Medical Device Link.

Originally Published MDDI November 2004

Regulatory Outlook

Martin A. Yahiro

Kiyohito Nakai

In 2005, there will be significant revisions to the Japanese Pharmaceutical Affairs Law (PAL). The revisions include introducing a third-party certification system for low-risk devices and prioritizing governmental reviews of high-risk medical devices. In April 2004, in preparation for the implementation of these revisions, 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) were merged (see Figure 1). This merger formed a consolidated organization for the regulation of pharmaceuticals, biologicals, and medical devices. This independent administrative agency, the Pharmaceutical and Medical Devices Agency (PMDA), will be the cornerstone of Japan’s medical product regulation.

The Japanese Review Process

Currently, the medical device approval process depends on the type of medical device being submitted. Medical devices that pose minimal risk to the human body, such as Global Harmonization Task Force (GHTF) Class I devices, have been designated by Japan’s Ministry of Health, Labor, and Welfare (MHLW) as exempt from the approval regulations. These devices include some hospital equipment, x-ray equipment and film, manual surgical instruments, and some medical devices that comply with certain Japanese industry standards. However, even medical devices that fall within these categories might need to be approved. An approval is necessary if a device’s structure, intended use, indications, effects, or performance differs significantly from those expected for devices in this category. Medical devices not exempt from the approval regulations fall into three categories: new devices, improved devices, and generic devices.

New medical devices and improved medical devices must be evaluated and approved by MHLW. Specifically, the medical devices group, Division 4, of PMDEC must evaluate and approve them. New medical devices are defined as those whose structure, intended use, indications, effects, or performance differs significantly from previously approved devices. Improved medical devices are defined as medical devices whose structure, effects, or performance are improved compared with previously approved devices.

Figure 1. Japan’s two medical device regulatory bodies, PMDEC and JAAME, and two pharmaceutical regulatory agencies, PMDEC (Divisions 1, 2, and 3) and OSPR, merged to form a consolidated agency for pharmaceutical and medical device regulation (click to enlarge).

JAAME evaluates generic devices that are comparable to already approved devices, or predicate devices. The devices are evaluated for equivalence in terms of structure, intended use, indications, effects, and performance, similar to FDA’s premarket notification 510(k) process.

In addition, certain medical devices have been designated by MHLW to have additional postapproval requirements related to possible malfunctions. These include cardiac pacemakers, pacemaker leads, cardiac defibrillators, prosthetic valves, and vascular grafts. The additional requirements include postapproval tracking and maintaining device user and patient records.

New Organization for Medical Device Evaluation

The overall regulation of pharmaceuticals and medical devices is the responsibility of MHLW. Currently, the Pharmaceutical and Food Safety Bureau within MHLW is responsible for pharmaceutical and medical device regulatory policy making.

The evaluation of the safety and effectiveness of medical devices is currently performed by two centers under the control of MHLW: PMDEC and JAAME. PMDEC was established in July 1997 under the National Institutes for the Health Sciences. It reviews manufacturing and import approval applications for drugs, quasidrugs, cosmetics, and medical devices. PMDEC Division 4 is analogous to CDRH and is responsible for evaluating all approval applications and clinical trial applications for new and improved medical devices. JAAME, a so-called designated organization, performs equivalence reviews of all generic, or me-too, medical device applications.

The evaluation of the safety and efficacy of pharmaceutical products is performed by PMDEC’s Divisions 1, 2, and 3, as well as OPSR. Similar to its regulation of medical devices, PMDEC is responsible for evaluating all new-drug approval applications. OPSR conducts compliance and equivalency reviews for generic drugs, pharmaceutical clinical trial application reviews, and new-drug good clinical practices (GCP) and good laboratory practices (GLP) compliance reviews.

With its consolidated resources and expertise, PMDA is now responsible for the review of all Class III and Class IV medical device premarket approval applications, which ensure the quality, safety, and effectiveness of medical devices. PMDA also will collect and analyze reports on defective medical devices. The new organization also is responsible for developing standards for reviewing medical devices. In addition, it will provide consultative services for pharmaceutical, biologic, and medical device companies in the development of clinical protocols.

New Application Documents

Figure 2. Changes in the medical device approval application format under the PAL revisions. MHLW will require a STED format for medical device approval applications (click to enlarge).

By 2005, under the new law, the medical device approval application format will be the Summary of Technical Documentation (STED) system. MHLW has already implemented a STED pilot program to assess the feasibility of this document format.

GHTF has established “Essential Principles of Safety and Performance of Medical Devices,” or “Essential Principles” (EP), as the new international standard for premarket approval of medical devices. Japan’s new medical device review system will incorporate this concept in evaluating devices. Currently, MHLW is evaluating the usefulness of STED, the GHTF format for medical device approval applications. STED is expected to be the accepted format by regulatory authorities worldwide. Having a universal format would reduce the time and cost required for manufacturers to produce device approval applications.

For example, when developing medical devices, manufacturers often conduct many tests, such as safety tests and clinical studies, and perform risk analyses. In doing so, they collect a large volume of information and documents to demonstrate the device’s safety and effectiveness. Currently, Japanese device approval applications must contain information on the device design, structure and dimensions, materials, intended use or effects, performance, specifications, operating methods, manufacturing methods, and shelf life. Required documents, which are attached to the application, include the history of the device development, data on the physical and chemical properties, device specification data, stability data, safety and performance data, and clinical data. In the new review scheme, the application must still contain this information. However, the STED document will act as the summary of these data subsets. The STED system will be used for demonstrating conformity to EP and will also provide the risk analysis, labeling, manufacturing, and quality control information (see Figures 2 and 3).

In addition to evaluating device approval applications, MHLW performs GLP and GCP inspections. When a device is approved, MHLW must confirm that the manufacturer conforms to good manufacturing practices (GMP) regulations and quality control standards. Currently, the prefecture governments inspect domestic manufacturers of Class II, III, and IV devices. MHLW inspects manufacturers of cellular- or tissue-based devices and all foreign device manufacturers. Under the new system, the prefecture governments will perform GMP inspections of Class III device manufacturers. MHLW will perform the inspections of foreign manufacturers of Class III and IV devices as well as domestic manufacturers of Class IV devices.

STED

Figure 3. The new Japanese medical device approval process (click to enlarge).

Japan supports GHTF efforts to harmonize device regulation. On February 1, 2002, MHLW initiated a STED pilot program. The program was designed to assess STED’s usefulness for device submissions that fall into the existing MHLW new and improved medical device categories.

The format of STED has been discussed by GHTF. However, the STED document describes only the format of the application. It does not say what kind of information, nor does it explain how much information, should be included in the STED. Therefore, each nation’s regulatory authority must resolve these issues. To achieve global harmonization, regulatory authorities from each participating country would need to agree on a single format.

Currently, a request for application documents varies from country to country. Some require simple test results while others require long, detailed test reports.
In Japan, MHLW requires that manufacturers provide safety and effectiveness testing results. However, it also requires the manufacturer’s own interpretation of the data in the form of a risk-benefit analysis.

Conclusion

Researching and developing new technology for medical devices is very important. One reason PAL was amended was to address this issue. MHLW also hopes to improve public health by promoting research and development.

Toward that end, MHLW published “The Vision of Medical Device Industry” on its Web site. MHLW will establish a system for promoting research and development of new medical devices according to that vision. These efforts will contribute to the improvement of safety, efficacy, and quality of medical devices. In addition, any new safety measures for medical devices will have a goal of eventual global harmonization.

Authors’ Note

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

Bibliography

Guide to Medical Device Registration in Japan, 6th ed. (Tokyo: Yakuji Nippo Ltd., 1997).
Medical Device Regulations in Japan: Questions and Answers, 1st ed. (Tokyo: Yakuji Nippo Ltd., 1993).

Pharmaceutical Administration in Japan, 10th ed. (Tokyo: Yakuji Nippo Ltd., 2001).

Revision of the Pharmaceutical Affairs Regulations 2002, Pharmaceutical Affairs Study Group (Tokyo: Yakuji Nippo Ltd., 2003).

Summary Technical Documentation for Demonstrating Conformity to the Essential Principles of Safety and Performance of Medical Devices (STED), Study Group 1 of the Global Harmonization Task Force, December 18, 2000.

The Vision of Medical Device Industry, [on-line] (Tokyo: Ministry of Health, Labor, and Welfare); available from Internet:
www.mhlw.go.jp/public/bosyuu/iken/p0319-1.html.

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