Association between characteristics of novel therapeutics and approval times by the Food and Drug Administration
Our main outcome measure was the “total review time”. Our main independent variables were key characteristics of the therapeutics and features of their applications. We classified novel therapeutics according to several characteristics including orphan status, priority review status, and designation as a small molecule or biologic. The features of the pivotal efficacy trials supporting the approval of each indication included in our sample were abstracted from FDA medical review documents. Pivotal trials were categorized according to their use of randomization and blinding, as well as their choice of comparator and endpoints. We estimated a Cox proportional hazards model to determine the characteristics of the pivotal efficacy trials of approved therapeutics that were associated with total review time prior to approval by the FDA.
A total of 122 novel therapeutics were approved by the FDA between 2005 and 2011: orphan status was granted to 17 (13.9%), priority review status to 41 (33.6%) and 15 (12.3%) were accelerated approvals. These 122 novel therapeutics were approved for use in 136 indications, over half of which were chronic treatments (n=74; 54.4%). A total of 312 efficacy trials supported the approval of these 136 indications; the median number of pivotal efficacy trials per indication was 2 (IQR: 1-3). Median overall subjects participating in pivotal efficacy trials for each indication was 663 (IQR: 250-1557). After multivariable adjustment, several key therapeutic characteristics and features of their applications were associated with total review time. Of note, total review time was shorter for therapeutic applications with priority review compared with standard review (Hazard ratio of shorter total review time=3.50; 95% CI 2.07-5.93; p<0.001); for therapeutic applications that used surrogate outcomes in all pivotal trials (HR: 1.53; 95% CI 1.06-2.21; p=0.022); and for therapeutics used for intermediate periods of time when compared with acute use (HR: 3.07; 95% CI 1.69-5.57; p<0.0001). The number of efficacy trials, the overall subjects, and the exclusive use of rigorously designed pivotal trials were not associated with faster review times.
Most characteristics of the pivotal clinical trials that supported the approval of novel therapeutics were not associated with total review time in our Cox proportional hazards model. The finding that surrogate outcomes were associated with shorter total review times is an important exception and suggests that industry’s efforts to generate the most meaningful information for patients about the effectiveness of novel therapeutics by measuring clinical outcomes do not lead to rapid review. Other features of pivotal trials that suggest thorough pre-market testing, including the number of trials, the number of rigorously designed trials, and their safety and efficacy populations, were not associated with total review time.