Revisions to the requirement of the Japanese clinical study data for biosimilar developments in Japan.

BACKGROUND: The 'Questions and Answers (Q&A)' document regarding Japanese biosimilar guideline elucidated that Japanese participant enrollment in at least one comparative clinical study was required for the marketing authorization application (MAA) of biosimilars in Japan. RESEARCH DESIGN AND METHODS: To discuss the requirement of Japanese clinical study data for biosimilar development, the trend in comparative clinical studies conducted for approved biosimilars of monoclonal antibodies and fusion proteins was analyzed, and the consistency of the results between the overall population and the Japanese population according to the publicly available information was reviewed. RESULTS: The number of comparative clinical studies enrolling Japanese participants was 25 cases, and the type and percentage were 13 (52%) and 12 (48%) cases of comparative pharmacokinetic study and comparative efficacy study, respectively. In all comparative clinical studies, consistent results between the overall population and the Japanese population were shown. CONCLUSIONS: Our study indicated that Japanese participant enrollment in comparative clinical studies may not always be necessary for biosimilar development when certain conditions are satisfied. This has been described in the revised Q&A document published by the Ministry of Health, Labour and Welfare in January 2024.

Survey of Data Package and Sample Size of Comparative Clinical Studies for Biosimilar Developments from PMDA Assessments.

BACKGROUND: The Japanese biosimilar guideline requires that the sponsors conduct clinical studies such as comparative pharmacokinetic (PK), pharmacodynamic (PD), or efficacy studies. In each biosimilar development, the sponsors consider the clinical data package, and thus clinical data packages vary among biosimilar developments. OBJECTIVES: The aim of this study was to elucidate the clinical data packages for the biosimilars approved in Japan. The details of clinical data packages and sample size for the regulatory approvals of biosimilars in Japan was reported. METHODS: We surveyed the clinical data packages and sample size based on the Pharmaceuticals and Medical Devices Agency (PMDA) website review reports between 2009 and 2023. RESULTS: Twenty-four biosimilars have been approved based on the comparative PK and efficacy studies, 10 biosimilars have been approved based on the comparative PK/PD study, and one biosimilar has been approved based on the comparative efficacy study. Regarding the sample size, comparative PK studies were conducted in healthy volunteers or patients for up to 300 cases, although the majority enrolled only 1-100 cases (68.1%, 32/47). Comparative PD studies enrolling 1-30, 31-60, and 61-90 cases totaled 4, 7, and 4 cases, respectively. Finally, comparative efficacy studies enrolling 1-300, 301-600, and 601-900 totaled 6, 10, and 11 cases, respectively. In particular, the oncology and rheumatology areas were the first and second disease areas recruiting 601-900 patients. CONCLUSION: Large numbers of patients were enrolled to conduct a comparative efficacy study. Efficient biosimilar development should be considered on the basis of the accumulation of scientific understanding of comparable features of biosimilars and their development.

Historical Overview of Regulatory Approvals and PMDA Assessments for Biosimilar Products in Japan During 2009-2022.

A biosimilar product is defined as "a biological product that is highly similar to an existing, approved biological product (known as originator or reference product) in terms of structure, function, quality, and clinical efficacy and safety". Recently, biosimilar products have been actively developed around the world, and part of the reason for this is to combat the rapid growth of medical expenses in many countries, including Japan, the United States (US), and Europe. The use of biosimilar products has been promoted as a measure to address this issue. The review of marketing authorization applications for biosimilar products in Japan is conducted by the Pharmaceuticals and Medical Devices Agency (PMDA), which reviews the comparability of the quality, efficacy, and safety based on the data submitted by the applicants. As of December 2022, 32 biosimilar products have been approved in Japan. Through this process, the PMDA has gained much experience and knowledge regarding the development and regulatory approval of biosimilar products; however, details of the regulatory approvals for biosimilar products in Japan have not been reported until now. Therefore, in this article, we present the details of regulatory history and revised guidelines for approval of biosimilar products in Japan, questions and answers, other relevant notifications, and consideration for comparability evaluations for analytical, non-clinical, and clinical studies. In addition, we provide details about the approval history, number, and types of biosimilar products that have been approved between 2009 and 2022 in Japan.

The uterus sustains stable biological clock during pregnancy.

Maternal circadian information has been reported to play an important role in fetal physiology and development. Hormones and nutrition have been mainly investigated as circadian cues from mother to fetus. However, the influences of circadian properties of the pregnant reproductive organs on fetuses have not been fully investigated. To gain an insight on the circadian functions of the reproductive organs, we examined molecular clocks in the pregnant rat uterus and placenta. By using a Period1-luciferase (Per1-luc) rat, whose tissues express luciferase corresponding to activation of Period1, a "key clock gene", we examined the uterus clock during non-pregnancy, on embryonic day 12 (E12), and on E22 (the end of pregnancy) in a light-dark (LD) cycle and constant darkness (DD). By in situ hybridization we further explored Per1 mRNA rhythms in the placenta on E12 and E22. The uterus in vitro showed clear circadian Per1-luc rhythms both in and out of pregnancy, having peaks at around the time corresponding to dusk in LD. Likewise, in DD, the uterus in vitro had the same Per1-luc rhythms. The decidua in LD showed circadian Per1 mRNA rhythms, peaking during night 6 h after dusk, while the decidua in DD showed the same Per1 mRNA rhythms only on E22. In contrast, the labyrinth showed no circadian Per1 mRNA rhythms in LD or DD during pregnancy. These results suggest that the uterus and decidua, a maternally-originated tissue of the placenta, but not the labyrinth, a fetus-originated tissue of the placenta, can provide the fetus with circadian information.