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

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 Results 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. 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.