As Snow Falls, We See a Flurry of Developments Related to FDA Efforts to Actively Regulate LDTs

By Jamie K. Wolszon –

Amidst the winter storms that have struck the East Coast this January and February, there has been, and will continue to be, a flurry of developments related to FDA efforts to actively regulate Laboratory-Developed Tests (LDTs).  Those developments include a White Paper authored by prominent constitutional and Administrative Procedure Act (APA) litigators on behalf of the American Clinical Laboratory Association (ACLA) challenging FDA’s statutory authority to regulate LDTs as medical devices; a January 8-9 public workshop hosted by FDA to obtain feedback on the Draft Guidances; the submission of hundreds of written comments to FDA; and an upcoming February 20 workshop hosted by FDA to discuss a white paper on next generation sequencing (NGS).  We provide a round up of those and other events below.

January 5: Deadline for LDT Comments to House Energy & Commerce Committee.

We previously reported that the House Energy & Commerce Committee, which has jurisdiction over FDA, has issued a “white paper” announcing that as part of its efforts to prepare a draft discussion legislative package in early 2015 related to the overall 21st Century Cures Initiative, that it seeks input on specific questions related to the FDA LDT proposed Framework.  The Committee sought comments by January 5.  Two major medical organizations – the American Medical Association and the Association of Molecular Pathology (AMP) – submitted comments to the Committee expressing significant concerns with the Draft Guidances.  We previously reported that on January 27, the Committee released the nearly 400 page draft discussion legislative package.  The discussion draft did not address LDTs. 

January 7: ACLA Unveils Tribe and Clement LDT White Paper.

On January 7, a day before FDA’s public workshop to discuss the draft guidances, ACLA unveiled a white paper authored by two distinguished constitutional and APA litigators Laurence H. Tribe and Paul D. Clement.  The timing of this can hardly be coincidental.  We previously reported that ACLA had retained Mr. Tribe and Mr. Clement to help the organization oppose the framework, a move perceived as a shot across FDA’s bow.  In the white paper, Mr. Tribe and Mr. Clement argued that: (1) FDA lacks the statutory authority to regulate LDTs, which are services, as medical devices; (2) FDA is violating the APA by proceeding through guidance instead of notice-and-comment rulemaking; (3) FDA’s Draft Guidances would stifle innovation and interfere with the practice of medicine.  Alan Mertz, President of ACLA, mentioned the white paper in his statement on January 8 at the FDA public workshop on the Draft Guidances.

January 8-9: FDA Public Workshop on Draft Guidances. 

At the January 8-9 FDA Public Workshop on Draft Guidances there was significant opposition expressed to the draft guidances. Even some of the groups that supported the draft guidances still expressed reservations, such as need for clarification on how risk categorization would be done and how the Quality System Regulation (QSRs) would be applied.  Some of the points expressed at the workshop include:

• Many speakers stated that the Draft Guidances would have unintended consequences, hurt patient access and innovation and interfere with practice of medicine
• Public health, state, and small reference laboratories stated that if FDA finalizes the Draft Guidances in their current format, some of those laboratories would cease to exist, and many tests will no longer be offered.
• ARUP Laboratories representative Edward Ashwood gave a blistering presentation using words such as “outrage, ”naïve,” “misguided,” “overreach, and “reprehensible”  to describe the draft guidances.  
• Kelly Slone of National Venture Capital Association (NVCA) said draft guidances would discourage venture capital in LDTs 
• Ms. Slone stated that LDTs already receive significantly less venture capital due to regulatory uncertainty and reimbursement issues.
• Many speakers stated that FDA has not provided evidence of harm caused by LDTs
• Curtis Hanson of the Mayo Clinic said his laboratory has performed over 21 million tests without so much as one sentinel adverse event.  In his introduction, Jeffrey Shuren, CDRH Director, talked about anecdotal reports of harm but provided no new evidence of the risks associated with LDTs.  FDA has apparently still not provided the evidence of harm that was requested back in September.
• Many speakers stated that FDA does not have resources to review influx of submissions it would receive if agency finalized the framework
• Curtis Hanson of the Mayo Clinic noted that his laboratory alone offers over 1,600 LDTs
• Some speakers stated that FDA clearances or approvals do not necessarily mean better tests
• Examples include 510(k)-cleared Lyme Disease tests (high false negatives) (two Lyme groups spoke, one of which noted that the LDT had better performance than the 510(k)-cleared version) and the recently approved Vemurafinib-Responsive BRAF V600K Melanoma companion diagnostic (reportedly misses mutations found by the LDT)
• Many speakers stated that FDA should go through notice-and-comment rulemaking and not use guidance
• Several speakers stated that FDA should allow use of research use only RUO products as components of LDTs
• Rare Disorder Exemption
• Several commenters said the 4,000 test limitation is too narrow and should be expanded to either 4,000 cases or 200,000 cases as in the Orphan Drug Act.  It is very likely that FDA will not adopt a 4,000 test cap, but it is entirely unclear what cap they will select instead.
• Definition of health care system
• With regard to LDTs for Unmet Needs and Traditional LDTs, one of the factors to consider whether the exemption applies is whether it is for use 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.  There was considerable discussion during the meeting of how to interpret that definition of healthcare system and the impact of various definitions on patient access.
• Modifications
• Many speakers stated that it is common practice within laboratories to modify FDA-cleared or approved tests to serve their patients, so the provision within the guidance requiring additional submissions to FDA for certain modifications will pose difficulties.  Some laboratories explained how the results would be worse if modifications were not allowed; an example came from a public health lab talking about tissue samples for sexually transmitted infections.  
• Multiple speakers identified a need for a clear explanation of risk-categorization before final guidance
• Several speakers called for clarity on application of QSRs prior to final guidance, specifically a cross-walk comparing CLIA and QSR requirements

A number of organizations stressed that FDA should reissue the Framework in draft to allow for further comments, since the agency will need to make multiple changes. 

For those interested in soaking up additional details about the public workshop.  FDA has provided a Transcript of the public workshop.

The FDA’s proposal did generate some support as well, with proponents arguing that FDA regulation was necessary to ensure test safety and that it does not matter to patients whether a test is an LDT or a kit.

February 2: FDA Deadline for Written Comments.

On February 2 (coincidentally Groundhog’s Day) written comments to FDA related to the Draft Guidances and the January 8-9 public workshop were due to the agency.  As of February 17 at midnight, regulations.gov listed 235 comments submitted to the Framework draft guidance: Of those, 144 comments were posted, including comments from ACLA, the American Association for Clinical Chemistry, state public health laboratories and departments of health (including the Wadsworth center in New York, the only state that requires LDTs to be approved), the Biotechnology Industry Organization, which represents biotech companies, organizations representing patients, insurers, NVCA, individual laboratories, medical centers and hospitals (such as the American Hospital Association), representatives of kit manufacturers (such as the Advanced Medical Technology Association), accreditation bodies (such as the College of American Pathologists), the Coalition for 21st Century Medicine, AMP, and HPM. 

February 20: FDA Public Workshop to Discuss NGS.

Multiple LDTs utilize NGS technology.  A number of speakers during the FDA public workshop expressed concern that FDA regulation of LDTs would hamper introduction of NGS.  FDA issued a discussion paper on potential approaches to regulate NGS, and has announced that it will be holding a February 20 public workshop to obtain feedback on the NGS discussion paper.  How the agency will approach tests that use this technology is a key aspect of any regulatory framework to regulate LDTs.  This is also important as a bellwether for how FDA will handle new technologies that do not fit the traditional model.

May 4: Discussion of Draft Guidances at ACLA Annual Meeting.

Although hopefully we will see the end of winter weather well before this time, on May 4, Mr. Tribe, Mr. Clement, Viet Dinh, Partner at the same law firm as Mr. Clement and Professor of Law at Georgetown University Law Center, and Elizabeth Mansfield, Director of Personalized Medicine at FDA’s Center for Devices and Radiological Health, will discuss the Draft Guidances at ACLA’s annual meeting.  It should be entertaining.