On November 17, 2015, leaders from both the Food and Drug Administration (FDA) and the Centers for Medicare & Medicaid Services (CMS) testified before the U.S. House of Representatives Committee on Energy and Commerce, Subcommittee on Health regarding regulation of Laboratory Developed Tests, or LDTs.1 The House committee is currently considering legislation that would direct the future regulation of LDTs. Leaders from both agencies advocated that the draft legislation would improve the regulation of such tests. FDA testimony signaled that the Agency intends to continue forward with plans to actively regulate LDTs under the existing FDA framework, despite significant opposition and legislative activity.

FDA’s Proposal to Regulate LDTs

Unlike traditional in vitro diagnostic (IVD) tests, LDTs are developed and used within a single laboratory. Historically, IVD tests have been actively regulated by FDA under the medical device provisions, while LDTs have not typically been subject to active oversight by FDA. In October 2014, FDA issued a draft guidance proposing to regulate all LDTs as medical devices, citing the increased complexity and greater impact on diagnosis and treatment decision-making.2 (Previously covered here). Opponents of this position argue that the laboratories that develop and validate LDTs are already subject to regulation by CMS under the Clinical Laboratory Improvement Amendments (CLIA). Under FDA’s draft guidance, LDTs would further be regulated by FDA according to the risk associated with their specific intended, diagnostic use.

Approximately 24 hours in advance of the hearing and in further support of FDA’s position, the Agency issued a report entitled “The Public Health Evidence for FDA Oversight of Laboratory Developed Tests: 20 Case Studies.”3 The report provides 20 recent examples where LDTs not regulated by FDA were viewed by the agency as having harmed or potentially to have harmed patients. The examples included tests with false-positive and false-negative results, tests with no proven relevance to the disease or condition, tests based on disproven scientific concepts, and tests undermining drug treatment selection. In one case study, FDA claimed that a false-positive result from ovarian cancer screening tests could have resulted in patients receiving needless surgery to remove their ovaries. In another case, FDA argued that an insufficiently validated autism biomarkers test resulted in children undergoing inappropriate and harmful treatment based on test results. FDA estimated that the issues associated with the autism test would result in a total public health cost of US$66.1 million.

The FDA report argues that current CMS oversight under CLIA is not adequate to ensure the safety and efficacy of LDTs offered to the market. FDA indicated that “all of these tests described as problematic in this report were offered from laboratories following the minimum requirements of CLIA.” The Agency claimed that the harmful consequences could have been avoided with FDA oversight.

The Role for FDA and CMS

The laboratory community and many other stakeholders believe that regulation of LDTs by FDA would be potentially problematic. In light of that view, industry groups have submitted proposals and suggested that the regulation of LDTs could be improved by giving CMS greater jurisdiction. Under one such proposal from the Association for Molecular Pathology (AMP), CMS would have more power and play a role in the evaluation of clinical validity of the test.4 In another proposal, the College of American Pathologists (CAP) advocated for a tiered risk-based regulation which would focus FDA oversight to high-risk tests and leave moderate- and low-risk tests to CMS.5

The laboratory community has also been working with legislators to develop legislation that would redefine FDA’s ability to regulate LDTs. The House Energy and Commerce Committee is currently considering draft legislation that would establish a new regulatory framework for “in vitro clinical tests” (IVCTs).6 The draft legislation proposes to create a new product category for IVCTs, distinct from the current medical device definition, and establish a new regulatory entity, the Center for In Vitro Clinical Tests, within FDA. Other key features of the proposed legislation include:

  • Risk-based classification: While the draft legislation has adopted a risk-based classification, the burden of proof would be on FDA to reject a developer’s proposed moderate- or low-risk classification. FDA would be required to explain why the information and explanations submitted by the developer do not support the proposed classification.In addition, classification could be appealed to advisory panels consisting of experts in the fields.
  • Mitigating factors: An otherwise high-risk test could be classified to be moderate-risk if one or more mitigating factors are available. These factors include well-characterized technology and clinical use, clinical presentation, and availability of confirmatory or adjunctive tests.  
  • Third-party review for moderate-risk tests: Instead of being subject to premarket review by FDA, moderate-risk tests could be cleared for marketing by an accredited third-party reviewer. Review by FDA would be reserved for high-risk tests.
  • Special pathway for certain tests: The proposed legislation would create expedited review pathways for IVCTs for unmet needs, rare diseases, or moderate-risk tests that offer a clinically significant advantage over tests previously approved.

At the hearing, Jeffrey Shuren, M.D., speaking on behalf of FDA, rejected these approaches, saying these proposals would create a duplicative or bifurcated program and lead to inefficiency and inconsistency. With respect to current regulation by CMS, Shuren testified that while CLIA includes oversight of pre-analytic, analytic, and post-analytic policies and procedures for laboratory testing, clinical validity for individual tests is not typically reviewed. In addition, Shuren argued that regulation by FDA could enhance consistency and uniformity across laboratories for similar test types.

Patrick Conway, Deputy Administrator for Innovation & Quality and Chief Medical Officer in CMS's Office of the Administrator, also testified at the hearing on behalf of CMS. His comments were in general agreement with those of FDA. Like Dr. Shuren, he commented that the assessment of premarket clinical validity for LDTs is important. He noted that initiation of premarket review would be most appropriately placed with FDA due to the Agency’s existing staff of physicians, Ph.D.s, biostatisticians and scientists who are trained to assess clinical validity. By comparison, CMS’ focus has always been on laboratory procedures and equipment standards. He told the House committee that the CLIA program would continue to oversee lab operations and review the performance of tests within these labs in the post-market setting. “FDA and CMS can work together,” he noted, “utilizing their respective authorities and strengths to assess premarket clinical validity and laboratory standards, respectively."

Challenges From the Legislators   

At the hearing, several legislators expressed reservations regarding the FDA’s position. For example, Representative Michael Burgess (R-Texas), a leading critic of the FDA’s proposal, said requiring premarket review for LDTs would impose unnecessary requirements and costs on clinical laboratories and healthcare providers, and stifle innovation. Shuren responded by highlighting FDA’s recent approaches to regulating LDTs, including recent clearance of 23andMe's Bloom syndrome test, in which FDA created a new classification of “autosomal recessive carrier screening gene mutation detection system” and exempted products of this classification from premarket review requirements. Shuren stated that such “innovative approaches” would help the agency to be more responsive to the industry’s need.

Representative Chris Collins (R-New York) raised concerns that the proposed premarket review by FDA would be too time-consuming. Shuren argued that FDA's existing staff is equipped to conduct premarket reviews, and that FDA intends to phase in the enforcement over the course of nearly a decade so that the agency can accommodate the increased workload with existing resources.

Other legislators raised concerns that FDA approval of a test would somehow suggest that it would always provide accurate results. In addition, others noted that the FDA’s report focused on 20 examples taken from a universe of thousands of tests. Shuren did not directly address these additional concerns. 

According to Shuren, FDA has completed its review of the public comments on the draft guidance documents and expects to finalize the guidance in 2016.

The testimony at the hearing, together with recent FDA enforcement letters directed to LDT providers, signal FDA’s continuing push to implement its LDT framework, absent Congressional intervention.