On July 31, 2014, the U.S. Food and Drug Administration (FDA or the Agency) announced plans to formally regulate laboratory developed tests (LDTs). The announcement came in the form of letters to Congress attaching the preliminary drafts of two guidance documents describing the Agency’s proposed risk-based framework for regulatory oversight of LDTs. The first draft guidance, Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs), addresses the proposed regulatory framework, while the second, FDA Notification and Medical Device Reporting for Laboratory Developed Tests (LDTs), describes the methods that industry may be able to use to address the requirements the Agency is proposing. 

The documents were provided to Congress in order to satisfy Section 1143 of the Food and Drug Administration Safety and Innovation Act, which required the FDA to notify Congress at least 60 days prior to issuance of draft or final guidances on the regulation of LDTs. The FDA will now wait at least 60 days before issuing the regulatory framework in official draft form for public comment. The Agency expects to have a 90-day comment period for interested stakeholders prior to implementation of the proposed regulatory plan. 

In providing the draft documents, the FDA commented that it was taking this step in part because it does not feel that the Clinical Laboratory Improvement Amendments (CLIA), which also contain regulatory requirements applicable to laboratories, are sufficient to “ensure that LDTs are properly designed, consistently manufactured, and are safe and effective for patients.” While this position has been very controversial, the FDA asserts that external review of test validity, as well as clinical assessment of validity, by regulators is important to assuring good test design. The Agency further cites the complexity and widespread use of LDTs as an important factor in the FDA’s decision to change the existing regulatory policy. The Agency states that its proposed regulatory framework recognizes that, as with in vitro diagnostic devices (IVD), LDTs also have different risks depending on their use and thus “a risk-based approach to regulatory oversight is appropriate and necessary to protect patient safety.”

FDA’s Definition of an LDT

The FDA defines an LDT as IVD that are designed, manufactured, and used within a single laboratory and intended for clinical use. The FDA further clarifies that, for purposes of an LDT, a single laboratory is a clinical laboratory that has a single CLIA certificate for high-complexity testing. The Agency has also reiterated its long-standing view that tests offered by clinical laboratories that meet the following characteristics do not fall within the definition of an LDT because the design, manufacture, and use of the test is not performed by a single laboratory:

  • an entity that owns several laboratories and develops a test in one lab but transfers it to other labs within its network;
  • an academic institution that develops a test and then licenses that test to a company that owns a CLIA lab and manufactures and uses that test;
  • a laboratory that contracts with a third-party manufacturer to produce a key component (e.g., coated microtiter plate, specialized specimen collection kit); or
  • a laboratory that contracts with a specification developer to design a new test, which the specification developer then transfers to the clinical laboratory for validation, manufacture, and use.

Nonetheless, the FDA notes that under the status quo many labs are offering tests that meet one of the criteria above. Therefore, the Agency plans to apply the same risk-based enforcement approach regardless of whether the test meets the FDA’s technical definition of an LDT (i.e., is not in one of the categories above).

The Proposed Risk-Based Regulatory Framework

As described above, the FDA’s proposed regulatory framework is a risk-based approach. Under this framework, LDTs would be classified consistent with the approach taken for existing medical devices, placing the tests into class I (i.e., low risk devices), class II (i.e., moderate risk devices) or class III (i.e., high risk and not substantially equivalent devices). Using this approach, the level of regulatory oversight and the timeframe for compliance with applicable requirements would be based, ultimately, on the test’s classification. The FDA plans to develop the classification scheme for LDTs through a process involving both industry and expert advisory panels.

The guidance describes the main elements of the FDA’s regulatory oversight for LDTs and includes:

  • either notification to the FDA of LDTs manufactured by a laboratory or the FDA’s existing registration and listing requirements;
  • medical device reporting requirements (MDR) for LDTs (e.g., adverse event reporting);
  • continued enforcement discretion with respect to premarket review requirements for low-risk LDTs, “traditional LDTs,” LDTs used for rare diseases, and “LDTs for unmet needs”;
  • risk-based, phased-in approach to enforcing the premarket review requirements for other high-risk and moderate-risk LDTs;
  • use of clinical literature to support a demonstration of clinical validity, which the FDA expects would reduce the need for additional clinical studies to show clinical validity for LDTs where the analytes/markers that are measured/assessed have had their clinical validity established in the literature;
  • facilitation of third-party review for many moderate risk LDTs;
  • phased-in approach to enforcing the quality system regulation; and
  • continued enforcement discretion for premarket review of class I LDTs.

Factors that will be used in determining the risk classification of an LDT include:

  • whether the device is for use in high risk disease/condition or patient population;
  • whether the device is for screening or diagnosis;
  • nature of the clinical decision that will be made based on the test result;
  • whether other information would be used in addition to the LDT result;
  • availability of alternative diagnostic and treatment options;
  • potential effect of erroneous result; and
  • number and type of adverse events.

Certain LDTs will continue under the FDA’s enforcement discretion and will not be subject to regulatory oversight. These include LDTs used solely for law enforcement purposes and LDTs used in CLIA-certified high-complexity histocompatibility laboratories to assess transplantation compatibility (e.g., allele typing, antibody screening, and monitoring and cross-matching).

Initial Notification Requirements

The FDA intends to collect information regarding LDTs that are already on the market through a notification process. The FDA’s second guidance document provides specific information that a clinical laboratory will be required to provide in the notification to the FDA including, in part, the name of the lab, the test name, intended use and clinical use, test methodology, and monthly test volume. Furthermore, the FDA intends to make publicly available disclosable information about the LDT. Notification need only occur once for each specific LDT offered at each laboratory. However, if significant changes are made to the LDT (e.g., intended use) the FDA expects that a new notification will be made for the test.

Although all LDTs, with few exceptions, would be subject to registration and listing requirements per 21 C.F.R. 807, the FDA plans to exercise enforcement discretion concerning these requirements if a clinical laboratory opts to provide the FDA with notification as described above.1 Conversely, if the laboratory fails to register and list, no enforcement discretion will be exercised with regard to the applicable tests and those laboratories will be forced to comply with registration and listing requirements and pay the associated facility registration fees. Furthermore, once the FDA clears or approves an LDT for a specific intended use, the manufacturing laboratory will be subject to medical device registration and listing regulations with respect to that test.

Adverse Event Reporting Requirements

The FDA intends to collect safety and effectiveness information by requiring clinical laboratories that offer LDTs to report any known or suspected adverse event related to an LDT through 21 C.F.R. Part 803 MDR requirements.

Similar to other medical device manufacturers, clinical laboratories that offer LDTs would be subject to the MDR requirements under Part 803 and would need to have written MDR procedures in place. MDR reporting requirements are in addition to existing user facility reporting requirements.

Premarket Review Requirements

The FDA typically requires premarket review (i.e., 510(k) clearance or premarket approval application (PMA) approval) prior to marketing of medical devices, unless the product is subject to a particular exemption. However, the FDA proposes to exempt a number of LDTs from premarket review, including tests for:

  • Rare Diseases – Laboratories would have the option of seeking humanitarian use designation (HUD) and humanitarian device exemption (HDE)2 if the LDT is developed for use in diseases or medical conditions that occur in fewer than 4,000 patients per year. However, the FDA does not intend to require premarket approval of an HDE for those LDTs that meet the definition of a HUD.
  • “Traditional LDTs” – Those LDTs that were available when the FDA’s 1976 initial policy of enforcement discretion was put into effect. These tests would be considered by the Agency as candidates for exemption from premarket review requirements taking into consideration the following factors:
    • whether the device meets the definition of an LDT;
    • whether the device is manufactured and used by a healthcare facility for a patient being diagnosed/treated at the same facility (or in the same network);
    • whether the LDT is comprised of only legally marketed components and reagents (analyte specific reagents, general purpose reagents, classified instruments); and
    • whether the LDT is interpreted by qualified lab professionals, without automated instrumentation or software for interpretation.
  • LDTs for Unmet Needs When No Approved/Cleared Alternative is Available – for these types of LDTs, the FDA will consider the following factors:
    • whether the device meets the definition of an LDT;
    • whether there are no FDA-approved or cleared alternatives; and
    • whether the device is manufactured and used by a healthcare facility for a patient being diagnosed/treated at the same facility (or in the same network).

Furthermore, for those LDTs intended for use for Unmet Needs, the FDA indicates that the Agency likely will not take into account factors such as whether the LDT is comprised of only legally marketed components and instruments or whether the LDT is interpreted by qualified laboratory professionals as it is the view of the FDA that more flexibility is needed for LDTs in this category. However, once a new device is approved/cleared for the same use, other LDTs of the same type will no longer be exempt from premarket review.

All other LDTs would be subject to premarket review requirements, including submission of a 510(k) or PMA, depending on the classification. Categories that will be the initial focus of the FDA’s regulatory oversight, due to their high-risk nature, include:

  • Companion Diagnostics and other High-Risk Diagnostic LDTs – these devices, as previously outlined, include: 1) LDTs with the same intended use as currently cleared or approved companion diagnostics; 2) LDTs with the same intended use as current FDA-approved class III medical devices; and 3) LDTs used to determine the safety and effectiveness of blood or blood products. Under the proposed framework, the FDA intends to focus on regulating “high-risk” LDTs, including LDTs that have the same intended use as cleared or approved Companion Diagnostic tests, but to exercise greater enforcement discretion over LDTs for unmet needs (i.e., for which there are no FDA-cleared or approved tests). This leaves a degree of ambiguity because there may be new LDTs developed in the future (or available now) that are Companion Diagnostic tests or that act like Companion Diagnostic tests that meet an “unmet clinical need” and for which there are not yet any FDA-cleared or approved IVDs. Under the new LDT framework, these kinds of LDTs should be eligible for the greater enforcement discretion. But, the new framework also indicates that “devices that act like companion diagnostics,” in the agency’s view, “generally pose a higher risk to patients than other LDTs, and for which enforcement of premarket review requirements [will] likely commence earlier (following adequate public notice…).” How quickly the FDA develops these requirements will likely be closely scrutinized by impacted stakeholders.
  • Blood Donor, Transfusion Compatibility and Human Tissue-Based Products (HCT/P)

For other categories of LDTs that do not fall within any of the LDTs described above (e.g., high-risk, blood or tissue screening LDTs, or those exempted from premarket review), the FDA plans to categorize the LDTs based on risk.

Furthermore, the FDA’s proposed plan contemplates that high-risk, class III LDT premarket submissions (i.e., PMAs) will be reviewed by the Agency, but notes that it is likely that third-party review of 510(k) submissions may be an option for most lower risk class II LDTs. Third-party review for many products has been available for years with mixed success so it is unclear whether the FDA’s desire for expanding third-party review to these LDTs will prove a viable option.

Clinical Utility Evaluation

The FDA intends to leverage, where possible, literature to support clinical validity so that new or additional studies will not be required to establish the clinical validity of LDTs if existing data is available. However, where clinical investigations of an LDT are found to be necessary, the studies will be subject to the investigational device regulations (IDE) under 21 C.F.R. Part 812, unless the study qualifies as IDE-exempt given existing criteria for such exemption.3 In addition, the studies would be subject to review by an institutional review board (21 C.F.R. Part 56) and informed consent (21 C.F.R. Part 50) requirements. Furthermore, in some cases, new studies for analytical performance may be required.

Quality System Regulations

With respect to the Quality System Regulation (QSR) under 21 C.F.R. Part 820, the Agency intends to exercise enforcement discretion until a clinical laboratory that manufactures a LDT submits a PMA or when the FDA grants 510(k) clearance for the LDT. The FDA explains that it intends to assist clinical laboratories in understanding their responsibilities under QSR prior to enforcing these regulations. Furthermore, for LDTs that the FDA determines to be low-risk, the Agency intends to exercise enforcement discretion with respect to QSR and will provide notice if that policy changes in the future.

Timeline for Implementation

If and when the guidance documents are finalized, the FDA plans to initiate enforcement using a phased approach. First, registration and listing (or notification, as appropriate), as well as adverse event reporting requirements will become effective six months after guidance finalization.

Second, premarket review requirements would begin immediately for any new (i.e., not previously marketed) LDTs or 12 months after guidance finalization for any “Companion Diagnostics and other High-risk Diagnostic LDTs” or HCT/P (see above) already on the market at the time of guidance finalization.

Importantly, if the required premarket submission for a Companion Diagnostic or other High-Risk Diagnostic LDT were made prior to the conclusion of the initial 12-month period, the FDA indicates that the Agency plans to exercise enforcement discretion while that submission is pending. Thus, such products may effectively be subject to enforcement discretion for even longer than 12 months. It is not clear whether the same would be applicable to the HCT/P category.

After the initial enforcement wave begins, the FDA plans to use a public process (not yet defined) to develop a priority list for all other types of high-risk LDTs. That list would be due within 24 months of guidance finalization, and enforcement of premarket review requirements would begin to be phased in, in accordance with that list, no less than 12 months after the list is released.

The Agency indicates that it anticipates that the process of phased enforcement for premarket review requirements for class III tests would be complete in five years or less from the time of guidance finalization. Class II enforcement would begin after class III enforcement initiation is completed. A priority list for class II devices is expected within four years of guidance finalization and initiation of all enforcement activities is expected to be complete within nine years of guidance finalization.

Key Takeaways

  • The proposed framework reasserts the FDA’s view that the Agency has jurisdiction over both IVDs made by device companies and those made by clinical laboratories. This position has been very controversial in the past and is likely to spark heated debate and possible legal actions in the coming months.
  • The FDA also explicitly states that LDTs developed at academic medical centers will not be treated any differently, although this is listed as a factor for consideration for certain types (“Traditional LDTs,” for example).
  • For LDTs already on the market when the guidance is finalized, grace periods for premarket submissions are allowed, but not for new LDTs introduced after that time.
  • The FDA elected to forgo requiring registration and listing in exchange for notification and MDR reporting; this also presumably may mean, for now, that there will be no routine inspections of laboratories that comply with notification.
  • The FDA is proposing to require CLIA-certified laboratories currently marketing tests that do not meet the FDA’s technical definition for an LDT to comply with the same risk-based framework as “true” LDTs.
  • Although premarket review requirements would be phased in and provide for a grace period for all tests already on the market, new tests not yet marketed would be subject to those requirements immediately upon guidance finalization.