1. Enforcement of the Amended Clinical Trials Act, etc.
The Act Partially Amending the Act on the Safety of Regenerative Medicine, etc., and the Clinical Trials Act was promulgated on June 14, 2024, and will come into effect on May 31, 2025.1 Accordingly, the Regulation for Enforcement of the Clinical Trials Act will also be amended and come into effect on the same day. This article will focus on changes in these amendments that are considered to have a significant impact on companies.
1.1 Application of the Clinical Trials Act on observational studies
Under the Pre-Amendment Clinical Trials Act, "clinical trials" that are subject to the application of the Clinical Trials Act are defined as research to clarify the efficacy or safety of pharmaceuticals in humans, excluding (i) research using medical information or samples obtained as a result of providing the most appropriate medical care for patients without controlling the presence and degree of inspections, medications or other diagnosis, or medical practice for treatment for research purposes (so-called observational studies), (ii) clinical trials conducted under the Pharmaceuticals and Medical Devices Act for marketing authorizations, (iii) post-marketing surveillance, etc., and (iv) research conducted to collect information on compliance with certification standards of medical devices.2 Following the amendment, the phrase "including cases where, in the use of such pharmaceuticals for diagnosis, treatment, or prevention of human disease, or affecting the structure or function of the human body, additional inspections and other actions necessary to clarify the efficacy or safety of pharmaceuticals (limited to those specified by an Ordinance of the Ministry of Health, Labour and Welfare as imposing a significant burden on the person's mental or physical condition)" has been added to the definition of "clinical trials" and even so-called observational studies are subject to the Clinical Trials Act when such inspections that impose a significant burden on research subjects are conducted for research purposes.3 Furthermore, the Post-Amendment Regulation for Enforcement provided that "acts that impose a significant burden on a person's mental or physical condition" will now include "inspections or other acts conducted on subjects of clinical trials, where the frequency of the occurrence of serious illness, disability or death, or infection or other events concerning the safety of clinical trials, or the degree of mental or physical suffering or burden is found to be considerably higher when such act is conducted than regular inspections or other acts"4.
[The scope of coverage of Post-Amendment Clinical Trials Act]
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(The Ministry of Health Labour and Welfare Website (https://www.mhlw.go.jp/content/10800000/001264187.pdf ), translated by authors)
1.2 Scope of specified clinical trials on the use of off-label pharmaceuticals
Under the Post-Amendment Clinical Trials Act, "specified clinical trials" refer to clinical trials that (i) are conducted with research funds or other benefits provided by a manufacturer with marketing authorization for pharmaceuticals or a specially related person and/or (ii) use unauthorized pharmaceuticals or use pharmaceuticals for off-label purposes, and require compliance with clinical trial standards and submission of a trial plan.5 In cases of off-label use, if the use of pharmaceuticals in the actual clinical trial slightly differs from the authorized dosage, administration, efficacy, and effect, it was uniformly considered to fall under the category of specified clinical trials. Therefore, there were opinions that the burden imposed on researchers is greater than the expected risk to research subjects. In response to such opinions, the amendment provides that if the risk to life and health of research subjects is equivalent to or less than the level associated with the authorized usage etc. of the pharmaceutical product, they are not considered as specified clinical trials6.
In addition, the Post-Amendment Regulation for Enforcement provides that the following methods of use, etc., are low risk and do not fall under the category of specified clinical trials7 (however, this excludes dosage or the like that have not been frequently used for medical care or causes hazards to public health and hygiene in Japan).
(i) Methods of use promoted by academic medical societies through the publication of guidelines for the implementation of appropriate medical care, etc. or similar measures.
(ii) Methods of use where the efficacy, effect, and performance are within the scope of marketing authorization, and its efficacy and safety for research subjects are recognized.
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(The Ministry of Health, Labour and Welfare Website (https://www.mhlw.go.jp/content/10808000/001354318.pdf ), translated by authors)
1.3 Introduction of "general manager"
Under the Pre-Amendment Regulation for Enforcement, the responsibility for each action concerning the conduct of research was entrusted to the principal investigator8, and in the case of multicenter joint research, the principal investigator assigned to each participating medical institution handled certain matters, such as audits, monitoring, and disease reporting. It has been pointed out that this was cumbersome, and that the determination of causality and each procedure were different even within the same research. Therefore, based on international trends, the amendment newly established a general manager to supervise the overall clinical trial and to take responsibility for the planning and operation of research, which is a part of the responsibility that had previously been assigned to the principal investigator. In the case of multicenter joint research, one general manager is to be appointed for a single clinical trial9, and corporations and organizations may also serve as the general manager10.
1.4 Review of the scope of disease reporting
Under the Pre-Amendment Regulation for Enforcement, periodic reporting (about once a year) was required for cases where pharmaceuticals were unauthorized or were used for off-label purposes, whereas reporting within 30 days was required for cases involving authorized pharmaceuticals. Therefore, it has been pointed out that the expected risks and reporting due dates are contradictory. Under the amendment, the deadline for reporting known serious diseases to the CRB (Certified Clinical Research Review Board) in clinical trials of unauthorized or off-label pharmaceuticals is, in principle, within 30 days. On the other hand, the reporting of known adverse reactions, including serious reactions, occurring in clinical trials of authorized pharmaceuticals is changed to periodic reporting, since such events can also occur in usual medical care.11
2. Enactment of the revision bill to the Pharmaceuticals and Medical Devices Act, etc.
On May 14, 2025, the Act Partially Amending the Act on Securing Quality, Efficacy, and Safety of Products Including Pharmaceuticals and Medical Devices, and other Acts (the "Amended Pharmaceuticals Act") was enacted without any particular modification. The main points of the Amended Pharmaceuticals Act were previously introduced in the January issue of this Newsletter, but supplementary resolutions were adopted by both houses of the Diet in preparation for the vote.12 Most of the adopted supplementary resolutions were in relation to the review of the conditional marketing authorization system. The amendment allows conditional marketing authorization to be granted at the stage of exploratory trials with provisions for the rescindment of marketing authorization for pharmaceuticals that fulfill particularly high medical needs and whose efficacy or effect can be reasonably predicted. In this regard, supplementary resolutions were adopted to provide that the deadline for submission of data on the content of the confirmatory clinical studies after marketing authorization shall be stipulated as specifically as possible, and the authority to rescind marketing authorization shall be appropriately exercised in cases where efficacy and safety cannot be confirmed by confirmatory clinical studies within the deadline without justifiable reasons. The supplemental resolutions were also adopted to ensure appropriate operation based on lessons learned from the US Accelerated Approval Program, to provide details on post-marketing safety measures, to specify and provide information on products that are authorized under the conditional marketing authorization system and marketing authorization conditions, etc., and to provide relief through the Relief System for Sufferers from Adverse Drug Reactions.
In addition, from the viewpoint of the utilization of real world data, the phrase in the provision concerning the data required at the time of application for marketing authorization for pharmaceuticals has been generalized from "data concerning the results of clinical studies and other pertinent data" to "data provided by the Order of the Ministry of Health, Labour and Welfare as data concerning the quality, efficacy, and the safety of pharmaceuticals, quasi-pharmaceutical products or cosmetics pertaining to the application." Regarding such amendment, it was resolved to confirm that there is no change in the fact that controlled clinical studies are the most reliable, that supporting data shall, in principle, be data on the results of clinical studies, and that marketing authorization based solely on real world data should be carefully considered.
Moreover, regarding the provision of orders to change officers responsible for operations related to the pharmaceutical affairs, it was resolved that necessary guidance should be thoroughly provided in advance so that a business operator can review its constitution of officers autonomously while giving sufficient consideration to the management rights of the business operator, and that the considerations and procedures for making judgments for issuing an order to change officers should be publicly announced in advance.
Furthermore, a total of 34 supplementary resolutions were adopted, including those concerning the stable supply of pharmaceuticals, the practical application support fund for innovative pharmaceuticals, regulations on sales of non-prescription pharmaceuticals, and sales restrictions on designated antiabuse pharmaceuticals. Although the supplementary resolutions have no legal effect13, there is a view that the government bears certain political responsibility to respect them. The supplementary resolutions may also have an impact on practical operations through the content of the enforcement orders and enforcement regulations based on the Amended Pharmaceuticals Act or through administrative notifications, etc., and therefore, close monitoring of these developments remains important.
We are preparing a seminar regarding the amendments to the Pharmaceuticals and Medical Devices Act. Details of the seminar will be announced on our website shortly.
Footnotes
1. The Clinical Trials Act and the Regulation for Enforcement of the Act on the Clinical Trials Act before the amendment are hereinafter referred to as the "Pre-Amendment Clinical Trials Act" and the "Pre-Amendment Regulation for Enforcement" respectively, and the Clinical Trials Act and the Regulation for Enforcement of the Clinical Trials Act after the amendment are hereinafter referred to as the "Post-Amendment Clinical Trials Act" and the "Post-Amendment Regulation for Enforcement" respectively.
2. Article 2, paragraph (1) of the Pre-Amendment Clinical Trials Act, and the items of Article 2 of the Pre-Amendment Regulation for Enforcement.
3. Article 2, paragraph (1) of the Post-Amendment Clinical Trials Act
4. Article 2-2 of the Post-Amendment Regulation for Enforcement
5. Article 2, paragraph (2), Article 4, paragraph (2), and Article 5 of the Pre-Amendment Clinical Trials Act
6. Article 2, paragraph (2), item (ii) of the Post-Amendment Clinical Trials Act
7. Article 5 of the Post-Amendment Regulation for Enforcement
8. Article 14 of the Pre-Amendment Clinical Trials Act and Article 17, 18, etc. of the Regulation for Enforcement of the same Act
9 .Article 12, paragraph (1) of the Post-Amendment Regulation for Enforcement
10. Article 1, item (i)-2 and Article 10, paragraph (1) of the Post-Amendment Regulation for Enforcement
11. Article 54, paragraph (2), item (iii) and item (v) of the Post-Amendment Regulation for Enforcement
12. Supplementary Resolutions to the Bill for Partial Amendment of the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals and Medical Devices, etc. —Bill No. 15 of the 217th Diet Session
House of Representatives: (https://www.shugiin.go.jp/internet/itdb_rchome.nsf/html/rchome/Futai/kourou5A89C5134451C2B749258C6E000 4183E.htm)
House of Councillors: (https://www.sangiin.go.jp/japanese/gianjoho/ketsugi/current/f069_051301.pdf)
13. Tokyo District Court Judgment, September 27, 2002 (Hanreijihou No. 1181, p. 113)
The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.
