Japan: New Regulations On Clinical Research

On April 7, 2017, the 193rd Diet of Japan passed a legislation regarding clinical researches – this "Law on Clinical Research (rinsho kenkyu hou)" will come into effect within one year. Discussions on a new regulation on clinical research had been underway, for the purpose of regaining credibility of Japanese clinical researches, which had substantially deteriorated after the recent series of scandals involving them.1

This Law on Clinical Research (the "Law") aimed to secure the quality of, and to protect the subjects in, certain types of clinical researches, which play critical roles in the advancement of medicine but, nevertheless, have only been conducted pursuant to ethical standards, and to prevent any further inappropriate behaviors, through strengthening the regulatory power of the authorities, while avoiding excessive burdens on researchers and without breaching their freedom over research.

Below, you will find a summary of the Law2, followed by "key points to consider" from the perspective of marketing authorization holders (the "MAH") of Drugs and Medical Devices3.

1. Scope of Law

In general terms, "clinical research" encompasses a wide variety of researches; however, the "clinical researches" that would be subject to the certain obligations set forth in this Law are those that fall under the definition of "Specified Clinical Research."

"Specified Clinical Research" is a Clinical Research that falls under either of the followings:

  1. Clinical Research (i) conducted by using certain MAH's Drugs and Medical Devices, currently marketed or planned to market, and at the same time, (ii) that receives Research Grants4 from such MAH5 (Article 2, Paragraph 2, Item 1).
  2. Clinical Research (i) conducted by using Drugs and Medical Devices not approved under the Pharmaceutical and Medical Device Law or (ii) involving off-label use6 of the Drugs and Medical Devices (Article 2, Paragraph 2, Item 2).

The term "Clinical Research" is also defined under this Law7, and this definition excludes "clinical trials and other matters prescribed in the MHLW Ordinance (the "Clinical Trials")8; accordingly, the scope of the Specified Clinical Research, regulated under this Law, would be: (i) Clinical Research (excluding, by definition, the Clinical Trials) that (ii) either (a) involves receiving Research Grants from a MAH, when the Drugs and Medical Devices of such MAH are being used, or (b) involves non-approved Drugs and Medical Devices or off-label use thereon.

It is important to understand the scope of the Specified Clinical Researches, and to accurately analyze the ongoing clinical researches to see whether any researches fall under such definition.

2. Obligation of Clinical Researcher

The persons/institutions conducting the Specified Clinical Research (the "Specified Clinical Researcher") have the following obligations under this Law, in conducting the Specified Clinical Research. They can be broadly categorized into three categories: (i) obligation to comply with standards set by MHLW, (ii) obligation to submit research plans and request for review by the Certified Clinical Research Review Committee9 and (iii) other obligations. The aim here shall be to secure credibility of the outcomes of the clinical research – similar to that of clinical trials under GCP regulations10 – by upgrading the rules from ethical standards to regulations that has legal binding power and penalties.

(1) Compliance of Clinical Research Standards

MHLW would need to establish "standards for conducting clinical researches" (the "Clinical Research Standards"; Article 3, Paragraph 1), and the Specified Clinical Researcher is required to comply with the Clinical Research Standards in conducting its Specified Clinical Research (Articles 4, Paragraph 2).11 The details of the Clinical Research Standards are not yet clear, but the following items will be stipulated accordingly to the Law (Article 3, Paragraph 2), and therefore, it is anticipated to have standards on, among other matters, (i) conflict of interests between the MAH and the Specified Clinical Researcher and (ii) monitoring of the adequacy of the clinical research.

  • Matters concerning implementation structure (Item 1)
  • Matters concerning structure and equipment of facilities (Item 2)
  • Matters concerning monitoring of status (Item 3)
  • Matters concerning compensation and provision of medical services, in case of occurrence of health hazards (Item 4)
  • Matters concerning involvement of MAH (and persons with special relationships) (Item 5)
  • Other matters necessary for the clinical research (Item 6)

(2) Submission of Specified Clinical Research Plans and Review by Certified Clinical Research Review Committee

Specified Clinical Researcher is required to prepare and submit an execution plan (the "Plan") with respect to the Specified Clinical Research to the MHLW (Article 5, Paragraph 1). The Plan needs to describe matters set forth in the Clinical Research Standard, and also as an attachment to the Plan, the opinion, regarding adequacy of that certain Specified Clinical Research as well as other relevant points, from the Certified Clinical Research Review Committee12 is required (Article 5, Paragraph 2, Item 1).

Specified Clinical Researchers shall conduct the Specified Clinical Research in accordance with the Plan (Article 7), and appropriate reporting to the MHLW is required in case of amendments to the Plan or the termination of the Specified Clinical Research (Articles 6, 8). As such, in summary, the Specified Clinical Researcher would need to submit the Plan, which should comply with the Clinical Research Standards, to the MHLW in advance, and further, the adequacy of such Plan would need to be reviewed beforehand by the Certified Clinical Research Review Committee consisting of persons who have professional knowledge and experience on clinical researches.13

(3) Other Obligations

As other obligations, Specified Clinical Researchers shall, among others, (i) obtain informed consent from the subjects of the Specified Clinical Research (the "Subjects") (Article 9), (ii) protect the personal information and confidential information of the Subjects (Articles 10, 11), (iii) prepare and maintain records of the Specified Clinical Research (Article 12) and (iv) report adverse events to the MHLW and the Certified Clinical Research Review Committee.

In addition, Specified Clinical Researchers are required to regularly report the status of the Specified Clinical Research to the MHLW and the Certified Clinical Research Review Committee, in accordance with the MHLW Ordinances (Articles 17, 18).

3. Obligation of Marketing Authorization Holders of Drugs and Medical Devices

Under this Law, the MAHs are recognized as the grantor of Research Grants to the Specified Clinical Researches. The provision of Research Grants by the MAH would contribute to the advancement of clinical researches; however, at the same time, it may lead to conflicts of interests issues if the clinical research involves the Drugs and Medical Devices of such MAH (the "Own Products") as the grantor.

In response to such conflict of interests that may arise, this Law imposes the following obligations to the MAH:

(1) Obligation to execute Contracts for Research Grants

The MAH providing the Research Grants without any clear grounds/documents would make the relationships between the two parties unclear. Accordingly, the Law mandated the MAH to execute a contract when providing Research Grants to a Specified Clinical Research involving its Own Products, setting forth the (i) amount and content of the Research Grant, (ii) content of the Specified Clinical Research and (iii) any other matter prescribed in the MHLW Ordinance (Article 32). While it is still not clear on how extensive such contracts would need to be, it would at least likely need to specify the rights and obligation of the parties, with respect to the Specified Clinical Research in question, so that the parties would have a clear base for the actions they take.

(2) Disclosure Obligation regarding Provision of Research Grants

In order to gain credibility of the Specified Clinical Researches, it is important to appropriately manage conflicts of interests, and to secure transparency by disclosing such conflicts of interests arising from the provision of the Research Grants from the MAH to the Specified Clinical Researchers. Given such perspective, as it is widely known, the pharmaceutical and medical devices industry associations have established "transparency guidelines" as its voluntary controls, on which the member companies have created its own policies, for the disclosure of information, relevant to the provision of funds and other goods, through its website or other appropriate means.

Similarly, but as a legal obligation, this Law requires the MAH to disclose information on (i) the provision of Research Grants to Specified Clinical Researches involving its Own Products and (ii) while the scope is still subject to the MHLW Ordinance, other provisions of monetary and other benefits to the Specified Clinical Researchers14 (Article 33). The detailed differences between this disclosure and the disclosure based on the industry associations' transparency guidelines should become clear, once the MHLW Ordinance is issued.

4. Supervisory Authorities of MHLW and Penalty Provisions

In addition to having rights to issue reporting orders and inspection rights (Article 35) as necessary to implement this Law, MHLW may issue emergency orders (Article 19) or improvement/suspension orders (Article 20) to the Specified Clinical Researchers, under certain circumstances such as health hazards or a violation of this Law. Also, in case the MAH violates the obligations to execute contracts or to make disclosures, as mentioned above, MHLW can issue warnings or publicly announce such violation (Articles 34, 35). One thing also worth highlighting is the fact that the MHLW has the right to issue improvement orders or revoke certification of the Certified Clinical Research Review Committee, as reviewers of the Plans (Articles 30, 31).

Note the violations of this Law may be subject to criminal charges (Article 39 ~).

5. Points to keep in Mind for Marketing Authorization Holders of Drugs and Medical Devices

Given the contemplated implementation of this Law, MAH of Drugs and Medical Devices may want to basically keep in mind the following matters:

(1) Clear Standards for Classification of Specified Clinical Researches

Each company shall establish clear classification standards on whether a particular clinical research falls under the Specified Clinical Research, as defined in the Law. These classification processes and the final decision-maker shall be made explicit in the SOPs, and trainings shall be conducted for the relevant employees. Failure to complete required procedures of this Law for the Specified Clinical Research, due to errors/misunderstandings must be avoided.

(2) In case classified as Specified Clinical Research, following points should be confirmed:

  1. Has the Contract been Executed?

    As mentioned above, MAH must execute contracts with Specified Clinical Researchers, in certain circumstances pursuant to the Law. If the provision of Research Grants to Specified Clinical Researches involving its Own Products is anticipated, it may be worthwhile to prepare in advance a contact template that reflects the elements required by this Law and the MHLW Ordinance.
  2. Has Specified Clinical Researchers completed its Required Procedures?

    Procedures such as the submission of the Plan and the request for review by the Certified Clinical Research Review Committee are Specified Clinical Researchers' obligations. However, as the MAH providing the Research Grants, it can be blamed by the authorities if the Research Grant is made "recklessly" without conducting any checks on whether those required procedures have been completed. Accordingly, when Research Grants are provided in relation to a Specified Clinical Research, the MAH should confirm, pursuant to its own SOPs, that the Specified Clinical Researchers have completed all procedures required by laws and regulations, and the contracts to be executed by and between the MAH and the Specified Clinical Researcher shall make such confirmation as a condition to the provision of the Research Grant.
  3. Risk of Inappropriate Provision of Labor?

    With the enactment of this Law, it is probably true that the burden on the Specified Clinical Researcher in conducting a clinical research has increased. Even if that is the case, if the medical representatives, or other employees of the MAH, assist the Specified Clinical Researcher's obligations/procedures under this Law, that would trigger issues from the perspective of the Specified Clinical Researcher's independence, and also could become an inappropriate provision of labor as prohibited under the fair competition codes. It should be important for the MAH to conduct thorough trainings in this respect.

(3) Appropriate Disclosures regarding Specified Clinical Research

As mentioned previously, MAH of Drugs and Medical Devices are required by this Law to disclose necessary information pertaining to the provision of funds/benefits. Therefore, while each company may already have implemented disclosure policies based on the industry association's transparency guidelines, review should take place to ensure that the current disclosure is sufficient also from the viewpoint of this Law and the MHLW Ordinances. For example, considerations shall be made as to whether the current disclosure format is sufficient, whether the disclosed items are enough and whether the disclosure methods (e.g., the two step disclosures and the consolidated disclosures of group companies) are appropriate.

Footnotes

[1] "Committee for Reconsidering the Clinical Research System" established by the Minister of Health, Labour and Welfare (the "MHLW") initiated discussion in April 2016.

[2] The Article numbers set forth herein are those of the Law, unless specified otherwise. The MHLW ordinances (the "MHLW Ordinance"), delegated by the Law to prescribe detailed rules are not issued yet.

[3] Article 2, Paragraph 3. Collectively include, Drugs, Medical Devices and Regenerative Medicine Products defined under The Law on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical devices (the "Pharmaceutical and Medical Device Law").

[4] This is defined as funds for the Clinical Research; this will include benefits to be prescribed in the MHLW Ordinance.

[5] To be precise, provision of Research Grants from persons who have special relationship, as prescribed in the MHLW Ordinance, with the MAH is within the scope here. The same hereafter under the same context.

[6] For Drugs / Regenerative Medicine Products, using it differently from the quantity, dosage and other matters prescribed in the MHLW Ordinances, described under the approval; and for Medical Devices, using it differently from the method of use or other matters prescribed in the MHLW Ordinances, described under the approval, certification or filings.

[7] Defined as, research aimed to analyze the efficacy and safety of Drugs and Medical Devices, through use on humans.

[8] Awaiting the MHLW Ordinance, but aside from clinical trials defined in Article 80-2, Paragraph 2 of the Pharmaceutical and Medical Device Law, clinical researches such as those sponsored by companies or regulated by other laws and regulations may be the exclusions.

[9] Clinical Research Review Committee certified pursuant to Article 23, Paragraph 4.

[10] Good Clinical Practices, set forth by MHLW Ordinances.

[11] The Law stipulates that persons/institutions conducting Clinical Researches, other than Specified Clinical Researches, need to make efforts to comply with the Clinical Research Standards (Article 4, Paragraph 1).

[12] Reviews and issues opinions on the Specified Clinical Researches. Specific Functions are listed in Article 23, Paragraph 1.

[13] The Law stipulates that persons/institutions conducting Clinical Researches, other than Specified Clinical Researches, need to make efforts to request review of the Certified Clinical Research Review Committee, in formulating the Plan and modifying it (Article 21).

[14] Note persons with special relationships, as set forth in the MHLW Ordinance, to the Specified Clinical Researcher are also included here.

Because of the generality of this update, the information provided herein may not be applicable in all situations and should not be acted upon without specific legal advice based on particular situations.

© Morrison & Foerster LLP. All rights reserved

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Authors
Shusaku Iwasaki
 
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