Japanese Pharmaceutical Regulations of Engineered Viral Vectors for Medical Use Compared With Those in the United States and the European Union.

Abstract

Pharmaceutical regulation of genetically modified organisms (GMOs) is one of the critical issues for developing viral vector-based medicines. In this perspective, we introduce the recent improvement of regulatory operations in GMOs like viral vector-based products in Japan by comparing those in the United States and the European Union. The recent advancements in genetic modification and editing techniques have accelerated the development of advanced-therapy medicinal products using genetically modified viral vectors and cells.1 Despite the increase in use of GMOs/living modified organisms (LMOs) in medicine, the potential risk of GMOs/LMOs on the environment is a concern. To address internationally the environmental issues related to biological diversity, including the usage of GMOs/LMOs, 196 nations as of 2021 have concluded or signed the Convention on Biological Diversity (CBD), which is the first global agreement to cover all aspects of biological diversity. The Cartagena Protocol based on CBD aims to ensure the safe handling, transport, and use of GMOs/LMOs, produced by modern biotechnology, which may have an impact on biological diversity. The Cartagena Protocol was entered into force on September 11, 2003. The Cartagena Protocol requires the parties to consider the necessity of the standard of handling of GMOs/LMOs and, if necessary, to establish the standard. The EU countries had already established domestic laws based on Directive 2001/18/EC that addressed the handling of GMOs/LMOs for medical use before the establishment of the Cartagena Protocol. Therefore, the EU countries did not have to take any additional actions to regulate the handling of GMOs/LMOs for pharmaceuticals. In 2003, the Japanese government established the Act on the Conservation and Sustainable Use of Biological Diversity through Regulations on the Use of Living Modified Organisms,2 known as the Cartagena Act, for the handling of the GMOs/LMOs. This Act is similar to Directive 2001/18/EC and the domestic laws established in the EU countries. In contrast to the European Union and Japan, the United States is one of the few countries that have not signed the CBD and the Cartagena Protocol. The United States enacted one specific environmental law named the National Environmental Policy Act of 1969 (NEPA) that regulates all kinds of environmental assessments. For initiating clinical trials, developers should submit appropriate clinical trial-related applications (investigational new drug (IND) application in the United States, clinical trial application (CTA) in the European Union, and clinical trial notification (CTN) in Japan) to each regulatory agency. In the European Union and Japan, approval of the usage of the GMOs/LMOs in the clinical trials is also mandatory before starting clinical trials (Figure 1). The objective of the EU domestic laws is to protect humans and the environment when carrying out deliberate release of GMOs/LMOs into the environment. Thus, developers (academia and/or industry) planning clinical trials in the EU countries should submit an environmental risk assessment (ERA) of each GMO to each country where the clinical trial will be conducted. In Japan, the Cartagena Act has two types of GMO/LMO regulations, the deliberate release, with GMO/LMO-specific rules for usage (Type-1 Use Regulation (T-1R)) and containment use for closed production sites and laboratories (Type-2 Use Regulation (T-2R)). Clinical trials are within the scope of T-1R, therefore developers planning to conduct clinical trials in Japan should submit an ERA and the T-1R application for GMOs/LMOs. In the United States, the submission of an ERA is not required for IND applications. However, when GMOs/LMOs may affect the quality of the environment, the US Food and Drug Administration (FDA) will request an ERA during the review process of the IND (the Title 21 of the Code of Federal Regulations (CFR) 25.21 and 25.31). In both the European Union and the United States, applicants should submit an ERA result of GMOs/LMOs when applying for marketing authorization, and the FDA or European Medicines Agency (EMA) reviews the appropriateness of the usage of drugs in clinical practice based on the ERA result (Figure 1). In Japan, the resubmission of an ERA is not mandatory when applying for marketing authorization. If developers obtain new data that indicates the environmental risk is lower than expected, resubmission is acceptable at any time to relax the T-1R. Some clinical researchers in Japan recently commented that the Cartagena Act delays the development of medicines containing GMOs/LMOs when compared to that of the medicines regulated by the similar laws in the European Union and the United States.3 But the regulatory framework of Japan is not significantly different from that of at least the European Union (Figure 1). The Pharmaceuticals and Medical Devices Agency (PMDA) is the Japanese regulatory agency responsible for a scientific review of new drug applications and Cartagena Act-related applications. The PMDA believed that such opinions came from the differences between the scheme of the Cartagena Act implementation and the procedure of actual development of drugs, and a lack of information on the Cartagena Act applications among academia. To solve these problems, since 2019, the Ministry of Health, Labor, and Welfare and the PMDA have started to improve the implementation of the Cartagena Act to ensure faster development of drugs (Table 1). The first improvement made in 2019 was the establishment of the PMDA official consultations to address specific measures of the Cartagena Act. The consultations for the Cartagena Act were the first established at the PMDA for the environmental law, and the developers can officially discuss the Cartagena Act-related matters with the PMDA since the establishment. It takes < 3 months to complete the official consultations and for official minutes to be published. The applicant can then submit the T-1R application as soon as the issues pointed out in the consultations are resolved. The administrative processing time after the submission is officially < 6 months, and the median actual administrative processing time and total processing time in 2021 were ~ 2.7 months and < 5 months, respectively. Section 42 of the German Drug law indicates that the evaluation period of CTA for trials dealing with GMOs/LMOs is 90 days after receiving the application conforming to the regulations. Thus, the actual administrative processing time before starting clinical trials is similar between Japan and the European Union. Since 2021, the parallel application of CTN and T-1R is acceptable. Now, developers should receive the approval of the T-1R application before at least the first patient enrollment of the clinical trial in Japan. In the European Union, several countries, such as France, accept the parallel application of CTA and ERA, but some countries, such as Poland, demand the approval of usage of the GMOs in the clinical trials before submitting a CTA.4 The PMDA has published a considerable number of instructions, such as the specific descriptions of ERA for adeno-associated virus (AAV) vectors,5 to provide information about the Cartagena Act to future applicants. The specific ERA for AAV vectors includes the general information and prior knowledge about AAVs and the general principles of risk assessment for AAV vectors. The European Commission has also published specific ERA for AAV in June 2022.6 These instructions and specific descriptions will significantly reduce the burden on applicants and regulators in Japan. Because the ERA submission is not mandatory when applying for marketing authorization, the regulation of the development of gene therapy products in Japan is not more time-consuming than that in the European Union and the United States. No funding was received for this work. The authors declared no competing interests for this work.