Exploratory Analysis of Associations Between Postmarketing Safety Events and Approved Doses of New Drugs in Japan.
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ABSTRACT:
SUBMITTER: Okubo TK
PROVIDER: S-EPMC5504476 | biostudies-literature | 2017 Jul
REPOSITORIES: biostudies-literature
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Exploratory Analysis of Associations Between Postmarketing Safety Events and Approved Doses of New Drugs in Japan.
Clinical and translational science 20170331 4
While efficient and less onerous for the industry, the globalization of clinical drug development may lead to limited efforts to optimize drugs for regional conditions. We examined the association between clinical development pathways, approved doses, and postmarketing safety risks in Japan for 135 new molecular entities approved between 2004 and 2011. The risk of drug-related deaths seemed higher when pharmaceutical companies chose exactly the same dose as in the United States, even after condu ...[more]
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Project description:BackgroundPostmarketing all-case surveillance (PACS) is a safety monitoring activity predominantly conducted for drugs with few domestic clinical trials, orphan drugs, or anticancer drugs that potentially cause serious adverse events.AimThis study comprehensively analyzed drugs in Japan requiring PACS as an approval condition and those implementing PACS-results-based safety measures.MethodWe included drugs approved in Japan between 1999 and 2019.ResultsDuring the 20-year survey, 1871 drugs were approved in Japan, including 277 (14.8%) requiring PACS as an approval prerequisite. The drug number requiring PACS for approval and its ratio to the total approved-drug number is increasing annually. In 2018, the number and percentage of PACS-requiring drugs reached a 37-drug maximum (32.5%). Additionally, among the 277 PACS-requiring drugs, upon examining the results of 87 drugs for which reexamination results had already been obtained, all 87 drugs (31.4%) were found to be in Category 1 which means there is no need to revise drug-approval conditions, indicating that their usefulness is consistent with approval. Furthermore, measures such as revising the package insert and providing information to medical institutions were adopted for 53 drugs, 14 of which had PACS-results-based safety measures.ConclusionPACS implementation for drug approval will potentially continue increasing. Normally, PACS is not conducted overseas, as it is a safety-monitoring activity exclusive to Japan, and the burden on institutions, such as medical sites and pharmaceutical companies, is heavy. Thus, ensuring a balance between the obtained effect and this burden is imperative.
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Project description:We examined the relationship of regulatory and review characteristics to postmarketing safety-related regulatory actions for 61 new therapeutic biologics (NTBs) approved between October 1, 2002 and December 31, 2014. We also compared NTBs with small-molecule new molecular entities (NMEs) on these measures. Postmarketing safety-related regulatory actions were defined as a safety-related withdrawal or a safety-related update to a safety section of the label through June 30, 2018. Four NTBs were withdrawn, two for safety reasons. At least one safety-related update was added to the labels of 54 (88.5%) NTBs. Label updates occurred throughout the follow-up period. Time to the first safety-related regulatory action was shorter for NTBs approved under accelerated approval. The occurrence of safety events was more likely to occur with NTBs than with NMEs. This may be explained in part by the higher proportion of NTBs in the anatomical therapeutic chemical classification categories with higher frequency of safety-related updates. NTBs also had shorter time to safety events than NMEs. These findings underscore the importance of continued development of the life cycle safety surveillance system for both drugs and biologics with consideration for product type and its characteristics, including pharmacologic action.
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Project description:Postmarketing surveillance of Japanese patients with unresectable, previously treated, advanced or recurrent non-small-cell lung cancer treated with nivolumab was undertaken during the conditional approval period. The study aim was to evaluate the occurrence of treatment-related adverse events of nivolumab in the real world. Patients were registered between December 2015 and March 2016 at 536 sites. Nivolumab was given intravenously (3 mg/kg every 2 weeks); the observation period was 12 months after the first dose of nivolumab. Patients were evaluated for safety (n = 3601; 18.2% ≥75 years, 22.4% ECOG performance status ≥2) and effectiveness (n = 3570). The frequencies of any grade and grade 3 or higher treatment-related adverse events were 47.1% and 15.9%, respectively. The most frequent treatment-related adverse events (any grade) were interstitial lung disease (6.4%), hypothyroidism (5.7%), and diarrhea (4.4%). Treatment-related adverse events of special interest (priority items) occurring at a frequency of 5% or more were adverse events related to interstitial lung disease, thyroid dysfunction, liver dysfunction, colitis/severe diarrhea, infusion reaction, and infusion reaction within 24 hours. Significant risk factors for these priority items were identified by competing risk analysis: interstitial lung disease (previous/comorbid interstitial lung disease, abnormal findings on chest imaging, and smoking history); liver dysfunction (previous/comorbid liver disease, smoking history, and metastasis); thyroid dysfunction (previous/comorbid thyroid disease and performance status); and colitis/severe diarrhea (treatment line 2 vs ≥3). The 12-month survival rate was 40.7%. In conclusion, the safety profile of nivolumab in this postmarketing surveillance was similar to that in clinical trials, and no new safety signals were identified. The study was registered with the Japan Pharmaceutical Information Center (clinicaltrials.jp: Japic-163271).
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