Japan has a unique set of processes and agencies for the regulation of drugs. The Ministry of Health, Labour and Welfare (MHLW) and Pharmaceuticals and Medical Devices Agency (PMDA) are the two main Regulatory Agencies that oversee the approvals of the drugs as per the regulatory prerequisites in Japan. The Pharmaceuticals and Medical Devices Agency (PMDA) is the government organization in Japan in charge of reviewing drugs and medical devices, overseeing post-market safety, and providing relief for adverse health effects. The current PMDA was established in 2004 by incorporating the Pharmaceuticals and Medical Devices Evaluation Center of the National Institute of Health Sciences (PMDEC), the Organization for Pharmaceutical Safety and Research (OPSR/KIKO), and part of the Japan Association for the Advancement of Medical Equipment (JAAME).
Japan’s regulatory system demands the IND Application documents to be prepared in the Common Technical Document (CTD) format. Before sending an application for Investigational New Drug (IND) to the PMDA, the applicant may schedule a pre-IND meeting (consultation with PMDA), which ensures streamlined processing of IND approval. Subsequent to the application submission, PMDA evaluates the application with respect to the preclinical data, and protocols for clinical studies etc. It may probably take 30 days for initial IND and 14 days for second and consecutive INDs.The queries received from PMDA should be answered by the applicant. After PMDA completes its review, the IND application will be transferred to Institutional Review Board (IRB) for the review. IRB takes 1-4 weeks of time for the completion of the review. Once IRB provides a favorable response, IND application will be approved after which, clinical trials can be initiated on human subjects.
The PMDA working together with MHLW understands that some of the information it receives from the USFDA may include non-public information exempt from public disclosure under the laws and regulations of the Government of the United States of America, such as confidential commercial information; trade secret information; personal privacy information; law enforcement information; or internal, pre-decisional information. The PMDA understands that this non-public information is shared in confidence, and that the USFDA considers it critical that the PMDA maintain the confidentiality of the information. Public disclosure of this information by the PMDA could seriously jeopardize any further scientific and regulatory interactions between the USFDA and PMDA. The US FDA will advise the PMDA of the non-public status of the information at the time that the information is shared.
The PMDA is part of the Ministry of Health, Labor, and Welfare (MHLW) and they both handle a wide range of activities, from approval reviews to post-market surveillance. Within the PMDA, the Office of Medical Devices Evaluation supervises the manufacturing of medical devices, enforces standards, and grants approval to manufacture and market devices.
- Some Class III medical devices are able to undergo third party certification.
- Medical software programs are independently regulated.
- Manufacturers are required to be registered rather than be licensed.
- Quality management systems (QMS) are streamlined. QMS inspection is conducted on the Marketing Authorization Holder and is conducted per product family, not on individual products.
Under Japan PMDA regulations, a medical device can be classified as a General Medical Device (Class I), Controlled Medical Device (Class II), or a Specially Controlled Device (Class III and Class IV), depending on the risk level. For General Medical Devices, only a notification/self-declaration is required, and the product does not need to undergo the approval process by the MHLW and PMDA. Controlled Medical Devices can be designated to be certified by an authorized third-party certification party or reviewed by the PMDA. Specially Controlled Medical Devices must be reviewed and approved by the PMDA and MHLW.
Once the applicant files NDA, PMDA reviews the application and schedules a face-to-face meeting with the applicant during which queries from PMDA are discussed. Meanwhile, GMP investigation of manufacturing site will be carried out. After the face-to-face meeting, the PMDA reviewer prepares a Review Report 1. If there are any major issues, PMDA organizes the Expert Discussion 1, which involves a discussion between the PMDA reviewer and external expert on the proposed major issue. Subsequent to the discussions with the external expert, PMDA reviewer will prepare a summary of the main issues and discuss with the applicant in a direct meeting (can be held 2 times).
Following the head-on review meeting, PMDA may organize Expert Discussion 2 with (if necessary) and prepare the Review Report 2. PMDA reviewer will submit the results of the review along with the results of GMP conformity investigation reports to Minister of Health and Labour Welfare (MHLW). MHLW upon consultation with the Pharmaceutical Affairs and Food Sanitation Council will give approval for NDA to the applicant.
As for a new drug, an assessment report is published right after the approval post which the outline of application documents (Module 1 (partially) and 2 of CTD) is published after 3 months. The standard time for approval of an NDA is approximately 12 months on an average.
The PMDA reviews new drugs, generic drugs, OTC drugs/”behind-the-counter” (BTC) drugs, and quasi-drugs, and conducts re-evaluations of previously approved drugs. Orphan drugs and other priority drugs are given priority reviews in accordance with their clinical significance.
- Has the reliability of the conducted studies and submitted documents been ensured?
- Is the efficacy in the study population considered to be more effective than placebo according to the results of properly designed clinical studies?
- Do the obtained results have clinical significance?
- Are there any unacceptable risks as compared to the benefits?
- Can the drug be supplied continuously with stable efficacy and safety from a quality assurance standpoint?
- The reconstruction, repair, or formation of structures or functions of the human body
- The treatment or prevention of diseases
- Gene therapy
The PMD Act significantly shortens the phased clinical trial period for regenerative medical products so that they can be used on a conditional authorization basis in a much timelier manner. Japan, which was once a difficult market to enter, is now becoming an attractive investment opportunity for several global pharmaceutical companies due to the harmonization of Japan’s regulatory process with the US and EU regulatory agencies.
As the targets for generic share are expected to grow extensively in coming years, the domestic suppliers will face difficulties accomplishing it. However, on the other hand, there is a huge pool of opportunities for foreign generic manufacturers to enter the untapped Japan market. For generic drug manufacturers, to establish or expand their business in emerging markets like Japan, collaborating with a global Submissions and Publishing partner, offering flexible, end-to-end submission and publishing services would be recommended to effectively meet all their specific and unique submission requirements for quick market approvals.