Medical Device & Diagnostic Industry Magazine
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Originally Published MDDI July 2005

Regulatory Outlook

Medical Device Clinical Trials in Japan

In an effort to globally harmonize medical device clinical trials, Japan has implemented new regulations on how to develop and conduct them.

Kiyohito Nakai and Martin A. Yahiro
Japanese Pharmaceuticals and Medical Devices Agency and FDA Office of Device Evaluation

Clinical trials for medical devices are becoming more common worldwide as medical devices become more complex. The increased complexity demands clinical data that demonstrate devices' safety and effectiveness. U.S. firms are now looking to expand into Japan's growing medical device market. However, clinical and regulatory affairs managers must understand how the newly amended Japanese Pharmaceutical Affairs Law (PAL) will affect the development of clinical trial strategies.

The Japanese government is modernizing its medical device regulatory system to keep pace with advances in science and in the international medical device industry. In April 2004, the Ministry of Health, Labor, and Welfare (MHLW) implemented the first phase of its sweeping modernization program. It merged the Pharmaceuticals and Medical Devices Evaluation Center (PMDEC), the Japan Association for the Advancement of Medical Equipment (JAAME), and the Organization for Pharmaceutical Safety and Research (OPSR) into the consolidated Pharmaceuticals and Medical Devices Agency (PMDA). Previously, PMDEC, JAAME, and OPSR were the three pillars of Japan's device and pharmaceutical regulatory system. The next phase, which began in April 2005, consists of a third-party review program for low-risk medical devices. In this phase, PMDA began using the new Summary of Technical Documentation (STED) application format originally developed by the Global Harmonization Task Force (GHTF).

Japanese clinical trial regulation has also undergone substantial changes as the government has sought to improve both patient protection and the quality of clinical investigations. The government also hopes to streamline the ministry's clinical trial evaluation processes. This article focuses on the new PAL provisions related to the development of clinical trials and to conducting them.

Clinical Trial Notification

The PAL amendment now requires that clinical investigation sponsors submit a clinical trial notification (CTN) 30 days before starting a trial for a new device. The amendment also requires mandatory reports to MHLW of adverse events that occur during a clinical trial. It also includes patient confidentiality protection provisions. The CTN contains a device description, preclinical data, clinical trial protocol, and an analysis plan, much like a U.S. IDE application.

New Good Clinical Practice Regulation

MHLW published a good clinical practice (GCP) regulatory guidance document in 1992. Specific provisions in the new PAL that relate to medical device clinical trials have now superseded this guidance. The new Japanese GCP is essentially a modified version of the rule developed by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. However, the Japanese GCP takes unique features of medical devices into consideration.

The Japanese medical device GCP describes the principal investigators' qualifications and responsibilities. The description includes the investigators' responsibility for all aspects of the clinical trial at the investigational site, such as patient selection criteria, patient care, monitoring, and reporting.
The new GCP requires each clinical trial protocol to be reviewed by an institutional review board (IRB). IRBs can be established by an academic organization or other legally authorized organization. Alternatively, heads of other institutions can jointly organize them.

The GCP describes the specific requirements of an IRB, including its responsibilities, composition, function, and operation. Each IRB is required to have at least five members. At least one of the five members' primary area of interest must be in a nonscientific area. One member must be independent of the institutional site, and one member must not have any relationship with the clinical trial.

The GCP outlines specific requirements for a written informed consent, which in the past was often given verbally. The ethical principles embodied in the Declaration of Helsinki form the basis for the new informed-consent document.

Other provisions in the GCP include packaging requirements and a revised definition of adverse events. It also includes a guidance on the clinical trial protocol and data analysis, data handling, and recordkeeping; a description of data safety monitoring boards (DSMB); and requirements for educating and training end-users.

In addition, the new GCP no longer requires that a clinical trial auditor be an independent section of the company, because smaller medical device companies conduct many clinical trials with small sample sizes. This enables companies to reduce the number of administrative employees necessary. Figure 1 outlines the requirements set out in the new GCP.

Sponsor-Investigator Studies

The PAL amendments have provisions that encourage the development of orphan medical devices, or devices intended only for small patient populations with rare conditions. Although the new PAL does not define small patient populations, the general criterion for orphan devices is that the intended population be fewer than 50,000 people.

The amendments also provide for devices that are based on highly advanced technology, but also have higher risks than most devices. Medical manufacturers may hesitate to develop such devices. However, many clinicians want to participate in clinical investigations and provide care for such patients. In these sponsor-investigator studies (SISs), the clinician investigator serves as the sponsor of the study. The principal investigator must develop the SIS protocol and submit the CTN to PMDA. The investigator must also develop standard procedures for conducting the clinical trials. The PAL amendment enables manufacturers to provide nonapproved devices to the investigators to conduct an SIS. It also specifies that these data can be used in application documents. Figure 2 provides an overview of the new GCP requirements for SISs.

Clinical Trials Network

In 2003, the Japanese Medical Association (JMA) initiated a clinical trial promotion program called the Network for Multi-Center Clinical Trials (NMCCT). The project is being subsidized by the Japanese MHLW. NMCCT has created a network of national hospitals, hospitals with residency training programs, and other clinical research–oriented facilities. The network's goal is to facilitate large clinical trials that generate high-quality clinical data. Until 2006, MHLW will create oversight and administrative offices to help coordinate, organize, and evaluate distinct clinical trial networks for 10 specific disease entities defined by NMCCT.

NMCCT also focuses on SIS trials that investigate drugs and devices that are already marketed in the European Union or United States, but that are not marketed in Japan for economic reasons. MHLW provides NMCCT with the grants that enable companies to develop such drugs and devices for the Japanese market.

MHLW also set up a grant program to establish clinical trial management offices in 45 national hospitals. The goal of this program is to improve clinical trial management in Japan.

Foreign Clinical Data

The ability to use data derived from a clinical trial conducted in a foreign country has historically been misunderstood by medical device firms. The MHLW guidelines published in 1997 contain specific criteria for the use of such data in Japanese marketing applications data. In order to be recognized as usable by MHLW, the foreign data must meet all of the following requirements:

• The clinical trial must meet Japanese regulatory requirements, such as criteria, international standards, and PMDA guidances, or it must be consistent with Japanese medical and clinical conditions.
• The clinical trial must be conducted by qualified investigators at qualified hospitals, such as public or nonprofit hospitals or university facilities.
• The clinical trial must be conducted in compliance with Japanese GCP regulations, or the foreign country's equivalent GCP regulations, in conformance with the Declaration of Helsinki. Clinical trial processes and methods are included in this requirement.
• All clinical information, including the raw data, case report forms, and statistical analyses, must be available for audit.

The applicant must describe how the clinical trial data meet the above criteria. The description should include the medical conditions for which the clinical trial was conducted and how the clinical trial conditions fit Japanese conditions.

Documentation that adequately demonstrates that the investigators who conducted the clinical trial had the appropriate abilities, skills, and experience required to conduct the trial, including academic backgrounds, qualifications, publications, and professional society memberships, should be included. Also, documentation that demonstrates that the clinical trial was conducted with appropriate processes and methods, such as a clinical trial protocol, must be included. In addition, the applicant must maintain these data for future audit purposes. All submitted documents associated with a foreign clinical trial must be translated into Japanese.

Early Consultation Meetings

One practical step that MHLW has taken to provide industry assistance in preparing clinical investigations is the new early consultation program at PMDA. When the PMDA predecessor was created in 1997, one of its major functions was to serve as a consultation service for pharmaceutical clinical trial development.

The establishment of PMDA in April 2004 enabled the formal consultation program for medical devices to begin. The purpose of providing early consultations is to ensure the ethics, science, and reliability of clinical trial protocols; ensure the safety of study subjects; improve the quality of clinical trials to comply with international standards; and reduce review times. These steps will increase the approvability of new device applications and ultimately provide higher-quality medical devices to the public.

There are three types of meetings defined under the early consultation program: the preconsultation meeting, the brief consultation on procedures, and the clinical trial and preapplication consultation. Figure 3 explains the procedure for clinical trial consultations. The preconsultation meeting serves two roles. One is to explain the regulations to and advise companies that have little knowledge of device regulation. The other is to make advance arrangements for clinical trial and preapplication consultations, select subjects for future consultations, briefly consult on procedures, and discuss the kinds of data that should be submitted.

In general, brief consultations consist of discussions about specific products. The discussions may deal with the product application category, interpretations of GCP and GLP requirements, or distinctions between product approval application types, e.g., whether product improvements cause the device to be considered a new device or a partially changed device. These consultations are not intended to discuss the necessity of device approval or matters concerning quality systems, labeling, or advertising. They should not include discussions related to the appropriateness of study results, necessity of domestic trials, or acceptability of preclinical studies.

Clinical trial consultations, however, are in-depth meetings pertaining to all aspects of medical device clinical trials. Such consultations include planning for preclinical studies, preclinical testing methodology, the trial's necessity, the clinical trial protocol's validity, and the scientific assessment of the clinical protocol.

Prior to the face-to-face meetings, the sponsor must submit the relevant documents to PMDA. The PMDA review team, as well as any consultants or advisory experts it deems necessary, review the material. At the meeting, the review team and the applicant exchange questions and answers. PMDA provides the applicant its opinions and advice during the meeting. A formal record of the consultation is later provided to the applicant by the agency.

The PAL made provisions for fast-track reviews of approval applications for medical devices considered to be urgently needed as orphan medical devices. The priority reviews pertain to medical devices concerned with treating lethal diseases, diseases that are progressive and irreversible and significantly affect the patient's life, and for which no existing therapy is available or the new device is considered to be superior to its existing counterparts. In these instances, a priority consultation may be requested. Priority consultations are, in essence, clinical trial consultations that are given preference over normal consultation requests.

There is no charge for preconsultation meetings, but companies must pay approximately $340 for a brief consultation and approximately $15,500 for a clinical trial consultation.

Future Directions

Japan was one of the founding members of the GHTF and has been actively participating in its efforts to produce globally harmonized standards for medical device clinical trials. Ideally, clinical trials would be conducted simultaneously under the same protocol and then simultaneously submitted to the regulatory body in each country. Japan is also participating in GHTF's newly established Study Group 5, which was created to specifically address clinical trial harmonization. MHLW and FDA are also participating in Harmonization By Doing, a project that promotes simultaneous multinational clinical trials. These activities may help countries harmonize clinical trials in the future. The Japanese government, in taking these steps, has positioned itself to play an important international role in developing a globally harmonized medical device regulatory system.

Conclusion

Clinical trial data are an essential part of medical device application. Data resulting from a clinical trial are often the most time-consuming and expensive element of the application. In an effort to improve its medical device regulatory processes, Japan made significant changes in the PAL addressing clinical trials. These revisions will help Japan keep pace with rapid advances in medical technology, as well as helping it become more globally harmonized.

Authors' Note

This article represents the professional opinion of the authors and is not an official document, guidance, or policy of HHS, FDA, or MHLW, nor should any official endorsement be inferred.

Copyright ©2005 Medical Device & Diagnostic Industry