The proliferation of biosimilars has garnered significant attention, with their development being highly sought after. However, there is a paucity of systematic information demonstrating the comparability evaluation of biosimilars to biotechnology-derived drugs already approved in Japan as new active ingredient-containing pharmaceuticals. This study aimed to elucidate trends in clinical trials conducted for biosimilar development by investigating and analyzing clinical trial information for currently approved biosimilars. We examined 31 biosimilars approved in Japan by March 2023, extracting data from review reports on trial phase, sample size, number of Japanese participants in multi-regional clinical trials (MRCTs), trial locations (domestic/international), endpoints, and observation periods. All 31 products were approved using Japanese data. Of the 18 products approved in Japan subsequent to overseas approval, 14 were approved using information from overseas sources, either in studies to clinical pharmacology or studies to verify efficacy equivalence. Between 2017 and 2022, 12 products (50.0％) were approved based on MRCTs. On January 25, 2024, The Ministry of Health, Labour and Welfare of Japan issued “Questions and Answers (Q & A) on Guidelines for Ensuring the Quality, Efficacy, and Safety of Biosimilars” (Administrative Notice, January 25, 2024). This notice is expected to expedite the time to marketing approval through increased participation in MRCTs and modifications to the criteria for utilizing Japanese data. Our study elucidates the current landscape of biosimilar development in Japan and the characteristics of associated clinical trials, underscoring the necessity for vigilant monitoring of future trends.

 The Japan Pharmaceutical Manufacturers Association’s Regulatory Affairs Committee has reported on the differences between Japan, the United States, and Europe with regard to the description of quality-related approval document, categories of approval item change procedures and review periods, and the operation of GMP investigations. Since discussions have started in Japan toward the realization of a risk-based change management system for international harmonization, we report on the current understanding of “risk-based change management” as the third survey.

 The Pharmaceutical Affairs Committee of the Japan Pharmaceutical Manufacturers Association (JPMA Pharmaceutical Affairs Committee) has been conducting questionnaire survey on the status of development projects in Japan from JPMA Pharmaceutical Affairs Committee member companies. In fiscal year 2024, we conducted a survey on the actual situation of obtaining data in the Japanese population on global products developed for rare diseases or pediatric diseases, taking into account the factors to be considered for filing a marketing approval application without clinical study results in Japanese patients. As of March 2024, a total of 1,106 projects were being developed in Japan for drugs or regenerative medicine products, of which 1,018 (92％) projects were being developed globally. Among the globally developed products, 343 projects (34％) were being developed for adults with rare diseases [rare diseases (adults) projects], and 103 projects (10％) were being developed for pediatric use (pediatric projects). Japan’s participation rate in global clinical trials of these projects was high, with rare disease (adults) projects and pediatric projects accounting for 274 projects (80％) and 73 projects (71％), respectively. However, there were 35 rare disease (adults) projects and 21 pediatric projects that did not or will not participate in global clinical trials due to the timing of development in Japan or based on the development strategy. Many of these projects chose to conduct local clinical trials in Japan. In addition, a total of 7 projects for rare diseases (adults) or pediatrics were confirmed, in which they were planning to use only the overseas confirmatory studies to constitute the marketing approval application data package. It was captured in this survey that despite the small number of patients, in principle, each company recognized the necessity of Japanese patient data and either considered participating in the global clinical trials or conducting clinical trials locally in Japan for the development plan. Considering the issuance of a new notification on the necessity of Japanese population data when a confirmatory clinical trial for rare disease is conducted overseas, this survey result will be useful for future comparison of the development trends in Japan.

 Regenerative medical products have been recognized as a distinct regulatory category in Japan for over a decade, with over 20 therapies approved as of May 2025-a notable increase since 2020. Among these, six received conditional and time-limited approvals under the amended Pharmaceuticals and Medical Devices Act, introduced in 2014 to address challenges unique to regenerative medicine, including product heterogeneity and imperative to address unmet medical needs. This system enables the approval of up to seven years of data, contingent upon the collection of additional data, thereby ensuring both expeditious patient access and continuous safety and efficacy evaluations. Internationally, comparable frameworks such as the U. S. FDA’s Accelerated Approval and the EU EMA’s Conditional Marketing Authorization similarly rely on surrogate endpoints and post-approval studies. Despite the enhancement of regulatory predictability through the implementation of guidelines, challenges persist in Japan regarding the confirmation of efficacy through post-approval studies, insurance reimbursement, and the sustainability of public healthcare expenditures, particularly in the aftermath of product withdrawals. Nevertheless, Japan’s conditional time-limited approval system is widely regarded as a flexible and innovative approach, balancing regulatory rigor with the need for expedited innovation in regenerative medicine.

 In the development of regenerative medicine products, the methods for estimating efficacy under the conditional and time-limited approval system are unclear, and there is a significant evidence gap between estimating efficacy and providing sufficient evidence for full approval. The conditional and time-limited approval system is intended to work based on a development strategy with the ultimate goal of obtaining full approval. If gaps in trial design, such as sample size, endpoints, and comparison methods, are too large, it becomes extremely difficult to predict the probability of success for full approval at the time of estimating efficacy. This paper proposes the application of a dual boundary approach, inspired by the concept of the “Promising Zone” in adaptive design. This approach does not require pre-determining samples sizes and allows for the estimation of efficacy by statistically evaluating the probability of success in confirming efficacy. It also has the advantage of minimizing the sample size when efficacy is clear and allowing for earlier stopping in cases of no efficacy. If the Promising Zone is achieved early, it is possible to apply for conditional approval, or to continue the trial as an expanded trial aiming for full approval. In cases where it is difficult to fully compare with a randomized control group, one option is to apply the Hybrid Control method, which combines external controls and randomized controls in the expanded trial part, or to seamlessly transition to confirmation based on endpoints with higher clinical significance than those used in the efficacy estimation part, even if confirmation using true endpoints is difficult. The proposals in this paper are expected to contribute to scientific discussions on more rational utilization of the system.

 Regenerative medical products are innovative treatments utilizing cells and genes, and Japan has implemented an early approval system, called “Conditional and Time-limited Approval” to accelerate their practical application. As of the end of May 2025, 22 regenerative medicine products have been approved. By utilizing the conditional and time-limited approval system, products with presumed efficacy can be provided to patients at an early stage. However, post-marketing efficacy and safety verification, known as “post-marketing approval condition evaluation,” is required. If efficacy is not confirmed through this evaluation, continued approval will not be granted. Of the 22 approved products, six were approved through the early approval system. However, two products―HeartSheet and Collategen Intramuscular Injection 4 mg―have been discontinued. Going forward, improvements in regulatory operations, such as the disclosure of review reports and enhanced approval predictability, are expected in Japan. The key challenge remains the appropriate utilization of this system to swiftly deliver safe and effective regenerative medical products to patients. This article provides an overview of the trends in the development and regulatory status of regenerative medical products in Japan.

 Pharmaceuticals and Medical Devices Agency (PMDA) aims to “implement consultation services and reviews that appropriately respond to innovation, through the means include issuing Early Considerations and formulating clinical evaluation guidelines based on the latest scientific knowledge” in their Fifth Medium-Term Plan, Early Considerations are reference information for promoting the practical application of innovation and the development of innovative drugs etc. It presents the current review concept on the direction of development, although it is at the stage where sufficient information has not yet been accumulated. In order to create innovative new drugs, predictability in development, and consultation and support on pharmaceutical regulations to promote practical application are needed for not only pharmaceutical companies but also researchers and developers in academia and startups. PMDA’s publication of various regulatory requirements and points to consider will lead to understanding and support of pharmaceutical regulations when formulating development plans for drugs, etc., and we believe that the publication of the Early Considerations will be of help in this regard. We also hope that the publication of Early Considerations will stimulate discussion and exchange opinions with stakeholders toward the practical application of innovations. This article introduces the background and outline of the seven Early Considerations published between February and March 2025, following the eight Early Considerations published between April 2024 and January 2025, which were introduced in this journal in May of this year.