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The association between concerns toward adverse reactions during pre‐approval drug reviews and the post‐approval addition of clinically significant adverse reactions to package inserts: A retrospective analysis of pre‐approval drug review reports and safety updates
Author(s) -
Watanabe Ko,
Murakami Masayasu,
Masuyama Koichi,
Ishiguro Chieko,
Matsuda Tsutomu
Publication year - 2018
Publication title -
pharmacoepidemiology and drug safety
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.023
H-Index - 96
eISSN - 1099-1557
pISSN - 1053-8569
DOI - 10.1002/pds.4662
Subject(s) - medicine , adverse effect , drug , odds ratio , confidence interval , package insert , drug approval , pharmacology , emergency medicine
Purpose To determine if concerns toward adverse reactions (ARs) identified during the drug approval process are associated with their post‐approval addition to package inserts. Methods Pre‐approval concerns toward 24 target ARs were identified in the drug review reports and initial package inserts of 126 target drugs approved for use in Japan between April 2004 and March 2009. Each target drug was monitored for 5 years after approval for the addition of these ARs as clinically significant adverse reactions (CSARs) in the package inserts. Positive predictive values (PPVs) and negative predictive value (NPVs) were calculated. The odds ratios (ORs) and 95% confidence intervals (CIs) were also analyzed to test the association between pre‐approval concerns and post‐approval CSAR additions. Results Target ARs with pre‐approval concerns were added as CSARs in 88 of 406 AR‐drug pairs (PPV: 21.7%). In contrast, target ARs without pre‐approval concerns were added as CSARs in 93 of 2304 drugs (NPV: 96.0%). Hypoglycemia had the highest PPV (100%), whereas hepatitis and myocardial infarction had the lowest PPVs (0.0%). Abnormal hepatic function had the lowest NPV (85.4%), whereas myocardial infarction and convulsions had the highest NPVs (100%). Pre‐approval concerns showed a significantly positive association with post‐approval CSAR additions (OR: 6.57, 95% CI: 4.74, 9.11; P < 0.001). Conclusions The significant association between pre‐approval concerns and post‐approval CSAR additions indicates that Japan's drug regulatory agency has generally conducted rigorous examination of the safety information available in the submitted data packages during drug review for approval.