"FDA review of new drug applications is guided by the Federal Food, Drug, and Cosmetic Act, which requires ‘adequate and well controlled investigations' to determine efficacy," according to background information in the article. "Many patients and physicians assume that the safety and effectiveness of newly approved therapeutic agents is well understood; however, the strength of the clinical trial evidence supporting approval decisions by the U.S. FDA has not been evaluated."
Nicholas S. Downing, A.B., of the Yale University School of Medicine, New Haven, Conn., and colleagues evaluated the strength of clinical trial evidence supporting FDA approval decisions for new therapeutic agents by characterizing key features of pivotal efficacy trials (clinical trials that serve as the basis of FDA approval), such as trial size, design, duration, and end points.
The researchers used publicly available FDA documents to identify 188 novel therapeutic agents approved between 2005 and 2012 for 206 indications on the basis of 448 pivotal efficacy trials. The vast majority of pivotal trials were randomized (89 percent) and double-blinded (79.5 percent). More than half of the trials used a placebo for comparison (55 percent), and 32 percent used an active (such as another drug) comparator, and 13 percent had no comparator.
The median (midpoint) number of patients enrolled per indication among all pivotal trials was 760. Among 201 indications, 74 (37 percent) were approved on the basis of a single trial, 77 (38 percent) on 2, and 50 (25 percent) on 3 or more. Trials using surrogate end points as their primary outcome formed the exclusive basis of approval for 91 indications (45 percent).
At least 1 pivotal trial with a duration of 6 months or greater supported the approval of 68 indications (34 percent). Trial features differed by therapeutic and indication characteristics, such as therapeutic area, expected length of treatment, orphan status (drug used to treat rare medical condition), and accelerated approval.
"The variation in the [amount and type] of clinical trial evidence used by the FDA to assess the efficacy of novel therapeutic agents highlights the agency's flexible standards for approval," the authors write. "Such regulatory flexibility allows for a customized approach to approval, including the ability to rapidly approve potentially effective therapies for life-threatening diseases, such as certain cancers, or those diseases for which there is no existing effective treatment, such as orphan diseases. These approvals can be made without requiring costly and time-consuming randomized, double-blinded, controlled trials, although these trials are regarded as the gold standard for evaluation."
The researchers note that understanding the clinical trial evidence underlying newly approved therapeutic agents has important implications for patients and physicians. "When medications become available on the market, decisions must be made about their use, likely informed by how well safety and effectiveness are understood. Comparative effectiveness information, which is not required as part of FDA approval and involves comparison of an intervention with an active control, was available for less than half of indications, consistent with prior research, but leaving uncertainty about the benefits and safety of these medications when compared with other available therapeutic agents."
The authors write that the wide variation in clinical trial evidence "has the potential to inform current FDA regulatory approval standards and postmarket surveillance initiatives."
Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.
Editorial: Opening the FDA Black Box
In an accompanying editorial, Steven N. Goodman, M.D., M.H.S., Ph.D., of Stanford University, Stanford, Calif., and Rita F. Redberg, M.D., M.Sc., of the University of California, San Francisco, and Editor, JAMA Internal Medicine, comment on the three studies in this issue of JAMA that examine the FDA approval process.
"Although these reports represent important steps in improving understanding of FDA decision making, further commitment to and progress toward ensuring transparency, including reducing report redactions, is needed to help the scientific community and other interested parties answer the questions these studies raise, thereby helping the FDA in its mission to find the right balance between allowing innovation and protecting the public's health."
Editor's Note: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Redberg reported being a member of the U.S. Food and Drug Administration Circulatory System Devices Panel and a member of the California Technology Assessment Forum. No other conflicts of interest were reported.
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