When an investigational prescription drug shows promise for treating a serious illness or filling an unmet medical need, the Food and Drug Administration (FDA) has special programs available to expedite its clinical testing and approval. One is the "Accelerated Approval" pathway, in which the FDA will accept weaker-than-usual evidence of the drug's efficacy from its pre-clinical trials. In exchange, the FDA requires that the manufacturer conduct post-approval confirmatory studies.
To understand how this pathway is implemented, in a recent study published in JAMA, researchers at Brigham and Women's Hospital and the London School of Economics and Political Science (LSE) examined the pre-approval and post-approval clinical trials of drugs granted FDA Accelerated Approval between 2009 and 2013. During that time, the FDA granted 22 drugs Accelerated Approval and ordered 38 post-approval studies to confirm the safety and efficacy of these drugs. Three years after the last drug's approval, the researchers found that only half of those post-approval studies had been completed. They also found that the characteristics of those completed studies did not differ much from the pre-approval studies. The researchers found that the proportion of randomized or blinded trials didn't differ and that many of the confirmatory trials still relied on surrogate measures of effect--that is, blood tests or radiological studies that may not correlate with real clinical endpoints.
"One might expect Accelerated Approval confirmatory trials to be much more rigorous than the pre-approval trials," said Aaron S. Kesselheim, MD, JD, MPH, of the BWH Division of Pharmacoepidemiology and Pharmacoeconomics and senior author of the study. "But we found that there were few differences in these key design features of the trials conducted before or after approval." In 17 out of the 18 completed studies, surrogate measures were still the primary endpoints of the studies.
"It is important to use clinical endpoints in testing investigational drugs whenever possible because there are numerous cases of drugs approved on the basis of a surrogate measure that turn out to later not effect actual clinical outcomes - or even make them worse," said Kesselheim.
To address these issues and improve the quality of Accelerated Approval confirmatory studies, Kesselheim suggests that the FDA clearly describe the limitations in the pre-approval data that will need to be addressed in post-approval studies and that they work with manufacturers to ensure that post-approval studies are conducted using design features that will be optimally useful for confirming the efficacy of the drug.
Article: Characteristics of Preapproval and Postapproval Studies for Drugs Granted Accelerated Approval by the US Food and Drug Administration, Huseyin Naci, PhD, MHS; Katelyn R. Smalley, BSc; Aaron S. Kesselheim, MD, JD, MPH, JAMA, doi: 10.1001/jama.2017.9415, published 15 August 2017.