CAP Proposals for LDTs Highlighted
Before certain high-risk, life-sustaining medical devices like implantable pacemakers and defibrillators become commercially available, they are subjected to the Food and Drug Administration's (FDA's) premarket approval process to reasonably assure their safety and effectiveness. However, until recently, the FDA has exercised "enforcement discretion" over a subset of in vitro diagnostic products called laboratory developed tests (LDTs).
While the FDA maintains that it has had the authority to regulate all IVDs since the 1976 enactment of the Medical Device Amendments (MDA) to the Federal Food, Drug, and Cosmetic Act (the FD&C Act), it has generally not enforced its authority with respect to LDTs. However, the increasing reliance on LDTs in clinical decision-making, combined with the expanding geographic reach of LDTs, the sheer number and complexity of modern LDTs (e.g., simultaneously testing multiple biomarkers or the escalating use of complex algorithms in LDTs) and reports of patient harm resulting from LDTs being launched without adequate clinical validation has compelled the FDA to revisit its stance regarding its oversight of moderate- to high-risk LDTs.
In October 2014, the FDA published the draft guidance, proposing a regulatory framework for its oversight over moderate- to high-risk LDTs and, subsequently, breaking the agency's nearly 40 year status quo of enforcement discretion. To solidify its stance, the FDA released a report on November 16, 2015, describing 20 case studies in which patient safety was compromised by inadequately vetted LDTs that were of questionable utility and/or provided inaccurate results. The report states that, in some cases, life-threatening diseases went undetected as a result of LDTs prone to false-negative results. In other cases, false-positive test results gave rise to improper diagnosis of patients as having conditions that they did not really have. In one instance, the FDA noted that false-positive results from a commercially available ovarian cancer screening test may have caused women to undergo unnecessary surgery to remove healthy ovaries.The FDA has also determined that the existing regulatory oversight of LDTs under the Clinical Laboratory Improvement Amendments (CLIA) alone does not address patient safety concerns, primarily because CLIA accreditors neither validate these tests prior to marketing nor do they assess the clinical validity of a LDT.
On November 17, 2015, the FDA announced at a House Energy and Commerce Committee hearing that it expects to finalize its plan to require moderate- to high-risk LDTs to gain FDA approval or clearance in 2016. This announcement was met with opposition from various stakeholders within the medical community, fearing that the FDA's involvement will lead to onerous regulation that stifles patient access and progress in personalized medicine. Estimates suggest that thousands of diagnostic tests, including the majority of genetic tests, are currently offered as LDTs. Of the more than 11,000 LDTs on the market, approximately half would qualify as moderate- and high-risk LDTs, thus requiring some degree of oversight under the FDA's proposal. Under the FDA's proposed risk-based framework, moderate-risk LDTs will be subject to premarket review requirements within 5-9 years after its final guidance is implemented.
In the wake of the House E&C Committee hearing, questions and concerns remain as to whether the FDA has the capacity to efficiently review the thousands of existing LDTs on the market, not to mention those that will be developed in the coming years. Commentators suggest that the FDA currently lacks the resources necessary to regulate LDTs in a timely manner, and that LDT premarket submissions may turn into a "hurry-up-and-wait scenario." Such circumstances are likely to hamper both innovation and patient access because longer lead times may be required to implement new LDTs. Moreover, providers of moderate-risk and high-risk LDTs that were once largely shielded from FDA oversight will be required to expend significant resources to successfully navigate and comply with the FDA's elaborate approval or clearance process. Certain LDT providers may not be able to cope under these circumstances, which may have the unintended consequence of having fewer LDT providers control larger portions of the LDT market share. An additional concern is that the increased costs of regulatory compliance may be passed on to patients, which may deter patients and healthcare providers from utilizing such tests.
Such concerns beg the question: Is there an optimal framework for ensuring efficient and proper oversight of LDTs? Indeed, this question has gained the attention of various groups, including the Diagnostic Test Working Group (DTWG), the Association for Molecular Pathology (AMP) and the College of American Pathologists (CAP) whom have put forward their own proposals regarding the appropriate regulatory construct to promote the advancement of these clinical tests.
AMP's proposal suggests updating CLIA regulations so that the Centers for Medicare & Medicaid Services (CMS) can establish a public database that houses validation information on test procedures, and relies on third party reviewers like CAP to ensure clinical and analytical validity of high- and moderate-risk lab developed procedures. According to AMP's plan, the FDA's role would be restricted to regulating certain tests (i.e., multi-analyte assays with algorithmic analysis) under limited circumstances. DTWG, on the other hand, proposes spreading oversight responsibilities across the FDA, CMS and the states. Under DTWG's framework, the FDA would have authority over test development and validation; CMS would retain authority over traditional lab operations necessary to perform tests; and the states would continue to oversee the proper interpretation of test results.
Thus, while LDT providers face uncertainty as to whether the regulation of LDTs will ultimately be shared between the FDA and CMS or fall under the jurisdiction of a single agency, it is becoming increasingly evident that LDT providers will be held to certain regulatory standards in terms of demonstrating the clinical validity of their tests prior to entering the market.
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