Introduction

It might seem strange for clinicians that medical devices which are popularly used outside their countries are not available in their own country. It should be recognized that each country and/or region has their own regulation of medical devices. Basically, medical devices which are not registered or listed cannot be used.

The principal objective of medical device regulation is to protect the patients and medical care of the country. A medical device should provide effectiveness, safety and quality depending on the purpose of use. This means that the regulation of medical devices is not always convenient for manufacturers and users.

It might be assumed that the variety of medical device regulations is caused by differences in the thinking and range of responsibility of the user, manufacturer and country. However, approaches have been made to discuss the global convergence of medical device regulations despite these different situations.

Multiregional clinical trials

It is well-known that there are several steps in medical device development. For clinicians and patients, a clinical trial is the first exposure to devices in the development stage. Although not all medical devices require pre-market clinical trials to obtain market approval, clinical trials are the most important step to evaluate the safety and effectiveness, especially for novel devices. The safety, performance and effectiveness of medical devices are often evaluated by well-controlled clinical trials before marketing authorization. To obtain approval in various countries and regions at similar times, it is necessary to perform global clinical trials. A simultaneous global development approach is not limited to medical devices. Several articles have discussed the importance of multiregional clinical trials in the simultaneous worldwide clinical drug development [1–5]. However, global clinical trials are not easy to set up because many things have to be taken into account. Global development is more difficult than development in a single country for drugs as well as medical devices. Drugs have a long history of worldwide development and many things have to be considered in global development. For example, the International Conference on Harmonization (ICH) E5 guideline entitled “Ethnic Factors in the Acceptability of Foreign Clinical Data,” issued in 1998 [6], describes factors that could lead to different responses in different ethnic groups, including differences in pharmacokinetics, pharmacodynamics, and clinical properties. Furthermore, some organizations have established a center for multiregional clinical trials like Harvard MRCT center [7] and other organizations like APEC harmonization center provide training opportunities for multiregional clinical trials [8].

Because of the enormous variety of medical devices, development is usually based on an individual case-by-case basis rather than by following uniform guidance. Although many medical devices are not considered pharmacokinetic or pharmacodynamic, some developers have to consider evaluating product safety and effectiveness with non-negligible ethnic factors for certain types of devices.

Harmonization by doing

In order to overcome barriers against global medical device development, a unique program was started in 2003 called ‘harmonization by doing’ (HBD [9–11]. HBD is an international effort to develop global clinical trials and address regulatory barriers that may be impediments to timely device approval. The program has been operating using volunteers from industry, academia and government from both the USA and Japan.

The HBD had 4 working groups: (1) WG1— Global Cardiovascular Device Trials; (2) WG2—Post-market Registries (e.g., artificial heart); (3) WG3—Clinical Trials Infrastructure and Methodology; and (4) WG4—Regulatory Convergence and Communication (Fig. 1). The goal for each working group is the achievement of speedy and efficient medical device development in Japan and the USA (Table 1). Furthermore, the program has held multiple international meetings to deal with obstacles facing efficient medical device development and to share information and experiences with stakeholders [9, 12]. This process was a cooperative effort to move both Japan and the USA toward international regulatory harmonization. Participants in this process include the US Food and Drug Administration (FDA) Center for Devices and Radiological Health (CDRH), Japan’s Pharmaceutical and Food Safety Bureau (PFSB) of the Ministry of Health, Labour, and Welfare (MHLW) and its review agency, the Pharmaceutical and Medical Devices Agency (PMDA), the Duke Clinical Research Institute (DCRI), the Japanese academic community, and the Japanese and US medical device industry.

Fig. 1
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Structure of harmonization by doing

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Table 1 Goals of the HBD working groups [9]
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Among these working groups, WG1 was commissioned by the HBD steering committee to promote the convergence of parallel clinical trials in Japan and the USA toward single clinical trial protocols that advance toward global device evaluation. Successful execution of single protocol clinical trials is intended to facilitate more rapid and cost-effective generation of more informative clinical data for pre-marketing, and potentially for post-marketing device evaluation in both the USA and Japan. Considering the difficulty of worldwide medical device development, to understand each country’s specific situation is an important first step in reducing the operational burden on clinical trials while maintaining the quality of the study.

As Uchida et al. reported, development of the drug eluting stent, which was a coronary stent placed into narrowed diseased coronary arteries in Japan, fell behind development in the USA when HBD started [13]. The HBD WG1 group discussed how to make the development speed of the two countries the same. The Japanese academia group decided to take a step-by-step approach. The first stage was to perform clinical trials in Japan following worldwide study protocols retrospectively to clarify and improve the problems that existed. The second stage involved Japanese sites joining a global drug eluting stent trial.

Good clinical practice

In order to conduct clinical trials, investigators have to follow a good clinical practice (GCP), which is an ethical and scientific quality standard for designing, recording and reporting trials that involve the participation of human subjects [14, 15]. Compliance with this standard provides public assurance that the rights, safety and wellbeing of trial subjects are protected and that clinical trial data are credible. However, since each country and region has their own GCP, discrepancies between GCPs makes the mutual use of results from a clinical trial difficult. Furthermore, it also appears to be a major barrier to conducting multiregional clinical trials.

In 2013, the HBD WG4 group compared the GCPs [16] that are most applicable to USA and Japanese marketing approval—US FDA regulation and guidance, Japanese GCP ordinances and notifications, ISO14155:2011 Clinical Investigation of Medical Devices for Human Subjects—Good Clinical Practice and ICH E6 (R1) Guideline for Good Clinical Practice [17]. While the ICH E6 guideline is specifically applicable to drug and biological products, it has been applied as a GCP reference standard for some device studies, and was therefore included in this analysis. They concluded that when a clinical investigation design is appropriate and acceptable to various regulatory authorities, non-substantive and administrative differences among GCPs can be addressed with supplemental information and should not be a barrier to transportability and acceptance of clinical investigation data from elsewhere. Historically GCPs have been revised repeatedly. In 2010, a previous study also performed a comparison of four well-known GCPs—The ICH Guideline for GCP E6 (R1), ISO14155:2003, Japanese regulations (JGCP) and US FDA regulations [18]. They reported no substantive differences with respect to the four fundamental criteria. Moreover, there were no contradictory requirements, i.e., no requirement that one GCP would necessarily cause noncompliance with one or more of the other GCPs studied.

Post-market phase data pooling

The medical device registry is one of the key issues for total product life cycle management [19]. The Japanese registry for Mechanically Assisted Circulatory Support (J-MACS) is a post-market data-collection initiative for ventricular assist devices (VAD) in Japan [20]. This prospective, multisite, observational registry achieves a 100 % participation rate and is a collaborative effort that involves manufacturers of VADs, the Japanese government, and academia. The registry design of J-MACS is harmonized with that of INTERMACS [21], a North American registry established in 2005 for patients who have received mechanical circulatory support devices to treat advanced heart failure. J-MACS is therefore intended to design itself to future data pooling with INTERMACS as part of HBD WG2 activities [19].

Global harmonization activities

In the medical device field, simultaneous global development of medical devices has not been performed in the same positive way as pharmaceutical products. The reason for this is due to differences in thinking, history, and the framework regarding the regulation of pharmaceutical products and medical devices. Medical device regulations do not have a long history. For example, as foodstuffs, chemicals and pharmaceuticals were already regulated in the EU before 1985, a new legislative and technical frame was created in 1985 for other products circulating in EU countries [22]. This new approach concept is a legislative technical frame for harmonization in Europe. Elaboration of directives and technical standards leads to European conformity. In the United States, the US Federal Food, Drug and Cosmetic Act was enacted in 1938 and the Medical Device Amendments Act came into law in 1976 [23].

Global Harmonization Task Force [24]

The Global Harmonization Task Force (GHTF) was conceived in 1992 in an effort to achieve greater uniformity between national medical device regulatory systems. A partnership between regulatory authorities and regulated industry, the GHTF comprised five Founding Members—the European Union, United States, Canada, Australia and Japan. Since its inception, the GHTF now comprises of voluntary representatives from five founding members grouped into three geographical areas—Europe, Asia–Pacific and North America, each of which actively regulates medical devices using their own unique regulatory framework. The chairmanship is rotated among the founding members.

The purpose of the GHTF was to encourage convergence in regulatory practices related to ensuring the safety, effectiveness/performance and quality of medical devices, promoting technological innovation and facilitating international trade, and the primary way in which this was accomplished was via the publication and dissemination of harmonized guidance documents on basic regulatory practices. These documents, which were developed by five different GHTF Study Groups, can be adopted/implemented by member national regulatory authorities. The relationships between the works of each Study Group can be represented schematically.

The GHTF also serves as an information exchange forum through which countries with medical device regulatory systems under development can benefit from the experience of those with existing systems and/or pattern their practices upon those of GHTF founding members.

However, the GHTF terminated its activities at the end of 2012 by changing the situation surrounding medical devices; GHTF guidance documents (Table 2) can be seen on the website of the International Medical Device Regulators Forum (IMDRF), as described below.

Table 2 GHTF major guidance documents [24]
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International Medical Device Regulators Forum [25]

Representatives from the five founding members of the GHTF proposed participation from Brazil, Russia, China and India as management committee members of a new forum to discuss true globalization because of their population and economic influence. At the same time, the World Health Organization was also invited to be an observer. In 2012, a new forum was created (IMDRF) with Australia, Brazil, Canada, the European Union, Japan and the United States (in 2013, China officially joined the management committee member) [26]. The IMDRF is a voluntary group of medical device regulators from around the world who have come together to build on the strong foundation work of the GHTF on medical devices and their aim is to accelerate international medical device regulatory harmonization and convergence.

Conclusion

Krucoff et al. [27] reported that professional societies were uniquely positioned to help facilitate such transformation and revitalize the medical device innovation ecosystem based on their valuable experience on cardiovascular device innovation. Collaboration within one professional society is the first step. As the next stage, inter-society communication is important to create a dynamic, open-ended, transparent collaborative forum among stakeholders, whose objective is to develop consensus definitions and nomenclature and related processes, optimize applications in pivotal clinical trials of specific classes of new medical devices, and to disseminate such definitions and recommended processes into the public domain. The Academic Research Consortium (ARC) which was founded in 2006 invited the FDA to be an advisory participant [28]. Collaborative relationships between societies and countries are valuable. The HBD itself performs small activities only in the cardiovascular field by volunteers from industry, academia and governments of both the USA and Japan. However, they made remarkable progress in the cardiovascular field by having good communication with their stakeholders. It is also important for clinicians in the gastroenterology field to establish and maintain good communications with regulators, industry and other related participants. International medical device regulatory convergence has continued despite replacing the GHTF by the IMDRF. The simultaneous global development of medical devices is helped if the participants act in a positive way.