Biologics are widely used but expensive medicinal products because significant costs are needed for the sophisticated and state-of-the-art technologies and facilities necessary for the manufacturing processes, compared to chemical drugs with low molecular weight. Biosimilars are expected to be one of the solutions to reduce healthcare costs and improve patient access to medical treatments. Due to their complicated high-order structures, biologics are fundamentally different from generic drugs in terms of difficulties in verifying the full comparability to the brand-name biopharmaceutical with physicochemical analysis data at the manufacturing stage. Essentially, regulations in ICH regions require nonclinical and clinical studies to demonstrate the comparability of quality, safety and efficacy to the brand-name biopharmaceutical for marketing approval. Our research was conducted to reveal the key factors in the data-package strategy for marketing authorization and to contribute to the establishment of optimized biosimilar development following patent expirations of best-seller biologics after 2015. Comparing data of each low molecular biosimilar product approved in Japan; i.e. somatropin, epoetin (EPO), granulocyte-colony stimulating factor (G-CSF), and insulin, this research analyzed data-packages, and identified each development strategy and the impact of regulatory guidelines released by PMDA, FDA, and EMA in chronological order. Cross-sectional comparison revealed the contrast between data-packages of somatropin and EPO, both of which were developed prior to the release of regulations for biosimilar (follow-on-biologics) in Japan. EPO has almost the same data package as a new active ingredient, while somatropin has a minimal and reduced data-package relatively similar to generic drugs. Somatropin was developed when EMA guidelines for somatropin biosimilars was open and could be referred by the applicant. It is though that the difference in those applicants' strategies reflects the fact that somatropin is a relatively small molecular biologics and does not have complicated structure or glycosilations which could affect the biological activity. In contrast, all 3 filgrastim biosimilars and the insulin glargine biosimilar took full advantage of the regulations for biosimilars in Japan. However, the data-packages are characteristically different among the 3 filgrastim biosimilars, attributable to the level of impurity and the availability of supportive safety/efficacy data from the clinical studies conducted overseas. Significantly, the insulin glargine biosimilar still has a minimal nonclinical data-package similar to generic drugs, and has succeeded with the quite efficient global development strategy in terms of the shorter development period until approvals in major biosimilar markets within ICH regions; namely the EU and Japan. In conclusion, the comparative analysis of 6 biosimilars indicates the critical factors required for planning an overall development strategy in the future as follows: (1) difficulty of identification of impurity profiles by physicochemical analyses and control at the manufacturing stage, (2) estimation of nonclinical data-package for appropriate assessment to mitigate risks in advance of clinical development, (3) selection of the appropriate endpoint of clinical studies including surrogate markers and the rationale for the extrapolation to other approved indications, and (4) utilizing results of overseas clinical studies as reference data and/or global clinical trials.

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Medical devices' safety and efficacy of the device are evaluated in review process. Varieties of medical devices in terms of working principles, user environment, risk levels, and so on make it difficult to evaluate the efficacy and safety of medical devices systematically. In some cases, development of utilization technology to maximize the performance of the medical devices is not well prepared in the early stages in the market immediately after its commercialization. In this case, it is difficult to evaluate the potential value of the device appropriately. Knowledge on efficacy and safety must be continuously accumulated through clinical application of the device. In the process of development, academic activities such as studies in universities and academic societies contribute to the acquisition of such knowledge. Training and setting guideline for application of medical devices are important activities in this context. One of the advantages of academic activities is their transparency in nature which is indispensable for medical device regulation. For promotion of innovation of medical device technologies, both research and development divisions and regulatory bodies should collaborate to share the common framework of thinking to optimize development and the review process of novel medical devices.

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The medical device industry in Japan is considered as a growth industry and the government strengthens a variety of measures to boost its growth. On the other hand, the social security costs, especially the growth of healthcare costs has been taken up as an issue of the country. The mission of the medical device industry is to provide medical devices with reasonable cost as well as a contribution to the patients by improving the quality of medical services. It is necessary to consider overseas business development with a view to contribute to the world healthcare for accelerating the development of products needed on the market. The article overviews the feature of medical device and its world market situations for the global business strategy.

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Medical device industry in the world is growing. The current meditech industry in Japan is not very active, resulting in over 7bilion US dollar annual deficit in trade. However, given lots of technologies, high capability of manufacturing, and high-level healthcare, Japan has potentials to lead the meditech industry in the world. In order to be more competitive in the arena, global strategies should be necessary. There are several points to consider for a global strategy in medical device development. Those include the Obama Care, Cost-effectiveness, Reverse innovation, Global clinical trial, and Digital-health. Given these keywords, strategies in medical device innovation among startups should become more global rather than just for a country.

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Timely development of medical devices is placed as one of the main features of the Japan Revitalization Strategy. The old Pharmaceutical Affairs Law was replaced by the new “Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics (PMD Act)”, in order to simplify the regulations and facilitate quick access to the medical devices based on their principal characteristics. We evaluate the balance of benefit and risk of a medical device and only when the benefit overweighs the risk, approval can be given. This benefit-risk balance assessment is the fundamental method in regulating drugs and medical devices, as being accepted globally. Many people tend to think that bench tests and/or in-vivo tests are sufficient in evaluating medical devices, as they are only “tools” to cause physical actions. However, medical devices are used clinically, therefore, clinical efficacy and safety should be evaluated based on the clinical data. The regulations on the requirements for premarketing clinical trial data may vary among the countries, however, innovative medical devices need to be evaluated with clinical trial data. The author(s) think(s) that it is very important to discuss among industry, academia and regulators, on how we should optimize the design of the clinical trial to push forward effective development of medical devices.

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Harmonization By Doing (HBD), whose activities include the exploratory study on the implementation of global clinical trials, consisting of the members from industry, academia and regulators of the United States and Japan, is one of the role models for promoting the development of medical devices. In the coronary area, global clinical trials have been conducted on multiple drug-eluting stents, and the trend to implement global clinical trials on the medical devices is spreading to other cardiovascular areas. Also, faster review of medical devices has become possible, by exchanging information and by discussing the review method with US Food and Drug Administration (FDA), through the pilot program regarding collaborative consultation and review of medical devices for cardiovascular disease, such as superficial femoral artery stent, between Ministry of Health, Labour and Welfare/Pharmaceuticals and Medical Devices Agency (PMDA) and FDA, which was derived from HBD activities. Furthermore, the medical experts and regulators (FDA and PMDA) of the US and Japan have discussed on the basic concept of the global clinical trials for the critical limb ischemia endovascular treatment devices (CLI devices), for which no established evaluation method is available, in order to promote development and to speed up the review. As a result of the discussion, the basic concept of the global clinical trials for CLI devices has been formulated, taking into account the difference of medical environment between the US and Japan, which is expected to be utilized in the future clinical trials and to contribute to the reduction of the review time. We think that it is important to spread the activities for exploring the solutions to the issues in other areas, by having extensive discussion for accelerating the development of medical devices through collaboration with the associated academia and industry.

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Pharmaceuticals and Medical Devices Agency (PMDA) has evaluated the safety of drugs primarily relying on the traditional information such as spontaneous adverse drug reaction (ADR) reports or post-marketing surveillance results, etc. ADR reports have contributed to safety assessment by PMDA, but have some limitations such as underreporting, incomplete and a lack of denominator. Consequently, for further reinforcement and enhancement of safety measures, the PMDA has launched the MIHARI (“Medical Information for Risk Assessment Initiative”) Project in the second mid-term plan (FY 2009 to FY 2013) to develop a new safety assessment framework of quantitative evaluation using electronic health records (EHRs). The PMDA is applying this framework into a real situation of risk management of drug safety in the third mid-term plan (FY 2014 to FY 2018). In addition, the PMDA has started to develop a new database system (MID-NET) in collaboration with Ministry of Health, Labour and Welfare (MHLW) and 10 selected collaborative medical institutions.In the MID-NET system, EHRs (including ordering data and laboratory test data) and medical claims data are converted and integrated into databases in each institution. To utilize these databases, users including the PMDA are supposed to send “data extraction script set” from “the data center” to these institutions. Each institution accepts the script set and sends the output results back to the data center, which will then be summarized and analyzed by the user. The PMDA has been working to validate the integrity of the MID-NET system for full implementation in 2018. The MID-NET system is expected to allow users to conduct quantitative safety assessments and to take more effective safety measures.

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