Comparison of the Basis for Approval and Pivotal Studies on Hematological Malignancies between the US and Japan.
Authors: Nagamura Fumitaka , Nagamura-Inoue Tokiko , Tojo Arinobu 
Published: October 2019

Abstract
Introduction: Clinical trials are designed based on certain hypotheses and to meet the requirements for approval from regulatory agencies. We previously reported on differences in the trends of drug approvals for hematological malignancies between the US and Japan (Proc ASH #3120, 2005). This time, we report on differences in the basis for approval and designs of pivotal studies between the two countries.
Methods: Drugs approved for hematological malignancies from January 1985 to December 2005 in both the US and Japan were selected. Of these candidates, only indications common to both countries were considered. Supportive care drugs, immunomodulators, biochemical modulators, and off-label use were excluded. Package inserts, reviews and analyses by regulatory agencies, and publications on clinical trials were examined.
Results: Ten drugs (mitoxantrone, idarubicin, pentostatin, fludarabine, cladribine, tretinoin, rituximab, arsenic trioxide, imatinib mesylate, and gemtuzumab ozogamicin) were met the criteria. “Line or type of therapy (e.g. 1st line, or for remission induction)” was specified for all drugs in the US and three in Japan. Limitations on age, e.g., adults, were indicated in the package inserts of 5 drugs in the US and 1 in Japan. The phase of pivotal studies are summarized in Table 1. In Japan, no description on phase was seen in 2 drugs, and the result of 1 comparative study was applied. The number of patients enrolled into pivotal studies are summarized in Table 2. The number of efficacy parameters examined in each pivotal study (range, mean, and median) were 1–11, 4.7, and 3 in the US and 1–5, 2.3, and 2 in Japan, respectively. Survival was used as an efficacy parameter in 7 drugs in the US, but none in Japan (PFS: 1 drug). Differences in efficacy parameters between the two countries have decreased, and inappropriate uses of efficacy parameters, e.g., overall response rate for mitoxantrone and idarubicin, have disappeared recently in Japan.
Conclusion: The high ratio of RCT and the large number of patients enrolled into clinical trials are characteristics of the US. The approved indications in Japan are broad-based, however, the description of package inserts, number of patients, and the use of efficacy parameters were inferior. The basic principle for approval of regulatory agencies in Japan had been response rate, however, the policy has become changing. So, the criticisms of Japanese clinical trials, such as poor design, insufficient information, and less utilization for approval by other countries, could be resolved.
Table 1: Number of pivotal studies classified by phase # of drugs Randomized comparative trial (RCT) Single arm stdy (SA) Phase 1 study Combined data Others US 10 9 15 0 5 1 (data after cross-over) Japan 8 1 14 2 4 (foreign data) 0 Table 2: Number of patients enrolled into pivotal studies SA study (range, mean, range) RCT* (range, mean, median) *Number of patients on study arm US 31–532, 130.1, 89 40–553, 149.1, 111 Japan with foreign data 10–532, 88.9, 47.0 31: 1 study Japan without foreign data 10–74, 37.4, 38.5 31: 1 study