Disease-Specific Analysis of Drug Approval Delay in Hematologic Malignancies between Japan and the U.S. and between Europe and the U.S

Background: Since novel therapeutic agents are developed rapidly for hematological malignancies mainly in the U.S., an effort should be done to shorten the interval of approval timing between the U.S and other countries, which was called "drug lag.” Although registration trials required for marketing authorization are generally conducted in each disease, most previous studies failed to analyze the drug lag according to its target disease. Therefore, it has not been clear how the drug lag differs among disease entities. To elucidate this, we analyzed drug lag between Japan and the U.S., and between Europe and U.S. in hematologic malignancies according to each disease: leukemia, myeloma, and malignant lymphoma.

Study Design and Methods: Using Pharmaceuticals and Medical Devices Agency (PMDA) public databases from April 2010 to March 2022, we identified 31 new molecular entity drugs for hematological malignancies that were approved in Japan during this period and already approved in the U.S. Similarly, we identified 24 new molecular entity drugs that were approved in Europe during this period and already approved in the U.S., based on the European Medicines Agency (EMA) public database. Drug lag was estimated based on the approval date in the US using a public database of the Food and Drug Administration (FDA). Cellular products including chimeric antigen receptor (CAR)-T cells were excluded from the current analysis. Global clinical trials were defined as those which included institutions in the U.S. The review period was defined as the time from the date the company submitted an application to the regulatory agency until the date of marketing authorization.

Results: Of the 31 drugs approved in Japan during the period, 12 were approved for leukemia, nine for myeloma, and 10 for malignant lymphoma. The median drug lag between Japan and the U.S. was 3.3 years for leukemia, 1.3 years for myeloma, and 4.2 years for malignant lymphoma. The proportion of drugs approved based on global clinical trials was significantly higher in myeloma (seven of nine, 78%) than in leukemia (three of 12, 25%) or malignant lymphoma (two of 10, 20%) (p=0.022). A total of two global clinical trials (17%) were phase II, and the remaining 10 were phase Ⅲ. Among 24 drugs approved in Europe during the relevant period, 11 were approved for leukemia, nine for myeloma, and four for malignant lymphoma. The median drug lag between Europe and the U.S. was 11 months for leukemia, 6.2 months for myeloma, and 8.1 months for malignant lymphoma. The proportion of drugs approved based on global clinical trials was not significantly different between groups (p=0.641): nine of 11 (82%) for leukemia, nine of nine for myeloma, and four of four for malignant lymphoma. A total of 10 global clinical trials (45%) were phase II, and the remaining 12 were phase III. The median review period was significantly shorter in Japan than in the EU (304 vs. 423 days, p=0.001).

Discussion and Conclusion: Our study suggested that the drug lag was larger between Japan and the U.S. than between Europe and the U.S., despite the shorter review period in Japan than in Europe. In Europe, most drugs were approved based on the results of global clinical trials, while in Japan, with the exception of myeloma, few drugs were approved based on global clinical trials. As a result, the drug lag was particularly large in Japan, especially for non-myeloma drugs. Phase II trials may be difficult for non-European countries to participate in because of the small number of recruited patients and the short duration of the registration.

Matsuda:Asclepia: Honoraria; Ono Pharmaceutical: Honoraria; Sanofi: Honoraria; Kyowa Kirin: Honoraria. Nagai:Otsuka Pharmaceutical: Honoraria; Takara Bio Inc: Honoraria. Sugimoto:Ono Pharmaceutical: Honoraria.