New FDA Guidance on LDTs

On September 30, 2014, the Food and Drug Administration (“FDA”) released its controversial new draft guidance entitled Framework for Regulatory Oversight of Laboratory Developed Tests to provide more consistent regulatory oversight of laboratory developed diagnostic testing (the “Draft LDT Framework Guidance”). The FDA defines laboratory developed tests (“LDTs”) as in vitro diagnostic devices intended for clinical use and designed, manufactured and used within a single laboratory. Historically, the FDA has not enforced applicable regulatory provisions with respect to LDTs. However, due to technological advances leading to increasingly complex LDTs and growth in personalized medicine, the FDA has determined that heightened review of LDTs is necessary to mitigate risks to patients.

The Draft LDT Framework Guidance creates a risk-based framework applied in phases to LDTs in a manner that the FDA asserts is consistent with the agency’s current regulation of in vitro diagnostic devices and complements oversight under the Clinical Laboratory Improvement Amendments (“CLIA”). FDA’s new oversight framework for LDTs includes prioritizing premarket review starting 12 months after the guidance is finalized for higher-risk LDTs, such as those that have the same intended use as a Class III FDA-approved or cleared companion diagnostic currently on the market, as well as post-market clinical and analytical review through adverse event reporting. The Draft LDT Framework Guidance anticipates phasing in premarket review of additional high and moderate-risk LDTs over approximately 9 years. Notably, however, the FDA will accept premarket submissions for LDTs at any point, even prior to the FDA’s enforcement of premarket review for that category.

Classifying LDTs

According to the Draft LDT Framework Guidance, the FDA plans to rely upon the existing medical device classification system (i.e., Class I, II, or III) to evaluate the risk of LDTs. The FDA also plans to use expert advisory panels to help classify LDTs. The FDA expects to publish classification guidance within 18-24 months of the finalized guidance.1 However, in order to classify LDTs, the FDA needs information about the universe of LDTs currently in use by laboratories. Toward that end, the FDA also published draft guidance entitled FDA Notification and Medical Device Reporting for Laboratory Developed Tests (the “Draft Notification Guidance”), which will provide a process for the FDA to collect information about LDTs from laboratories and outlines procedures for laboratories to report adverse events.

Per the Draft Notification Guidance, within 6 months of the guidance becoming final, laboratories manufacturing only LDTs (i.e., not also manufacturing other medical devices) that are currently on the market and new LDTs on the market within six months of the publication of the finalized guidance should notify the FDA and provide basic information on all of their LDTs. The FDA will continue to exercise enforcement discretion with respect to the FDA’s registration and listing requirements for laboratories manufacturing only LDTs that comply with this notification process. Notification should occur only once for each LDT unless significant changes to the LDT require additional notification.

For LDTs entering the market more than six months after the publication of the final guidance, manufacturers should provide the FDA with information on the new LDTs, including significant changes to LDTs previously reported, prior to offering them for clinical use to qualify for the FDA’s enforcement discretion with regards to registration and listing requirements. Additionally, manufacturers must begin reporting significant adverse events caused by their LDTs to the FDA, which the FDA expects will allow problems to be quickly discovered and corrected.

High-Risk LDTs

According to the Draft LDT Framework Guidance, LDTs classified by the FDA as high-risk (i.e., LDTs classified by the FDA as Class III medical devices) will be subject to all applicable FDA requirements, including registration and listing, adverse event reporting, premarket review and quality systems requirements. High-risk LDTs will be required to meet the registration and listing requirements (with the option to instead provide notification as described above) and the adverse event reporting requirements within six months after the Draft LDT Framework Guidance is finalized.

With respect to premarket review, the FDA plans to prioritize the highest risk LDTs. The highest-risk LDTs will be subject to premarket review requirements beginning 12 months after the Draft LDT Framework Guidance is finalized. The FDA will focus first on (a) high-risk LDTs with the same intended use as a cleared or approved companion diagnostic, (b) LDTs with the same intended use as an FDA-approved Class III medical device, and (c) certain LDTs for determining the safety or efficacy of blood or blood products. The FDA believes that these categories of LDTs are among the highest-risk because they are used either to direct patient therapy or have the same intended use as a device the FDA has already determined to be in the highest risk classification, i.e., Class III. Thereafter, premarket review will be phased-in over a four-year period for the remaining LDTs classified as high-risk based on a priority list issued by the FDA within 24 months of the finalized guidance. During this process, high-risk LDTs currently on the market may remain on the market, but new LDTs developed would need to comply with premarket review requirements prior to marketing.

The FDA suggests that where LDTs have had their clinical validity already established in literature, it may not be necessary for sponsors to conduct extensive new studies to demonstrate clinical validity and that it intends to work with the laboratory community, the healthcare professional community and other stakeholders to identify those LDTs for which clinical validity is already established in the literature.

Moderate-Risk LDTs

As with high-risk LDTs, LDTs classified as moderate-risk (i.e., LDTs classified by the FDA as Class II medical devices) will be subject to FDA enforcement of all applicable regulatory requirements, but on a delayed time frame. Registration and listing (with the option to instead provide notification) and adverse event reporting begin six months after the guidance is finalized. Premarket review for moderate-risk LDTs will begin only after premarket review for high-risk LDTs is completed, i.e., five years after the guidance is finalized, and will be phased-in over four years. The FDA expects to announce a prioritization for Class II LDTs premarket review once it has completed the phase-in of Class III LDTs. Also, the FDA hopes to accredit third-parties to review most premarket submissions for this category of LDTs.

Low-Risk LDTs

The Draft LDT Framework Guidance states that the FDA will not enforce applicable premarket review requirements and quality systems requirements for all low-risk LDTs (i.e., LDTs classified by the FDA as Class I medical devices), as well as “traditional LDTs”2  and those intended to treat rare diseases and unmet needs. The FDA will, however, enforce registration and listing (with the option to provide notification) and adverse event reporting requirements for these categories of LDTs.

Enforcement Discretion

The FDA plans to continue to exercise enforcement discretion with respect to all applicable regulatory requirements for LDTs used solely for forensic (law enforcement) testing and certain LDTs for transplantation when performed in a CLIA-certified, high complexity histocompatibility laboratory.

Industry Response

The FDA released this guidance despite accusations by stakeholders that issuance of guidance in lieu of a formal rule allowed the agency to bypass the formal rulemaking process. A guidance document shares the FDA’s thoughts on the matter and provides recommendations, but does not establish any rights or bind the FDA.

Views on all sides of the “FDA regulation of LDTs” debate were recently expressed to the U.S. House of Representatives Energy and Commerce Committee Subcommittee on Health during its hearing on “Health 21st Century Cures: Examining the Regulation of Laboratory Developed Tests” held on September 9, 2014.3 Jeffrey Shuren, director of the FDA’s Center for Devices and Radiological Health (“CDRH”), testified that the new Draft LDT Framework Guidance only changes the FDA’s enforcement policies. Amidst heated questioning, Shuren contended that the FDA has had authority to enforcement discretion of LDTs since the 1976 Medical Device Amendments. Shuren stated that the FDA would continue to rely on enforcement discretion for low-risk LDTs and focus its review on higher-risk LDTs.

Critics of the guidance, such as the American Clinical Lab Association (“ACLA”), assert that the FDA does not have the statutory authority to regulate LDTs; and, that FDA regulation would be unnecessarily duplicative of the CLIA regulatory framework and stifle innovation. Supporters, including the Advanced Medical Technology Association (“AdvaMed”) and the American Association for Cancer Research (“AACR”), laud the guidance as reconciling the gaps in oversight of diagnostic testing caused by the current regulatory framework, which endangers patient care. Organizations in favor of the FDA’s new LDT draft guidance claim that the risk-based approach actually fosters new technological advances in that it allows for timely access to new technologies.

The effect of the new guidance on innovation, personalized medicine, and patient care remains to be seen and will likely be a topic of contention for some time.

Practical Implications

In response to the publication of this new guidance, laboratories should consult with counsel to evaluate how the FDA’s regulation of LDTs will impact their testing and plan for the necessary processes to ensure compliance, including FDA notification procedures and adverse event reporting. In addition, laboratories may want to prepare to address questions from outside stakeholders and payors related to the FDA classification of their testing and their plans for ensuring compliance.


The draft LDT framework guidance appears internally inconsistent by referencing 18 months initially on page 12 but later referencing 24 months on pages 17 and 26.

The draft guidance defines “Traditional LDTs” as those IVD devices that reflect the types of LDT available when the FDA began its policy of generally exercising enforcement discretion over LDTs in 1976. In determining whether to exercise enforcement discretion for Traditional LDTs, FDA intends to consider the following factors: (1) Whether the device is designed, manufactured and used by a single laboratory); and (2) Whether the LDT is both manufactured and used by a health care facility laboratory (such as one located in a hospital or clinic) for a patient that is being diagnosed and/or treated at that same health care facility or within the facility’s healthcare system; and (3) Whether the LDT is comprised only of components and instruments that are legally marketed for clinical use (e.g., analyte specific reagents (21 CFR 864.4020)…); and (4) Whether the LDT is interpreted by qualified laboratory professionals, without the use of automated instrumentation or software for interpretation.

U.S. House of Representatives Energy and Commerce Committee Subcommittee on Health, Hearing on 21st Century Cures: Examining the Regulation of Laboratory Developed Tests (Sept. 9, 2014).