Regenerative Medicine Is Advancing Japan

nnovation and collaborative initiatives have been promoted as national imperatives in the field of regenerative medicine in Japan ever since Professor Shinya Yamanaka of Kyoto University was awarded the Nobel Prize in Medicine or Physiology in 2012 for his pioneering work on iPS cells. To develop regenerative technologies and treatments, it is critical that industry, academic, and regulatory stakeholders collaboratively discuss challenges in developing these products systematically, comprehensively, and without sectional or functional borders. Non-clinical toxicology, clinical planning and development, and manufacturing processes are only a few examples of current challenges in regenerative medicine.

Learning how to identify and listen to the voices of various stakeholders (e.g., regulatory policy, healthcare system, pricing/reimbursement system, human rights and ethics, patient access and education, etc.), along with the global nature of modern healthcare, further stresses the importance of such collaboration in regenerative medicine.

Since 2016, DIA Japan has convened these and other stakeholders involved in developing cell therapy products, particularly those from industry and academia, for an annual cell therapy products symposium. In response to requests from these stakeholders and developments in this field, the 3rd DIA Cell & Gene Therapy Products Symposium in Japan in December 2018 incorporated gene therapy products in its agenda.

Day 1: Evolution of Japan Environment for Cell Therapy Products

Professor Jun Takahashi opened the symposium by presenting updates from the cell-based therapy for Parkinson’s disease research that he is leading at the Center for iPS Cell Research and Application (CiRA), Kyoto University. This ongoing, promising development program will be “fast tracked” by its SAKIGAKE designation.

Dr. Kiyohito Nakai (Director, Pharmaceutical and Food Safety Bureau, MHLW) illustrated the agency’s regulatory leadership to promote industrialization of regenerative medical products originating in Japan. A second example of such leadership was delivered through insights based on results from the AMED-MEASURE project, the Multisite Evaluation Study on Analytical Methods for Non-clinical Safety Assessment of hUman-derived REgenerative Medical Products public-private partnered research project led by the Japan Agency for Medical Research and Development (AMED) to lay the foundation for international scientific and regulatory harmonization on tumorigenicity assessment of cell therapy products.

An update from and panel discussion on the patient registry for regenerative medical products led by the National Consortium established by The Japanese Society of Regenerative Medicine highlighted its important leadership role in establishing definitive patient registry platforms and mechanisms that align with those promoted by other academic and research societies.

Day 2: Challenges for Gene Therapy Product Development & Manufacture in Japan

Although some presentations and discussions highlighted advancements in gene therapy in Japan, this second day primarily focused on challenges to these advancements, especially the impact of the Cartagena Protocol on Biosafety, an international agreement ratified by Japan which aims to ensure the safe handling, transport and use of living modified organisms (LMOs) resulting from modern biotechnology that may have adverse effects on biological diversity. (The US and other nations with regulatory agencies with their own gene therapy policies are not ratifying countries.)

Japan applies this protocol to a wide variety of LMOs, from gene therapy products to genetically engineered agricultural soybeans, through its Cartagena Act. Discussants and presenters outlined the process challenges this Act has introduced. For example, academic and industry researchers wishing to conduct clinical research with LMOs must first obtain confirmation/approval from the MHLW, which can only be requested after comprehensive review of CMC and quality-related materials by the PMDA. This process for obtaining confirmation/approval basically takes six months, which does not even include the time for document preparation.

This process in Japan is fundamentally different from the clinical study initiation process in other ratifying countries. As part of these discussions, Dr. Kazunobu Oyama (Principal Reviewer, Office of Cellular- and Tissue-Based Products, PMDA) provided several examples of PMDA providing solid advice to help engender environmental risk assessment of LMOs that are successful and compliant from both the scientific and regulatory perspectives in Japan.

Collaborative discussions among expert stakeholders in the regenerative medicine field have also led to more flexibility in the regulatory framework for other products in Japan, such as, for example, the early or conditional approval scheme which has been extended beyond regenerative medicines and was just applied to medicine development for small molecules.