Endpoints of Clinical Trials for Marketing Authorization of Drugs for Hematologic Malignancy in Japan, the US and the EU
Authors: Nagai Sumimasa 
Published: November 2019

Background: Pharmaceuticals and Medical Devices Agency (PMDA) in Japan, the US Food and Drug Administration (FDA) in the US and the European Medicines Agency (EMA) in the EU review drug applications for market approval. It was shown that most new molecular entity (NME) agents were first approved in the US because the FDA has reviewed applications more quickly (N Engl J Med. 2012; 366: 2284-93). However, differences in regulatory actions among Japan, the US and the EU in terms of relationship between the approval date and primary endpoints of pivotal trials in marketing applications including supplemental applications for additional indications have never been analyzed comprehensively.
Methods: 93 indications of 55 hematologic anticancer drugs approved in Japan, the US or the EU (only central marketing authorization by the European Commission) between August 2000 and June 2014 were examined in this research. Information concerning regulatory decisions made by PMDA, the FDA and the EMA was obtained from publicly accessible data only such as PMDA’s review reports, the PMDA website, the FDA’s review reports, the Drugs@FDA website, the European public assessment reports published by the EMA’s Committee for Medicinal Products for Human Use (CHMP) and the EMA website.
Results: 24, 60, and 9 indications were first approved in Japan, the US, and the EU, respectively. 2 NME agents were first approved in Japan and the EU each; mogamulizumab for relapsed CCR4-positive adult T-cell leukemia/lymphoma as well as relapsed CCR4-positive peripheral T-cell lymphoma/cutaneous T-cell lymphoma and tamibarotene for relapsed acute promyelocytic leukemia in Japan and pixantrone dimaleate for relapsed aggressive non-Hodgkin B-cell lymphoma and histamine dihydrochloride for acute myeloid leukemia in the EU. 17 indications were approved only in the US and 13 of these were approved based on response rate in single-arm trials. The other 4 indications were approved based on results of comparative trials. Of the 13 indications approved based on single-arm trials, 8 indications were approved through the accelerated approval scheme in the US. 5 indications (pixantrone dimaleate, histamine dihydrochloride, temsirolimus for relapsed mantle cell lymphoma, rituximab as maintenance therapy for relapsed follicular lymphoma and decitabine for acute myeloid leukemia) were approved only in the EU and 4 other indications (ibritumomab tiuxetan as consolidation therapy for follicular lymphoma and rituximab for diffuse large B-cell lymphoma, newly diagnosed chronic lymphocytic leukemia, and relapsed chronic lymphocytic leukemia) were approved the earliest in the EU. All these 9 indications were approved based on results of comparative trials. Of these 9 indications, only pixantrone dimaleate was approved through the conditional approval scheme and only histamine dihydrochloride was approved through the approval under exceptional circumstances scheme. Although 23 indications were approved only in Japan, most of them were additional indications of old drugs and not based on results of comparative trials. Primary endpoints were different between the US and the EU in 3 of 41 indications approved in both the US and the EU. All these 3 indications were approved earlier in the US and response rate or time to progression (TTP) in the US instead of progression-free survival (PFS) or overall survival (OS) in the EU was adopted as the primary endpoints as follows; thalidomide for newly diagnosed multiple myeloma (TTP in the US and OS in the EU), pomalidomide for relapsed multiple myeloma (overall response rate in the US and PFS in the EU), and azacitidine for myelodysplastic syndrome (complete remission rate in the US and OS in the EU).
Conclusions: The conditional approval scheme or the approval under exceptional circumstances scheme in the EU and the accelerated approval scheme in the US are available, while there are no similar schemes for oncologic drugs in Japan. However, this analysis suggests that the FDA has taken a more active attitude to acceptance of surrogate endpoints. Therefore, not only shorter review time but also this attitude may lead to earlier marketing authorization of drugs for hematologic malignancy in the US.

Disclosures
Off Label Use: I will discuss off-label drug use in the US which has been approved in the EU or Japan..