Dataset Information

Postmarket safety of drugs approved by Health Canada on the basis of clinical and surrogate outcomes: a cohort study.

ABSTRACT:

Background

Health Canada approves drugs on the basis of evidence from clinical trials using clinical or surrogate outcomes. This study compares the postmarket safety of these 2 groups of drugs.

Methods

Information about whether clinical or surrogate outcomes were used and the date of market approval were obtained from Health Canada's Summary Basis of Decision documents issued from Jan. 1, 2005, to Dec. 31, 2014. Safety warnings and the dates they were issued were identified through advisories on the MedEffect Canada website. Kaplan-Meier survival curves were calculated to determine the likelihood that drugs in the clinical and surrogate outcome groups would receive a serious safety warning. The time from market authorization to first serious safety warning was compared for the 2 groups of drugs.

Results

A total of 124 drugs were approved by Health Canada using clinical outcomes and 114 using surrogate outcomes. Kaplan-Meier curves did not differ between the 2 groups (p < 0.9). The median time from market authorization to first serious safety warning was 722 days in the clinical outcome group and 818 days in the surrogate outcome group (difference 96 days, 95% confidence interval -295 to 425).

Interpretation

We found no statistically significant difference in postmarket safety between drugs approved using clinical outcomes and those approved using surrogate outcomes. Because drugs in the surrogate outcome group are approved before their benefit:harm ratio is fully established, these drugs should be used with caution until their clinical benefits are better understood.

SUBMITTER: Lexchin J

PROVIDER: S-EPMC4593464 | biostudies-literature | 2015 Jul-Sep

REPOSITORIES: biostudies-literature

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Publications

Postmarket safety of drugs approved by Health Canada on the basis of clinical and surrogate outcomes: a cohort study.

Lexchin Joel J Ahmed Tareq T

CMAJ open 20150717 3

<h4>Background</h4>Health Canada approves drugs on the basis of evidence from clinical trials using clinical or surrogate outcomes. This study compares the postmarket safety of these 2 groups of drugs.<h4>Methods</h4>Information about whether clinical or surrogate outcomes were used and the date of market approval were obtained from Health Canada's Summary Basis of Decision documents issued from Jan. 1, 2005, to Dec. 31, 2014. Safety warnings and the dates they were issued were identified throug ...[more]

PMID: 26442227

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Project description:ImportancePostmarket 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.ObjectivesTo 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 settingCohort study of all novel therapeutics approved by the FDA between January 1, 2001, and December 31, 2010, followed up through February 28, 2017.ExposuresNovel 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.ResultsFrom 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 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.

Project description:BackgroundWe examined how often new serious safety signals were identified by the U.S. Food and Drug Administration within the first 2 years after approval for new molecular entities (NMEs) for treatment of cancer that required specific regulatory actions described here.MethodsWe identified, for all NMEs approved for treatment of cancer or malignant hematology indications between 2010 and 2016, substantial safety-related changes within the first 2 years after approval, which included a new Boxed Warning or Warning and Precaution; requirement for (or modification of existing) Risk Evaluation and Mitigation Strategies (REMS); and withdrawal from the market because of safety concerns.ResultsFifty-five NMEs were approved between 2010 and 2016: 32 (58%) under regular approval (RA) and 23 (42%) under accelerated approval (AA). Of these 55 NMEs, 9 (16%) had substantial safety-related changes after approval. Across all 55 NMEs, one was temporarily withdrawn from the market for safety reasons (1.8%); one (1.8%) required a new REMS; nine required labeling revisions-new Boxed Warnings were required for two NMEs (3.6%), and new Warnings and Precautions subsections were required for eight (14.6%). One drug (ponatinib) was responsible for several of the substantial safety-related changes (withdrawal, REMS, Boxed Warnings). One of 32 NMEs approved under RA required a new Warning and Precaution, whereas 7 of 23 NMEs approved under AA had substantial safety-related changes in the first 2 years after approval.ConclusionBased on our analysis we conclude that although there was a greater incidence of substantial safety-related changes to AA drugs versus RA drugs, the majority of these were changes to the Warnings and Precautions and did not substantially alter the benefit-risk profile of the drug.Implications for practiceThe majority of new cancer drugs (84%) approved in the U.S. do not have new substantial safety information being added to the label within the first 2 years of approval. Unprecedented efficacy seen in contemporary cancer drug development has led to early availability of effective cancer therapies based on large effects in smaller populations. More limited premarket safety data require diligent postmarketing safety surveillance as we continue to learn and update drug labeling throughout the product lifecycle.

Dataset Information

Postmarket safety of drugs approved by Health Canada on the basis of clinical and surrogate outcomes: a cohort study.

Background

Methods

Results

Interpretation

Publications

Postmarket safety of drugs approved by Health Canada on the basis of clinical and surrogate outcomes: a cohort study.

Similar Datasets

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