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. 2017 May 9;317(18):1854-1863.
doi: 10.1001/jama.2017.5150.

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

Nicholas S Downing  1 , Nilay D Shah  2 , Jenerius A Aminawung  3 , Alison M Pease  4 , Jean-David Zeitoun  5 , Harlan M Krumholz  6 , Joseph S Ross  7
Affiliations

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

Nicholas S Downing et al. JAMA. .

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.

Design and setting: Cohort study of all novel therapeutics approved by the FDA between January 1, 2001, and December 31, 2010, followed up through February 28, 2017.

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 measures: A 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.

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Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Zeitoun reported receiving personal fees from Cepton, Oliver Wyman, Roland Berger, McCann Health, Omnicom, Grey Healthcare, Saatchi & Saatchi, Sudler, TBWA, Havas, Agipharm, Mayoly Spindler, Teva, Menarini, Pierre Fabre, Merck, and AbbVie. Dr Krumholz reported receiving a grant from the US Food and Drug Administration and Medtronic; having a research agreement with Johnson & Johnson (Janssen) through Yale University; serving as chair of a cardiac scientific advisory board for UnitedHealth; being a founder of Hugo; being a participant and participant representative of the IBM Watson Health Life Sciences Board; and serving as an advisory board member for Element Science. Dr Ross reported receiving grants from the US Food and Drug Administration, Medtronic, Johnson & Johnson, Centers for Medicare & Medicaid Services, Blue Cross Blue Shield Association, and the Laura and John Arnold Foundation. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Timeline of Novel Therapeutics Approved by the US FDA, 2001-2010, That Experienced Postmarket Safety Events, Grouped by Therapeutic Area
Figure 2.
Figure 2.. Proportion of Novel Therapeutics Approved by the US Food and Drug Administration (FDA) From 2001 Through 2010 Affected by Any Postmarket Safety Event as of February 2017
The median time from approval to the first event was 4.2 years (interquartile range, 2.5-6.0 years).
Figure 3.
Figure 3.. Proportion of Novel Therapeutics Approved by the US Food and Drug Administration (FDA) From 2001 Through 2010 Affected by Any Postmarket Safety Event, According to Drug Class, Therapeutic Area, and Priority vs Standard Review
Figure 4.
Figure 4.. Proportion of Novel Therapeutics Approved by the US Food and Drug Administration (FDA) Between 2001 and 2010 Affected by Any Postmarket Safety Event, According to Accelerated Approval, Orphan Status, Near–Regulatory Deadline Approval, and Regulatory Review Time
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