Postmarket Safety Events Among Novel Therapeutics Approved by the US Food and Drug Administration Between 2001 and 2010

Abstract

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.

New and incremental FDA black box warnings from 2008 to 2015

“…We supplemented our MedWatch-based dataset by examining every FDA Drug Safety Communication between January 2008 and June 2015 (614 communications), and included additional BBWs not listed on MedWatch. We also included BBWs identified in relevant BBW literature [4,7]. …”

“…Of novel therapeutics approved between 1996 and 2012, almost three quarters of BBWs were issued at the time of FDA approval, but over 40% of drugs receiving BBWs acquired the warnings in the post-marketing period [3]. Additionally, a recent study found that FDA took significant post-marketing safety actions for approximately one-third of novel therapeutics approved between 2001 and 2010, most commonly issuing a new BBW [4]. Further, the likelihood of drugs approved since the passage of the Prescription Drug User Fee Act (PDUFA) in 1992 receiving post-marketing BBWs or being withdrawn has increased compared to drugs approved before this period [5].…”

Healing an ailing pharmaceutical system: prescription for reform for United States and Canada

“…Such evidentiary changes may increase the risk that unsafe drugs will enter the market 7684. And most,7374758586 but not all,84 studies suggest that shorter review times are deleterious.…”

Pathways to faster access to medicines

“…28 In Canada, drugs with a priority review were more likely to acquire a serious safety warning than those with a standard review. 29 On the one hand, authorisation of medicines after limited evaluation may be viewed as putting patients at unnecessary risk.…”