Postmarket safety events among novel therapeutics approved by the US food and drug administration between 2001 and 2010

Nicholas S. Downing, Nilay D Shah, Jenerius A. Aminawung, Alison M. Pease, Jean David Zeitoun, Harlan M. Krumholz, Joseph S. Ross

Research output: Contribution to journalReview article

81 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1854-1863
Number of pages10
JournalJAMA - Journal of the American Medical Association
Volume317
Issue number18
DOIs
StatePublished - May 9 2017

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United States Food and Drug Administration
Safety
Therapeutics
Drug Labeling
Biological Products
Incidence
Drug Approval
Biological Psychiatry
Communication
Orphaned Children
Life Cycle Stages
Pharmaceutical Preparations
Psychiatry
Decision Making
Cohort Studies

ASJC Scopus subject areas

  • Medicine(all)

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Postmarket safety events among novel therapeutics approved by the US food and drug administration between 2001 and 2010. / Downing, Nicholas S.; Shah, Nilay D; Aminawung, Jenerius A.; Pease, Alison M.; Zeitoun, Jean David; Krumholz, Harlan M.; Ross, Joseph S.

In: JAMA - Journal of the American Medical Association, Vol. 317, No. 18, 09.05.2017, p. 1854-1863.

Research output: Contribution to journalReview article

Downing, Nicholas S. ; Shah, Nilay D ; Aminawung, Jenerius A. ; Pease, Alison M. ; Zeitoun, Jean David ; Krumholz, Harlan M. ; Ross, Joseph S. / Postmarket safety events among novel therapeutics approved by the US food and drug administration between 2001 and 2010. In: JAMA - Journal of the American Medical Association. 2017 ; Vol. 317, No. 18. pp. 1854-1863.
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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.",
author = "Downing, {Nicholas S.} and Shah, {Nilay D} and Aminawung, {Jenerius A.} and Pease, {Alison M.} and Zeitoun, {Jean David} and Krumholz, {Harlan M.} and Ross, {Joseph S.}",
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T1 - Postmarket safety events among novel therapeutics approved by the US food and drug administration between 2001 and 2010

AU - Downing, Nicholas S.

AU - Shah, Nilay D

AU - Aminawung, Jenerius A.

AU - Pease, Alison M.

AU - Zeitoun, Jean David

AU - Krumholz, Harlan M.

AU - Ross, Joseph S.

PY - 2017/5/9

Y1 - 2017/5/9

N2 - 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.

AB - 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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