Groundhog Day: FDA and Proposed Oversight of LDTs

FDA v LDTOnce again, attention in Washington, DC has turned to the Food and Drug Administration (FDA) and its proposed oversight of all laboratory developed tests (LDTs). The occasion for this attention was the FDA’s separate releases on October 3, 2014 of its proposed LDT framework and proposed notification and medical device reporting guidance. The former describes the basic structure for how the FDA intends to exercise its authority over LDTs as medical devices (e.g., risk classification and enforcement discretion categories), and the latter describes the process by which laboratories offering LDTs must notify the FDA of all LDTs (i.e., registration) and the adverse event reporting requirements that would apply to LDTs as medical devices (i.e., reporting of deaths, serious injuries, malfunctions, etc.). The agency hosted a public meeting on January 8-9, 2015 to discuss the proposed guidance and is accepting written public comments until February 2, 2015. [No joke: Comments are, in fact, due on Groundhog Day.]

• Comments on the proposed LDT framework (Docket No. FDA-2011-D-0360) can be submitted here.
• Comments on the proposed notification and medical device reporting (Docket No. FDA-2011-D-0357) can be submitted here.

The public meeting featuring speakers and panelists was organized into six topical sessions covering test components and labeling; clinical validity and intended use; categories for continued enforcement discretion; notification and adverse event reporting; classification and prioritization; and quality system regulation. The FDA has promised to post the transcript (and, in the meantime, some live tweets from the meeting will remain available on @DNAlawyer’s feed). Dr. Jeff Shuren started the meeting with a reminder that the FDA’s proposed guidance was based on discussions held five years ago, in 2010. (Prior GLR coverage is here.)

Most speakers and panelists avoided challenging or defending the FDA’s legal authority to regulate LDTs altogether and, instead, engaged in productive dialogue focused on deficiencies, ambiguities, and anticipated consequences of the proposed guidance. The legal heavy-hitters representing the American Clinical Laboratory Association (ACLA), Paul D. Clement and Lawrence H. Tribe, published a White Paper on January 6, 2015 detailing the argument against the FDA’s claimed authority to regulate all LDTs. GLR’s own John Conley provided a devil’s advocate counter-argument to Clement and Tribe in a recent Q&A for Genome Web. Participants in the FDA’s public meeting generally acknowledged that the important question of authority must be resolved. Many speakers suggested opposition to or support for FDA authority while indicating that they would focus their limited allotted time on other topics, and some even expressed outrage (notably including Edward Ashwood (ARUP) who was applauded following remarks that he was “absolutely outraged” by the FDA). One panelist, Bradley Merrill Thompson, attempted to lead the meeting’s attendees in a useful mental exercise to help identify the crux of the challenges involved with FDA oversight of LDTs. Thompson used hypothetical scenarios to ask a series of questions designed to identify underlying factors relevant to identifying the legal line between the provision of professional medical services and the the manufacturing of pharmaceuticals—in other words, when does the LDT become an in vitro diagnostic (IVD) that is unquestionably subject to oversight by the FDA? Unfortunately, the exercise was disrupted by a disgruntled audience member and left unfinished as the session moderator had the panel move forward. Thompson subsequently published his exercise and accompanying thoughts online; he noted that both sides in the authority debate may be overlooking limitations in their arguments and concluded that some LDTs are outside the scope of the FDA’s reach and the legal distinction is not as simple as identifying the actor (i.e., laboratorians versus manufacturers).

“Do you ever have déjà vu, Mrs. Lancaster?” – Phil Connors
“I don’t think so, but I could check with the kitchen.” – Mrs. Lancaster
Groundhog Day (1993)

The gist of the discussions from the public meeting can be conveyed with a number of clichés (e.g., Tilting at Windmills, Lost in Translation, Devil is in the Details, Long Row to Hoe, etc.). And it definitely feels as if we have had this conversation and heard many of the frustrations expressed before. Nevertheless, the public meeting’s discussions can be distilled into a few points. First, the FDA’s draft guidance struggles with fundamental definitions that must be resolved. These definitional problems are not semantic quibbles but, rather, fundamental issues with big impacts regarding who needs to comply with what requirements and when. Second, the anticipated costs and benefits of the proposed oversight appear to have not yet been adequately weighed. For example, at the end of the day, will this framework be a net gain and improve safety and efficacy of LDTs? Some participants suggested current industry practices and existing oversight already ensure validity of results and that the real dangers of LDTs are their misapplication and misinterpretation. Both of the latter are beyond the reach of the FDA and thus would remain unchanged even if the proposed guidance were implemented. Are the added administrative burdens justifiable? Third, details regarding the risk-classification system and use of expert panels should be provided sooner rather than later. A frequent remark was that the draft guidance is an outline and more details need to be provided so that stakeholders can consider the FDA’s plans as a whole before compliance can be expected.

Here are some more detailed thoughts on each of these three points:

You say tomato, I say tomahto. Ok, but is it a fruit or a vegetable? It depends on the context. And what about Ketchup by extension?
Scientific facts are not always synonymous with public perceptions or legal facts and distinctions. Terms can make all the difference in how the problem is conceptualized, how the draft guidance is finalized and operationalized, and how the guidance is understood. A number of troublesome areas have been highlighted and require us to consider not only what question is being asked but also why we are asking the question and who gets to decide the answer. Meeting participants expressed angst, confusion, and concern about a number of terms, including test, intended use, clinical validity, rare disease, and health care system. For example, is an LDT performed in multiple sites the same test? Does each minor modification done routinely in industry practice trigger obligations to submit as a “new test”? Intended use might not be the same as indicated use, and new FDA terminology for laboratories may be a source of confusion. Clinical validity encompasses much more than just performance characteristics. Defining rare disease for purposes of LDT oversight discretion illustrates just how difficult it is for the FDA to function in the era of next generation sequencing. Multiple participants challenged the threshold of fewer than 4000 individuals tested per year and compared the threshold for orphan drug classification of a disease affecting fewer than 200,000 patients nationwide. Moreover, numerous concepts of health care system were mentioned (such as facilities under the same CLIA number, facilities within the same accountable care organizations, facilities within a payer or insurance provider’s network, etc.), each with different challenges for implementation and different consequences for individual access and patient care. Some of the confusion from the terms and language in the draft guidance is, as Catherine Hammett-Stabler (American Association for Clinical Chemistry) and others noted, attributable to “‘FDA speak’ versus ‘lab speak.’”

Costs and Benefits Analysis Needed
How will the FDA handle the flood of submissions? Delays are inevitable, but how will those delays affect health care and public health responses? Will the administrative burden of this proposed undertaking unnecessarily divert scarce FDA resources from other areas that should take priority? Nick Harris (IGeneX) questioned why the FDA would even think of adding to its existing bottleneck. Ultimately, will patients and consumers see improved quality of LDTs and improved care? Curtis Hanson (Mayo Clinic) spoke about the need to understand what problem we’re trying to fix here. After citing that Mayo has had over 21 million LDTs and zero sentinel events, Hanson directly asked, “What’s the problem?”

The proposed guidance describes an FDA LDT framework that will create a very large workload, a topic mentioned by many, including James Prescott (PathGroup). Some speakers, such as Paul Kim (Foley Hoag), suggested that the FDA could overcome some of the administrative challenges by exploring outside expertise and resources. A number of participants commented that the new oversight framework is all but guaranteed to stifle innovation and development, increase costs, and limit LDT options. Infectious disease and public health stakeholders weighed in, emphasizing the need for flexibility. For example, Amanda Jezek (Infectious Disease Society of America) warned that many clinical microbiology labs might stop using LDTs entirely as a result of the FDA’s proposed framework. Similarly Stephanie Pang (National Coalition of STD Directors) detailed how sexually transmitted disease screening could be hampered by the proposed guidance. The implementation of the proposed guidance, in the context of existing routine payer practices, could have serious unintended effects as well and may not have been adequately anticipated. For example, if a lab obtains novel FDA approval for an LDT for a particular condition, that FDA approval will disrupt access and likely increase the cost of health care for many individuals for whom the lab is considered by payers to be “out of network.”

When weighing costs and benefits, it would be useful to compare the proposed FDA framework with an enhanced CLIA framework and to consider savings that could be generated through harmonization efforts and unified regulatory submission systems (e.g., in which one submission would elicit information about the LDT at sufficient levels of granularity for multiple purposes). Andrew Hoofnagle (University of Washington) explained at the meeting that a side-by-side comparison of current CLIA requirements for laboratories and proposed FDA requirements for LDT manufacturers has been created, but that comparison has not yet been shared with the public. Such transparency would assist all stakeholders in understanding what the proposed guidance is intended to do and would enrich the quality of feedback that could be provided to the FDA prior to finalization.

Details on Risk Classification and Expert Panels Remain Fuzzy
As Paul Radensky (Coalition for 21st Century Medicine) pointed out at the meeting, risk classification on a case-by-case basis cannot start until a baseline of details are known. For example, what factors are to be considered? What duties follow the particular risk classification? Paul Kim (Foley Hoag) stated that broad classifications for LDTs will simply not be possible, and—given the continuous innovation of LDTs—companies themselves might possess the best expertise for assessing and classifying risk. Amy Miller (Personalized Medicine Coalition) similarly noted that current conflicts of interest rules create challenges for the expert panels and that creativity is needed to ensure that individuals with the right expertise are able to answer the necessary questions. Miller underscored the importance of a robust public examination of the FDA’s plans and emphasized that diverse stakeholders must continue to be engaged in the policymaking process. Leonard Lichtenfeld (American Cancer Society) highlighted that the expert panels need to verify that claims about LDTs are supported but, to do so, those expert panels must understand what evidence would be reasonable. From the discussions, it seemed that many believe that multiple expert panels are necessary and further believe that each expert panel must be discipline-specific. The expert panels are charged with classifying LDTs and then making case-by-case determinations on LDT submissions. Given all this, the proposed framework invites questions as to whether it is needed at all. For example, how is this an improvement over the current CLIA oversight and self-governance of the industry through existing mechanisms of quality control (e.g., reliance upon literature that passes rigorous peer review; laboratory reputations that spread quickly; flexible standards of care in the medical profession to accommodate modifications and advances in testing; emerging standards and databases that improve transparency; etc.)?

Looking Ahead
In light of the discussions at this public meeting, most would agree that finalizing the guidance on the LDT framework and notification and medical device reporting this year is a highly unlikely outcome. Given the ambiguities in basic terminology, lack of details, and scope of the regulatory burdens the proposed oversight would usher in, another round (or two) of draft guidance and discussion is warranted. For better or worse, the FDA seems interested in wrapping this up quickly and has put final guidance on both matters on its “A-List” of policy priorities for FY2015.

“Excuse me, where is everybody going?” – Phil Connors
“To Gobbler’s Knob. It’s Groundhog Day.” – Person on the Street
“It’s still just once a year, isn’t it?” – Phil Connors
Groundhog Day (1993)

Many are likely to balk at pressing ahead with LDT guidance when it is clear that the FDA continues to struggle with how to handle genetic/genomic technologies and information. While the agenda has not yet been announced, the FDA will host a public meeting titled “Optimizing FDA’s Regulatory Oversight of Next Generation Sequencing Diagnostic Tests” on February 20, 2015. The timeline for draft guidance on DTC genetic tests and individual access to information remains a mystery, but both items do remain on the FDA’s “B-List” of policy priorities for FY2015.

For additional reading, see:
• Bradley Merrill Thompson. The LDT Debate: Understanding FDA’s Jurisdiction Over IVDs Made at a Clinical Lab. Pharma MedTech Insights. January 16, 2015. Available at
• Turna Ray. Q&A: Lawyer John Conley Counters Lab Industry Arguments against FDA Regulatory Authority over LDTs. Genome Web. January 15, 2015. Available at
• Turna Ray. Stakeholders Ask FDA to Educate Labs on Agency Thinking, Terminology Before Finalizing LDT Guidance. Genome Web. January 12, 2015. Available at
• Turna Ray. At Workshop, Labs Tell FDA to Let them Tweak LDTs; Give Their Take on Labeling and Clinical Validity. Genome Web. January 9, 2015. Available at
• Turna Ray. Q&A: FDA’s Alberto Gutierrez Fields Questions on Evolving LDT, CDx Regulations. Genome Web. December 30, 2014. Available at
• Jamie K. Wolszon. LDT Battle Lines Drawn: FDA Announces Jan.8-9 Public Meeting on LDT Framework; Lab and Medical Groups Send Letter to FDA Commissioner Urging Notice-and-Comment Rulemaking; FDA and Patient Groups Advocate for LDT Framework on Hill. FDA Law Blog. November 24, 2014. Available at