2. General Questions

2.1 Name of Regulatory Authority

Japan’s Ministry of Health, Labor and Welfare (MHLW) is the regulatory body that oversees food and drugs in Japan. The Pharmaceuticals and Medical Device Agency (PMDA) is an independent agency that is responsible for reviewing drug and medical device applications. 

2.2 Name of Ethics Committee

All clinical trials have to be approved by an Institutional Review Board (IRB). These are established at an institutional level. However, Central Review Boards (CRBs) were established in 2019 and present an alternative to institutional committees. 

The MHLW is responsible for ensuring review boards meet the required standards.

2.3 Clinical Trial Application Language

All applications should be submitted in Japanese.

2.4 Is regulatory approval required from both regulatory authorities and/or EC?

Yes, approval is required from both PMDA and the Ethics Committee prior to initiating a trial.

The legal system concerning clinical research in Japan consists mainly of two laws or guidelines. One is the Clinical Trials Act (“Rinsho-Kenkyuu hou” in Japanese) for interventional research, which was established in April 2018. This applies to clinical trials involving unapproved medicines or trials funded by a pharmaceutical company. 

The other is an ethical guideline for medical research, such as observational clinical studies. This guideline is known as the Ethical Guidelines for Medical and Biological Research Involving Human Subjects, which was developed by merging the existing Ethical Guidelines for Medical Research Involving Human Subjects and the Ethical Guidelines for Human Genome/Analysis Research. The new merged guideline was announced in March 2021.

https://hourei.net/law/429AC0000000016

2.5 Can regulatory authority and EC submission be done in parallel?

No, the ethical committee needs to approve the trial prior to submitting it to the regulatory authorities. The clinical trial approval process is sequential in Japan.

2.6 Requirement of any import permit/license before investigational product/study product is shipped from point of origin

Yes. PMDA regulates the import of investigational products into Japan. This process is best managed by an “In-Country Caretaker who can liaise directly with PMDA”.

2.7 Biological Specimen Export Requirements

Biological Specimens may be exported from Japan but should be the subject of an International Special Commodities (ISC) Contract. Samples for which there is minimal risk of pathogens being present are not subject to other provisions of the Regulations provided they are marked with the words “Exempt human specimen”. 

2.8 Are studies of GMOs permitted (e.g., GMOs used in vaccines/vaccine manufacture and other modified products)? 

Japan is party to the Cartagena Protocol which defines standards for the handling of GMOs. In Japan, the Cartagena Act has two types of GMO/LMO regulations:

1. Deliberate release, with GMO/LMO-specific rules for usage (Type-1 Use Regulation (T-1R))
2. 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 Environmental Risk Assessment and the T-1R application for GMOs/LMOs as part of the overall Clinical trial application. 

2.9 Is in-country sponsor presence/representation required?

The sponsor is not required to be located in Japan. However, if a person who intends to sponsor a clinical trial is not located in Japan, the sponsor or prospective sponsor will need to appoint an “in-country clinical caretaker” who has residency in Japan (including the representative of a foreign legal person holding office in Japan) so that person can carry out the necessary procedures for sponsoring a clinical trial. 

https://www.bakermckenzie.com/-/media/files/insight/publications/2019/healthcare/ap/dsc125067_clinical-trials-handbook--japan.pdf?sc_lang=en&hash=271774894A2BF72BCD49B5E00FA5148D 

2.10 Is there any mandatory requirement to identify a local PI or can a PI be based in a foreign country?

Yes, the PI must be located in Japan.

2.11 Is there any mandatory requirement to identify a local chief or coordinating investigator?

Yes, a lead investigator should be assigned whenever a trial includes multiple sites.

2.12 If the applicant is CRO or a third party, does regulatory authority need any authorization or transfer of obligations from the sponsor? Does the authorization letter need to be notarized and/or apostilled?

Yes, the delegation of activities should be documented. There is no standard template for this and the letter does not need to be notarized or apostilled.

2.13 Is there a requirement to register clinical trials on a local registry or database?

Trials conducted in Japan should be registered on the Japan Register of Clinical Trials (JRCT) which was established in 2018. 

2.14 What is the local requirement for clinical study documents archival; minimum of years for the archival, specific format followed (electronic/paper and/or both)?

In accordance with the “Ministerial Ordinance on Good Clinical Practice for Drugs (2012)”: 

The sponsor shall appropriately retain the following records (including documents and data) related to the clinical trial until the day on which marketing approval of the test drug is obtained (or the day 3 years after the date of notification in the case of a notification pursuant to Article 24, Paragraph 3) or the day 3 years after the date of premature termination or completion of the clinical trial, whichever comes later: 

(1) Protocol, contracts, clinical trial reports, and other documents prepared by the sponsor in accordance with this Ministerial Ordinance, or copies thereof. 

(2) Case report forms, the written notification pursuant to Article 32, Paragraph 6, and other records obtained from the heads of medical institutions or investigators, etc. in accordance with this Ministerial Ordinance. 

(3) Records of the duties related to sponsoring and managing the clinical trial, such as monitoring and audits (excluding those specified in the preceding two items and Item (5)) 

(4) Data generated in conducting the clinical trial 

(5) Records specified in Article 16, Paragraph 521 

2. The sponsor who resides outside Japan shall have a clinical trial in-country representative retain the records specified in Article 16, Paragraph 5, during the period specified in the preceding paragraph.

2.15 Requirements around periodic safety reporting and timelines on SAEs/AEs/ADRs/SUSARs/DSURs.

In accordance with the "Ministerial Ordinance on Good Clinical Practice for Drugs (2012)”:

Article 20. Information on Adverse Drug Reactions etc. 

1. The sponsor shall collect and examine information necessary to conduct the clinical trial properly, such as information on the quality, efficacy, and safety of the test drug, and provide the heads of the medical institutions with such information. 

2. Whenever the sponsor becomes aware of any event concerning the test drug that is specified in Article 80-2, Paragraph 6 of PAA, the sponsor shall notify the investigators and the heads of the medical institutions of such events in a list, etc. for each of the test drugs, annually after the date of submission of the first clinical trial notification, etc. within 3 months after the end of each period of 1 year.

3. Whenever the sponsor becomes aware of any event, that is unexpected based on the information provided in the Investigator’s Brochure for the test drug, among those specified in the preceding paragraph, the sponsor shall immediately notify the investigators and the heads of the medical institutions of the fact. 

4. Whenever the sponsor becomes aware of any information relevant to the proper conduct of the clinical trial, such as information on the quality, efficacy, and safety of the test drug, the sponsor shall revise the protocol and the Investigator's Brochure as necessary. In such cases, the sponsor shall obtain the consent of the investigators on the revision of the protocol. 

2.16 Requirement on any periodic clinical study update, specific template, and its frequency (e.g., interim or annual progress report and final report, etc.)? 

Sponsors typically report back to PMDA annually on the clinical trial, in line with the Drug Safety Updated Reporting (DSUR) schedule. 

2.17 Do the country regulations allow a Decentralized Clinical Trial (DCT) model (e.g. eICF, ePRO administration, remote investigator site, etc.)?

There are no regulations preventing the implementation of DCTs in Japan. 

2.18 Does the local regulation require notification of “serious breaches” of GCP or the trial protocol?

Yes, serious breaches of GCP must be reported to the PMDA. 

"The Ministerial Ordinance on Good Clinical Practice for Drugs (2012)" also states: 

If it is found that a medical institution has violated this Ministerial Ordinance or the protocol, resulting in interference with the proper conduct of the clinical trial the sponsor-investigator shall prematurely terminate the clinical trial at the medical institution.

2.19 Does RA/CA require insurance and indemnity to cover the sponsor and investigator’s potential liability?

"The Ministerial Ordinance on Good Clinical Practice for Drugs (2012)" also states: 

Article 14. Compensation to Subjects 

The person who intends to sponsor a clinical trial shall beforehand take necessary measures such as purchasing insurance in preparation for compensation to the subject in the event of trial-related injuries (including those attributable to the duties performed by the contractor). There is no specified amount of how much insurance coverage should be provided.