IMPORTANCE Postmarket safety events of novel pharmaceuticals and biologics occur when new safety risks are identified after initial regulatory approval of these therapeutics. These safety events can change how novel therapeutics are used in clinical practice and inform patient and clinician decision making.OBJECTIVES To characterize the frequency of postmarket safety events among novel therapeutics approved by the US Food and Drug Administration (FDA), and to examine whether any novel therapeutic characteristics known at the time of FDA approval were associated with increased risk. EXPOSURES Novel therapeutic characteristics known at the time of FDA approval, including drug class, therapeutic area, priority review, accelerated approval, orphan status, near-regulatory deadline approval, and regulatory review time. MAIN OUTCOMES AND MEASURESA composite of (1) withdrawals due to safety concerns, (2) FDA issuance of incremental boxed warnings added in the postmarket period, and (3) FDA issuance of safety communications.RESULTS From 2001 through 2010, the FDA approved 222 novel therapeutics (183 pharmaceuticals and 39 biologics). There were 123 new postmarket safety events (3 withdrawals, 61 boxed warnings, and 59 safety communications) during a median follow-up period of 11.7 years (interquartile range [IQR], 8.7-13.8 years), affecting 71 (32.0%) of the novel therapeutics. The median time from approval to first postmarket safety event was 4.2 years (IQR, 2.5-6.0 years), and the proportion of novel therapeutics affected by a postmarket safety event at 10 years was 30.8% (95% CI, 25.1%-37.5%). In multivariable analysis, postmarket safety events were statistically significantly more frequent among biologics (incidence rate ratio [IRR] = 1.93; 95% CI, 1.06-3.52; P = .03), therapeutics indicated for the treatment of psychiatric disease (IRR = 3.78; 95% CI, 1.77-8.06; P < .001), those receiving accelerated approval (IRR = 2.20; 95% CI, 1.15-4.21; P = .02), and those with near-regulatory deadline approval (IRR = 1.90; 95% CI, 1.19-3.05; P = .008); events were statistically significantly less frequent among those with regulatory review times less than 200 days (IRR = 0.46; 95% CI, 0.24-0.87; P = .02).CONCLUSIONS AND RELEVANCE Among 222 novel therapeutics approved by the FDA from 2001 through 2010, 32% were affected by a postmarket safety event. Biologics, psychiatric therapeutics, and accelerated and near-regulatory deadline approval were statistically significantly associated with higher rates of events, highlighting the need for continuous monitoring of the safety of novel therapeutics throughout their life cycle.

Objective To characterize the prospective controlled clinical studies for all novel drugs that were initially approved by the Food and Drug Administration on the basis of limited evidence. Design Systematic review. Data sources Drugs@FDA database and PubMed. Study inclusion All prospective controlled clinical studies published after approval for all novel drugs initially approved by the FDA between 2005 and 2012 on the basis of a single pivotal trial, pivotal trials that used surrogate markers of disease as primary endpoints, or both. Results Between 2005 and 2012 the FDA approved 117 novel drugs for 123 indications on the basis of a single pivotal trial, pivotal trials that used surrogate markers of disease, or both (single surrogate trials). We identified 758 published controlled studies over a median of 5.5 years (interquartile range 3.4-8.2) after approval, most of which (554 of 758; 73.1%) were studies for indications approved on the basis of surrogate markers of disease. Most postapproval studies used active comparators—67 of 77 (87.0%) indications approved on the basis of single pivotal trials, 365 of 554 (65.9%) approvals based on surrogate marker trials, and 100 of 127 (78.7%) approvals based on single surrogate trials—and examined surrogate markers of efficacy as primary endpoints—51 of 77 (66.2%), 512 of 554 (92.4%), and 110 of 127 (86.6%), respectively. Overall, no postapproval studies were identified for 43 of the 123 (35.0%) approved indications. The median total number of postapproval studies identified was 1 (interquartile range 0-2) for indications approved on the basis of a single pivotal trial, 3 (1-8) for indications approved on the basis of pivotal trials that used surrogate markers of disease as primary endpoints, and 1 (0-2) for single surrogate trial approvals, and the median aggregate number of patients enrolled in postapproval studies was 90 (0-509), 533 (122-3633), and 38 (0-666), respectively. The proportion of approved indications with one or more randomized, controlled, double blind study using a clinical outcome for the primary endpoint that was published after approval and showed superior efficacy was 18.2% (6 of 33), 2.0% (1 of 49), and 4.9% (2 of 41), respectively. Conclusions The quantity and quality of postapproval clinical evidence varied substantially for novel drugs first approved by the FDA on the basis of limited evidence, with few controlled studies published after approval that confirmed efficacy using clinical outcomes for the original FDA approved indication.

No abstract