Expediting Drug Development in Japan: A PMDA Perspective

Abstract

Review time for a new drug in Japan has shortened dramatically since the establishment of the Pharmaceuticals and Medical Devices Agency (PMDA). Nonetheless, Japan faces a new challenge so‐called “Drug Loss”, which means that new drugs approved overseas have not yet been developed in Japan or that development is delayed. In this manuscript, we describe how PMDA facilitates Japan’s drug development to continuously provide innovative drugs to patients.

CHANGES IN THE DRUG DEVELOPMENT ENVIRONMENT AND DRUG LOSS IN JAPAN

Since the establishment of the PMDA in 2004, the PMDA has contributed much to new drug approval in Japan ¹ and Japan’s review time for new drugs has decreased dramatically (See Table S1 for more details related to discussions of this article). The median total review time was over 600 days in 2005 and 333 days in 2023. Even though new drug review time in Japan is “on par” with that of other regulatory agencies, such as the US Food and Drug Administration (FDA), Japan faces a new challenge known as “Drug Loss.” This is because of Japan’s limited participation in the clinical development of drugs, resulting in no new drug applications or approvals in Japan. For example, approximately 65% of new molecular entities approved in the United States have not been approved in Japan, and Japan has participated in only approximately 57% of Multi‐Regional Clinical Trials (MRCTs) recently conducted in the United States and European Union. One of the prevailing reasons is the change of drug developers. Many recent, innovative, new drugs have been discovered and developed by emerging bio‐pharmaceutical companies (EBPs), rather than traditional big pharmaceutical companies. For instance, nearly half of the recent unapproved drugs in Japan were developed by EBPs. To mitigate “drug loss” in Japan, PMDA works proactively with the Ministry of Health, Labour and Welfare (MHLW) of Japan, as described below.

JAPAN’S REGULATORY INITIATIVES FOR ACCELERATING DRUG DEVELOPMENT AND APPROVAL

PMDA has actively responded to evolving landscapes of drug development and has taken various measures to accelerate drug development in Japan (Figure 1 ).

Figure 1.

Recent regulatory efforts to accelerate drug development in Japan.

Consultation Center for Development of pediatric and orphan drugs

For many years MHLW and PMDA have contributed to global drug development for orphan diseases. ² The Consultation Center for Pediatric and Orphan Drug Development (CCPODD) at PMDA was established in July 2024 to promote the development of drugs for pediatric and orphan diseases because many unapproved drugs in Japan were intended to treat orphan diseases or pediatric populations. The CCPODD offers a fee reduction program for scientific consultation conducted by PMDA for pharmaceutical companies and academic institutions. This program is supported by subsidies from MHLW. The relevant PMDA office for new drug review provides scientific advice on development plans for pediatric and orphan drugs, along with regulatory support to ensure compliance with the latest requirements and processes. It also facilitates smoother approval pathways by disseminating up‐to‐date information on regulatory changes, guidelines, and best practices related to pediatric and orphan drug development.

Proactive publication of guidelines including “Early Consideration”

To facilitate cutting‐edge technology and science implemented in drug development, PMDA has proactively published many guidelines related to drug development and approval. Since 2024, the first fiscal year of PMDA’s Fifth Mid‐term Plan (FY2024‐FY2028), a new publication entitled “Early Consideration” has been started. “Early Consideration” is not actually a guideline. Rather, it provides timely reference information (usually available in both Japanese and English almost simultaneously), similar to a reflection paper in the EU. It describes PMDA’s point of view at the time of publication, seeking to promote drug development and practical applications of new technologies and science, even in situations in which science related to the topic has not yet fully matured. Contents of Early Consideration may be updated as new knowledge and scientific advances become available and/or by communication with industries and/or academia. Recent examples of Early Consideration published in Fiscal Year 2024 include “Statistical considerations when planning phase I clinical trials in oncology: from the safety perspective,” “Principles on clinical evaluation of drug‐drug interaction with use of biomarkers,” and “Consideration in the development of drugs for pulmonary arterial hypertension.”

Promoting global drug development and MRCTs including Japan

To further promote global drug development and MRCTs that include Japan, a new guideline to clarify the necessity of Phase I trials in Japanese participants prior to initiating MRCTs has recently been published. ³ In this guideline, an unnecessary case of Phase I trials in Japanese participants was described so that an MRCT including Japan was smoothly initiated without a delay, following drug development in other regions. For orphan drugs, a possible new drug application without Japanese clinical trial data was described in a guideline published in October 2024. ⁴ PMDA has also been working with designated clinical trial sites to maximize efficiency and reduce costs of clinical trials in Japan. These initiatives will enable more flexible development strategies for pharmaceutical companies including EBPs to conduct MRCTs including Japan.

Use of RWD/RWE for drug approval

Real‐world data (RWD) and real‐world evidence (RWE) have a major role in promoting drug development, especially in cases in which feasibility to conduct randomized clinical trials is low. RWD/RWE have provided useful and supportive information for practical regulatory approval of drugs for many orphan diseases in Japan. A recently published “Early Consideration” on an external control, ⁵ outlines key considerations for utilizing RWD/RWE at all stages of a study, including planning, analysis, and interpretation.

PMDA overseas offices in the United States of America and the Kingdom of Thailand

PMDA opened overseas offices in Bangkok, the Kingdom of Thailand on 1 July 2024 as the first Asian base, and in Washington, DC, the United States of America on 1 November 2024 as the first US base. Roles of the Asian office include promoting regulatory cooperation and harmonization with Asian regulatory authorities by facilitating information exchange and discussions of pharmaceutical regulations, and by facilitating clinical development to improve access to innovative medical products in Asia. Furthermore, the Asian office collaborates with Japanese academia under a comprehensive agreement in conducting MRCTs, including the ARISE (ARO Alliance for Southeast & East Asia) project with the Japan Institute for Health Security (formerly National Center for Global Health and Medicine) and the ATLAS (Asian Clinical Trials Network for Cancers) project with the Japan National Cancer Center. The US office enhances collaboration with US administrative organizations including the FDA, and focuses on supporting EBPs including start‐ups, venture companies, and venture capital companies by providing the latest accurate information about Japanese regulations and by offering general consultations on development strategies for drug approval in Japan. ⁶

Elevating engagement in international activities

International cooperation and collaboration are essential to promoting drug development in this era of globalization. PMDA has been strengthening regulatory cooperation and collaboration not only with FDA and EMA, but also with many regulatory agencies (including Asian regulatory agencies) through international platforms such as the International Coalition of Medicines Regulatory Authorities (ICMRA), the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), the Pharmaceutical Inspection Co‐operation Scheme (PIC/S), and bilateral regulatory schemes. Seminars by the PMDA’s Asia Training Center for Pharmaceuticals and Medical Devices Regulatory Affairs (PMDA‐ATC), which commenced in April 2016, in which more than 3,100 regulators participated from more than 65 countries in Asia and other parts of the world, have greatly enhanced regulatory capacity building as well as strengthening cooperation among regulatory agencies globally. In addition, recognition of Japan as a “Reference Country” by many countries, such as Thailand, Taiwan, Indonesia, Malaysia, Vietnam, and the Philippines will form dynamic relationships to advance drug development and approval in Asia. Furthermore, PMDA has actively participated in international conferences, such as the American Society of Clinical Oncology, Drug Information Association (DIA), and BIO International Convention to discuss regulatory‐related issues with various stakeholders, and to facilitate understanding of Japanese regulations and PMDA considerations.

FUTURE STEPS AND CHALLENGES

Other initiatives have also been taken in addition to those described above: (1) Expedited pathways such as “Sakigake” and “Conditional early approval” are available in Japan, ⁷ (2) Practical review operations about engineered viral vectors in terms of the Cartagena Protocol have also been dramatically improved in recent years to avoid developmental delays in Japan, ⁸ (3) An PMDA webpage has been created in English to facilitate better understanding of Japanese regulations and promotion of medical product development in Japan by foreign companies, including EBPs. ⁹ Regulatory efforts described above will create synergism with other initiatives, including efforts to improve clinical trial site environments (e.g., use of central IRB), and price benchmarking, on drug pricing policy in Japan, such as a price premium for promoting innovation, and financial support such as subsidization and tax credits for orphan product development. The 3^rd Healthcare Policy for 5 years approved by the Cabinet in February 2025 clearly illuminates the direction of the Japanese government’s strong support for scientific innovation and drug development. ¹⁰ The recently announced action plan by the Cabinet Secretariat provides more detailed measures to be undertaken over the next few years to strengthen Japan’s drug discovery capabilities. Promoting these initiatives is expected to help resolve drug loss in Japan. PMDA strives to foster and support scientific and technological advancement by enhancing science‐based regulatory systems. In the short term, use of artificial intelligence in drug development and regulatory practice is a critical challenge. It will be crucial to work internationally to ensure its appropriate application without impeding scientific advances.

Finally, PMDA aspires to have its initiatives widely recognized by various stakeholders and to expedite drug development in Japan. PMDA is ready for the next challenge and its doors are always open.

FUNDING

All authors are employees of PMDA and have received no external funding.

CONFLICT OF INTEREST

The authors declared no competing interests for this work.

Supporting information

Table S1.