생동성시험시의 추가시험에 관한 일본의 현황

Information on the supplementary bioequivalence (BE) test in Japan was personally obtained from Dr. Aoyagi Nobuo by Dr. Shim. This information may aid the understanding of Korean industry and KFDA on the supplementary test (or add-on test) in detail. Supplementary BE test is accepted in Japan based on a guideline (http://www.nihs.go.jp/drug/be-guide(e)/Generic/be97E.html), which states “A sufficient number of subjects for assessing BE should be included. If BE cannot be demonstrated because of an insufficient number, an add-on subject study can be performed using not less than half the number of subjects in the initial study”. It means that supplementary BE test have to be done using not less than 10 subjects if the pharmaceutical company failed to show BE using 20 subjects in the pivot study. The acceptance criteria in Japanese guideline is not consistent with the worldwide criteria (90% confidence interval values of log-transformed AUC and Cmax should be between 80~125%), and is that even if the confidence interval is not in the above range, test products are accepted as bioequivalent, when the point estimates of AUC and Cmax are between 90~110% (Not 80~120%) in the BE test using 20 subjects and in vitro dissolutions are similar. Concerning the acceptance criteria, Japanese guideline describes “Products are considered to be bioequivalent, if the 90% confidence interval of difference in the average values of logarithmic AUC and Cmax between test and reference products is within the acceptable range of log(0.8) - log(1.25). However, even though the confidence interval is not in the above range, test products are accepted as bioequivalent, if the following three conditions are satisfied; 1) the total sample size of the initial BE study is not less than 20 (n=10/group) or pooled sample size of the initial and add-on subject studies is not less than 30, 2) the differences in average values of logarithmic AUC and Cmax between two products are between log(0.9) - log(1.11), and 3) dissolution rates of test and reference products are evaluated to be equivalent under all dissolution testing conditions under Sec. 3 A.V. However, the 3rd rule can not be applied to slowly dissolving products from which more than 80% of a drug does not dissolve within the final testing time (2hr in pH 1.2 medium and 6hr in others) under any conditions of the dissolution tests described in Sec.3 A.V.” The supplementary BE tests have always been allowed before and after the revision of guideline. The tests are allowed in every cases when the company failed to show BE using the estimated sample size. No specific guideline(s) are present for the supplementary test procedure. For the statistical basis/method for deciding the BE for the pooled data (i.e., pooled results for original BE study and the supplementary BE study), QA Ed. by I.J. McGilveray, et al., Proceedings Bio International ’89, Issues in the evaluation of bioavailability data, October 1-4, 1989, Pharma Medica Research Inc., Toronto, Canada, p. 138 (1990)]. During the preparation of our BE guideline, Japanese government had a tough discussion on the add-on test, leading to a consensus that whether the add-on test is acceptable or not should not be determined from the statistical viewpoint only where it is more important to consider the characteristic of BE tests, that is, if the original and supplementary tests are considered to be identical (e.g. Same protocol, No period and carry-over effects, No formulation-subject interaction), the two tests can be combined. Based on this consideration, add-on tests are introduced in Japanesed BE guideline. Thanks should be given to Dr. Aoyagi, Senior Advisor of Pharmaceuticals and Medical Devices Agency (PMDA), Japan for his kind and detailed explanation on Japanese situation.

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