Analysis and enhancement of risk management for ethnic differences in antineoplastic drugs in Japan.

BACKGROUND: Risk management in the post-marketing phase is crucial to minimize health problems caused by drugs. Because ethnic factors may affect drug safety, the objective of this study was to explore concrete approaches to reflecting ethnic factors in risk management under multi-regional drug development. METHODS: We assessed Pharmaceuticals and Medical Devices Agency (PMDA) review reports on antineoplastic drugs approved as new molecular entities in the last 10 years to identify any differences in the incidence of adverse drug reactions (ADRs) related to myelosuppression, hepatic impairment, renal impairment, and interstitial lung disease between Japanese and non-Japanese populations. In addition, we investigated how those ADRs were handled in the labeling of each drug. RESULTS: In total, 44 drugs were available for comparing the incidence of ADRs between Japanese and non-Japanese populations. Of these, 32 drugs had a higher incidence of ADRs in the Japanese population. However, the incidence of ADRs in the Japanese population was described in the labeling for 7 drugs, and only the incidence in the overall population in multi-regional phase III trials was described in the labeling for the remaining 25 drugs. Of these 25 drugs, two drugs were immediately placed under emergency safety control measures after approval because of the high incidence of ADRs in Japanese patients. CONCLUSIONS: For drugs that might cause serious ADRs and with a higher incidence in the Japanese population, information should be provided on the incidence in the Japanese population as well as in the overall population.

Assessment of the impact of Japanese-specific long-term safety data on new drug approval.

Under the International Council for Harmonization (ICH)-E1 guideline for drugs intended for chronic or repeated intermittent use in non-life-threatening diseases, data from 100 patients exposed for a minimum of 1 year are required to be included in the safety data base of a new drug application. In response to the recent globalization of drug development, the Ministry of Health, Labour, and Welfare of Japan requires that the data according to the ICH-E1 guideline should be collected from 100 Japanese patients by the administrative notice of Basic Principles on Global Clinical Trials (reference cases) by considering ethnic differences in safety between Japanese and foreigners. In this study, we assessed Pharmaceuticals and Medical Devices Agency (PMDA) review reports of new drugs from 2016 to 2020 that include safety data for 100 Japanese patients exposed to these drugs for a minimum of 1 year to see if the study data led to the detection of Japanese-specific safety issues. The result showed that the safety data from these patients provided only marginal value to identify Japanese-specific safety issues, and no drugs were subjected to regulatory measures. Based on these studies and the fact that Japanese-specific safety differences detected for a few drugs did not lead to adaptations of drug regulatory measures, we would like to propose not to make it a rule to collect safety data from 100 Japanese patients exposed at least 1 year, while keeping the ICH-E1 guideline.

Steps toward harmonization for clinical development of medicines in pediatric ulcerative colitis-a global scientific discussion, part 1: efficacy endpoints and disease outcome assessments.

OBJECTIVES: There is a pressing need for drug development in pediatric ulcerative colitis (UC). Lack of scientific consensus on efficacy endpoints and disease outcome assessments presents a hurdle for global drug development in pediatric UC. Scientists from 4 regulatory agencies convened an International Inflammatory Bowel Disease Working Group (i-IBD Working Group) to harmonize present thinking about various aspects of drug development in pediatric UC globally. METHODS: The i-IBD Working Group was convened in 2012 by scientists from the US Food and Drug Administration, European Medicines Agency, Health Canada, and the Pharmaceuticals and Medical Devices Agency of Japan. The members of this group considered reasons for differences in their acceptance of efficacy endpoints and disease activity indices used in pediatric UC, reviewed the available literature, and developed consensus opinions regarding approaches for evaluating outcomes in pediatric UC trials. RESULTS: There is lack of harmonization in using efficacy endpoint and outcome assessments including disease activity indices to assess clinical benefit in pediatric UC trials. Many disease activity indices have been developed, but their biometric properties, such as responsiveness, reliability, and validity, have not been properly validated. Biomarkers, such as fecal calprotectin and lactoferrin, are being investigated for their potential as noninvasive surrogate endpoints in UC. CONCLUSIONS: Consensus on the efficacy endpoints, disease activity indices, and outcome assessments is needed for globalization of pediatric UC trials. The i-IBD Working Group offers several perspectives to facilitate harmonization across regions. The development of noninvasive biomarkers as reliable surrogate endpoints needs to be explored further.

Steps toward harmonization for clinical development of medicines in pediatric ulcerative colitis-a global scientific discussion, part 2: data extrapolation, trial design, and pharmacokinetics.

OBJECTIVES: To facilitate global drug development, the International Pediatric Inflammatory Bowel Disease Working Group (i-IBD Working Group) discussed data extrapolation, trial design, and pharmacokinetic (PK) considerations for drugs intended to treat pediatric ulcerative colitis (UC), and considered possible approaches toward harmonized drug development. METHODS: Representatives from the US Food and Drug Administration, European Medicines Agency, Health Canada, and the Pharmaceuticals and Medical Devices Agency of Japan convened monthly to explore existing regulatory approaches, reviewed the results of a literature search, and provided perspectives on pediatric UC drug development based on the available medical literature. RESULTS: Although pediatric UC, when compared with UC in adults, has a similar disease progression and response to intervention, the similarity of the exposure-response relation has not been adequately established. Consequently, clinical endpoints should be selected to optimally assess efficacy in children. The inclusion of a placebo control in pediatric trials to assure assay sensitivity may be appropriate under limited circumstances. In clinical studies, although the drug under investigation could provide possible direct benefit, placebo treatment should present no more than a minor increase over minimal risk to children with UC. CONCLUSIONS: Partial extrapolation of efficacy from informative adult studies may be appropriate. Placebo-controlled efficacy trials are scientifically and ethically appropriate for pediatric UC given appropriate patient selection and the use of early escape. Clinical studies in pediatric UC may include initial dose-finding studies and exposure-response modeling followed by an efficacy and safety study to further explore the exposure-response relation.