVDs are tests intended for use as blood donor screening
tests or HCT/P donor screening tests subject to Sec. 610.40 and
1271.80(c), respectively, or tests for determination of blood group
and Rh factors subject to Sec. 640.5. As explained in the NPRM (88
FR 68006 at 68021), FDA's general enforcement discretion approach
for LDTs has never applied to such tests. Therefore, we anticipate
that there would be a limited number of IVDs subject to the
registration and listing requirements in part 607 that would fall
within this policy or other policies for which FDA intends to
request laboratories to provide labeling information in connection
with listing the device. Should FDA receive listing information
under part 607 for an IVD that is not licensed, we will consider if
any additional action is appropriate, including with respect to
information regarding IVD performance.
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Finally, as noted elsewhere in this preamble, regardless of this or
any other enforcement discretion policy, FDA retains discretion to
pursue enforcement action at any time against violative IVDs when
appropriate. We intend to carefully monitor tests falling within this
policy and to take action when appropriate to protect the public
health.
3. Enforcement Discretion Policies With Respect to Premarket Review and
Certain QS Requirements
FDA also intends to exercise enforcement discretion and generally
not enforce premarket review and most QS requirements for three
categories of IVDs. These enforcement discretion policies have been
added to the final phaseout policy after consideration of comments
received on the NPRM.
First, for the reasons discussed further below, FDA intends to
exercise enforcement discretion and generally not enforce premarket
review requirements and QS requirements (except for requirements under
part 820, subpart M (Records)) \32\ for LDTs manufactured and performed
by a laboratory integrated within a healthcare system to meet an unmet
need of patients receiving care within the same healthcare system. This
enforcement discretion policy does not apply to any IVDs identified in
section V.A.2 as falling outside the scope of the phaseout policy or as
discussed in section V.B.
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\32\ As noted in footnote 17, for the categories of IVDs
discussed in section V.B.3, FDA generally expects compliance with
requirements under part 820, subpart M (Records) but not Sec. Sec.
820.20, 820.22, 820.40, and 820.50 (which are cross-referenced in
subpart M), or comparable provisions of ISO 13485 in accordance with
the amendments to part 820 once that rule takes effect in February
2026.
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In the NPRM, FDA discussed LDTs for unmet needs, stating that a
specific enforcement discretion policy for such LDTs was not included
in the proposed phaseout policy because we anticipated that programs
currently in place (e.g., the Humanitarian Use Devices (HUD)/HDE
program and the Breakthrough Devices program) may facilitate the
development and premarket authorization of IVDs for unmet needs.\33\
See 88 FR 68006 at 68026. We received over 100 comments addressing
whether FDA should adopt a specific enforcement discretion policy for
LDTs for unmet needs (see section VI.L.5). In particular, we received
numerous comments that asserted that the perceived burden of premarket
review and QS requirements would lead laboratories to stop developing
such LDTs, leaving patients without access to the LDTs they need. For
this reason, many comments recommended that FDA adopt an enforcement
discretion policy for LDTs for unmet needs. Two public interest groups
recommended against adopting a separate policy for LDTs for unmet needs
for various reasons, including so that LDTs for patients with unmet
needs would have the same assurances of safety and effectiveness as
LDTs for other patients. Stakeholders further commented that the
existing HUD/HDE and Breakthrough Devices programs are insufficient to
mitigate the perceived burden that laboratories face with respect to
development of LDTs for unmet needs. Specifically, commenters noted the
numerical limit of 8,000 tests nationwide per year is too restrictive,
the requirements for use of tests under HDE (e.g., institutional review
board approval) dissuade physicians from using them, and the program
has only been used for 6 IVDs despite existing for over 30 years. We
also received information in comments indicating that laboratories
integrated within healthcare systems, including AMCs, often make tests
to meet the unique needs of their patients, and that patients may be
referred to those systems because of their ability to meet patient
needs that cannot be met elsewhere. The comments stated that this is
often the case for patients with rare diseases for which the market is
so small that there is no financial incentive for non-laboratory
manufacturers to meet their needs and for which collecting data to
validate a test is particularly challenging due to small patient
populations (for example, rare immunohematology problems, Huntington
disease, Prader-Willi/Angelman syndrome, and genetic tests for certain
cancers).
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\33\ As described in the NPRM, FDA considered a possible
premarket-review approach specific to LDTs for unmet needs in the
``Discussion Paper on Laboratory Developed Tests (LDTs)'' issued by
the Agency on January 13, 2017 (2017 Discussion Paper) (Ref. 57) (88
FR 68006 at 68026).
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With respect to AMCs in particular, the Agency sought comment in
the NPRM on whether FDA should have a different enforcement policy for
tests manufactured by AMC laboratories. See 88 FR 68006 at 68023-24. We
asked about various aspects of such a policy, including whether any
continued enforcement discretion policy should take into account
``whether an FDA cleared or approved test is available for the same
intended use as the test manufactured by an AMC laboratory,'' and the
public health rationale for how integration of a laboratory into
patient care might support a different approach for tests manufactured
by AMC laboratories. Id. at 68024. We received over 100 comments
addressing whether FDA should adopt a specific enforcement discretion
policy for tests offered by AMC laboratories and/or other laboratories
integrated within healthcare systems (see section VI.F.4 of this
preamble). Many of the comments we received addressing whether FDA
should adopt a specific enforcement discretion policy for LDTs for
unmet needs addressed LDTs for unmet needs manufactured by AMC
laboratories/other laboratories integrated within healthcare systems.
These comments were from patients, healthcare providers, AMCs, other
healthcare systems, and various entities representing such groups.
The majority of comments recommended that FDA adopt an enforcement
discretion policy specific to tests manufactured by AMC laboratories
given risk mitigations provided by the integration of the laboratory
within the AMC that is providing care to the patient. Many comments
stated that because other laboratories are similarly integrated within
healthcare systems, any such enforcement discretion policy should not
be limited to AMC laboratories. Many of these comments emphasized the
built-in communication mechanisms between the laboratory and AMC/other
healthcare system within which the laboratory is integrated. For
example:
<bullet> ``[T]he close connection between the clinical pathologists
developing the tests and the care providers at AMCs
[[Page 37302]]
further validates the alignment between diagnostic results and clinical
presentation and helps to provide real-time feedback to the LDT
developers on test performance and outcomes.''
<bullet> ``As hospital-based labs, we are integrated into patient
care within the healthcare system. Treating clinicians will contact us
directly when tests don't make sense and we adjust our testing
strategies if needed. I personally get around 3-10 questions per week
from clinicians as a laboratory medical director. At AMCs, while we
implement LDTs we seek information and feedback from our clinical
colleagues . . . . This direct connection and information flow allows
for quality control and real-time communication if a test is not
performing as expected.''
<bullet> ``As a CLIA director of a hospital-based lab, I
occasionally see patients with specimens that were sent to our
laboratory as well as an off-site, disconnected reference lab for the
same test at nearly the same time. The results are often not
consistent. I am able to investigate further by getting a new specimen
and communicating with the clinician about the patients' signs,
symptoms, and radiology results. I review our other test results,
including some of our other LDTs. The reference labs are often not
aware of the issues because they do not have the same line of
communication and access to the electronic health record. They continue
to offer the same test with no knowledge of the problem.''
<bullet> ``There is a direct connection or ability to directly
connect between the laboratory provider/director and the treating
clinician, and laboratory professionals have access to patient
electronic medical records, details of which often inform the nuance of
laboratory testing that is managed locally. This direct connection and
information flow allows for quality control that cannot be engendered
by an off-site, disconnected reference lab model for testing and allows
for issues associated with any particular testing modality to be
identified; thus it provides quality control at both the patient and
assay level.''
Several comments recommended against a separate enforcement
discretion policy for tests manufactured by AMC laboratories, including
because they argued that AMC laboratory tests have the same problems as
other IVDs (which FDA acknowledged in the context of the COVID-19
pandemic) and having the same enforcement policies for these tests as
for other tests will level the playing field and promote the
development of new and improved tests.
As an initial matter, we understand that laboratories that develop
LDTs for unmet needs, often laboratories integrated within a healthcare
system, may be more likely to stop developing many of these LDTs for
unmet needs if the proposed phaseout policy were finalized. The cost of
compliance with premarket review and QS requirements may be deemed too
high given the limited market for many of these LDTs for unmet needs,
and so laboratories may not have financial incentives to develop these
types of LDTs in particular (for example, FDA's primary estimates
anticipate the cost per premarket submission to range from
approximately $250,000 to $4.5 million depending on the type of
submission required, in addition to costs associated with QS
requirements, annual reporting requirements (for PMAs) and applicable
user fees, as described in sections II.F.3, II.F.4 and II.H of the FRIA
(Ref. 10)). In their comments, various laboratories noted challenges
and limitations associated with the HDE pathway that would dissuade
them from seeking HDE approval for their LDTs. Specifically, commenters
noted the numerical limit of 8,000 tests nationwide per year is too
restrictive in that it applies to the cumulative testing volume of all
patients who would be tested with a diagnostic device annually, and the
requirements for use of tests under HDE (e.g., administration of the
test in a facility having oversight by an institutional review board,
monitoring whether the national testing volume exceeds 8,000 patients
per year, and limitations on profit, etc.) dissuade laboratories from
developing such tests and submitting them for HDE approval. Although we
think that the HDE pathway could help to facilitate the manufacture and
premarket authorization of certain LDTs for unmet needs, based on these
comments, we are concerned that many laboratories would stop
manufacturing LDTs for unmet needs altogether, instead of seeking HDE
approval for the LDTs, in light of the perceived financial costs of
premarket review and QS requirements. Moreover, although we think that
the Breakthrough Devices program would help to facilitate the premarket
review process for LDTs for unmet needs, again based on the comments,
we are concerned many laboratories would stop manufacturing LDTs for
unmet needs altogether if they are expected to comply with premarket
review and QS requirements.
As such, and upon further consideration, FDA has determined that a
targeted enforcement discretion policy is appropriate to help avoid
patients being deprived of critically needed LDTs where certain risk
mitigations exist. Specifically, FDA intends to exercise enforcement
discretion and generally not enforce premarket review and QS
requirements (except for requirements under part 820, subpart M
(Records)) for LDTs manufactured and performed by a laboratory
integrated within a healthcare system to meet an unmet need of patients
receiving care within the same healthcare system. FDA intends to phase
out the general enforcement discretion approach for these LDTs with
respect to all other applicable requirements consistent with the stages
described in section V.C. Should experience with this policy indicate
that changes are warranted, FDA would consider appropriate policy
changes through guidance in accordance with good guidance practices
(see Sec. 10.115).
This policy is limited to LDTs for patients who are receiving care
within the healthcare system within which the laboratory offering the
LDT is integrated. FDA does not consider this to include patients that
are being treated at an affiliated hospital with different corporate
ownership than the laboratory. Where the laboratory and the treating
physicians are in the same corporate entity, there is shared
responsibility and potential liability for patient outcomes, which
helps mitigate risk. Moreover, the policy is limited to LDTs that are
ordered by a healthcare practitioner on the staff or with credentials
and privileges at a facility owned and operated by the same healthcare
system employing the laboratory director and performing the LDT. In
these circumstances, FDA believes that the risk mitigations present
help to address some of the concerns raised regarding problematic IVDs
offered as LDTs discussed in the NPRM and this preamble.
For LDTs manufactured and performed by laboratories integrated
within healthcare systems, FDA generally has greater confidence that
ordering physicians will communicate any questions about LDTs or
concerns regarding the safety and effectiveness of the LDT (e.g., when
the patient's symptoms point to another diagnosis; when subsequent test
results contradict the original test result) to a laboratory given the
built-in communication mechanisms present. Moreover, FDA generally has
greater confidence that laboratories will communicate any limitations
of the LDT or other relevant information to the ordering physician
given these mechanisms. We think this is particularly likely to happen
in the context of LDTs for unmet needs, which
[[Page 37303]]
are likely to be a focus of attention and communication between
laboratorians and providers given the uncommon nature of the issues
presented.
Communication from ordering physicians to laboratories may help
laboratories to identify any problems with their LDT and make necessary
adjustments, improvements, and other changes to the LDT. Although we
acknowledge that any identification and subsequent modification of the
LDT would happen postmarket, and thus would not prevent potentially
problematic LDTs from ever being used, subsequent modification would
benefit future patients and providers who are relying on the LDT. In
addition, communication from laboratories to ordering physicians may
help to underscore to the ordering physicians any limitations with the
LDT and provide other relevant information to ordering physicians, for
example that is specific to the unique needs of their patient, which in
turn should help inform appropriate use and interpretation of the
LDT.\34\
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\34\ See Ref. 58 (``more aggressive laboratory involvement in
[the interpretation and reporting] step may be necessary to ensure a
more nearly perfect hit rate on proper interpretation and action
after reporting of laboratory results''); see also Ref. 59. Shaw and
Miller compared hospital laboratories and hospital-independent
reference laboratories, and highlighted the following advantages,
among others, of the former over the latter: (1) tracking problems
(hospital laboratories ``[c]an easily work with medical and nursing
services to coordinate patient care efforts'' whereas hospital-
independent reference laboratories ``[c]an only track internal
problems effectively'') and (2) physician consultation (this is
``[r]eadily available'' for hospital laboratories whereas it is
``[n]ot as readily available'' for hospital-independent reference
laboratories).
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We believe that generally these features associated with
integration of a laboratory within the healthcare system, along with
enforcement of other applicable regulatory requirements as described in
the phaseout policy (see section V.C), help to mitigate the risk of
harm from inaccurate and unreliable LDTs. While we recognize that these
features do not mitigate all risk and there may still be some
uncertainty about the performance of LDTs that fall within this policy,
we believe that these features support an enforcement discretion policy
for premarket review and most QS requirements in the specific context
of LDTs for unmet needs.
This policy is limited to LDTs for unmet needs. FDA considers an
LDT to be for an unmet need where there is no available FDA-authorized
IVD that meets the patient's needs. This may be because: (1) there is
no FDA-authorized IVD for the disease or condition (for example,
because it is for a rare disease or condition); (2) there is an FDA-
authorized IVD for the disease or condition but it is not indicated for
use on the patient, or a unique attribute needs to be added to the LDT
to meet the patient's needs; or (3) there is an FDA-authorized IVD but
it is not available to the patient. Examples of LDTs for unmet needs
are:
<bullet> An LDT that is intended for cytogenetic analysis of
certain genes and chromosomes associated with rare diseases or
conditions, certain metals testing, viral load monitoring for some
transplant-associated viruses, or diagnosis of certain mosquito- and
tick-borne-diseases, where there is no FDA-authorized IVD for the
disease/condition (rare disease or condition);
<bullet> An LDT to accommodate an alternative specimen type that is
infrequently tested when the specimen type required for the FDA-
authorized IVD is not and cannot be made available (variation from the
indications for use of an FDA-authorized IVD);
<bullet> An LDT for use on pediatric patients when FDA-authorized
IVDs are indicated for use on adults only (variation from the
indications for use of an FDA-authorized IVD);
<bullet> An LDT that generates results in a significantly shorter
period (e.g., hours versus days) than an FDA-authorized IVD with the
same indication where, due to the circumstances of the patient, the
shorter time period to get results is critical for the clinical
decision being made (unique attribute needed to be added to an FDA-
authorized IVD);
<bullet> An LDT for the same indication as an FDA-authorized IVD
that is offered only in another healthcare system that is not
accessible to the patient and the developing laboratory will not make
the IVD available outside its system (FDA-authorized IVD is not
available); and
<bullet> An LDT for an emerging pathogen for which there is no FDA-
authorized IVD and for which FDA has not identified an emergent
situation (no FDA-authorized IVD).
In contrast, FDA does not consider an LDT to be for an unmet need
when there is an available FDA-authorized IVD that would sufficiently
meet the needs of the patient. For example, potential improvements in
performance or lower cost in comparison to an FDA-authorized IVD that
meets the patient's needs does not fall within this policy.
FDA intends this policy to be targeted. It is not intended to serve
as an alternative ``pathway'' to market for LDTs for unmet needs. FDA
intends to provide additional guidance on this enforcement discretion
policy, which would be issued in accordance with good guidance
practices (see Sec. 10.115).
We note that if there is no longer an unmet need for an LDT
because, for example, FDA authorizes an IVD that meets the needs of the
patient, then the LDT would no longer fall within this enforcement
discretion policy. This will encourage manufacturers, including the
manufacturers of LDTs falling within this policy, to seek premarket
authorization, without delaying patient access to the LDT. It also will
provide patients and providers with greater confidence that once an IVD
has been authorized by FDA, all similar devices, regardless of who
makes them, should have appropriate assurance of safety and
effectiveness because all such devices should comply with premarket
review and QS requirements. Moreover, such a limitation helps to ensure
that the enforcement discretion policy will ultimately target only
those LDTs where there is insufficient financial incentive to seek
authorization for the LDTs (in such cases, there is unlikely to ever be
an available FDA-authorized IVD).
Notably, this unmet needs LDT policy applies only to LDTs that are
validated. We acknowledge that validation may vary depending on many
factors, including the accessibility of specimens and the number of
affected patients. FDA intends to consider whether issuing additional
guidance regarding validation of tests, including those for rare
diseases that takes into consideration the challenges in obtaining a
robust number of samples for validation, would be helpful.
In developing this policy, FDA took into consideration various
factors that mitigate the risk that LDTs offered as described in this
policy may not have appropriate assurance of safety and effectiveness.
As an initial matter, the phaseout of the general enforcement
discretion approach for all other applicable requirements will provide
greater assurances regarding these LDTs than the Agency, healthcare
providers, and patients currently have. Compliance with registration
and listing requirements, for example, will provide FDA and the public
with insight into what LDTs for unmet needs are being offered by
laboratories integrated within healthcare systems. Moreover, compliance
with labeling requirements, including those in Sec. 809.10(b)(12),
will help to ensure that healthcare providers and patients have
information on the performance of the LDT and thus will help to enable
more informed decision making. In addition, FDA generally intends to
request that laboratories that offer LDTs as described in this policy
submit labeling information to FDA in
[[Page 37304]]
connection with the listing of the device as provided in Sec.
807.26(e) (this regulation is discussed above). This labeling will
facilitate FDA surveillance for potentially poor performing LDTs that
should otherwise be addressed.
Finally, as noted elsewhere in this preamble, regardless of this or
any other enforcement discretion policy, FDA retains discretion to
pursue enforcement action at any time against violative IVDs when
appropriate. We intend to carefully monitor LDTs falling within this
policy and intend to take action regarding such LDTs as appropriate
taking into account any public health concerns as evaluated on a case-
by-case basis.
We considered various alternative policies proposed in comments
regarding LDTs for unmet needs and LDTs manufactured by AMC
laboratories or laboratories integrated within other healthcare
systems, but we believe this policy best serves FDA's public health
mission by helping to assure the safety and effectiveness of LDTs while
also accounting for patient access. For example, an enforcement
discretion policy whereby FDA generally does not enforce premarket
review and most QS requirements for any LDT manufactured by AMC
laboratories and laboratories integrated within other healthcare
systems would appear to be overly broad, including because it would
encompass LDTs for which there are FDA-authorized alternatives that we
know have appropriate assurances of safety and effectiveness.
Similarly, an enforcement discretion policy whereby FDA generally does
not enforce premarket review and most QS requirements for all LDTs for
unmet needs would also appear to be overly broad, as there are not the
same risk mitigations present for all such LDTs that would help address
and avoid the use of problematic LDTs. We also considered several
narrower enforcement discretion policies, such as an enforcement
discretion policy where a premarket submission would be expected after
an LDT is offered for use and where the LDT is offered until FDA makes
a final decision on the LDT (see, e.g., the 2017 Discussion Paper (Ref.
57)) or a longer phaseout policy for QS requirements. We do not think
such policies would make sense here because many laboratories would
likely be dissuaded from developing LDTs in this space if compliance
with premarket review and QS requirements is routinely expected at any
point in time due to the lack of financial incentives and perceived
costs associated with premarket review and QS requirements.
Second, FDA intends to exercise enforcement discretion and
generally not enforce premarket review and QS requirements (except for
requirements under part 820, subpart M (Records)) \35\ for currently
marketed IVDs offered as LDTs that were first marketed prior to the
date of issuance of this rule (hereinafter, ``currently marketed IVDs
offered as LDTs''). FDA intends for this policy to apply to currently
marketed IVDs offered as LDTs as long as they are not modified
following the issuance of this final rule, or are modified but only in
certain limited ways that are described below. This enforcement
discretion policy does not apply to any IVDs identified in section
V.A.2 as falling outside the scope of the phaseout policy or as
discussed in section V.B.
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\35\ As noted in footnote 17, for the categories of IVDs
discussed in section V.B.3, FDA generally expects compliance with
requirements under part 820, subpart M (Records) but not Sec. Sec.
820.20, 820.22, 820.40, and 820.50 (which are cross-referenced in
subpart M), or comparable provisions of ISO 13485 in accordance with
the amendments to part 820 once that rule takes effect in February
2026.
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As part of this policy, FDA intends to request submission of the
labeling for currently marketed IVDs offered as LDTs under Sec.
807.26(e) and to use this information, along with information obtained
through laboratory compliance with other relevant requirements (such as
adverse event reporting), to identify and address those currently
marketed IVDs offered as LDTs that specifically raise concerns. We
recognize that patients, the healthcare community, and the laboratory
industry have likely made decisions in reliance on access to, or the
continued manufacturing of, many currently marketed IVDs offered as
LDTs, and that loss of beneficial currently marketed IVDs offered as
LDTs could cause harm and undermine those reliance interests. We
believe this policy appropriately balances the various competing
interests at issue to best serve public health because it helps
facilitate continued access to those IVDs offered as LDTs that are
beneficial while incorporating targeted use of available tools to
identify and act against currently marketed IVDs offered as LDTs that
are problematic. As IVDs evolve, compliance with premarket review and
QS requirements will be phased in according to the natural lifecycle of
test development and use.
FDA is adopting this policy after a review of the comments, which
leads us to conclude that an expectation of compliance with premarket
review and QS requirements for currently marketed IVDs offered as LDTs
may be more harmful than helpful to the public because, for example, it
will prompt many laboratories to stop offering tests even if they are
safe and effective. One commenter stated that ``[i]f the rule is
implemented, it is likely that we would consider no longer offer [sic]
[IVDs offered as LDTs] due to the administrative and financial burdens
of the regulations.'' Another commenter stated that ``the most
prominent reason [the proposed rule should not move forward] is that
patient care will suffer as most small laboratories will be forced to
close because of increased cost and need to reduce their test menu.''
These comments corresponded to data in FDA's Preliminary Regulatory
Impact Analysis (PRIA) suggesting a potentially high burden on
laboratories associated with compliance for currently marketed IVDs
offered as LDTs--a burden that could potentially cause some
laboratories (particularly small laboratories) to close (Ref. 60). As
reflected in section II.F of the FRIA (Ref. 10), a significant fraction
of the estimated overall costs of compliance with applicable
requirements under the FD&C Act and FDA's regulations is attributable
to premarket review (where applicable) and QS requirements.
Specifically, out of the total estimated discounted costs to industry
of $1.17 billion, the average estimated costs of compliance with stages
1 and 2 of the phaseout policy (as described in section V.C below) are
approximately $9,522 per test ($74,783 per laboratory) and the average
estimated costs of compliance with premarket review and QS requirements
are approximately $3.02 million per test ($1.26 million per
laboratory).
In the NPRM and this preamble, FDA explained that relevant evidence
points to a high degree of variability in the performance of IVDs
offered as LDTs today, but FDA does not take the view that all
laboratory-manufactured IVDs are problematic (see, e.g., 88 FR 68006 at
68010-68012 and responses to comments 28, 32-33). We believe that an
appreciable proportion of IVDs currently offered as LDTs likely help
patients and are important to patient care (see section II.E.1 of the
FRIA (Ref. 10)), and as noted above, we understand that patients, the
healthcare community, and the laboratory industry have likely made
decisions in reliance on access to, or the continued manufacturing of,
such IVDs. The loss of such IVDs could cause harm and undermine those
reliance interests.
FDA is aware, for instance, that certain patients may have embarked
on a course of treatment in reliance on regular testing to help monitor
their treatment or condition, and the loss of that testing could pose
serious risks and
[[Page 37305]]
complications for that patient. For example, consistent access to tests
that are already being used to measure plazomicin to aid in the
management of patients with complicated urinary tract infection
receiving plazomicin therapy and tests to measure levels of
immunosuppressants--such as cyclosporine, tacrolimus, everolimus, and
sirolimus--in transplant patients are important for treating physicians
to make well-informed treatment decisions for those patients. In the
context of patients receiving tests that are not well-standardized to
monitor their diseases or conditions, consistent access to the same
test at the same laboratory over time is also important for treating
physicians to make accurate diagnostic and treatment decisions.
Examples of such tests include thyroid hormone tests that are used to
monitor thyroid disease, adrenal function tests that are used to
monitor adrenal disorders, and flow-cytometry-based minimal residual
disease tests that are used to monitor patients with cancer that have
undergone treatment to determine if they are at risk for relapse.
FDA also recognizes that healthcare professionals may have made
significant financial investments in reliance on access to certain
tests (e.g., contracts for certain tests that they need for long-term
patient monitoring, where such monitoring must continue with the same
test because test results are compared over time and results from a
different test are not interchangeable), and that the loss of access
could harm their practice and, ultimately, the patients they serve. In
addition, laboratories may have made financial investments and other
decisions based on a past assumption about the presence of the general
enforcement discretion approach.
In light of these reliance considerations and, in particular, the
risk that laboratories may stop offering safe and effective tests on
which patients and the healthcare community currently rely, we do not
think it is appropriate to expect compliance with premarket review and
most QS requirements for all currently marketed IVDs offered as LDTs.
Instead, we have determined it is in the best interest of the public
health to expect compliance with premarket review and QS requirements
in a more targeted fashion--i.e., for those currently marketed IVDs
offered as LDTs that specifically raise concerns. As new IVDs come on
the market following issuance of this rule, they will be expected to
comply with premarket review and QS requirements--in accordance with
the phaseout policy--gradually phasing in those requirements for the
overall market. In the meantime, compliance with other applicable
requirements will help enable FDA to identify and address safety and
effectiveness problems that may arise.
In deciding on this policy, FDA considered alternatives to address
the concerns identified above, including the risk of market exit, such
as: (1) extending the phaseout timeline to give more time for currently
marketed IVDs offered as LDTs to come into compliance with premarket
review and QS requirements and (2) expecting compliance with premarket
review and QS requirements only for high-risk currently marketed IVDs
offered as LDTs. However, based on FDA's economic projections, neither
of these alternatives resolves the concern about market exit resulting
in loss of access to beneficial IVDs on which patients and others
currently rely because neither substantially changes the economic
burden on laboratories. For example, under Alternative 3 in section
II.J of the PRIA, FDA evaluated the reduction in burden of an extended
phaseout policy, and based on the calculations there, we doubt that the
reduction would be sufficient to prevent the outcomes described above
(see Ref. 60). In addition, the PRIA shows that the greatest costs in
the phaseout policy are those associated with high-risk IVDs, so a
policy that involves compliance for currently marketed high-risk IVDs
offered as LDTs also would not resolve the concern about market exit.
Given this information, and given the information we received in
comments, FDA has concluded that the best course is to adopt the policy
for currently marketed IVDs offered as LDTs outlined above. (This
policy is keyed to the date of this final rule, rather than the
proposed rule, because patients and the healthcare community may have
begun relying on IVDs during the period between publication of the
proposed and final rule.)
Based on FDA's understanding of the current IVD industry, we expect
IVDs offered as LDTs to continue to advance to meet new patient needs,
accommodate new technologies, and incorporate the latest scientific
findings. Under this policy for currently marketed IVDs offered as
LDTs, when such IVDs are modified in certain significant ways that
would, under FDA requirements, generally prompt the need for premarket
review relative to the original currently marketed IVD, FDA expects
laboratories to comply with premarket review and QS requirements for
that modified IVD. This policy is intended to preserve access to
beneficial IVDs on which patients and the healthcare community
currently rely, including versions of that IVD with minor changes.
However, we expect compliance with premarket review and QS requirements
once the IVD is changed in certain, more significant ways that could
affect its basic safety and effectiveness profile. In particular, under
this policy, FDA generally expects compliance with premarket review and
QS requirements for currently marketed IVDs offered as LDTs when a
laboratory's modifications (individually or in aggregate):
<bullet> change the indications for use of the IVD;
<bullet> alter the operating principle of the IVD (e.g., changes in
critical reaction components);
<bullet> include significantly different technology in the IVD
(e.g., addition of artificial intelligence or machine learning to the
test algorithm, a change from targeted sequencing to whole genome
sequencing, a change from immunoassay to mass spectrometry, or a change
from manual to automated procedures); or
<bullet> adversely change the performance or safety specifications
of the IVD.\36\
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\36\ Under FDA regulations, the listed modifications to an IVD
would generally require a new submission, such as a new 510(k), PMA,
BLA, or De Novo, or certain types of PMA or BLA supplements. See,
e.g., 21 CFR 601.2, 601.12, 807.81(a)(3), 814.39, and 860.200; see
also ``Deciding When to Submit a 510(k) for a Change to an Existing
Device'' (Ref. 61).
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FDA believes this approach appropriately limits the scope of this
policy and reduces the risk for patients.
As noted above, FDA also intends to take targeted steps to address
currently marketed IVDs offered as LDTs that are problematic. In
particular, we intend to use available tools to identify and act
against currently marketed IVDs offered as LDTs that specifically raise
concerns, such as IVDs that are potentially inaccurate or poorly
validated. In this way, FDA can work to assure the safety and
effectiveness of currently marketed IVDs offered as LDTs without
creating the risk of widespread market exit. FDA has a range of tools
to assist in this effort.
First, FDA intends to request that laboratories offering currently
marketed IVDs offered as LDTs submit labeling to FDA as provided in
Sec. 807.26(e). Labeling includes IVD performance information and a
summary of supporting validation, as applicable. This information will
help FDA more closely monitor currently marketed IVDs offered as LDTs
and identify those that may lack analytical validity, clinical
validity, or safety. As part of its review of labeling, FDA also
intends to
[[Page 37306]]
look closely at claims of superior performance and whether those claims
are adequately substantiated.\37\ Such claims are of particular public
health concern because, in FDA's experience, they have led to
escalating claims from competitors that can ultimately mislead the
public. FDA generally intends to take action where the labeling of a
currently marketed IVD offered as an LDT is false or misleading, and/or
the IVD offered as an LDT lacks the appropriate assurance of safety and
effectiveness for its intended uses as a result of any such claims that
are not adequately substantiated.
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\37\ See, e.g., FDA, Final Guidance for Industry: Medical
Product Communications That Are Consistent With the FDA-Required
Labeling--Questions and Answers at 18 (June 2018) (``[P]romotional
material is misleading'' when ``it makes a claim of superior
effectiveness for Drug A versus Drug B based on a study that was not
designed to establish superiority of Drug A to Drug B.''). See Ref.
62.
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Second, FDA intends to enforce records requirements in part 820,
subpart M, for manufacturing activities related to a currently marketed
IVD offered as an LDT that occur after the date of issuance of this
final rule. Compliance with these requirements will facilitate FDA's
review of these IVDs during inspections, enabling FDA to understand the
validation bases and processes underlying these IVDs, and will support
appropriate adverse event reporting (MDRs).
Third, under the policy, FDA expects laboratories to comply with
applicable requirements other than premarket review and most QS
requirements, including MDR requirements, corrections and removals
reporting requirements, registration and listing requirements, and
labeling requirements. Compliance with these requirements will provide
FDA with additional important information regarding currently marketed
IVDs offered as LDTs, such as information enabling FDA to track
adverse-event trends.
Finally, based on our experience with other devices, we anticipate
that laboratory manufacturers will alert us to potential problems with
their competitors' IVDs once IVD performance information is
transparent, which will help direct FDA's attention to problematic
tests.
FDA emphasizes that these tools are not a substitute for premarket
review or full QS compliance. FDA continues to believe that premarket
review and full QS compliance are important tools to help assure the
safety and effectiveness of IVDs going forward. However, there are
sufficient countervailing reasons to take a more targeted approach for
currently marketed IVDs offered as LDTs, including the risk of market
exit and the potentially significant reliance on currently marketed
IVDs offered as LDTs. Thus, FDA has determined that the enforcement
discretion policy outlined above best serves public health.
The third category of tests for which FDA intends to exercise
enforcement discretion and generally not enforce premarket review and
QS requirements (except for requirements under part 820, subpart M
(Records)) \38\ is non-molecular antisera LDTs \39\ for rare RBC
antigens when such tests are manufactured and performed by blood
establishments, including transfusion services and immunohematology
laboratories \40\ and when there is no alternative IVD available to
meet the patient's need for a compatible blood transfusion. This policy
does not apply to molecular tests used for genotyping RBC antigens.
This policy also does not apply to any IVDs identified in section V.A.2
as falling outside the scope of the phaseout policy or as discussed in
section V.B.
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\38\ As noted in footnote 17, for the categories of IVDs
discussed in section V.B.3, FDA generally expects compliance with
requirements under part 820, subpart M (Records) but not Sec. Sec.
820.20, 820.22, 820.40, and 820.50 (which are cross-referenced in
subpart M), or comparable provisions of ISO 13485 in accordance with
the amendments to part 820 once that rule takes effect in February
2026.
\39\ Consistent with what FDA has generally considered to be an
LDT (as discussed elsewhere in this preamble), this enforcement
discretion policy applies only to tests that are designed,
manufactured, and used within a single CLIA-certified laboratory
that meets the requirements under CLIA for high complexity testing.
\40\ In our experience, establishments that perform
compatibility tests for blood transfusion include establishments,
such as reference laboratories, that are not integrated within a
healthcare system. Therefore, the non-molecular antisera LDTs at
issue may not fall within the policy described above for LDTs
manufactured and performed by a laboratory integrated within a
healthcare system to meet an unmet need of patients receiving care
within the same healthcare system.
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Some individuals develop antibodies to certain antigens that they
lack on their own RBCs following exposure to foreign RBC antigens
through blood transfusion or pregnancy. These may be clinically
significant, causing a hemolytic transfusion reaction if the patient
receives a transfusion of RBCs that have the corresponding antigen(s).
As of July 2023, there are currently 45 recognized blood group systems
containing 360 RBC antigens (Ref. 63). FDA understands that there are
occasions where licensed antisera IVDs are not available for rare RBC
antigens but testing for such rare antigens is necessary to help ensure
that patients receive a compatible blood transfusion \41\ and avoid
potentially life-threatening reactions. Although FDA has also approved
molecular tests for use in genotyping RBC antigens, there may not be an
available, approved molecular test to use as an alternative for all
rare antigens.
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\41\ Such tests are not subject to the requirements in Sec.
640.5. As noted elsewhere in this document, FDA's general
enforcement discretion approach for LDTs has not applied to tests
for determination of blood group and Rh factors that are subject to
Sec. 640.5.
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FDA is adopting this policy after consideration of comments that
requested that FDA continue to exercise enforcement discretion with
respect to antisera LDTs for rare RBC antigens and/or molecular tests
for genotyping rare RBC antigens. This included comments pointing to
FDA's existing 2018 final guidance (Ref. 64), which, among other
things, recognized that blood establishments sometimes use unlicensed
antisera tests or unapproved molecular tests for RBC antigen typing in
circumstances where a licensed reagent for a rare antigen is not
available.
The non-molecular antisera LDTs within the scope of this policy
share certain characteristics with ``1976-Type LDTs,'' as they use
manual techniques performed by laboratory personnel with specialized
expertise. For such LDTs, in instances where there is no available
alternative to ensure that a patient receives a compatible transfusion,
FDA has determined it is in the best interest of public health to adopt
this enforcement discretion policy. However, this policy does not apply
to molecular tests for genotyping RBC antigens. Compared to serologic
tests, molecular RBC typing is a relatively new and complex technique
for detection of RBC antigens. Some limitations of molecular RBC typing
tests include that the genotype does not always correlate with the
phenotype due to samples with rare null phenotypes, and the assay may
not be designed to detect all rare or new variants of an antigen. As
such, FDA has greater concern regarding risk of error with molecular
tests for genotyping RBC antigens that do not comply with applicable
FDA requirements.
For LDTs offered as described in this policy, FDA expects the LDT
to be validated. As discussed previously, we acknowledge that such
expectations may vary depending on many factors, including the
accessibility of specimens and the number of affected patients.
In addition, this enforcement policy applies only to premarket
review and QS requirements (except for
[[Page 37307]]
requirements under part 820, subpart M (Records)). FDA expects
compliance with records requirements in part 820, subpart M, for non-
molecular antisera LDTs that fall within this policy. Compliance with
these requirements will facilitate FDA's review of these LDTs during
inspections and will support appropriate adverse event reporting. The
phaseout of the general enforcement discretion approach for other
applicable requirements will provide greater assurances regarding tests
that fall within this policy than the Agency, healthcare providers, and
patients currently have.
Finally, as noted elsewhere in this preamble, regardless of this or
any other enforcement discretion policy, FDA retains discretion to
pursue enforcement action at any time against violative IVDs. We intend
to carefully monitor LDTs falling within this policy and intend to take
action regarding such LDTs as appropriate, taking into account any
public health concerns as evaluated on a case-by-case basis.
C. Stages
As previously discussed, FDA has determined to gradually phase out
its current general enforcement discretion approach for LDTs so that
IVDs manufactured by a laboratory will generally fall under the same
enforcement approach as other IVDs. In particular, FDA has structured
the phaseout policy to contain five key stages:
<bullet> Stage 1: beginning 1 year after the publication date of
this final rule, FDA will expect compliance with MDR requirements,
correction and removal reporting requirements, and QS requirements
under Sec. 820.198 (complaint files).
<bullet> Stage 2: beginning 2 years after the publication date of
this final rule, FDA will expect compliance with requirements not
covered during other stages of the phaseout policy, including
registration and listing requirements, labeling requirements, and
investigational use requirements.
<bullet> Stage 3: beginning 3 years after the publication date of
this final rule, FDA will expect compliance with QS requirements under
part 820 (other than requirements under Sec. 820.198 (complaint
files), which are already addressed in stage 1).
<bullet> Stage 4: beginning 3\1/2\ years after the publication date
of this final rule, FDA will expect compliance with premarket review
requirements for high-risk IVDs offered as LDTs, unless a premarket
submission has been received by the beginning of this stage in which
case FDA intends to continue to exercise enforcement discretion for the
pendency of its review.
<bullet> Stage 5: beginning 4 years after the publication date of
this final rule, FDA will expect compliance with premarket review
requirements for moderate-risk and low-risk IVDs offered as LDTs (that
require premarket submissions), unless a premarket submission has been
received by the beginning of this stage in which case FDA intends to
continue to exercise enforcement discretion for the pendency of its
review.
These stages, along with certain narrower enforcement discretion
policies specific to certain stages, are discussed in further detail
below.
We note that FDA generally does not intend to enforce requirements
to include certain information (e.g., registration numbers, premarket
submission numbers) in reports or other submissions to the Agency until
the information is addressed in a later stage of the phaseout policy.
We received several comments on the structure, sequencing, and
timing of the proposed phaseout policy described in the NPRM (see
section VI.F.6 of this preamble). Some indicated that the proposed
timing for all phases was appropriate while others recommended it be
shortened or lengthened. Some also proposed different approaches for
organizing or implementing the phaseout.
FDA carefully considered these comments, and also considered the
impact of other policies included in the final phaseout policy on the
considerations noted in these comments. For the reasons discussed below
and in section VI.F.6, FDA has determined that it should retain the
general structure, sequencing, and timelines proposed in the NPRM (88
FR 68006 at 68021) for the phaseout policy in this final rule.
FDA encourages laboratory manufacturers to begin early and work
toward compliance with requirements sooner than the end of the
timeframes specified for each stage of the phaseout policy, as
described below. FDA also intends to consider providing more targeted
guidance and/or making additional resources available on specific
topics, such as compliance with applicable labeling requirements, over
the course of the phaseout period, as discussed in section VI.P.
1. Stage 1: Beginning 1 Year After the Publication Date of This Final
Rule, FDA Will Expect Compliance With MDR Requirements, Correction and
Removal Reporting Requirements, and QS Requirements Under Sec. 820.198
(Complaint Files)
As detailed elsewhere in this preamble, FDA is concerned that some
IVDs offered as LDTs may be posing risks to patients; therefore, FDA
seeks to obtain information about potentially harmful IVDs offered as
LDTs as soon as feasible. In light of that objective, and after
reviewing the comments, FDA continues to believe that 1 year is an
appropriate time for laboratory manufacturers to come into compliance
with MDR and correction and removal reporting requirements. Among other
things, this timeline is reasonable in light of the estimates in the
FRIA, and under CLIA, laboratories should already have some processes
in place for detecting problems with their IVDs. In addition, the new
enforcement discretion policies set forth in section V.B (particularly
the policy for currently marketed IVDs offered as LDTs) may help
laboratories with limited resources focus on compliance with
requirements at stage 1. Therefore, FDA is retaining the 1-year period
for the phaseout of the general enforcement discretion approach with
respect to MDR and correction and removal reporting requirements, in
order to prioritize the phaseout of the general enforcement discretion
approach for requirements that would help FDA identify and monitor
significant issues with IVDs offered as LDTs.
Enforcement of the MDR requirements under 21 U.S.C. 360i(a) through
(c) and part 803 (21 CFR part 803), in particular, will enable FDA to
systematically monitor significant adverse events to identify
problematic IVDs offered as LDTs, such as those with poor performance
or other safety issues. FDA has made a determination that gathering
this information early in the phaseout period is important for IVDs
that do not have the safeguards associated with compliance with other
FDA requirements, such as manufacturing under QS requirements or
confirmation of appropriate safety and effectiveness through premarket
review.
For similar reasons, FDA is prioritizing the collection of
information about when a manufacturer has initiated a correction or
removal of its IVD to reduce a risk to health or to remedy a violation
of the FD&C Act that may present a risk to health. Under 21 U.S.C.
360i(g) and part 806 (21 CFR part 806), manufacturers are required to
report
[[Page 37308]]
such corrections or removals to FDA, and FDA intends to phase out the
general enforcement discretion approach for these requirements at the
same time it does so for MDR requirements.
In addition, FDA has determined that it should include compliance
with one additional regulatory provision at stage 1 of the phaseout
policy. In particular, while FDA generally expects compliance with most
QS requirements beginning in stage 3 of the phaseout policy (as
described below), FDA intends to phase out the general enforcement
discretion approach with respect to the QS requirements under Sec.
820.198 (complaint files) \42\ in stage 1 of the phaseout policy, given
the connection between the complaint investigation and complaint file
requirements under Sec. 820.198 and the MDR reporting regulations.
Under Sec. 820.198, manufacturers are required to document complaints,
investigate them, and determine if they require reporting under MDR
requirements. Absent compliance with these requirements under Sec.
820.198, manufacturers would not be able to comply with applicable MDR
requirements (see Sec. 803.18(e)), and FDA believes that developing
procedures for compliance with Sec. 820.198 can be accomplished on the
same timeline as compliance with MDR requirements.
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\42\ 21 CFR 820.198 generally requires that a manufacturer
maintain complaint files and establish and maintain procedures for
receiving, reviewing, and evaluating complaints, including requiring
that certain complaints which are required to be reported to FDA
under part 803 be promptly reviewed, evaluated, and investigated.
When the final rule to amend part 820 takes effect in February 2026,
the comparable requirements can be found in International
Organization for Standardization (ISO) 13485 subclause 8.2.2 as
modified by part 820. Under these provisions, manufacturers will
generally be required to document procedures for timely complaint
handling, including minimum requirements and responsibilities for
receiving and recording information, evaluating whether the
information constitutes a complaint, investigating complaints,
determining the need to report information to appropriate regulatory
authorities, handling of complaint-related product, and determining
the need to initiate corrective action. Additionally, new Sec.
820.35 will require, among other things, that manufacturers maintain
records of such review and report to FDA complaints that are
required under part 803.
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2. Stage 2: Beginning 2 Years After the Publication Date of This Final
Rule, FDA Will Expect Compliance With Requirements Not Covered During
Other Stages of the Phaseout Policy, Including Registration and Listing
Requirements, Labeling Requirements, and Investigational Use
Requirements
After considering the comments, FDA has determined to phase out the
general enforcement discretion approach for requirements not covered
during other stages of the phaseout policy (i.e., requirements other
than MDR, correction and removal reporting, QS, and premarket review
requirements) 2 years after publication of this final rule. These other
requirements include registration and listing requirements under 21
U.S.C. 360 and parts 607 and 807 (excluding subpart E); labeling
requirements under 21 U.S.C. 352 and parts 801 and 809, subpart B (21
CFR parts 801 and 809, subpart B); and investigational use requirements
under 21 U.S.C. 360j(g) and part 812 (21 CFR part 812).\43\ We have
included compliance with investigational use requirements at this
stage, in recognition that there has been some confusion about our
enforcement approach in this area. Our understanding is that
laboratories often are not complying with investigational use
requirements currently, even though FDA has generally expected
compliance with these requirements.\44\ We are therefore including
these requirements in the phaseout policy.
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\43\ An IVD that is also a biological product and subject to
licensure under section 351 of the PHS Act may be studied under an
IND and subject to the investigational use requirements in section
351(a)(3) of the PHS Act and 21 CFR part 312, instead of the IDE
requirements in part 812 (see, e.g., 21 CFR 312.2(a) and Ref. 65).
IVDs studied under an IND are generally those intended for use as
blood donor screening or HCT/P donor screening tests to which FDA's
general enforcement discretion approach for LDTs has not applied
(see section V.A.2). Therefore, we anticipate that there would be a
limited number of IVDs offered as LDTs, if any, subject to
investigational use requirements under 21 CFR part 312 for which the
phase out of enforcement discretion would be relevant. However, to
the extent such IVDs offered as LDTs exist, we intend to phase out
enforcement discretion with respect to those investigational use
requirements at stage 2, consistent with our policy regarding other
investigational use requirements.
\44\ For example, FDA stated in the ``Framework for Regulatory
Oversight of Laboratory Developed Tests (LDTs)'' draft guidance that
``FDA intends to continue to enforce investigational device
requirements under 21 CFR part 812 for all clinical investigations
of LDTs that are conducted under clinical protocols that require
institutional review board approval'' (Ref. 38).
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As described in the NPRM (88 FR 68006 at 68025), FDA anticipates
that it will best serve the public health to phase out the general
enforcement discretion approach for these requirements at the 2-year
mark, and FDA did not receive information changing its view with
respect to that timeline. Under this timeline, FDA will obtain
registration and listing information before the enforcement discretion
phaseout for premarket review requirements, which may give the Agency a
better understanding of the universe of IVDs offered as LDTs to
facilitate premarket review of those IVDs. Relatively few commenters
raised concerns about this timeline, and FDA's estimates of the
resources required for compliance with the requirements covered by
stage 2 suggest 2 years is adequate time (see FRIA section II.F.2).
Furthermore, the new enforcement discretion policies set forth in
section V.B may free up time and resources for laboratories to focus on
compliance with requirements at stage 2. FDA has determined that this
timeline appropriately balances the importance of compliance with
registration and listing, labeling, and investigational use
requirements, among others, relatively quickly--in order to address
IVDs offered as LDTs that are problematic, among other things--with the
recognition that laboratories generally have not complied with FDA
requirements and may need time to order their affairs and build out
FDA-compliant systems.
FDA notes that the labeling requirements under part 801 include
unique device identification (UDI) requirements, as applicable (see
part 801, subpart B).
3. Stage 3: Beginning 3 Years After the Publication Date of This Final
Rule, FDA Will Expect Compliance With QS Requirements
At the 3-year mark, FDA generally will expect compliance with the
CGMP requirements of the QS requirements under 21 U.S.C. 360j(f) and
part 820. (FDA notes that we expect compliance with requirements under
Sec. 820.198 (complaint files) during stage 1 of the phaseout policy.)
We recognize that the costs of compliance with QS requirements are
comparatively high among the range of costs quantified in the FRIA (and
as suggested in certain comments), but FDA continues to believe that
the 3-year timeline is appropriate given, in particular, the new
enforcement discretion policies in section V.B.3, which we anticipate
will significantly reduce laboratories' work at this stage (see section
II.F.3 of the FRIA). FDA has determined that this timeline is
consistent with our goal of improving the quality of IVDs manufactured
by laboratories as soon as feasible while also taking into account the
resources and time required to set up quality systems.
FDA also notes that we expect laboratories to retain manufacturing
records they may already have or may create for certain IVDs prior to
stage 3 of the phaseout policy. In particular, for any IVDs for which
FDA generally intends to exercise enforcement discretion for all QS
requirements other
[[Page 37309]]
than requirements under part 820, subpart M (Records), FDA expects
laboratories to retain existing records and records created prior to
the start of stage 3 that are relevant to validation and the other
topics covered under part 820, subpart M (Records)). This documentation
will help FDA understand the manufacturing for IVDs offered as LDTs
that are marketed prior to stage 3, including helping FDA identify IVDs
that are potentially problematic.
FDA issued its final rule amending the QSR on February 2, 2024,
which will take effect on February 2, 2026, meaning that the amended QS
requirements will be in effect before the beginning of stage 3. When a
laboratory undertakes to comply with QS requirements, FDA will expect
compliance with the QS requirements that are in effect at that time
whether that be at the start of stage 3 or earlier (if the laboratory
complies with QS requirements prior to the start of stage 3).\45\ For
further information on the QS requirements established pursuant to the
amendments to the QSR, please refer to 89 FR 7496.
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\45\ As noted elsewhere in this phaseout policy, FDA intends to
phase out the general enforcement discretion approach with respect
to requirements under Sec. 820.198 (complaint files) during stage 1
of the phaseout policy. However, upon the start of stage 1, and
prior to the effective date of the amended QSR, FDA intends to
exercise enforcement discretion and generally not enforce
requirements under Sec. 820.198 for laboratories that are in
compliance with Subclause 8.2.2 of ISO 13485. Following the
effective date of the amended QSR (February 2, 2026), laboratories
must comply with the QS requirements that are in effect at that
time.
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In addition, specifically for LDTs,\46\ FDA is adopting the
enforcement discretion policy proposed in the NPRM under which FDA
generally will expect compliance at the 3-year mark with some, but not
all, of the QS requirements (88 FR 68006 at 68025). FDA continues to
believe this policy is helpful and appropriate. Although FDA and CMS
regulation are different and complementary, compliance with CLIA
requirements provides some quality assurances that may be relevant to
laboratories' manufacturing practices. In particular, laboratories may
in practice be able to apply concepts set forth under CLIA requirements
for laboratory operations to certain manufacturing activities regulated
by FDA. For FDA to effectively take into account the CLIA requirements,
this policy will apply only for LDTs (i.e., when all manufacturing
activities occur within a single laboratory and the IVD is not
transferred outside that laboratory). However, this policy is limited
in scope because CLIA regulations do not provide relevant assurances
for certain QS requirements. These requirements include design controls
under Sec. 820.30; purchasing controls (including supplier controls)
under Sec. 820.50; acceptance activities (receiving, in-process, and
finished device acceptance) under Sec. Sec. 820.80 and 820.86; CAPA
under Sec. 820.100; and records requirements under part 820, subpart
M.<SUP>47 48</SUP> Because CLIA does not provide assurances relevant to
these requirements, FDA has determined to phase out the general
enforcement discretion approach for these specific requirements 3 years
after publication of this final rule (except for requirements under
Sec. 820.198 (complaint files), for which FDA intends to phase out the
general enforcement discretion approach during stage 1 of the phaseout
policy).
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\46\ As explained elsewhere in this preamble, FDA has generally
considered the term ``laboratory developed test (LDT)'' to mean an
IVD that is intended for clinical use and that is designed,
manufactured, and used within a single CLIA-certified laboratory
that meets the regulatory requirements under CLIA to perform high
complexity testing.
\47\ For LDTs, FDA generally expects compliance with
requirements under part 820, subpart M (Records) but not Sec. Sec.
820.20, 820.22, and 820.40 (which are cross-referenced in subpart
M), or comparable provisions of ISO 13485 in accordance with the
amendments to part 820 once that rule takes effect in February 2026.
\48\ Upon the effective date of the amendments to the QSR, the
requirements relating to design controls, purchasing controls,
acceptance activities, CAPA, and records requirements will be set
forth in the following ISO 13485 clauses as modified by the codified
for part 820: Clause 4. Quality Management System, Subclause 4.2.5;
Clause 6. Resource Management; Clause 7. Product Realization,
Subclause 7.1, Subclause 7.3, Subclause 7.4, and Subclause 7.4.3;
and Clause 8. Measurement, Analysis, & Improvement, Subclause
8.2.2., Subclause 8.2.5, Subclause 8.2.6, and Subclause 8.3.
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Finally, FDA notes that under section 515(d)(2) of the FD&C Act,
the Agency may not approve a PMA if the applicant fails to demonstrate
conformity with the QS requirements. Therefore, compliance with the QS
requirements is needed to support approval of a PMA. As provided in
section 520(f)(2) of the FD&C Act, any person subject to the QS
requirements may petition for an exemption or variance from any QS
requirement (see also Sec. 820.1).
4. Stage 4: Beginning 3\1/2\ Years After the Publication Date of This
Final Rule, FDA Will Expect Compliance With Premarket Review
Requirements for High-Risk IVDs Offered as LDTs, Unless a Premarket
Submission Has Been Received by the Beginning of This Stage in Which
Case FDA Intends To Continue To Exercise Enforcement Discretion for the
Pendency of Its Review
FDA has determined that the phaseout for the general enforcement
discretion approach with respect to premarket review requirements for
high-risk IVDs offered as LDTs should occur 3\1/2\ years from
publication of this final rule, consistent with the timeline proposed
in the NPRM (88 FR 68006 at 68026). The premarket review requirements
for PMAs are set forth in 21 U.S.C. 360e and part 814 (21 CFR part
814). The information in the record has not changed our view that 3\1/
2\ years will provide sufficient notice and opportunity for
laboratories manufacturing IVDs to plan for and prepare PMAs.\49\
Although we received comments indicating that it would be difficult for
laboratories to comply within this 3.5-year timeline, the new
enforcement discretion policies included in this final phaseout policy
should help address those concerns. For example, the policy for
currently marketed IVDs offered as LDTs and the policy for certain
unmet needs LDTs mean FDA generally does not expect compliance with
premarket review requirements for a substantial subset of IVDs.
Overall, in light of these policies, FDA has determined that a 3.5-year
period is a reasonable amount of time to expect laboratories to come up
to speed on PMA requirements, gather the information required for PMAs,
and complete their PMA submissions (see section II.F.4 of the FRIA).
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\49\ Under the phaseout policy, laboratories that intend to
submit an HDE application or a BLA should do so within the same 3\1/
2\-year timeframe for submission of PMAs. As in the case of PMAs,
under the phaseout policy, FDA generally does not intend to enforce
against IVDs after a complete HDE application or BLA has been
submitted (within the 3\1/2\-year timeframe) until FDA completes its
review of the application. Premarket review requirements specific to
HDE applications are set forth in 21 U.S.C. 360j(m) and part 814,
subpart H. Licensure requirements are set forth in 42 U.S.C. 262 and
21 CFR part 601.
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This timeline is also intended to align the phaseout for the
general enforcement discretion approach for premarket review
requirements for high-risk IVDs offered as LDTs with the start of
fiscal year 2028, which coincides with the beginning of a new user fee
cycle. This alignment will provide an opportunity for industry
participation in
[[Page 37310]]
negotiations regarding the next user fee cycle with the knowledge that
laboratory manufacturers will be expected to comply with premarket
review requirements. (Although a trade association representing
laboratories previously has participated in Medical Device User Fee
Amendments (MDUFA) negotiations, the prior negotiations have not
incorporated similar expectations regarding laboratory compliance with
premarket requirements.) Thus, we have determined that this amount of
time is appropriate to foster stability and consistency in the
marketplace for the current MDUFA cycle, and FDA will take into account
the need for adequate FDA resources to implement the phaseout policy in
a manner that does not compromise the capacity to achieve MDUFA V
performance expectations. FDA anticipates that during this 3\1/2\-year
period, laboratories will work with FDA to determine whether PMAs
should be submitted for their IVDs.
Under this phaseout policy, FDA generally does not intend to
enforce against IVDs offered as LDTs for lacking premarket approval
after a complete PMA has been submitted until FDA completes its review
of the application, provided that the PMA has been submitted within the
3\1/2\-year timeframe. Given that such IVDs may already be on the
market and available to patients, FDA generally does not intend to
interrupt access at the point when a submission is made. IVDs for which
a PMA is submitted after the 3\1/2\-year timeframe would not fall
within this enforcement discretion policy; FDA approval is expected
prior to such IVDs being offered.
Based on a review of the comments, FDA is also adopting a policy
under which it generally does not intend to enforce premarket review
requirements for certain laboratory changes to another manufacturer's
lawfully marketed test. In particular, this policy applies when a
laboratory certified under CLIA and meeting the regulatory requirements
under CLIA to perform high complexity testing modifies another
manufacturer's 510(k) cleared or De Novo authorized test, following
design controls and other quality system requirements for which FDA
expects compliance as described in section V.C.3, in a manner that
could not significantly affect the safety or effectiveness of the test
and does not constitute a major change or modification in intended use,
and where the modified test is performed only in the laboratory making
the modification. FDA is adopting this policy to promote more efficient
and effective use of Agency resources and because it understands
laboratories may make such changes to, for example, integrate a test
into its operations, accommodate local conditions (e.g., storage
conditions), or address supply shortages. Under the policy, FDA would
expect premarket submissions from laboratories modifying a third
party's 510(k) cleared or De Novo authorized test for the same types of
changes for which FDA would expect a premarket submission from the
original manufacturer making changes to its own IVD. Taking into
account the risks associated with relatively minor changes to 510(k)
cleared or De Novo authorized tests when they occur in a single
laboratory (i.e., without broad distribution), at this time, we believe
the resources needed to review these types of changes generally can be
better spent on other Agency priorities and activities. For a
description of changes that could significantly affect the safety or
effectiveness of the test or constitute a major change or modification
in intended use under this policy, see FDA's regulations at Sec.
807.81(a)(3) and further discussion in the final guidance ``Deciding
When to Submit a 510(k) for a Change to an Existing Device'' (Ref. 61).
If the modification (individually or in the aggregate) could
significantly affect the safety or effectiveness of the test or does
constitute a major change or modification in intended use and the
modified test does not fall within an enforcement discretion policy
discussed in section V.B above, FDA expects laboratories to submit the
applicable premarket submission. If the laboratory modification is so
significant that the IVD is no longer substantially equivalent to the
original IVD and requires a PMA, FDA expects the PMA to be submitted
either by stage 4 or before the modified test is marketed, whichever
comes later.
We are not applying this enforcement discretion policy to
modifications to another manufacturer's PMA-approved or BLA-licensed
test because such tests are high-risk, and changes to such tests pose
corresponding increased risks. We note that relatively few IVDs are
considered high risk today, and, further, FDA has announced its intent
to initiate the reclassification process for most IVDs that are
currently class III into class II (Ref. 66). FDA aims to complete this
reclassification process before stage 4 of the phaseout policy. We
therefore anticipate that there will be even fewer class III (high-
risk) IVDs going forward. As such, these tests present resource
considerations that are different from those discussed above.
5. Stage 5: Beginning 4 Years After the Publication Date of This Final
Rule, FDA Will Expect Compliance With Premarket Review Requirements for
Moderate-Risk and Low-Risk IVDs Offered as LDTs (That Require Premarket
Submissions), Unless a Premarket Submission Has Been Received by the
Beginning of This Stage in Which Case FDA Intends To Continue To
Exercise Enforcement Discretion for the Pendency of Its Review
FDA has determined to phase out the general enforcement discretion
approach with respect to premarket review requirements for moderate-
risk IVDs offered as LDTs (IVDs that may be eligible for classification
into class II) and low-risk IVDs offered as LDTs (IVDs that may be
eligible for classification into class I) that require a premarket
submission 4 years from publication of this final rule. These premarket
submissions include 510(k) submissions, the requirements for which are
set forth at 21 U.S.C. 360(k), 360c(i), and part 807, subpart E. These
submissions also include De Novo requests, which laboratories may
submit for IVDs offered as LDTs for which there is no legally marketed
device upon which to base a determination of substantial equivalence,
and for which the laboratory seeks classification into class I or class
II. These requirements are set forth at 21 U.S.C. 360c(f)(2) and 21 CFR
part 860, subpart D.
FDA is retaining the same 4-year timeline that was proposed in the
NPRM for stage 5 for reasons similar to those for stage 4 (see 88 FR
68006 at 68027). Specifically, when taking into account the enforcement
discretion policies in section V.B, we believe the original timeline
for compliance with 510(k) and De Novo requirements is feasible,
particularly given that these submissions are generally less resource-
intensive than PMAs (for additional information see section II.F.4 of
the FRIA (Ref. 10)). As noted in the NPRM, the 6-month interval between
stages 4 and 5 will enable FDA to prioritize the review of applications
for high-risk IVDs offered as LDTs (subject to premarket approval
requirements), so that we can focus first on IVDs for which the
consequences of a false result are generally most significant (88 FR
68006 at 68027). In addition, this timeline aligns with the user fee
cycle, as previously discussed.
FDA generally does not intend to enforce against IVDs offered as
LDTs for lacking premarket authorization after a complete 510(k) or De
Novo request has been submitted until FDA completes its
[[Page 37311]]
review of the submission, provided that the 510(k) or De Novo request
has been submitted within the 4-year timeframe. Given that such IVDs
may already be on the market and available to patients, FDA generally
does not intend to interrupt access at the point when a submission is
made. IVDs for which a 510(k) or De Novo request is submitted after the
4-year timeframe would not fall within this enforcement discretion
policy; FDA clearance or authorization is expected prior to such IVDs
being offered.
FDA is also adopting the policy regarding laboratory modifications
to another manufacturer's lawfully marketed test that is discussed
under stage 4. As explained in that discussion, under this policy, FDA
generally does not intend to enforce premarket review requirements when
a laboratory certified under CLIA and meeting the regulatory
requirements under CLIA to perform high complexity testing modifies
another manufacturer's 510(k) cleared or De Novo authorized test,
following design controls and other quality system requirements for
which FDA expects compliance as described in section V.C.3, in a manner
that could not significantly affect the safety or effectiveness of the
test and does not constitute a major change or modification in inten
[…truncated; see source link]Indexed from Federal Register on May 6, 2024.
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