Dataset Information

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.

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?Conclusions and relevanceAmong 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.

SUBMITTER: Downing NS

PROVIDER: S-EPMC5815036 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Publications

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

Downing Nicholas S NS Shah Nilay D ND Aminawung Jenerius A JA Pease Alison M AM Zeitoun Jean-David JD Krumholz Harlan M HM Ross Joseph S JS

JAMA 20170501 18

<h4>Importance</h4>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.<h4>Objectives</h4>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 ...[more]

PMID: 28492899

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Project description:ImportanceThe US Food and Drug Administration (FDA) can use postmarketing requirements to mandate pharmaceutical companies to conduct clinical trials after the approval of novel therapeutics. Pharmaceutical companies can also agree to conduct nonmandated clinical trials as postmarketing commitments. However, when therapeutics are approved by the FDA without postmarketing requirements or postmarketing commitments, it is not well known how often pharmaceutical companies voluntarily conduct trials and report results monitoring safety or efficacy after approval.ObjectiveTo characterize postapproval clinical trials sponsored by pharmaceutical companies of therapeutics initially approved by the FDA without clinical postmarketing requirements or commitments.Design, setting, and participantsThis cross-sectional analysis included postapproval clinical trials conducted with at least 1 site in the United States sponsored by pharmaceutical companies of therapeutics first approved by the FDA from 2009 through 2012. Analyses were conducted June 11, 2018, to November 30, 2018.Main outcomes and measuresPostapproval clinical trials registered on ClinicalTrials.gov generating safety or efficacy data, characteristics including whether trials focused on approved or unapproved indications, study design elements, and rates of study completion and results reporting.ResultsFrom 2009 through 2012, the FDA approved 110 novel therapeutics for 120 indications, of which 37 novel therapeutics for 39 indications did not have postmarketing requirements or commitments for new clinical studies at the time of first approval. For 31 therapeutics (83.8%), there were 600 postapproval clinical trials sponsored by pharmaceutical companies. Most trials investigated therapeutics for new indications (363 [60.5%]) or expanded populations of the originally indicated disease (122 [20.3%]). Trials were often small (median [interquartile range] enrollment, 44 [21-131] participants), nonrandomized (359 [59.8%]), unblinded (455 [75.8%]), and lacked comparators (381 [63.5%]). Approximately half of the trials (311 [51.8%]) assessed at least 1 clinical outcome. Of 300 terminated or completed trials, 204 trials (68.0%) had reported results on ClinicalTrials.gov a median (interquartile range) 16 (13-25) months after their primary completion date. For the 96 trials (32.0%) without reported results, a median (interquartile range) 35 (13-62) months had passed since their primary completion date.Conclusions and relevancePharmaceutical companies frequently conducted clinical trials after approval, even when there were no clinical postmarketing requirements or commitments at approval. However, most of these trials evaluated new indications or expanded patient populations rather than monitored approved uses, and nearly half of the trials remained incomplete more than 5 years after original therapeutic approval.

Project description:IntroductionImmune-related adverse event (IRAE) onset may represent a clinical biomarker for anti-programmed cell death protein 1 (PD-1) antibody response based on emerging evidence from patients with various advanced malignancies. This phenomenon has not been previously reported in a multidisease cohort of patients with gastrointestinal (GI) cancer with Food and Drug Administration (FDA)-approved indications to receive immune checkpoint inhibitor therapy.Materials and methodsThe study was a multicenter retrospective cohort analysis of 76 patients with GI cancer who had received anti-PD-1 antibodies for FDA-approved indications. The primary and secondary outcomes of the study were progression-free survival (PFS) and overall survival (OS) in patients based upon IRAE presence, respectively. PFS and OS were estimated by the Kaplan-Meier method; a Cox proportional-hazards model adjusted for IRAE onset, patient age, and enrolling institution was used to analyze outcomes.ResultsMedian PFS and OS were prolonged in patients who experienced IRAEs compared with those who did not experience them (PFS: not reached [NR] vs. 3.9 months [hazard ratio (HR) 0.13, 95% confidence interval (CI) 0.05-0.3, p < .001]; OS: NR vs. 7.4 months [HR 0.11, 95% CI 0.03-0.36, p < .001]). Among patients who experienced IRAEs, there were no significant differences in PFS and OS by either initial IRAE severity, management, or time to onset.ConclusionPatients with gastrointestinal cancer who experienced IRAEs while on anti-PD-1 antibodies demonstrated significant improvements in PFS and OS compared with their counterparts who did not develop IRAEs. Although these findings add to results from studies in other tumor types, larger prospective studies are needed prior to clinical adoption of IRAE onset as a biomarker for immune checkpoint inhibitor response.Implications for practicePredictive clinical biomarkers for immune checkpoint inhibitor response have been understudied in the field of immuno-oncology. Immune-related adverse event onset appears to be one such biomarker. Across tumor types, immune-related adverse event onset has been associated with response to anti-programmed cell death protein 1 (PD-1) antibodies. The results of this study demonstrate this for the first time in patients with gastrointestinal cancer receiving anti-PD-1 antibodies. Before immune-related adverse event onset can be adopted clinically as a predictive biomarker for immune checkpoint inhibitor response, however, larger prospective studies are needed to better understand the nuances between immune-related adverse event characteristics (severity, site, management, timing of onset) and immune checkpoint inhibitor effectiveness.

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Dataset Information

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

Importance

Objectives

Design and setting

Exposures

Main outcomes and measures

Results

Publications

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

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