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October 2014 Draft Guidance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to begin regulating LDTs through draft guidance.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draft guidance, Framework for Regulatory Oversight of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

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FDA Regulation of Laboratory-Developed Tests (LDTs)

IF11389


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https://crsreports.congress.gov | IF11389 · VERSION 1 · NEW

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