Regulation of Laboratory-Developed Tests: FDA’s Proposed Rule

Regulation of Laboratory-Developed Tests: FDA’s Proposed Rule

April 8, 2024
Regulation of Laboratory-Developed Tests:
FDA’s Proposed Rule
The Food and Drug Administration (FDA) defines
an FDA user fee reauthorization bill in the Senate (S. 4348,
laboratory-developed tests (LDTs) as a class of in vitro
Subtitle C—In Vitro Clinical Tests); it was not ultimately
diagnostic (IVD) device that is designed, manufactured, and
included in the enacted user fee reauthorization law (neither
used within a single clinical laboratory. LDTs are an
in the user fee program reauthorization nor in the package
important part of personalized medicine and are often
of policy riders that passed separately as part of the 2023
modified iteratively, as they test for disease in the context
omnibus).
of evolving scientific knowledge (e.g., genomic testing for
cancer). LDTs increasingly rely on complex technology
In the absence of congressional action, in October 2023,
(e.g., artificial intelligence [AI] software applications) and
FDA published a proposed rule (88 Fed. Reg. 68006,
guide critical health care decisions.
October 3, 2023) to “make explicit that IVDs are devices
under the Federal Food, Drug, and Cosmetic Act, including
These considerations, most recently highlighted by
when the manufacturer of the IVD is a laboratory.” In
COVID-19 test development and deployment during the
addition, in August 2020 the Department of Health and
pandemic, have driven debate over the regulation of LDTs
Human Services (HHS) announced that, during the height
for more than three decades. In general, FDA has
of the COVID-19 pandemic, it was rescinding all guidance,
maintained that it has clear regulatory authority over LDTs,
compliance manuals, website statements, or other informal
as it does with all IVDs that meet the definition of device in
issuances concerning FDA premarket review of LDTs. This
the Federal Food, Drug, and Cosmetic Act (FFDCA).
announcement applied to all LDTs—including COVID-19
However, FDA has traditionally exercised enforcement
LDTs—and stated that FDA could not require premarket
discretion over LDTs—choosing not to enforce applicable
review for these tests absent a notice-and-comment
statutory and regulatory requirements with respect to such
rulemaking process. Although this policy was eventually
tests—meaning that most of these tests have neither
rescinded in November 2021, it highlighted potential
undergone premarket review nor received FDA clearance,
challenges for the agency proceeding with oversight of
authorization, or approval for marketing. To date, FDA has
LDTs through agency level guidance rather than formal
focused its oversight on IVD test kits or components, which
rulemaking. FDA received nearly 7,000 comments on the
are commercially marketed as opposed to developed and
proposed rule during a 60-day comment period (which the
carried out in a single laboratory. Some representatives of
agency declined to extend); the final rule is currently
clinical laboratories and manufacturers of LDTs, such as
anticipated in mid-2024.
the American Clinical Laboratory Association (ACLA),
have long asserted that LDTs are professional clinical
Overview of Proposed Rule
services and not medical products, and therefore should fall
The proposed rule would make a single amendment to the
outside FDA’s regulatory purview.
existing regulatory definition for “in vitro diagnostic
products” to clarify that IVDs, where the manufacturer is a
Relevant Congressional and FDA Activity
clinical laboratory, meet the definition of device under the
Given the growing use and complexity of LDTs, as well as
FFDCA (21 C.F.R. §809.3). The proposed amended
experience gained during the COVID-19 pandemic, both
definition is as follows (proposed change italicized): “In
Congress and FDA have again focused on the regulation of
vitro diagnostic products are those reagents, instruments,
LDTs. Since passage of the 21st Century Cures Act (P.L.
and systems intended for use in the diagnosis of disease or
114-255) in late 2016, various legislative approaches to the
other conditions, including a determination of the state of
regulation of IVDs and LDTs have been considered. The
health, in order to cure, mitigate, treat, or prevent disease or
Verifying Accurate, Leading-edge, IVCT Development
its sequelae. Such products are intended for use in the
(VALID) Act, the culmination of many of these earlier
collection, preparation, and examination of specimens taken
efforts, was first introduced in the 116th Congress (S.
from the human body. These products are devices as
3404/H.R. 6102) and again in the 117th (S. 2209/H.R. 4128)
defined in section 201(h) of the Federal Food, Drug, and
and 118th (H.R. 2369). The VALID Act proposes a
Cosmetic Act (the act), and may also be biological products
comprehensive, novel, risk-based regulatory regime for “in
subject to section 351 of the Public Health Service Act,
vitro clinical tests (IVCTs),” defined to include both IVDs
including when the manufacturer of these products is a
and LDTs, that is distinct from, although similar to, the
laboratory.”
existing regulatory regime for medical devices. The VALID
Act proposes a unique marketing pathway for moderate risk
In addition, the proposed rule outlines a “phaseout policy”
IVCTs predicated on a technology certification covering
for FDA’s general enforcement discretion approach for
similar tests marketed by a specific test developer, among
LDTs. Specifically, the rule notes that compliance with
many other requirements. In 2022, it was incorporated into
device regulatory controls (e.g., adverse event reporting,
https://crsreports.congress.gov

Regulation of Laboratory-Developed Tests: FDA’s Proposed Rule
labeling, premarket notification) would be phased in over a
Manufacturers would be required to
period of approximately four years with respect to tests
comply with premarket review
manufactured and offered as LDTs. The timing of the
requirements for moderate- and low-risk
cascading phaseout policy is based on time from
IVDs offered as LDTs (21 C.F.R. Part
publication of a final rule. In addition to addressing FDA’s
807, Subpart E, premarket notification; 21
stated public health concerns with LDTs, the phasing out of
C.F.R. Part 860, Subpart D, De Novo
FDA’s current general enforcement discretion approach
classification request).
was proposed by FDA to level-set the regulation of LDTs
FDA notes that its policy of enforcement discretion would
and traditional commercial IVDs. The current differential
continue with respect to certain categories of LDTs,
regulatory approach has regularly been highlighted as a
specifically (1) LDTs used for law enforcement purposes
concern by IVD manufacturers and their advocacy
(forensic tests); (2) human leukocyte antigen (HLA) LDTs;
organization, AdvaMed. The proposed phaseout policy
(3) public health surveillance tests; and (4) “1976-Type
would include five steps, as follows:
LDTs” (tests with characteristics similar to LDTs offered in
1976, for example, use of manual techniques). FDA also
1. One year after publication of the final
notes that certain subsets of LDTs are currently, and
rule: Manufacturers of IVDs offered as
generally have been, excluded from the policy of
LDTs would be expected to comply with
enforcement discretion, and that would continue
medical device adverse event reporting
unchanged. These categories include (1) tests used under an
(MDR, 21 C.F.R. Part 806) and reports of
Emergency Use Authorization (EUA); (2) direct-to-
corrections and removals (21 C.F.R. Part
consumer tests; and (3) tests intended as blood donor
803). This would allow FDA to begin
screening or human cells, tissues, and cellular and tissue-
monitoring the safety of LDTs as soon as
based products (HCT/Ps) donor screening tests required for
practically possible.
infectious disease testing.
2. Two years after publication of the final
rule: In addition to MDR and removal
Selected Policy Considerations
and correction notification requirements,
On March 21, 2024, the House Energy and Commerce
manufacturers of IVDs offered as LDTs
Committee’s Subcommittee on Health held a hearing,
would be required to comply with
“Evaluating Approaches to Diagnostic Test Regulation and
additional regulatory controls other than
the Impact of the FDA’s Proposed Rule.” Several witnesses
Quality System (QS) regulation (device
and Members addressed considerations around regulating
current good manufacturing practices)
LDTs through rulemaking or legislative action and
and premarket review requirements (e.g.,
provided a range of feedback on FDA’s proposed rule.
Premarket Approval [PMA]). These
Further, on March 13, 2024, the ranking member of the
additional controls include labeling (21
Senate Health, Education, Labor and Pensions (HELP)
C.F.R. Part 801 and 809), registration and
Committee formally requested stakeholder feedback on the
listing (21 C.F.R. Part 807 other than
regulation of clinical tests broadly, prompted in part by
Subpart E), and investigational use
FDA’s proposed rule.
requirements (21 C.F.R. Part 812).
3. Three years after publication of the final
Policy considerations raised by the proposed rule may
rule: Manufacturers of IVDs offered as
include, among others, the following:
LDTs would be required to comply with
• Does FDA need additional statutory authority to
the QS regulation (21 C.F.R. Part 820),
regulate LDTs as devices?
except for IVDs where all manufacturing
activities occur within a single clinical
• Is the existing medical device regulatory framework
laboratory and the IVD is not distributed
sufficiently flexible for the purpose of regulating LDTs?
outside that laboratory. In this case,
• How would the FDA’s proposed rule interact with
laboratories would have to comply only
Clinical Laboratory Improvement Amendments of 1988
with certain QS requirements, for
(CLIA) requirements for clinical laboratories?
example, design controls (21 C.F.R.
§820.30), records requirements (21
• FDA estimates there are about 80,000 LDTs currently
C.F.R. Part 820, Subpart M), and
available, with approximately 8,000 new tests expected
purchasing controls (21 C.F.R. §820.50),
per year. Could premarket review of LDTs be
among others.
adequately managed by FDA and third-party reviewers?
4. Three and a half years after publication
• Would premarket review and other regulatory control
of the final rule (but not before October 1,
requirements affect the availability of LDTs? If so, to
2027): Manufacturers would be required
what extent?
to comply with premarket review
requirements for high-risk (Class III)
Amanda K. Sarata, Specialist in Health Policy
IVDs offered as LDTs (PMA, 21 C.F.R.
Part 814).
IF12628
5. Four years after publication of the final
rule (but not before April 1, 2028):
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Regulation of Laboratory-Developed Tests: FDA’s Proposed Rule

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