Inside FDA's Proposed Rule to Regulate Laboratory Developed Tests (LDTs)

In September, the FDA proposed a rule that would end the enforcement LDTs by treating them as IVDs. Here's what you need to know.

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On September 29, 2023, the FDA proposed a rule that would end the enforcement discretion policy for laboratory-developed tests (LDTs) by treating them as In Vitro Diagnostics (IVDs) subject to regulatory requirements as medical devices.

The rule would add a statement to the definition of "in vitro diagnostic products" in 21 CFR Part 809.3(a), stating that IVDs are considered devices under the FDCA, even if a laboratory is the manufacturer.

The rule proposes a phased approach, with LDT manufacturers required to comply with regulatory requirements in stages. Compliance would begin one to four years after the final LDT rule is published. The final policy will be included in the rule's preamble.

It is currently unclear when the regulatory requirements would become effective. For now, laboratories that offer LDTs should stay informed and track any developments related to the Proposed Rule. It's important to note that the Proposed Rule does not intend to "grandfather" any LDTs that are currently available in the market.

A brief primer on the FDA's LDT regulation

According to FDA regulations, IVDs are defined 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 are classified by the FDA as medical devices, and as such, they are subject to a full range of premarket and postmarket controls, which include requirements related to 510(k) premarket notification or premarket approval (PMA), quality system (QS) regulation, medical device reporting (MDR), registration and listing, and labeling.

IVDs are regulated under the Clinical Laboratory Improvement Amendments of 1988 (CLIA). LDTs are IVDs designed, manufactured, and used within a single lab holding a clinical lab certification under CLIA.

Although the FDA can regulate LDTs as medical devices, it has not enforced pre-market review and other regulatory requirements for LDTs due to their limited use in small volumes, primarily in rare diseases, and with interpretation by a treating physician.

According to the FDA's new Proposed Rule, however, LDTs have become increasingly popular and are being used by a more diverse population. They are also being relied upon more frequently for making important healthcare decisions.

The Proposed Rule suggests that LDTs are now similar to other IVDs that have not been subject to the FDA's general enforcement discretion approach. Therefore, FDA believes phasing out the general enforcement discretion approach for LDTs is essential to protect public health. To ensure that only genuine LDTs are covered by the rule, the FDA is defining LDT broadly, as many manufacturers of high-complexity tests have been disguising their tests as LDTs.

Prior attempts at LDT regulation

The FDA has attempted to regulate LDTs before, with draft guidances dating back to 2006. Here’s a brief history of this activity, explained in greater depth in a 2022 issue of In Focus from the Congressional Research Service.

• In 2006 and 2007, the FDA released and revised a draft guidance regarding a specific category of Laboratory Developed Tests (LDTs) known as In Vitro Diagnostic Multivariate Index Assays (IVDMIAs). IVDMIAs are a type of test that provides results that are not transparent and cannot be independently derived by the end-user, typically a physician. However, the FDA never finalized its guidance for IVDMIAs and instead announced in June 2010 that it intends to regulate all LDTs.

• In July 2014, the FDA announced its intent to regulate LDTs through draft guidance. The October 2014 draft guidance presented a risk-based framework for regulating LDTs, classifying them into three groups based on their level of risk. The FDA would determine whether to enforce certain or all applicable regulatory requirements for an LDT based on risk evaluation. The FDA collected comments on the draft guidance document; however, in November 2016, it announced that it would be delaying finalization.

• In January 2017, the FDA published a Discussion Paper on LDTs that summarized the comments received on the 2014 draft guidance. The agency stated that it would not be issuing a final guidance on the oversight of LDTs, as requested by various stakeholders. Instead, they wanted to allow for further public discussion and allow their congressional authorizing committees to develop a legislative solution. The discussion paper proposed a framework for an approach to LDT oversight that mainly focuses on new and significantly modified high and moderate-risk LDTs. LDTs that have been marketed previously would not be expected to comply with most or all FDA regulatory requirements, such as premarket review, unless necessary to protect public health. Moreover, new and significantly modified LDTs in several specified categories, such as LDTs for rare diseases, would generally not be expected to comply with FDA regulatory requirements.

Key Issues in the FDA's Regulation of LDTs

Over the past few years leading up to 2023's Proposed Rule, the FDA has been regulating LDTs without any specific agency guidance. This includes DTC genetic tests that provide information about a patient's predicted response to medications and the risk of developing a disease or condition. These tests can facilitate precision medicine.

DTC genetic tests

Genetic testing has become widely available for direct consumer purchase, especially over the internet, for various diseases, including complex and common ones like cancer.

Historically, the FDA exercised enforcement discretion over LDTs. However, despite the lack of specific agency guidance, it has started asserting authority over these tests, especially DTC genetic tests providing disease risk or medication response information.