Japan's Perspective on Facilitating Drug Development Through Asian Cooperation in Multi‐Regional Clinical Trials: Insights From Regulatory Research

ABSTRACT

Multi‐regional clinical trials (MRCTs) have recently become a popular strategy for novel drug development, contributing to the early access to novel medicines in participating regions by enhancing development efficiency. To further facilitate MRCTs in Asia, the Japanese government has financially supported research activities in Japan for over 15 years that have studied the effect of ethnic factors on drug responses and identified practical challenges in conducting MRCTs in Asia. This mini‐review highlights these research outcomes and related articles and presents our perspective on the current situation and future direction of MRCTs to explore opportunities for more collaboration between Japan and other East Asian/South‐East Asian countries to facilitate drug development.

1. Introduction

The significance of multi‐regional clinical trials (MRCTs) has been recognized to increase drug development efficiency and decrease drug lag in Japan [1, 2]. Recently, drug development has focused more on Asia owing to the rapid economic growth and increased medical needs in the region [3]. However, factors such as ethnic differences and varying medical circumstances across regions, including Asia, should be considered when planning and designing MRCTs [4] as indicated in the harmonized guideline by International Conference on Harmonization of technical requirements for registration of pharmaceuticals for human use (ICH), “General principles for planning and design of multi‐regional clinical trials (ICH‐E17).”

To facilitate MRCTs with the participation of Japan and other Asian countries, the Ministry of Health, Labour, and Welfare of Japan (MHLW) and the Japan Agency for Medical Research and Development (AMED) have financially supported research activities in Japan for over 15 years that have studied the effect of ethnic factors on drug responses and identified practical challenges in conducting MRCTs in Asia. Outcomes from these research activities related to the development strategies of MRCTs in Asia have been published as research articles [5, 6, 7]. Other articles focused on ethnic factors that affect drug efficacy and safety in MRCTs have also been published [8, 9, 10, 11, 12]. Primarily based on the outcomes of these research activities, this mini‐review introduces the findings and related articles and presents our perspective on the current situation and future direction of MRCTs to explore opportunities for more collaboration between Japan and other East Asian/South‐East Asian countries to facilitate drug development.

2.

2.1. Ethnic Similarities and Differences Among Asian Populations

The effect of ethnic factors on the clinical pharmacokinetics (PK) of a drug is a major consideration when planning MRCTs. In this context, PK studies by Hasunuma et al. highlighted the significance of experimental conditions in accurately assessing the ethnic sensitivities in drug PK profiles across populations. The PK parameters of ethnically sensitive drugs—such as moxifloxacin, simvastatin, and meloxicam—did not differ among East Asian populations under strictly controlled experimental conditions [8]. Additionally, Kuorse et al. identified few differences in common PK‐related gene polymorphisms among Japanese, Korean, and Chinese populations, except for human lymphocyte antigen alleles crucial for cutaneous adverse drug reactions [9]. Genetic similarities among Asian populations [13, 14] and no distinct differences in the drug exposure and recommended doses in East Asian countries have been previously reported [15]. Moreover, Sai et al. compared the efficacy of two drugs, asenapine, a schizophrenia drug, and tadalafil, a dysuria drug for benign prostatic hyperplasia, using MRCT data from Japan, Korea, and Taiwan and concluded that no significant population/regional efficacy differences were found for the two drugs among the three regions. Effect modifiers, such as pretreatment drug status or concurrent diseases, were common among countries [10]. Other studies by Tohkin et al. including systematic reviews or meta‐analyses of relevant MRCT data, also demonstrated no differences in efficacy among Asian populations in certain drug categories, dipeptidyl peptidase‐4 inhibitors (anti‐diabetic), warfarin, and direct oral anticoagulants [11, 12]. On the other hand, significant differences in efficacy were observed between Asian and non‐Asian populations in these drugs [10, 11, 12]. A review by Ramamoorthy et al. indicated that approximately one‐fifth of new drugs approved in the past 6 years demonstrated differences in exposure and/or response across racial/ethnic groups, translating to population‐specific prescribing recommendations in a few cases [16]. Overall, these studies suggested that insight about ethnic differences in drug responses between the Asian and other regions as outlined in the ICH‐E5 guideline, “Ethnic factors in the acceptability of foreign clinical data”, are critical for implementing MRCTs, including those in Asian region. These differences are attributed not only to the genetic factor but also to regional‐specific issues such as differences in common foods/drinks, common diseases/treatments, clinical trial implementation systems, medical practices, and regulatory environments among different regions.

2.2. Situation of MRCTs Conducted in Asia

Asano et al. assessed the current status of Asian MRCT and factors that affect the drug development process in Asian MRCT, such as therapeutic areas, main metabolic enzymes, approval status in the industrial countries/regions, development strategies, influencing drug development strategies in Asian MRCT and in general MRCT for drug approval in Japan. Then, they demonstrated a significant increase in the use of MRCTs for drug approval in Japan, with a dramatic expansion in participating regions/countries, such as the USA, EU, and Japan, and other Asian countries, including China, South Korea, Taiwan, Singapore, Thailand, Malaysia, and Indonesia [5]. They also suggested that region‐specific diseases in Asia, intrinsic and extrinsic ethnic differences between Japanese/Asian and Caucasian populations, and the status of the drugs' development in the United States or the European Union all affected the drug development process in Asian MRCT [5]. Aoi et al. assessed characteristics of MRCTs for drugs approved in Japan, especially those with South‐East Asia and East Asia participation. They then clarified that South‐East Asia has participated in various types of MRCTs in terms of total numbers of subjects and participating countries, in addition to Japan. However, the number of South‐East Asia‐participated MRCTs was lower in large‐size MRCTs than in middle‐ and small‐size MRCTs. Furthermore, separate clinical trials in South‐East Asia countries alone for the same indications as the MRCTs without South‐East Asia were very few. From these observations, they indicated that South‐East Asia has lower participation in MRCTs with participation of Japan, suggesting further opportunities for collaboration among Asian countries [6].

2.3. Future MRCTs, Including Japan and Other Asian Countries

The outcomes of these articles offer significant insights into assessing the ethnic similarities and differences among Asian populations. For example, the systematic review analysis of DPP‐4 inhibitors suggested that a stratification of patients across regions using a biomarker related to efficacy may make it easier to demonstrate consistency of efficacy across regions and facilitate the analysis of effectiveness in MRCTs, including the Asian population [11]. Another example was a clinical PK study using the unified study protocol in four regions. This study suggested that the unified protocol may also help analyze the ethnic factor in PK studies more accurately for some drugs [8]. Although the scope of these studies was limited, the results suggested that an early exploratory study examining the impacts of ethnic factors was useful for planning and conducting a confirmatory clinical study, including East/South‐East Asian populations [8, 9, 10, 11, 12]. This may encourage industries to include these Asian populations in MRCTs. However, further studies are required to understand better how ethnic factors affect drug responses in these populations because certain geographic locations in Asia may underestimate the genetic diversity within them [17]. For example, Chinese, Malay, and Indian populations are living in Singapore and Malaysia, and the Indian population was known to be close to the Caucasian population in terms of frequencies of genetic polymorphisms on some drug metabolizing enzymes such as CYP2C9, UGT1A1, and NAT2 [9]. Therefore, more careful considerations may be necessary when including South‐East Asia in MRCTs because of the more diverse genetic backgrounds of populations. In addition, data on Asian populations can be enriched by jointly conducting an MRCT in Japan, East Asia, and South‐East Asian countries because the number of Asian subjects in MRCTs is significantly higher when including these regions [6]. The inclusion of countries from East Asia and South‐East Asia in MRCTs will substantially contribute to the accumulation of scientific data on ethnic factors affecting drug responses in Asian populations under a unified protocol.

Collaborative training in Asia on MRCTs, based on the E17 guideline of ICH, will enhance the understanding of the significance of considering the similarities and differences in ethnic factors in drug responses across different populations [7]. Recent efforts for regulatory convergence in Asia, in which numerous regulatory agencies from Japan, Singapore, China, Chinese Taipei, Indonesia, and Malaysia participate through the ICH, will facilitate cooperation and collaboration in Asia. The Asia Training Center for Pharmaceuticals and Medical Devices Regulatory Affairs of the Pharmaceuticals and Medical Devices Agency of Japan plays a crucial role in fostering international collaboration among regulatory agencies in Asia [18].

Although operational challenges in implementing the ICH‐E17 guidelines still exist [19], sharing scientific data on ethnic factors in Asian populations will result in the proper implementation of the E17 guidelines, including the pooling strategy. A recent report on the practical consideration of ethnic factors in comparing Asian populations with other populations for a phase III MRCT [20] may serve as a good example of applying the E17 guidelines in planning and designing an MRCT that includes Asian populations. Another option is to include Japan and other East Asian countries earlier in drug development, especially in the design of phase II/Proof of Concept studies. This option offers the advantage of generating data on ethnic similarities in PK, safety, and efficacy in the target patient population as valuable prior knowledge ahead of phase III MRCT design [21, 22].

The recent guideline published by the MHLW announced that phase I Japanese PK assessment ahead of such Japan‐inclusive MRCTs is not obligatory for Japan to join MRCTs [23]. However, assessing Japanese PK properties using clinical PK data in a phase II or later study is important to consider a proper dosage, even if a phase I study of the Japanese population has not been done according to that guideline. PK data of other Asian populations are also useful for planning an MRCT including the Asian population more appropriately.

Evaluating ethnic susceptibility and confirming that drugs are unlikely to be affected by ethnic factors will promote the implementation of first‐in‐human (FIH) studies in Asian countries such as Japan, and may contribute to efficient drug development. The ethnic susceptibility could be assessed based on the evaluation of PK characteristics predicted from nonclinical studies and gene polymorphism distribution, as well as the characteristics of somatic gene mutations found in tumors [24].

Strengthening Asian cooperation and collaboration will accelerate research to understand ethnic factors in drug responses better and result in efficient drug development, benefiting Asia and other regions.

Disclosure

The views expressed herein are the result of independent work and do not necessarily represent the views and findings of the Pharmaceuticals and Medical Devices Agency.

Conflicts of Interest

The authors declare no conflicts of interest.

Tohkin M., Saito Y., and Uyama Y., “Japan's Perspective on Facilitating Drug Development Through Asian Cooperation in Multi‐Regional Clinical Trials: Insights From Regulatory Research,” Clinical and Translational Science 18, no. 9 (2025): e70347, 10.1111/cts.70347.