FDA Considers Fundamental Shift in Federal Oversight of Laboratories

By Jamie K. Wolszon –

FDA is signaling that it is considering whether to fundamentally reshape how it regulates laboratories and laboratory-developed tests ("LDTs").  LDTs, which are diagnostic tests developed and performed by a laboratory, are widely used.  For example, virtually every genetic test is an LDT.  When new diseases emerge, the initial diagnostic tests are often LDTs. 

Starting in 1992, FDA asserted that it had authority over LDTs as devices.  FDA’s position is that all LDTs are devices subject to regulation under the Federal Food, Drug, and Cosmetic Act.  The legality of FDA’s position has been disputed, but not yet been the subject of a court challenge.

FDA has adopted a policy of “enforcement discretion” over laboratories and LDTs.  However, FDA now is considering jettisoning that enforcement-discretion approach and instead adopting a new, more forceful approach to regulation for LDTs.  FDA is seeking comment on a new-risk based premarket approach at a July 19-20 public meeting.

The meeting notice is one in a series of recent signs of a more activist approach to regulating LDTs.  Less than a week before the meeting announcement, on June 10, FDA sent letters to five companies stating that their genetic diagnostic tests were unapproved, a move seen as heralding increased interest in asserting regulatory power over LDTs. 

In addition, FDA commissioner Margaret A. Hamburg and National Institutes of Health Director Francis S. Collins recently authored an article in the New England Journal of Medicine that also suggested FDA interest in a more active role in LDT oversight.  The letters, article, and meeting appear to represent a coordinated effort to extend FDA regulation over LDTs.

The July 19-20 meeting notice, published in the Federal Register on June 17, 2010, stated that for years the agency has generally exercised enforcement discretion and not enforced the regulations it claims were applicable to devices.  The notice added that the agency generally has not actively regulated LDTs. 

There have been exceptions to the hands-off approach.  Over the years, FDA has occasionally challenged a test offered by a laboratory, e.g., asserting that the test was not a true LDT.  FDA also proposed regulating as devices a single, narrowly-defined subset of LDTs, In Vitro Diagnostic Multivariate Index Assays ("IVDMIAs"), which are tests where the results of multiple markers are combined to generate an “index score.”  As previously reported, it proposed premarket review requirements for those tests in a September 7, 2006, draft guidance, and a revised draft guidance issued July 26, 2007.  It has not proposed premarket review for other subsets of LDTs.

The IVDMIA approach was widely criticized.  One of the major criticisms was that it was not risk-based.  FDA has never finalized those IVDMIA draft guidances.  According to published reports, the agency will not issue the IVDMIA guidance, but instead will focus on the more comprehensive review of LDTs.
In its meeting notice, FDA states, “[T]he agency believes it is time to reconsider its policy of enforcement discretion over LDTs.”  Expanding on its goals, FDA added, “[a]t this time, FDA believes that a risk-based application of oversight to LDTs is the appropriate approach to achieve the desired public health goals….”  After the conclusion of the public meeting and the public comment period, “FDA will move forward expeditiously to develop a draft oversight framework for public comment to provide predictability as quickly as possible.  The FDA also intends to phase in such a framework over time based on the level of risk to the test.”

Discussing the factors that brought it to the conclusion that it should abandon its years-long policy of enforcement discretion, FDA said that in the past LDTs were simple, well-characterized and understood tests for rare diseases.  Now, according to the agency, LDTs often use unregulated components, assess high-risk but common diseases, and sometimes are marketed directly to consumers.  Whether FDA’s view of LDTs is correct, will certainly be the subject of comments at the meeting.

The agenda for the meeting includes sessions on patient and clinical considerations, clinical laboratory challenges, direct-to-consumer testing, and education and outreach.  The agency has posed the following questions for the patient and clinical considerations session:

• What would patients and clinicians like to see done by the FDA with respect to LDTs?  What is ideal?  What is practical?
• How might increased FDA oversight of LDTs affect patients and clinicians?  What might be the benefits?
• What are patient expectations with regard to results obtained by an LDT?  How might increased oversight of LDTs affect these expectations?
• What is the patient’s perspective regarding tests that are non-regulated versus regulated by the FDA?
• Are physicians aware that a given diagnostic test may not have been cleared or approved by FDA?  How might this knowledge affect clinical practice?
• What are the reasons that a patient or physician might choose an LDT over an FDA cleared/approved IVD?
• What are patient’s and clinician’s expectations regarding clinical validation of LDTs?
• Examples or case studies related to LDTs.

FDA has proposed the following questions as part of the clinical laboratory challenges session:

• What are the potential benefits of increased FDA oversight of LDTs?
• What would you like to see done with respect to FDA oversight of LDTs?  What is ideal?  What is practical?
• Suggested approaches of risk stratification of LDTs
• What might be some of the specific challenges faced by clinical laboratories in meeting FDA regulations?
• How might increased oversight of LDTs affect diagnostic test innovation?
• How could increased oversight of LDTs affect diagnostics used for rare conditions?
• How might increased oversight of LDTs affect reimbursement and/or the cost of diagnostic tests for the consumer?
• What are the challenges associated with validation of LDTs for clinical laboratories?
• What will the challenges be to clinical labs with respect to diagnostic test change control under greater oversight of LDTs?
• Should the clinical and analytical validation requirements be different between FDA regulated and non-FDA regulated diagnostic tests?   

The agency has proposed the following questions for the DTC session:

• What are the major concerns associated with DTC testing?
• What is the benefit of DTC testing?  What are the risks?  What is the cost?
• Are there concerns that DTC testing could lead to consumer fraud?
• Are patients taking medical action based upon preliminary diagnostic test claims?  What are the risks and benefits? 

FDA suggests the following topics for the education and outreach session:

• What resources or educational opportunities are currently available to assist clinical laboratories in meeting FDA regulations?  What would be needed?
• What specific support will be needed by clinical laboratories from the FDA given greater LDT oversight?
• How can physicians use new genetic information? 
• Whose responsibility is it to ensure that physicians can use the information provided to them by LDTs?

Given the increasingly important role in LDTs in health care in general, and in personalized medicine in particular, the meeting is almost guaranteed to provide FDA with diverse – and strongly expressed – viewpoints.