Medical Device Link.

Originally Published MDDI October 2004

Regulatory Outlook

Figure 1. Under the old PAL, manufacturers had to obtain a manufacturing license and a manufacturing approval. Under the PAL revisions, manufacturers of medical devices must obtain a marketing license from the local prefectural government and a marketing approval from MHLW (click to enlarge).

FDA’s Office of Device Evaluation and The Japanese Pharmaceuticals and Medical Device Evaluation Center

 The Japanese medical device arena is about to change radically. On July 31, 2002, the Japanese government enacted sweeping revisions of the Pharmaceutical Affairs Law (PAL). The revisions reflect the government’s efforts to ensure the quality, safety, and efficacy of medical products.

When the revisions are fully implemented in 2005, there will be significant changes to the preapproval and postmarketing regulatory systems. New biological product regulations, a third-party certification system for low-risk devices, and a Prioritization of the Ministry of Health, Labor, and Welfare’s (MHLW) reviews of high-risk medical devices are included in the revisions.

Before the revisions are implemented, changes will be made to the organizational structure of MHLW. The changes introduce new procedures and programs within the review system to streamline the process and to make it more consistent with global harmonization efforts.

The Japanese Medical Device Evaluation System

The definition of a medical device in Japan is similar to the U.S. definition. A device is defined as an instrument or apparatus intended for use diagnosing, curing, or preventing diseases in humans or animals, or intended to affect the structure or functions of the bodies of humans or animals.
Under the current PAL, a manufacturer must obtain a manufacturing or import approval, or shonin, from MHLW for each product. Manufacturers must also obtain a manufacturing or import license, or kyoka, from the prefectural government (see Figure 1).

Before issuing approvals, MHLW examines the application in detail with regard to the quality, efficacy, and safety of the proposed medical device. Before issuing a license, the prefectural government examines an applicant’s facilities and personnel to determine whether the manufacturer is qualified to make or import the medical devices.

Newly approved devices are required to be reexamined following their initial approval. Devices with new designs, structures, and principles must be reexamined four years after their approval. Devices with new effects, usages, or performances must be re-examined three years after approval.
At the time of a device’s approval, its effectiveness and safety are evaluated based on the knowledge of scientific technology available at that time. But these devices must undergo a follow-up evaluation to account for technological advances in medicine, pharmacology, biology, and electronics. During this initial postapproval period, devices cannot serve as predicates for generic device approval applications.

Marketing Authorization System

Figure 2. The old medical device review system. Class II, III, and IV medical devices were reviewed based on the whether the device was new, improved, or a generic me-too device (click to enlarge).

The current approval and licensing system is based on an applicant’s ownership of the manufacturing establishments. MHLW revised this system to account for new requirements for postmarketing safety measures and changes in corporate structures in Japan and worldwide.

The new system separates the manufacturing functions from the marketing functions. Moreover, a company is no longer required to own the manufacturing establishments. In the current system, MHLW approves the products’ manufacture; the new system approves the products’ marketing in addition to manufacture (see Figure 2).

For each product, a company is required to obtain a marketing approval and a marketing license. Licensed marketing-approval holders are required to have quality control systems and postmarketing safety control systems in place. Marketing licenses are renewable every five years. In addition, manufacturers who provide devices only to licensed marketing-approval holders, rather than to the market as a whole, must still be licensed to manufacture the devices.

Minor changes may be performed by notification without repeating the procedures to approve these partial changes.

Risk-Based Classification of Medical Devices

In the current PAL, medical devices are classified into four categories: Class I, Class II, Class III, and Class IV. The categories are based on the devices’ risk to humans. Class I devices and some Class II devices do not need preapproval for manufacturing, and their sales are not regulated. Most Class II devices and all Class III and IV devices require approval by MHLW.

Table I. Classifications under the current system (a) and under the new risk-based medical device classification scheme (b)(click to enlarge).

The new system also separates medical devices into four classes, which are based on the device classification of the Global Harmonization Task Force. Class I devices are renamed General Medical Devices and require a marketing license from the prefectural government. They do not need marketing approval, and their sale is not regulated. Class II devices are renamed Controlled Medical Devices and require third-party certification. Class III and Class IV devices are designated Highly Controlled Medical Devices. As the name suggests, these products are highly regulated and require marketing approval by MHLW (see Table I).

Third-Party Certification of Low-Risk Medical Devices

The new PAL revisions stipulate that low-risk medical devices (the new Controlled Medical Devices) be evaluated by third-party organizations. Using international guidelines and standards, MHLW is establishing standards for accrediting third parties. Such standards include those from the International Organization for Standardization and International Electrotechnical Commission. MHLW will regularly audit all third-party organizations.

These marketing-approval holders apply directly to a third-party certification body for marketing authorization. The third party determines whether the medical device conforms to the standards published by MHLW. The conformity certification is renewable.

The third party also confirms manufacturers’ compliance with quality control standards such as ISO 13485 by reviewing submitted documents or performing field investigations of manufacturing sites. If compliance is confirmed, the manufacturers or importers can sell the certified medical devices. After certification, the third parties regularly audit the manufacturers that use quality control standards.

MHLW accredits and supervises the third-party certification bodies through a renewal system to be established. MHLW will also establish operational duties, confidentiality obligations, operational standards, and other guidelines with which certification bodies must comply. MHLW will also provide guidance to the certification bodies.

Medical Device Nomenclature

To make communications with foreign regulatory agencies easier, the government developed The Japanese Medical Device Nomenclature (JMDN). The JMDN conforms to the international standards embodied in global medical device nomenclature.

Reliability of Medical Device Data

MHLW will establish clinical trial standards regulations similar to those for pharmaceutical clinical trials, including good clinical practices and good laboratory practices. The PAL revisions require manufacturers to notify MHLW 30 days before initiating a trial. Adverse events occurring during the clinical trial must be reported.

Biological Products Regulations

Many pharmaceutical and medical products are now derived from biological source materials, such as cells, tissues, and blood. The potential risk of unknown infectious agents derived from these source materials cannot be ruled out. In addition, the means of destroying infectious agents are limited because of the desire to maintain the integrity and function of cells and tissues in the products. Thus, the safety of the individual biological products is affected by the donor profiles of source materials, as well as how these materials are collected and processed. The PAL revisions address these concerns. MHLW established legal statutes for regulating biological products.

The old PAL provided no clear legislative statutes for biological products, nor were there regulations to handle their characteristics effectively. The PAL specified only “minimum requirements for biological products.” The requirements addressed a limited number of traditional pharmaceutical products, such as blood products and vaccines.

The PAL revisions provide a legal definition of biological product regardless of the product category. They also establish comprehensive regulations for biological products.

Biological products are defined as pharmaceuticals and medical devices manufactured of source material derived from human or animal cells or tissues. These products require special caution in terms of public health, such as gene recombinant preparations and vaccines.

Specified biological products are those that require special measures in order to prevent the onset or spread of health hazards. Such hazardous materials include human blood preparations, human allogenic cellular- or tissue-based products, and live animal cellular- or tissue-based products.

MHLW designates individual products as biological products following consultation with its Pharmaceutical Affairs and Food Sanitation Council. The PAL revisions identify additional requirements for these products that enhance quality and safety measures pertaining to manufacturing, distribution, and use. For example, one system ensures more-seamless records traceability from donors to users for higher-risk biological products.

For certain biological products, MHLW requires additional precautions to reduce the risk of infection transmission. These standards outline the methods of collecting and processing source materials, as well as recordkeeping. At the time of cell or tissue collection, donor screening, such as oral questionnaires and viral testing, is also specified. Records pertaining to source materials that have a higher potential risk for transmitting infectious agents must be kept and stored in accordance with MHLW ministerial safety measures ordinances.

Manufacturing standards for biological products include standards for facilities, equipment, manufacturing methods, and quality control. Other standards address pharmaceutical and medical device manufacturing.

Postmarketing Safety Measures

The current approval system is an establishment-based set of regulations. The corporate environment is changing due to market globalization, advancing technologies, and corporate structure reform.

The existing structure makes it difficult for corporations to obtain approvals and licenses. The difficulty arises from the fact that many corporations subcontract manufacturing to other companies or separate their manufacturing and processing functions. The existing system does not sufficiently address concerns for imported products.

The PAL revisions place greater emphasis on corporate organizations and systems that can perform postmarketing duties rather than manufacturing duties. MHLW believes that product follow-up in the postmarketing phase is equally important to—perhaps more important than—premarket and manufacturing functions.

Conclusion

The Japanese government has undertaken measures to adapt its medical device regulatory structure to address device safety and effectiveness. The PAL revisions account for the realities of global business structure, international harmonization efforts, and resource limitations within the Japanese government. Significant changes in the device regulatory system include device classification schemes, approval application formats, third-party certification systems, comprehensive biological product regulations, and stricter clinical investigation regulations. It will take time and experience for both industry and the regulatory community to navigate in this new medical device regulatory landscape.

Authors’ Note

This article represents the professional opinion of the authors. It is not an official document, guidance, or policy of the U.S. government, HHS, FDA, or the Japanese 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).

Copyright ©2004 Medical Device & Diagnostic Industry