December 16, 2019
FDA Regulation of Laboratory-Developed Tests (LDTs)
Laboratory-developed tests (LDTs) are a class of in vitro
diagnostic (IVD) device that is designed, manufactured, and
used within a single laboratory. LDTs are often used to test
for conditions or diseases that are either rapidly changing
(e.g., new strains of known infectious diseases) or that are
the subject of quickly advancing scientific research (e.g.,
genomic testing for cancer). The majority of genetic tests—
a type of IVD that analyzes various aspects of an
individual’s genetic material (e.g., DNA, RNA)—are
LDTs.
Federal agencies involved in the regulation of LDTs include
the Food and Drug Administration (FDA) and the Centers
for Medicare & Medicaid Services (CMS). FDA regulates
the safety and effectiveness of the diagnostic test, as well as
the quality of the design and manufacture of the diagnostic
test, pursuant to authorities in the Federal, Food, Drug, and
Cosmetic Act (FFDCA). CMS regulates the quality of
clinical laboratories and the clinical testing process
pursuant to the Clinical Laboratory Improvement
Amendments of 1988 (CLIA). This In Focus addresses only
FDA’s role in the regulation of LDTs.
The regulation of LDTs has been the subject of ongoing
debate over the past 20 years, driven in large part by the
increase in the number and complexity of genetic tests over
this time. In general, the FDA has maintained that it has
clear regulatory authority over LDTs, as it does with all
IVDs that meet the definition of medical device in the
FFDCA. However, the FDA traditionally exercised
enforcement discretion over LDTs—choosing not to
enforce applicable statutory and regulatory requirements
with respect to such tests—meaning that most of these tests
have neither undergone premarket review nor received
FDA clearance or approval for marketing. (For more
information about FDA regulation of medical devices,
including premarket approval and clearance, see CRS In
Focus IF11083, Medical Product Regulation: Drugs,
Biologics, and Devices.) Some representatives of clinical
laboratories and manufacturers of LDTs, such as the
American Clinical Laboratory Association (ACLA), have
asserted that LDTs are clinical services and not medical
products, and therefore should be outside of FDA’s
regulatory purview. Given the growing use and complexity
of LDTs and genetic tests, both Congress and the FDA have
once again revisited the regulation of LDTs.
FDA Activity on LDT Regulation
FDA has, to date, focused its enforcement efforts on
commercial IVD kits, which are broadly marketed, and has
not generally enforced premarket requirements for LDTs. In
recent years, however, FDA has indicated its intent to
regulate LDTs using a risk-based approach due to the
increasing number, significance, and complexity of LDTs.
In 2006 and 2007, FDA published and updated draft
guidance on a specific subset of LDTs called In Vitro
Diagnostic Multivariate Index Assays (IVDMIAs).
IVDMIAs are defined by the FDA as tests that, among
other things, provide results that are not transparent and that
the end user (usually a physician) could not independently
derive. The FDA never finalized its guidance concerning
IVDMIAs, and instead announced its intent to regulate all
LDTs in June 2010.
October 2014 Draft Guidance
In July 2014, FDA officially notified Congress of its intent
to begin regulating LDTs through draft guidance. This
notification was in fulfillment of a statutory requirement in
the Food and Drug Administration Safety and Innovation
Act of 2012 (FDASIA, P.L. 112-144), requiring FDA to
notify Congress at least 60 days before issuing any draft or
final guidance on regulation of LDTs. In the October 2014
draft guidance, Framework for Regulatory Oversight of
Laboratory Developed Tests (LDTs), FDA presented the
details of a risk-based framework for regulating LDTs. The
framework generally identified classes of LDTs that would
be (1) exempt from regulation entirely; (2) required to meet
only registration and listing (or notification) and adverse
event reporting requirements; and (3) required to meet
registration and listing (or notification), adverse event
reporting, applicable premarket review, and quality system
regulation requirements. The determination to continue
enforcement discretion—or to enforce certain or all
applicable regulatory requirements—for an LDT would be
based on risk evaluation. The agency collected comments
on the draft guidance document; however, in November
2016 FDA announced that it would be delaying finalization.
January 2017 Discussion Paper
FDA summarized the comments it had received on the 2014
draft guidance in its January 2017 Discussion Paper on
Laboratory Developed Tests (LDTs) and noted that it would
not be issuing “a final guidance on the oversight of [LDTs]
at the request of various stakeholders to allow for further
public discussion … and to give our congressional
authorizing committees the opportunity to develop a
legislative solution.” The discussion paper included a
proposed framework for an approach to LDT oversight that
would focus on “new and significantly modified high and
moderate risk LDTs.” Previously marketed LDTs would be
grandfathered and would not be expected to comply with
most or all FDA regulatory requirements, such as premarket
review, unless necessary to protect the public health. In
addition, new and significantly modified LDTs in several
specified categories (e.g., LDTs for rare diseases) would
generally not be expected to comply with FDA regulatory
requirements.
https://crsreports.congress.gov
FDA Regulation of Laboratory-Developed Tests (LDTs)
Key Issues in FDA Regulation of LDTs
In recent years, despite the absence of specific agency
guidance on the regulation of LDTs, FDA has nevertheless
begun to assert authority over LDTs, and specifically over
some direct-to-consumer (DTC) genetic tests. This has
included DTC genetic tests that provide information about
the risk of developing a disease or condition, or about a
patient’s predicted response to medications (which can
facilitate precision medicine).
DTC Genetic Tests
Genetic testing has become increasingly available for direct
purchase by consumers, generally over the internet, often
without the involvement of a health care provider and for
increasingly complex and common diseases (e.g., cancer).
As FDA has historically exercised enforcement discretion
over LDTs—and because many DTC genetic tests are
LDTs—DTC genetic test companies had generally operated
under the assumption that regulatory requirements
pertaining to LDT DTC genetic tests were not actively
being enforced by the FDA. Notably, however, the FDA
stated in its 2014 draft guidance that “FDA generally does
not exercise enforcement discretion for [DTC] tests
regardless of whether they meet the definition of an LDT
provided in this guidance.”
In the past several years, FDA has begun to enforce the
regulation of certain DTC genetic tests. In November 2013,
FDA sent a warning letter to 23andMe instructing the
company to discontinue marketing of its Personal Genome
Service (PGS) test until it received FDA clearance for this
test. Again in late 2015, FDA sent letters to companies
marketing DTC genetic tests without FDA clearance (e.g.,
Pathway Genomics, Inc.). These actions indicated that FDA
is taking steps to enforce regulatory requirements—and
specifically, premarket review—for DTC genetic tests that
the agency considers to be higher risk.
Alongside these actions, FDA has also authorized for
marketing some specific DTC genetic tests, in a reflection
of evolution in both DTC genetic tests themselves and FDA
oversight of these tests. In 2015, FDA cleared a 23andMe
test for carrier status for Bloom Syndrome, prompting the
agency to consider DTC genetic testing for carrier status
more broadly. In late 2015, FDA announced in the Federal
Register its “intent to exempt from the premarket
notification requirements autosomal recessive carrier
screening gene mutation detection systems, subject to
certain limitations.” In April 2017, FDA cleared the first
DTC genetic test that provides information about the risk of
developing disease. This test, 23andMe’s PGS Genetic
Health Risk, provides consumers information about their
likelihood of manifesting 10 diseases or conditions (e.g.,
Celiac Disease). Since then, FDA has cleared additional
tests developed by 23andMe that assess the risk of
developing a disease or condition.
Pharmacogenomic Testing and
Companion Diagnostics
In the context of asserting its authority over certain DTC
LDTs, FDA has taken recent action to address DTC—as
well as health care provider ordered—pharmacogenetic
tests (tests examining genetic variants with a link to
metabolism of medication). FDA cleared 23andMe’s PGS
Pharmacogenetic Reports test in October 2018, stating that
the test does not provide information about a patient’s
response to any specific medication, but that it may guide
discussions with health care providers by informing how a
patient may metabolize some medications. FDA released a
safety communication warning against the use of certain
DTC and provider-ordered tests that claim to predict
response to specific medications, stating that these tests’
claims have not been reviewed by FDA and are not
necessarily supported by evidence. There is concern that
patients and their health care providers may inappropriately
rely on information from these tests, and make adjustments
to medication and/or dosing that could be detrimental to
patient health. In April 2019, FDA sent a warning letter to
Inova Genomics Laboratory for marketing tests that claim
to predict a patient’s response to specific medications based
on genetic variants without FDA clearance or approval.
A test that informs the use of a specific medication—
termed a “companion diagnostic”—is regulated according
to FDA guidance and is a key component of personalized
medicine. A 2014 guidance document, In Vitro Companion
Diagnostic Devices: Guidance for Industry, defines
companion diagnostic as “an in vitro diagnostic device that
provides information that is essential for the safe and
effective use of a corresponding therapeutic product. The
use of an IVD companion diagnostic device with a
therapeutic product (e.g., drug) is stipulated in the
instructions for use in the labeling of both the diagnostic
device and the corresponding therapeutic product, including
the labeling of any generic equivalents of the therapeutic
product.” The guidance notes that if scientific evidence is
sufficient to support the use of a diagnostic with a class or
group of therapeutics, then the diagnostic labeling may
mention the therapeutic class rather than just one cleared
diagnostic. In December 2018, FDA issued guidance—
Developing and Labeling in vitro Companion Diagnostic
Devices for a Specific Group or Class of Oncology
Therapeutic Products: Guidance for Industry—that
addresses labeling a diagnostic for a class or group of
oncology therapeutic products. The FDA maintains that,
where sufficient evidence exists, labeling for use with the
class of therapeutics rather than a listing of specific
therapeutics would increase clinical flexibility for both the
provider and patient.
Recent Legislative Activity on LDTs
Over the past few years, after the passage of the 21st
Century Cures Act, various legislative approaches relating
to FDA regulation of IVDs and LDTs have been under
discussion. A discussion draft bill circulated in early 2017,
the Diagnostic Accuracy and Innovation Act (DAIA), was
crafted with industry and other stakeholder input. It
outlined a regulatory approach for IVD tests that was riskbased and flexible. FDA responded to this draft in August
2018 with a proposal for a novel regulatory approach for
these tests, including a mechanism for precertifying certain
related tests to streamline premarket requirements, among
other things. In December 2018, a new draft bill based on
DAIA and incorporating FDA’s feedback was released
entitled the Verifying Accurate, Leading-edge, IVCT
Development (VALID) Act.
Amanda K. Sarata, Specialist in Health Policy
https://crsreports.congress.gov
FDA Regulation of Laboratory-Developed Tests (LDTs)
IF11389
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