FDA draft guidance for laboratory developed tests

The FDA has announced availability of a draft guidance titled Framework for Regula­tory Oversight of Laboratory Developed Tests (LDTs). This document describes a risk-based framework for addressing the regulatory over­sight of a subset of in vitro diagnostic (IVD) devices called LDTs, intended for clinical use and designed, manufactured and used within a single laboratory. This document describes the FDA’s priorities for enforcing pre- and post-market requirements for LDTs, and the process by which the FDA intends to phase in enforcement of FDA regulatory requirements for LDTs over time.

IVD devices are subject to FDA marketing regulations. The FDA can exercise enforce­ment discretion and has not enforced its regu­lations on LDTs. In the past, LDTs were manu­factured in small volumes by local labs. Labs manufactured LDTs that were similar to well-characterized, standard diagnostic devices, as well as other LDTs intended for use in diag­nosing rare diseases or for other uses to meet the needs of a local patient population. LDTs at the time relied on manual tests used by lab personnel. LDTs were typically used and inter­preted directly by physicians and pathologists working within a single institution responsible for the patient. Also, LDTs were manufactured with components legally marketed for clinical use (e.g., general purpose reagents, immuno­histochemical stains and other components marketed in compliance with FDA require­ments).

Now, LDTs may be used by labs indepen­dent of the patient’s hospital. LDTs are fre­quently manufactured with components and instruments not legally marketed for clinical use and also rely more on complex, high-tech instrumentation and software to generate re­sults and clinical interpretations. Also, tech­nological advances increased the use of IVD devices in guiding critical clinical manage­ment decisions for high-risk diseases and con­ditions, particularly in the context of personal­ized medicine.

Business models for labs have changed. With the advent of overnight shipping and electronic delivery of information (e.g., test re­sults), a single lab now can provide test results nationally and internationally. Today, many new LDT manufacturers are large corpora­tions that nationally market a limited number of complex, high-risk devices. This is in con­trast with the past, when hospital and public health labs used a wide range of devices gener­ally either well characterized or similar to stan­dard devices, used to diagnose rare diseases or designed specifically to meet the needs of their local patients. These changes have resulted in a significant shift in the types of LDTs devel­oped, the business model for developing them and the potential risks they pose to patients.

Because of changes in the complexity and use of LDTs and the associated increased risks, the FDA believes the previous policy of gen­eral enforcement discretion toward LDTs no longer is appropriate. To move toward greater oversight, the FDA held a two-day forum in 2010 for stakeholders to discuss issues and con­cerns surrounding greater oversight of LDTs. Comments submitted to the public docket for the 2010 meeting have been addressed, as ap­propriate, in the draft guidance document.

Once final, this guidance will provide a risk-based oversight framework to ensure LDTs comply with the appropriate regulatory controls needed to ensure they are safe and effective. The FDA will continue to exercise enforcement discretion for requirements for LDTs used solely for forensic (law enforce­ment) purposes, as well as certain LDTs for transplantation when used in certified, high-complexity histocompatibility labs. The FDA will enforce certain regulatory requirements (e.g., registration, listing and adverse event reporting) for low-risk LDTs (class I devices), LDTs for rare diseases, LDTs for unmet needs and traditional LDTs as described in the guid­ance. For other high- and moderate-risk LDTs, the FDA will enforce regulatory requirements (registration, listing and adverse event report­ing as described previously), and will phase in enforcement of premarket review and quality system requirements in a risk-based manner.

The FDA is seeking feedback/comments on the following specific issues:

Traditional LDTs: This is based on whether the device is: (1) an LDT (designed, manufac­tured and used within a single lab); (2) manu­factured and used by a healthcare facility lab (such as one located in a hospital or clinic) for a patient being diagnosed and/or treated at that same healthcare facility or within the facility’s healthcare system; (3) comprised only of com­ponents and instruments legally marketed for clinical use; and (4) interpreted by qualified lab professionals without the use of automated in­strumentation or software for interpretation.

The FDA believes these factors mitigate risks for patients, so continued enforcement discretion with respect to premarket review and quality system requirements is appropri­ate. However, the FDA seeks public comment to confirm whether the following factors are sufficient to appropriately mitigate risks (1), (3) and (4).

LDTs Used for Rare Diseases: The FDA has proposed continued enforcement discre­tion for premarket review and quality system requirements for LDTs used for rare diseases and that meet the definition of a Humanitarian Use Device (HUD). The FDA has attempted to balance the need to mitigate the risks associ­ated with these tests with their potential ben­efit for patients. The FDA invites stakeholders to provide feedback on the suitability of these factors for LDTs for rare diseases. Further, the FDA is seeking feedback on whether a fac­tor other than the HUD definition should be considered, such as a factor based on the num­ber of tests for a rare disease or condition that would likely (based on the prevalence of the condition) be conducted annually in the U.S. and, if so, how many annual tests there should be for the purpose of defining an LDT as an LDT for a rare disease. The FDA also seeks feedback on whether enforcement discretion should be limited to tests designed, manufac­tured and used within a single laboratory.

Healthcare System: The FDA has identified factors it intends to consider in continuing to exercise enforcement discretion. One such fac­tor is whether the LDT is both manufactured and used by a healthcare facility laboratory (such as one located in a hospital or clinic) for a patient being diagnosed and/or treated at that same healthcare facility or within that facility’s healthcare system. The FDA requests feedback on whether enforcement discretion should be limited, as proposed, to those LDTs both manufactured and used by a healthcare facil­ity laboratory. The FDA also invites the public to comment on which types of facilities would or would not be considered within a healthcare system, or to offer an alternative description of healthcare system for FDA consideration.

Quality System (QS) Phase-in: The FDA has proposed to continue to exercise enforce­ment discretion with respect to QS (manufac­turing) requirements. Under this policy, the clinical laboratory manufacturing and using the LDT will be responsible for having a qual­ity system in place that meets the minimum requirements codified in 21 CFR 820, either at the time of marketing submission (the fa­cility must pass an FDA inspection), or prior to market launch for a 510(k) cleared device, as applicable. The FDA seeks feedback on the timeframe for phase-in enforcement of QS regulation requirements. The FDA is consid­ering whether those LDTs in the highest-risk category of devices, for which the FDA intends to enforce premarket review requirements 12 months following publication of the final Framework guidance, should remain under enforcement discretion for up to 24 months after publication.

Notification: Some laboratory networks offer the same test in multiple laboratories throughout their networks. Although devices in this scenario do not meet the FDA’s defi­nition of an LDT (i.e., they are not designed, manufactured and used within a single labora­tory), the FDA would like feedback on whether a single notification from the laboratory net­work for that test is sufficient, provided the lab­oratory network indicates in the notification to the FDA that the test is offered at multiple sites.

The FDA invites public comment on any related issue that should be addressed in the guidance. Although interested persons can comment on draft guidance at any time, to ensure the FDA considers your comments on this draft before it begins work on the final ver­sion, submit written or electronic comments on the draft by Feb. 2, 2015. Submit electronic comments to http://www.regulations.gov or written comments to the Division of Dockets Management (HFA-305), FDA, 5630 Fishers Lane, Room 1061, Rockville, MD 20852. It is necessary to send only one set of written com­ments; identify comments with Docket No. FDA-2011-D-0360. Comments also will be accepted at a public meeting tentatively sched­uled for early January 2015.

Final guidance on sex-specific data in medical device clinical trials

The FDA has announced availability of a guidance document titled Evaluation of Sex-Specific Data in Medical Device Clinical Stud­ies. This document provides guidance on the study and evaluation of sex-specific data in medical device clinical studies, and it outlines the FDA’s expectations regarding sex-specific patient enrollment, data analysis and report­ing of device study information. The guidance is intended to improve the quality and con­sistency of available data regarding the per­formance of medical devices in both sexes by encouraging appropriate enrollment by sex in clinical studies of devices and appropriate in­terpretation and assessment if data from such studies are analyzed by sex. Evaluation of sex-specific data in medical device clinical studies can benefit patients, their medical providers, clinical researchers and others.

The specific objectives of this guidance are to: (1) encourage the consideration of sex and associated covariates (e.g., body size, plaque morphology, etc.) during the study design stage; (2) provide recommendations for study design and conduct to encourage appropriate enrollment of each sex (e.g., in proportions generally representative of the demograph­ics of disease distribution, if appropriate); (3) outline recommended sex-specific statistical analyses of study data with a framework for considering sex-specific data when interpret­ing overall study outcomes; and (4) specify the FDA’s expectations for reporting sex-specific information in summaries and labeling for ap­proved or cleared medical devices.

The final document replaces the draft ver­sion published Dec. 19, 2011. The FDA received multiple comments. In response to these com­ments, the FDA revised the guidance docu­ment to clarify the processes of sex-specific data evaluation in clinical studies and policies as appropriate. For more clarity, a decision framework for different clinical study designs was added to the guidance in response to com­ments received requesting additional informa­tion on when various sex-specific statistical recommendations would apply. Additionally, several comments requested the recommen­dations in the guidance apply to the demo­graphic subgroups of age, race and ethnicity. However, this is outside of the scope of the re­vised guidance but, where applicable, the guid­ance was updated with links to other guidance documents and information related to these other demographic subgroups.

Interested parties may submit either elec­tronic or written comments on FDA guid­ance documents at any time as outlined above; identify comments with Docket No. FDA-2011-D-0817.

The Regulatory Update is excerpted from Re­search Practitioner, Volume 15, Number 5, September-October 2014, and Number 6, No­vember-December 2014.