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: 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.

Post-approval appending of CSARs to drug package inserts: an analysis of the types of adverse reactions and time to addition.

PURPOSE: The aim of this study was to quantitatively analyze clinically significant adverse reactions (CSARs) added to drug package inserts after approval and to investigate the time to these post-approval additions as an indicator of safety-related regulatory actions. METHODS: Drugs containing new active ingredients that had been approved in Japan from April 2001 to December 2010 were analyzed. We examined CSARs that had been reported in the first version of the package inserts and subsequent additions through notifications from Japan's Ministry of Health, Labour and Welfare until the end of 2011. Relative risks (RRs) for post-approval addition of CSARs were calculated for various categories of disorders. The median lengths of time to post-approval addition of CSARs were compared. RESULTS: A total of 238 drugs were examined. Of the 2487 CSARs associated with these drugs, 737 had been added after approval. The analysis revealed a higher likelihood for post-approval addition of CSARs for "Hepatobiliary disorders" (RR: 1.41; 95% confidence interval [CI]: 1.19-1.68), "Gastrointestinal disorders" (RR: 1.35; 95%CI: 1.10-1.66), and "Musculoskeletal and connective tissue disorders" (RR: 1.52; 95%CI: 1.11-2.07). In contrast, "Cardiac disorders" showed reduced likelihood in comparison with other disorders. For the time until post-approval addition of CSARs, "Skin and subcutaneous tissue disorders" showed the longest durations, with a median of 3020 days. CONCLUSIONS: Our quantitative analysis suggests that some CSARs were added more frequently to package inserts after approval and that time to post-approval additions of CSARs varied with the types of adverse drug reactions. These results can support the coherent implementation of pharmacovigilance activities.

Pharmaceutical company perspectives on current safety risk communications in Japan.

In 1987, a group infection of hepatitis in patients receiving a contaminated fibrinogen product was first reported to the Japanese regulatory agency. Eventually, this serious drug incident involved more than 10,000 cases of infection. In response, the Government of Japan established a responding inspection committee in 2008 to make recommendations for the restructuring of drug regulatory administration. The final report was issued in 2010. One agenda item of this restructuring was the improvement of drug-related safety risk communications. Our research group on drug safety risk communications, which is funded by the Government of Japan, surveyed pharmaceutical companies regarding their perspective on current risk communications. The survey was conducted using an anonymous questionnaire developed for this study which included the three operational domains of targets, contents, and measures of drug risk communication. Fifty-two of the 74 member companies of the Post-marketing Surveillance Subcommittee of the Japan Pharmaceutical Manufacturer's Association participated, and this response rate of more than 70% was considered sufficient to ensure the external validity of the survey results. Results showed that the most highly prioritized aspect of risk messaging was the strength of evidence, and that outcome evaluation of risk communication gained recognition. Further, while physicians and pharmacists were the most prioritized communication targets, pharmacovigilance departments devoted the most resources to regulators, at more than 30%. The Internet was recognized as a useful public source of risk information, whereas Drug Guides for Patients delivered on the web were considered under-recognized. Further discussion of these results with the aim of enhancing the restructuring of the Japanese drug regulatory administration system are warranted.