Coordinating Clinical Trials to Confirm Drug Safety and Efficacy-Resolving Uncertainty.

Abstract

How do we know whether a drug works? In the United States, the US Food and Drug Administration (FDA) has established guidance to inform drug development, including testing to establish safety and efficacy for a specific clinical indication, prior to market approval. The FDA generally requires that companies complete numerous clinical studies, including 1 or 2 pivotal trials, of which more than 80% are randomized; use double-blinded allocation; and include a placebo or active control comparator arm.1 Because these trials are often small, short, and use surrogate markers of disease for primary trial endpoints,1 some uncertainty remains as to drugs’ safety and efficacy at the time of approval. Nevertheless, once approved, clinicians may prescribe the drug for any clinical indication, not only the one that received FDA approval. This is known as off-label prescribing. But then how do we know whether a drug works for non– FDA-approved clinical indications? This question is quite a bit more complicated, because any company or noncompany researcher, such as an investigator based at an academic institution, can test the drug in a clinical study for any indication, and there is no requirement to establish safety and efficacy if FDA approval is not solicited. In this issue of JAMA Internal Medicine, Federico and colleagues2 offer unique insights into how this process naturally occurs by using pregabalin (Lyrica) as an illustrative example. The authors systematically reviewed the literature and found 238 clinical trials that tested the drug for 33 indications not yet approved by the FDA nor the European Medicines Agency. Of these trials, 74% were considered exploratory and 26% were potentially confirmatory. Although 5 indications (accounting for 40% of identified confirmatory trials) ultimately secured FDA or European Medicines Agency approval, clinical trials for 22 (67%) indications generated clinical agnosticism, a term the authors coined to describe exploratory, underpowered trials that suggested a new clinical benefit. Furthermore, 63% of tested indications were not followed within 5 years by a confirmatory trial. High-quality, rigorous testing of drugs for a wide variety of clinical indications maximizes our understanding of drugs’ use and benefit to patients. However, a medical literature replete with small, short clinical trials that suggest clinical benefit but are neither generalizable nor replicated creates even greater uncertainty among clinicians. Furthermore, these studies, when published, can generally be distributed as part of companies’ physician-detailing and marketing efforts, potentially encouraging off-label prescribing for uses that may not benefit patients and may cause harm.3 Efforts are needed to better coordinate testing of drugs for non–FDA-approved clinical indications and ensure that any studies suggesting clinical benefit and safety are confirmed, ideally in a generalizable patient population. While Congress may need to grant the FDA greater authority to require these postmarket evaluations, other payers, including the Centers for Medicare & Medicaid Services, could also play a role.3 In the end, evidence needs to be expeditiously and rigorously developed to confirm benefits (and safety) and inform patient and clinician treatment decisions.