FDA Consideration and Approval of New Drugs

To those not intimately involved in the process, FDA consideration of new drug applications must seem baffling.  Two articles in JAMA attempt to provide some basic data regarding the process.   (JAMA Article)  (JAMA Article)   In the first, the level and nature of evidence supporting those drugs that did receive approval in 2005-12 is examined.   In this time period, 188 novel drugs were approved for 206 indications.  The median number of pivotal trials per indication was 2, but 74 indications had only a single pivotal trial.  Ninety percent of trials were randomized, 80% were double-blinded, and 87% had an active or placebo comparator.  The median number of patients in a pivotal trial was 760, but was much smaller for orphan drugs and those using the accelerated approval pathway for medications to treat life-threatening illnesses.  Surrogate endpoints were used exclusively for 91 indications, clinical outcomes for 67 and clinical scales for 36.  There was significant variation in the characteristics of pivotal trials across therapeutic categories.  Comparative effectiveness information was available for only about half of approved indications, leaving practitioners with little data about whether the new drug has better clinical or cost outcomes than existing therapies.  While the variability in trial characteristics indicates appropriate regulatory flexibility, it is not clear that prescribers or patients have enough readily available data to understand the strength or weakness of evidence supporting the approval of a particular therapeutic.

The second article looks at the reasons for delay or denial of new drug applications from 2000-12.  There were 302 new applications, of which 151 received approval on first submission and 222 were ultimately approved.  Following initial submission, for those compounds which required an additional submission, the delay to approval had a median of 435 days. Some of the reasons for delay were avoidable, providing useful information for future study design and submissions.  For example, of the 151 drugs not approved on first submission, 24 had issues with dose selection, 20 with choice of end points, 20 had inconsistent results on different end points, 17 had inconsistent results when different trials or study sites were compared, and 20 had poor efficacy compared with standard of care.  The frequency of safety concerns was similar among drugs that never got approved and those with delayed approvals, but efficacy deficiencies were more common among never-approved compounds.  This suggests that the FDA is willing to accept potential adverse events if a new drug provides superior efficacy to existing treatments.  The high rate of non-approval on first submission is costly to drug companies and potentially to patients if the drug is ultimately approved and is a clear advance over existing therapies.  Given the FDAs willingness to work with companies on trial design and execution issues, it seems companies could do a much better job of avoiding non-approval.