HOW FDA APPROVE DRUGS

Although many patients and physicians assume that the safety and effectiveness of new drugs are well understood, the quality of clinical trial evidence the US Food and Drug Administration (FDA) uses for approvals varies widely, new research indicates.

Nicholas S. Downing, AB, from the Yale University School of Medicine, New Haven, Connecticut, and colleagues researched the strength of clinical trial evidence that led to FDA approvals for new drugs by studying key features of pivotal efficacy trials (the clinical trials that influence FDA approval), such as trial size, design, length, and endpoints.

The authors used FDA documents to study 188 new therapeutic agents approved between 2005 and 2012 for 206 indications on the basis of 448 pivotal efficacy trials. Among their findings, presented in an article published in the January 22-29 issue ofJAMA, are that

• The vast majority of the trials were randomized (89.3%) and double-blinded (79.5%).
• The median number of pivotal trials per indication was 2, although 74 indications (36.8%) were approved on the basis of a single pivotal trial.
• More than half of the trials used a placebo for comparison (55.1%), 31.9% used an active comparator (such as another drug), and 12.9% had no comparator.
• The majority of trials evaluating drugs indicated for chronic treatment lasted less than 1 year, "raising questions about the certainty of these medications' long-term efficacy and safety," the authors write.
• Pivotal trials using surrogate endpoints (those using a biomarker expected to predict clinical benefit) as their primary outcome were the exclusive basis of approval for 91 indications (45.3%).

However, along with varied strength of evidence comes flexibility, which can lead to rapid approval without lengthy and costly randomized, double-blind, controlled trials of therapies for life-threatening diseases or those for which there is no effective treatment, such as orphan diseases.

The new data have important implications for physicians and patients as they consider using new drugs, according to the authors. For example, they note, a recent Institute of Medicine committee report recommended that the FDA provide a risk/benefit analysis when they approve a new drug that would be regularly updated throughout the market life of the drug.

"Alternatively, or as part of this effort, the FDA could provide a summative statement, or even a grade, for each approval to signal the quality of clinical trial evidence used to determine safety and efficacy, allowing therapeutic agents approved on the basis of more robust evidence to be distinguished from those approved on the basis of less robust evidence," the authors write.

In an accompanying editorial, Steven N. Goodman, MD, MHS, PhD, from Stanford University in California, and Rita F. Redberg, MD, from the University of California, San Francisco, and editor, JAMA Internal Medicine, commented on the results: "Downing et al leave open the question of whether the FDA exercised reasonable judgment in accepting weaker designs both for regular and accelerated approvals. It would be helpful to know how many of these approvals, particularly those based on surrogate end points, had postmarketing requirements, how many postmarket studies were fulfilled, and what was the ultimate clinical assessment of the drugs approved in these various ways."

Support for this study and the authors was provided in part by the Pew Charitable Trusts; the National Heart, Lung, and Blood Institute; the National Institute on Aging; and the American Federation for Aging Research. One coauthor has reported receiving travel expenses from IMS Health. Two coauthors have reported receiving support from Medtronic Inc to develop methods of clinical trial data sharing, from the Centers of Medicare and Medicaid Services to develop and maintain performance measures used for public reporting, and from the FDA to develop methods for postmarket surveillance of medical devices. One of these coauthors also reported that he chairs a scientific advisory board for UnitedHealthcare, and the other reported serving as a member of a scientific advisory board for FAIR Health Inc. The other authors have disclosed no relevant financial relationships. Dr. Redberg has reported being a member of the FDA Circulatory System Devices Panel and a member of the California Technology Assessment Forum.