Clinical Researcher—December 2019 (Volume 33, Issue 10)

PEER REVIEWED

Mirei Matsukawa, MSN; Takashi Yokota, LLB, CCRP, CReP; Yumi Ikehara, MMS

 

In April 2017, the Clinical Trials Act was established in Japan as a result of several research misconduct issues related to studies that had been initiated by investigators or sponsored by industry. One of the issues included data manipulation in “a post-marketing trial of Diovan (valsartan) conducted by a team at Kyoto Prefectural University of Medicine [and led] by a former professor whose published papers on valsartan were withdrawn from medical journals after questions were raised over the validity of the findings.”{1}

The Clinical Trials Act encourages investigators and industries to follow appropriate processes and procedures, and to be transparent in the conduct and reporting of their studies by imposing penalties for violation of the law. It applies specifically to research involving interventional studies with unapproved or off-label medical products use, or on-label medical products use sponsored by industries.

The Act applies only to interventional studies, and not to prospective or retrospective observational studies. As a result, investigators and institutional review board/ethics committee (IRB/EC) staff need to take time to discuss and conclude if a proposed research project falls into this category, because the classification of observational or interventional studies defined by the Japanese Ministry of Health, Labor, and Welfare (MHLW) is complicated. The MHLW “is in charge of the improvement and promotion of social welfare, social security and public health … and [is] in charge of pharmaceutical regulatory affairs in Japan.”{2}

Further, the Act is very specific in regard to on-label or off-label usage as recognized by package inserts under the revised Pharmaceutical Affairs Law. It is a very time-consuming process to define on-label or off-label use following the highly detailed rules under the Act, and sometimes investigators need to inquire to MHLW to conclude if a particular usage is on-label or off-label. Even healthcare professionals may misunderstand off-label use as on-label use because some off-label uses are reimbursed by the national healthcare insurance by the notice of MHLW.

In the past, research was conducted under “ethical guidelines for medical and health research involving human subjects for other clinical research,”{3} but that has now been replaced with the Clinical Trials Act. The Act has newly established rules which were not included in previous guidelines, such as reinforcing the functions and managing the transparency of IRBs/ECs (now called certified IRBs), clarifying principal investigators’ responsibilities, and enriching the arenas of education and training, monitoring and auditing for data fabrication prevention, maintaining record archives, and handling conflict of interest (see Figure 1).

Figure 1: The Main Changes in the Clinical Trials Act

1. Procedure for clinical trial implementation

1.1 Measures for specific research implementation

1.1.1 Requirements for the quality of research (e.g., the obligation of monitoring and auditing, record archives)

1.1.2 Transparency between research sites and pharmaceutical industries (e.g., compliance with the management of conflict of interest)

1.1.3 Compliance with standards for the conduct of clinical trials

1.1.4 Patient advocates (e.g., protecting personal information and obtaining informed consent)

1.1.5 Submission of research plan reviewed by certified IRB

2. Reporting to MHLW and certified IRB about suspected unexpected serious adverse reactions
3. Guidance and supervision by MHLW for violation of implementation standards
4. Contracts between sponsor industries and the study sites and disclosure of provided funding

Source: Japan MHLW. The Summary of the Clinical Trials Act.

The Clinical Trials Act advocates direct communication between principal investigators and the MHLW by written notifications regarding clinical research plans, suspected unexpected serious adverse events, or serious noncompliance, which used to be via the investigator’s site director and IRB/EC in the previous guideline.

There also are laws, regulations, and guidelines with regard to clinical research in Japan other than the Clinical Trials Act, such as the revised Pharmaceutical Affairs Law, the tenets of Good Clinical Practice (GCP), ethical guidelines for medical and health research involving human subjects for other types of clinical research, and several others. Clinical research for Investigational New Drugs or Biologics License Applications for manufacturing and marketing approval must adhere to the International Council for Harmonization (ICH) GCP guideline or a Japan-specific GCP (J-GCP) guideline, and other clinical research adheres to the Clinical Trials Act or other guidelines.

There are similarities between ICH-GCP or J-GCP and the Clinical Trials Act (see Figure 2), whereas one difference is evident in the submission of adverse event reports, because the Act obligates submission only of reports on serious related adverse events with timelines and contacts that differ depending on whether the product in question is being studied on-label or off-label and whether the reaction is suspected or unsuspected, expected or unexpected, and serious or non-serious.

Figure 2: Similarities Between ICH-GCP or J-GCP and the Clinical Trials Act

Obtaining informed consent Protection of Personal Information IRB/EC review Reporting to IRB/EC and MHLW Monitoring and audits Compensation and indemnification Transparency of funding and conflict of interest Information disclosure Record archives

Source: European Medicines Agency. Guideline for Good Clinical Practice E6(R2).

The other difference is that study protocols should be reviewed by a certified IRB approved by MHLW and, typically, the Act requires central review for multisite studies, not multiple local ones, by a certified IRB to prevent deviation or differentiation in the quality of the review. Healthcare supplied specifically due to research conducted under the Act cannot use Japan’s medical care coverage system, which reimburses concomitant drug fees and examination fees during a test drug dosing period, whereas studies conducted only under ICH-GCP or J-GCP are covered, so one of the burdens for investigators under the Act is establishing operating research budgets and finding sponsors.

Educational Requirements for Becoming an Investigator

In the present circumstances, principal investigators in Japan usually work full-time in medical practice; they may have experience with a few sponsored studies following ICH-GCP or J-GCP, but little or no experience with investigator-driven, interventional studies.

The education of principal investigators offers few credit hours for research basics during college, so investigators typically learn how to conduct research after becoming physicians through on-the-job trainings. Therefore, when trying to start a study under the Act, less experienced investigators need to learn the expectations of the new regulation at the same time as basic clinical research practices in collaboration with the full clinical team. Governmental resources are limited for aiding investigators in their research, so the requirements of the Act may end up hobbling some proposed studies experiencing insufficient management and ineffective implementation systems.

The educational curriculum for physicians in clinical research depends on what resources are available through the universities or hospitals to which an investigator belongs, and the Act requires site directors to regularly provide opportunities for trainings and education. In Japan, training through external, membership-based, education and networking organizations such as the Association of Clinical Research Professionals is not yet recognized as foundational training for principal investigators. Rather, many sites require their investigators to undergo internal training within their organizations.

Even in order to follow the same protocol as an investigator for a multisite study, the minimum requirements for training to be an investigator for a single-site study can be different. The guideline for the Act says, “A principal investigator needs enough education and trainings for the research,”{4} but it does not mention specific qualitative and quantitative requirements. The new law needs to define what and how much education and trainings are enough. The training departments for employees at universities or hospitals develop the curricula for educational requirements, but do not often have interactive workshops for new kinds of research projects or coaching through onsite trainings for specific studies.

Investigators need interprofessional education of the sort with “activities [that] are perceived as more successful by learners when faculty have the ability to work creatively with small groups and have a legitimate knowledge base of the profession, enabling them to conduct exercises like shared storytelling.”{5} New principal investigators need to be provided interactive orientation and continuing education in order to ascertain their comprehension of research practices.

Obviously, interactive faculty development workshops take time to plan and require competent management to ensure their effectiveness for learners, and investigators need motivation for learning. Personnel from an organization’s protocol writing department and/or research operations unit often are adequate for introducing new investigators to the inner workings of clinical trials, and this education can progress to interactive workshops as a study continues along its life cycle.

Qualifications for a Certified IRB Administrator

Because the Act obligates review by certified IRBs approved by the MHLW for individual studies, certified IRB members and administrators have requirements in terms of training and experience. Particularly, for reinforcing a board’s functions and transparency management, the ordinance of the Clinical Trials Act requires certified IRB members to take training more than once a year to remain active in their positions. The enforcement notification of the Clinical Trials Act further requires that a board should have more than four administrators, including two dedicated administrators with at least a year of related experience, such as research administration of ICH-GCP, J-GCP, or ethical guidelines for medical and health research involving human subjects, plus taking trainings during their duties.

Although certified IRB management is important under the Act, Japan does not have a system of certified IRB/EC professionals (CIPs) such as is common in the U.S. A system of Certified Research Ethics Committee Professionals (CRePs) recently started in Japan,{6} and this is a similar certification as the CIP, which is available through PRIM&R (Public Responsibility in Medicine & Research).

Certified IRB administrators in Japan are usually university faculty staff who may or may not have medical licenses. Ideally, the new law should define how much and what kind of training and experience is adequate for a certified IRB administrator, because investigators and personnel in related departments often rely on their experience and special knowledge.

There are a variety of inquiries from other departments that the administrator may face, such as how to manage the formatting requirements for IRB/EC submissions, budgeting for IRB/EC fees, handling of test medical products, applying for indemnification, determining national insurance system coverage of research, creating and comprehending reports, and managing the archives of test medical products and records. The organization that established the certified IRB further needs to maintain an appropriate number of board members to adequately review studies and an appropriate level of staff for administrative duties.

Currently, some administrators have medical licenses and clinical research experience. The administrators need good interpersonal skills, the ability to detect possible regulatory issues such as poor documentation procedures, and research know-how based on their medical knowledge and experiences interacting with investigators.

Although the Act does not require certified administrators, the role requires a certain level of competency, and the qualifications of the administrator are critical to their ability to satisfy compliance. The administrator will be the compliance gatekeeper for explaining to investigators about ethical requirements of the Act and increasing investigators’ awareness. As the investigators interact with the administrator on a daily basis, the research administrator should be a certified professional with ample medical background and experience so that he or she can provide adequate responses to any inquires.

There are about 100 certified IRBs in Japan now, with probable variations in the quality of reviewing, though MHLW aims for there to be standardized, transparent, and efficient functioning of these boards. In the future, CRePs for about 100 certified IRBs could exchange information, mutually confirm and cooperate on operability issues, and verify their functions with each other to meet the aims of the Act.

Final Thoughts

Although we have our concerns about the complicated definition of the scope of research it covers, the Clinical Trials Act enables proper conduct of clinical trials when followed appropriately. The Act should be more specific about what kind of education is required for principal investigators and how to implement trainings. Furthermore, for proper certified IRB management, we should be aware of the importance of the CIP certification and cross-validation of the practices of certified IRBs.

Overall, and considering the past research misconduct issues it is intended to address through improvements in research transparency and ethics, the Act appears to be having a positive impact on clinical trials in Japan. However, no single law will resolve all the issues we face in the clinical research enterprise. Two challenges that we have experienced under the new law are what kind of and how to implement education for investigators and certified IRB administrators, and what qualifications certified IRB administrators should have in order to be more effective.

References

1. Gordon K. 2014. Novartis charged in Japan over Diovan data manipulation. PharmaTimes. www.pharmatimes.com/news/novartis_charged_in_japan_over_diovan_data_manipulation_1002136
2. Organization and function of the Ministry of Health, Labour and Welfare. 2017. Pharmaceutical Regulations in Japan. www.jpma.or.jp/english/parj/pdf/2017_ch01.pdf
3. Japan Ministry of Health, Labor, and Welfare. 2017. Review of ethical guidelines for medical and health research involving human subjects for other clinical research and a new law, the Clinical Trials Act, development. 1–34. www.jmacct.med.or.jp/about/h28/files/act20170204_1.pdf
4. Japan Ministry of Health, Labor, and Welfare. 2018. Notice of the Clinical Trials Act. https://www.mhlw.go.jp/file/06-Seisakujouhou-10800000-Iseikyoku/0000202843.pdf
5. Hammick M, Freeth D, Koppel I, Reeves S, Barr H. 2007. A best evidence systematic review of interprofessional education. Best Evidence Medical Education 735–51. https://www.bemecollaboration.org/downloads/781/beme_ipe__review_website_and_guide_version_25_june__07.pdf
6. Tokyo Medical and Dental University. Certified research ethics committee professionals. www.tmd.ac.jp/med/bec/ResearchIntegrity/pro.html

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Mirei Matsukawa, MSN, (matsukawa@wsu.edu) is with Yokohama City University Hospital in Japan.

Takashi Yokota, LLB, CCRP, CReP, is a Research Associate with Tohoku University Hospital in Japan.

Yumi Ikehara, MMS, is with University of Ryukyus Hospital in Japan.