MedCity Influencers, Diagnostics

The past, present and future of FDA regulation of LDTs

FDA is delaying finalizing its regulation of lab-developed tests, but in the meantime continued FDA enforcement discretion will be the norm as will its issuing of enforcement letters.

blood test

It has been more than two years since FDA notified Congress of its intention to issue draft guidance on a proposed regulatory framework for the oversight by FDA of laboratory developed tests (LDTs). The draft guidance was published on October 3, 2014, and FDA received a plethora of public comment until the comment period ended in February 2015.

It’s worthwhile to reflect on the history preceding FDA’s controversial guidance, assess the current status of FDA enforcement, and offer our own guidance on how to prepare for eventual FDA enforcement to companies marketing high-risk LDTs.

LDTs – Past
Many of us clearly recall the unprecedented two-day public meeting in Rockville, Maryland, on July 19-20, 2010, during which FDA articulated its case for regulatory oversight of LDTs. They then solicited feedback from industry, the public, and patient advocacy groups.

On Day 1, when asked why FDA chose to issue guidance rather than propose a new regulation, Dr. Jeffrey Shuren, Director of the Center for Devices and Radiological Health, stated: “The reason why not for notice and rulemaking is because the requirements already apply now. The law is in effect. So when we engage in enforcement discretion, that is a guidance process. It is a matter of policy. It is not imposing a new requirement.”

At mid-morning on Day 2, the FDA posted 14 untitled enforcement letters it had sent to CLIA labs offering diagnostic tests for a range of disease types marketed direct-to-consumer and which employed a regulated collection device in the home (e.g., cheek swab, saliva). The reason cited by FDA in each of these letters was “lacks clearance or approval.”

Two days later on July 22, 2010, the Government Accountability Office (GAO) issued its report Direct-to-Consumer Genetic Tests: Misleading Test Results Are Further Complicated by Deceptive Marketing and Other Questionable Practices.

That report containeed this incendiary claim: “One company told a donor that an above average risk prediction for breast cancer meant she was ‘in the high risk of pretty much getting’ the disease, a statement that experts found to be ‘horrifying’ because it implies the test is diagnostic.”

A Congressional hearing, held on the same day before the Subcommittee on Oversight and Investigations of the House Committee on Energy and Commerce, featured the testimony from senior executives of 23andMe, Navigenics, and Pathway Genomics, who were invited to explain why they thought the tests offered through their CLIA laboratories were safe for consumers.

Four years passed before FDA issued its October 2014 Draft Guidance: Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs). The reaction from the industry was swift. In November 2014, a coalition of nearly 40 laboratories, medical groups, and other organizations sent a letter asking FDA to withdraw the guidance in favor of rulemaking. In January 2015, FDA held a 2-day public workshop at which numerous stakeholders presented divergent views on the necessity for oversight of LDTs, many claiming that such would stifle innovation and deprive patients of life-saving therapies.

Later in January 2015, the American Clinical Laboratory Association released a white paper arguing FDA lacked the statutory authority to regulate LDTs as medical devices. In June 2015, the House Energy and Commerce Committee circulated a draft bill to establish a new FDA Center for In Vitro Clinical Tests. In August 2015, the Association of Molecular Pathology published its proposal in favor of modernizing the CLIA regulations rather than FDA regulation of LDTs. In September 2015, the College of American Pathologists published its own legislative proposal for FDA regulation of only the highest-risk LDTs. Finally, in November 2015, the FDA issued its controversial report, The Public Health Evidence for FDA Oversight of Laboratory Developed Tests: 20 Case Studies, which highlighted specific examples of what FDA claimed were erroneous results from LDTs that put patients at risk of harm.

LDTs – Present
In April of this year, Clinical Laboratory News published an article on the current status of the draft guidance document. In a section of the article headlined FDA Plowing Ahead, an FDA spokesperson stated, “We are in the final drafting phase…We have carefully considered the comments and concerns…FDA doesn’t want to stifle innovation or access, but we want to make sure that the public is safe.”

Once the draft guidance is final, it must go through review at both the Department of Health and Human Services (DHHS) and the Office of Management and Budget (OMB) before being announced and published in the Federal Register. On September 6, 2016, the FDA issued a public Safety Communication on its website that recommended against women using screening tests for ovarian cancer that were advertised on the internet.

In the advisory, FDA emphasized that there were no such tests that were either cleared or approved and it singled out ROCA Test commercialized by Abcodia in the United States. Abcodia posted a response to this on its US website on September 13, 2016, claiming its test results “compare favorably with currently approved and widely adopted screening modalities used as an aid in the detection of other cancers, and support the clinical utility of the ROCA Test to aid physicians in clinical referral decision making.”

LDTs – Future
So where does this debate stand?

In the same Clinical Laboratory News published in April, the prominent medical device attorney Jeff Gibbs of Hyman Phelps and McNamara stated, “The single most likely outcome in my view is that FDA will issue a final guidance this year, and there will be litigation.”

FDA recently announced that it will delay finalizing the regulation of LDTs. Regardless, we believe that continued FDA enforcement discretion will be the norm and that FDA will continue to send untitled enforcement letters to companies that operate CLIA licensed laboratories offering high-risk cancer diagnostics direct to the consumer.

The Final Word?
On September 23, 2016, in his opening remarks at the FDA Public Workshop on Adapting Regulatory Oversight of Next Generation Sequencing – Based Tests, Dr. Robert Califf, MD, Commissioner of the FDA had this to say, “I did end up on 60 Minutes, in something very pertinent to what you all are working on today, the use of mathematics in developing laboratory tests without proper systems of control and external review.”

At Halloran Consulting, we advise our clients to plan a phased approach to implementing a quality management system that includes the following controls in 21 CFR(code of Federal Regulations) Part 820 (QSRs) first:

  • Personnel (820. 25)
  • Design controls (820.30)
  • Document controls (820.40)
  • Purchasing controls (820.50)
  • Receiving, in-process, and finished device acceptance (820.80)
  • Corrective and preventive action (820.100)

Begin gathering the analytical and clinical performance data needed to support a Class 3 indication, including precision/reproducibility, clinical sensitivity/specificity and software validation. So that if you receive an untitled enforcement letter from FDA about your high-risk LDT, you will have the data in hand to facilitate a meaningful discussion.

Photo: Flickr user Rosmarie Voegtli

 


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Michael Wienholt

Michael joined Halloran Consulting Group in 2015. Despite his youthful look, he brings more than 25 years of experience in the medical device industry to his client engagements, including 15 years of experience in global regulatory affairs and quality management systems for medical devices and in vitro diagnostics. Michael provides expertise in regulatory strategies and submissions and the design, implementation, and audit of quality management systems. Clients also benefit from his uncanny ability to weave quotes from movies into conversations in a very appropriate way.
Prior to joining Halloran, Michael was the owner and principal consultant at FDA Consulting LLC where he built a reputation as a go to person for resolving sticky regulatory situations. His reputation for doing the right thing preceded him to Halloran as he came highly regarded from industry personnel and FDA contacts.
Michael earned a Bachelor of Science degree in Forestry from North Carolina State University. He is Regulatory Affairs Certified (RAC) in both US and EU regulatory requirements by the Regulatory Affairs Professional Society (RAPS). He is also an ANSI-RAB-accredited lead auditor for medical device quality systems.

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