Clinical trials used by the Food and Drug Administration (FDA) to approve new drugs between 2005 and 2012 vary widely in their characteristics, according to a study in the January 22/29 issue of JAMA.
"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."