Monday, September 8, 2014

House Energy & Commerce Holds Hearings on FDA LDT Proposal [September 9, 2014]

On September 9, 2014, the House Energy & Commerce committee held a hearing through which a range of stakeholders could discuss the FDA's recent proposal to regulate laboratory developed tests.   The six speakers included Jeffrey Shuren, MD JD, the head of the Center for Devices at the FDA, followed by a series of public stakeholders:  Christopher Newton-Cheh of MGH, representing the American Heart Association; Andrew Fish, representing AdvaMed Diagnostics; Alan Mertz, representing the Americal Clinical Laboratory Association (ACLA), Charles Sawyers MD, recent president of the American Association of Cancer Research, and Kathleen Wilsey PhD, co-founder of the Coalition for 21st Century Medicine.

This newly arising topic has been integrated into a months-long series of hearings by the "21st Century Cures Initiative" in the House:  here.

Resources About the FDA LDT Hearing

  • The Energy and Commerce homepage for this event is here.   
  • The full 2 hour, 48 minute video streams on Youtube, here
  • The six speakers' prepared testimony is available for download at that website, or as one zip file of PDFs at my cloud archive, here.  
    • (I've also copied the House committee's speaker listing and links directly into the bottom of this blog.)
  • Running Notes of 3-hour hearing:  not quite a transcript, but a detailed running summary of the whole hearing.  You can download these 25-page, here.  {Use the small down arrow button to download}.
  • Finally:  This blog which was based on my review of the PDFs, released the day before the hearing.
Update:  On October 3, 2014, the FDA's draft guidance was officially released for 120 days of public comment (here).

The Hearing:

The committee, under the chairmanship of Fred Upton (R-Michigan), released a brief memorandum noting that Section 1143 of the most recent FDA legislation (FDASIA) required the FDA to inform the Hill of any pending regulation of laboratory developed tests, and the FDA did so, on July 31st, 2014.   (See a formal Foley Hoag LLP summary of the FDA proposals here, and my detailed but less formal discussion here.)

The goal of the hearing was for the Committee to understand the clinical practice of using LDTs, their role in personalized medicine, and how to foster innovation in the LDT space.  In addition, the Hill sought an opportunity to hear from both the FDA and a range of public stakeholders.


The FDA, under Jeff Shuren MD, noted that the proposal was "long awaited" and would "close well known regulatory gaps" by providing clarity about FDA's enforcement "for those LDTs that pose greatest risk to patients if their results are not accurate."   The FDA is also concerned that through clarity and a balanced risk-based approach, it will continue to encourage investment and innovation. As in its guidance documents, the FDA notes that "an evolution in complexity and volume" of LDTs "increases patient risk of harm from higher risk LDTs" and the FDA has directly confronted some "faulty or unproven LDTs."   Various government agencies have recommended greater LDT oversight, including the Institute of Medicine.  The FDA will exercise enforcement discretion (I've called it "safe harbors") for low risk LDTs, LDts for rare diseases, traditional LDTs, and LDTs for unmet needs - that is, where there is no FDA approved test.   A year after the guidance is finalized (which could be a few years - Quinn) FDA would regulate (1) LDTs matching the use of FDA approved companion diagnostics, (2) LDTs with the same use as a PMA (high risk) test, and (3) certain LDTs for blood products.  Shuren closed by discussing the range of IVDs approved by the FDA, including in genetics, and the need for reliability and accuracy in personalized medicine.

Speaking for the American Heart Association, Dr Newton-Cheh of MGH, discussed his work as a cardiovascular geneticist and his concern about the lack of regulation of LDTs.   LDTs have come onto the market, without FDA review, purporting to diagnosis cardiovascular risk "based on an inaccurate or misleading result."  Expert consensus guidelines can be written, but there is no test verification by a government agency upon market entry. Some tests examine thousands of SNPs with little clinical verification.   Direct to consumer test marketing is "particularly alarming" and a 2010 US GAO study confirmed that consumers may be misled.   LDTs for some well characterized gene mutations (like Marfan's syndrome) have however been critical components of clinical care.  In contrast, Newton-Cheh has been confronted by confused and alarmed patients.  The American Heart Association believes that FDA regulation is in the long range interest of consumers and patients.  (See also the AHA website, here.)

Speaking for AdvaMed Diagnostics, its executive director Andrew Fish made the next presentation.  Diagnostics represent only 2% of healthcare spending but influence 70% of decisions.  Many stakeholders have publicly recognized the inadequacy of current controls on LDTs.  The FDA clearly can regulate both IVDs and LDTs, and the lack of LDT regulation is now recognized as "a clear gap."   CLIA is no substitute for FDA oversight, and lacks many of the features of FDA oversight such as demonstration of clinical validity and regulation of safety and effectiveness.  The "two mechanism" regimen (FDA/CLIA) for IVDs and LDTs is bad public policy.    He quotes the American Society of Clinical Pathology that with "the development of LDTs by larger corporations...some LDTs may not have been properly validated" [here].  (See also an AJCP article that DTC genetic testing had muddied the waters for LDTs; here.)   Just 15 of 8,245 tests listed in the Genetic Test Registry have been FDA approved or cleared.    Fish summarized and endorsed the framework being proposed by the FDA.  AdvaMed website, here.

Speaking for the ACLA, Alan Mertz, President, emphasized that LDTs ahavehelped to transform the standards of clinical care in the United States and provide great hope for the future.   ACLA members are committed to provided safe, reliable, and clinically meaningful diagnostic tests.   LDTs are innovative, fulfill unmet clinical needs, and often are creating when existing tests are "insufficient or fail to incorporate the latest scientific and medical research."  He underscored this point by citing a letter (on the ARUP website, here) from lab letters to the OMB last summer.   These are innovative powerful tools that improve care, save costs, and save lives.  He discussed specific examples, such as the Genomic Health Oncotype DX test which has "helped over a hundred thousand patients" and saved "an estimated more than $2.5B in treatment costs."   The CLIA regulatory environment is a stringent one.    In contrast, Mertz reiterated prior detailed ACLA positions that the FDA lacks legal authority to regulate laboratory developed tests.   This position has also been argued publicly by the Washington Legal Foundation (see my earlier FDA LDT blog).   Finally, the FDA LDT guidance leaves many substantial and troubling issues unanswered, ranging from whether anatomic pathology tests are considered LDTs to the impact of minor IVD modifications in performance to other issues.  The ACLA supports improved and modernized regulatory oversight, but the FDA proposal will overwhelm the FDA while inhibiting innovation.  ACLA website on LDTs, here.

Dr. Charles Sawyers is Chair of the Human Oncology & Pathogenesis Program at Memorial Sloan Kettering Cancer Center and an immediate past president of the American Association for Cancer Research.    The AACR believes that the proposal from the FDA will "protect patients, incentivize innovation, and advance the practice of personalized medicine."  The AACR has always aimed to marshal a broad spectrum of stakeholders - patients, physicians, scientists - for progress against cancer.  Personalized medicine is of enormous importance to oncology because of the inability for one-size-fits-all approaches to overcome the complexity of cancers.  Gleevec, a targeted medication, is a crucial example of this future direction and there are already 45 FDA-approved personalized (precision) medicines.   Generally, combination diagnostics are FDA approved along with the companion drug.  But LDTs do not follow this pathway and have "less certainty and cconfidencein [their] accuracy."  This is "particularly important for highly sophisticated DNA sequencing technology based tests."  Incorrect treatments from faulty tests are unacceptable.  A single regulatory pathway will be an improvement and the FDA's proposal strikes a thoughtful balance between safety, research, and innovation.

A new September 2014 AACR position paper on FDA LDT regulation, authored by Dr. Sawyers, is online in Clinical Cancer Research, here.  Stating in part:

Implementation of a risk-based framework by the FDA that would provide for evaluation of all high-risk molecular diagnostic tests would balance the need for encouraging innovative medical product development with the need for ensuring patient safety. A focus on high-risk tests would also help channel the FDA's limited resources toward those products that pose the greatest health risks for patients. Having a predictable and reliable regulatory environment is important for patients and for diagnostic and drug developers, since the success of a targeted therapy is inextricably linked to the successful development of its companion diagnostic test.
Therefore, a single regulatory standard for high-risk diagnostic tests is key to ensuring the safety and efficacy of molecular diagnostic tests.

The closing presentation was given by Kathleen Behrens Wilsey PhD, cofounder of the Coalition for 21st Century Medicine (website here).   Wilsey chaired a personalized medicine committee for PCAST (The President's Council of Advisors on Science and Technology) and is a past president of the National Venture Capital Association.  The US is at a "crossroads" for a revolution in personalized medicine and the FDA's approach could "facilitate or choke off" progress.   While the Coalition has been, and continues to be, supportive and collaborative with the FDA, the current regulatory uncertainty includes "lack of a clear path" due to an extended regulatory limbo.  However, an overlying burdensome framework would be unhelpful and accelerate offshore investment. Standards must be "clear and reasonable" and, as the ACLA stated earlier, much additional substantial guidance on key unanswered questions must be provided before, not after, the FDA begins a rolling process of LDT regulation.   Critical unanswered issues include:

 (1) identifying the “device” within the LDT service; (2) harmonizing FDA and CLIA quality systems regulations; which have different purposes; (3) providing clear guidance on requirements for obtaining labeling that is useful for clinicians and patients; and (4) accommodating medical communications between providers—laboratories and treating physicians—under an FDA regulatory framework that imposes substantial limitations on pro-active communications by medical product manufacturers.
As necessary, the committee should considerable legislation to fill gaps, reduce duplication across agencies, and insure a balance of decisions that preserves both safety and innovation.

The full hearing includes question-and-answers sessions, the first session directed to Dr. Shuren, the second session devoted to the other five panelists.

I discuss some aspects of "guidance versus rulemaking" here, with analogies from the ASR regulation of 1997.

See also:
  • Memorandum from Ranking Member Henry Waxman, here.  His opening statement, here.
  • The House summary of the FDA LDT issue, here.

Press Coverage
  • Bloomberg here.
  • Coverage at Genomeweb (subscription) here and their longer version here.
  • AAAS Summary here.


Panel I
Jeffrey Shuren, M.D., J.D.,
Panel II
Christopher Newton-Cheh, M.D.,
Andrew Fish
Alan Mertz
Charles Sawyers M.D.
Kathleen Wilsey, PhD
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