Introduction: Incorporation of the cost-effective perspective to health insurance system in Japan are scheduled to include medical devices, yet there has not been a systematic examination of the characteristics of medical devices required for cost-effectiveness analyses (CEA).
Objectives: To assess the quality of efficacy data submitted by manufacturers to the Pharmaceuticals and Medical Devices Agency (PMDA) for premarket approval (PMA) and postmarketing surveillance (PMS) of medical devices and to discuss the feasibility of conducting CEA of medical devices in Japan.
Methods: This study reviewed 122 summaries of efficacy data (83 for PMA and 39 for PMS) between April 1999 and August 2012. The methodological characteristics considered essential to minimize confounding and bias were examined.
Results: Thirty-two of the 83 PMA summaries (39%) were from randomized studies and 11 (13%) were from blinded studies. When analyzing the data stratified by country of study implementation, eight of the 34 PMA studies (24%) that included Japanese sites were randomized and 3 (9%) were blinded. The average (min-max) numbers of study hospitals in Japan for PMA with and without Summary Technical Documentation (STED) were 6.6 (2-15) and 4.4 (1-10), respectively. There was a substantial discrepancy between the total number of hospitals and the number of Japanese hospitals included in analyses.
Conclusion: The PMA of medical devices by the PMDA is often based on studies that lack adequate strength and may be prone to bias. It may be useful to conduct CEA for medical devices through PMS assessments of cost data and/or additional efficacy data.

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This study objectively and quantitatively determines a perception gap in terms of alliance between venture companies and pharmaceutical companies to fill the gap for the purpose of achieving practical use of innovative pharmaceuticals originated from Japan. Questionnaire and hearing surveys of venture companies and pharmaceutical companies were conducted. Results of the surveys revealed there is a perception gap between both sides regarding the reason of non-formation of alliance, the period that allows pharmaceutical companies to investigate licensing, and so forth. Also, there are problems associated with the gap. By investigating the causes of the gap, we examined a bottleneck inhibiting smooth alliance between both sides. Venture companies had an insufficient awareness or understanding of methods for evaluation performed by pharmaceutical companies and appropriate methods for selecting partners to offer an alliance proposal. Meanwhile, pharmaceutical companies provided insufficient explanation of the reason for declining an alliance proposal and insufficient information on the will to form an alliance and the contents of fields, technology, etc. of interest. These were considered to form a bottleneck. In particular, the fact is that pharmaceutical companies only state “it is premature to discuss at an early development stage” regarding an alliance proposal, which causes venture companies to inadequately understand the real intention of the reason for declination. This promotes misunderstanding of venture companies in that they may simply advance development without the improvement from the viewpoints of pharmaceutical companies, which could be a negative factor for alliance between both sides.

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Development of computer and information-communication technology has brought significant changes to clinical trials. The Action Plan for the 5-Year Clinical Trials Vitalization Plan 2012 set the target of “utilizing information technology further” and aims to have the Institutional Review Boards prepare review materials in electronic form for clinical trial procedures. Digitalization can simultaneously improve both the efficiency and quality of operations. However, it has some disadvantages, such as data corruption that instantly causes loss of visual readability and difficulty in detecting falsifications. This paper explains the points to be considered for correct digitalization of clinical trial procedures, including clarification of legal issues.

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PMDA is gearing up to build an advanced workflow of review/consultation using innovative assessment techniques. One who submit for a new drug approval will be required to provide individual data of clinical trials in the forms according to CDISC standards. Though the pharmaceutical industry agree to its goal, due to the unexpectedly fast speed of changes, vairous challenges and worries arise. However, author thinks those can be overcome. Most of the stakeholders confines their attentions to data conversion from data not conforming CDISC standards to data conforming them. Because such a data coversion is very costly and does not contribute to quality of study being conducted, we should stop or avoid it as soon as possible. With the end-to-end implimentation of CDISC standards, we could reduce ex-post cost of data conversion to ZERO and could enhance our process capability of data processing and our interoperability.

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The Japan Revitalization Strategy indicated that it is essential to strengthen the system of the PMDA with respect to both quality and quantity, and the Healthcare and Medical Strategy (an agreement among relevant ministers, June 14, 2013) further states that PMDA shall promote its analyses and research by utilizing study data (e.g., clinical data) and shall establish a rational and efficient process for making evaluations and decisions in its reviews and consultations. In order for PMDA to take initiative to conduct its analyses and research using data, it is important for the clinical data, first of all, to be submitted in an electronic format. Collecting clinical study results in the format of electronic data will enable various analyses to be conducted in application reviews for individual products, which will allow more objective and scientific decisions to be made and further contribute to an increase in the quality of its reviews. Uniform methods of collecting study data from various products will also allow product cross-sectional evaluations and may enable utilization of modeling and simulation. Meanwhile, electronic clinical study data submission on an application is thought to provide many advantages for the applicants as well. This article summarizes the current status on constructing the advanced review/consultation framework in Japan.

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Various initiatives by the Government are currently being implemented to form core hospitals that conduct quality clinical trials and to reform the Ethics Guidelines to ensure the reliability of clinical research. Important elements in these initiatives are human resource development, quality management and secure conduct of trials. The computerization in clinical research at medical institutions is essential to raise the efficiency in these elements but there are four issues: long term record keeping, raising the efficiency of application to institutional review board and reviewing, the collection and quality management of clinical data, and education and training through e-learning. In particular, electronic data capture (EDC) system is now becoming essential for the conduct and reliability, not only of investigator-initiated clinical trials aimed at approval, but also of numerous clinical researches running in medical institutions. For this purpose, some academic institutions developed their own user-friendly EDC systems. We have also developed our own EDC system that can be easily customized by researchers, titled the UHCT ACReSS, and, recently, the number of trials and participants registered in this system is rapidly increasing. On the other hand, we are also introducing a learning management system in which investigators can ascertain respective learning goals and update their learning history. Thus, computerization in medical institutions plays important role in the conduct and reliability of investigator-initiated clinical research.

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The data center of Nagoya Medical Center has been supporting clinical trials of rare diseases. In the field of rare diseases, it was difficult to drum up funding because of the small market size. We have been promoting efficiency by computerization while ensuring the quality of data management. In particular, we streamline case reporting, query operations, duplicate registration correspondence, safety information management, collected data standardization, international collaborative trial management, and lab data input and monitoring. As a result of workflow specific computerization such as development of own electrical data capture system and safety information management system, CDISC standards implementation and concept presentation of data transfer from electric health record, we have obtained quality improvement and cost reduction of the data management.

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Post-marketing surveillance (PMS) enables confirmation of the efficacy and safety of medical devices under clinical conditions that could not be obtained from clinical trials. In addition to producing beneficial clinical information for patients, PMS is important in the planning of post-market safety measures. However, PMS conducted only by private corporations would invariably face various problems. Currently, the development of post-market registries under industry-government-academic collaborations is gaining worldwide importance. Well-designed and high-quality post-market registries may facilitate the implementation of prompt safety measures, optimization of patient care, understanding of the actual performance of medical devices, and reduce the dependence on clinical trials. Japan has already initiated several post-market registries under industry-government-academic collaborations (J-MACS and TAVI registry), but it is hoped that there will be further discussions regarding the utility value of evidence obtained from these registries, with the continued implementation of various other registries in the future.

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The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) is intended to develop technical guidelines for new drug development in the quality, safety, efficacy, and multidisciplinary areas under the initiative of the regulatory authorities and pharmaceutical industry of Japan, the United States, and Europe. With these guidelines, the ICH provides the principles for regulatory documents concerning drug development by the tripartite regulatory authorities. ICH has continuously performed its activities for more than 20 years, and basic guidelines have been developed. Currently, to meet the need for greater international harmonization against the background of recent diversification of processes and new technologies in drug development, the organization is engaged in several new issues as well as the revision of important guidelines. Particularly in the efficacy area, based on the need for higher quality and cost reduction in clinical trials, as well as the universalization of global clinical trials, the ICH is addressing the revision of the Good Clinical Practice guidelines (E6), considering consensus on the concept of Multi-Regional Clinical Trials (E17), and exploring the collection and storage of genomic information (E18). Concerning the introduction of a next-generation review system and the trend toward global simultaneous NDA submissions and approvals in the industry, the organization has started discussions on the introduction of the benefit-risk assessment structure in the Common Technical Document (M4), and the significance of follow-up of dropouts/withdrawals in statistical analysis and the methodology of analysis (E9). These ICH activities have great impact on global drug development. The guidelines developed by the organization are expected to serve as a practical landmark for new drug development.

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At the same time that drug development is becoming more global, the discovery process has become more protracted and therefore more costly. To efficiently produce effective and innovative drugs, we have to promote education and research in regulatory science. As the largest drug market, as well as the springboard for new drug creation, we investigated the state of education and research in regulatory science in the United States (US). The results indicated that the regulatory bodies both in the US, Food and Drug Administration, and Japan initiated changes in regulatory science. Moreover each university provided its own distinctive education and research in this area. Three key issues surfaced in our analysis: 1) optimization of specialized education using alternative delivery methods including full-time on-line educational programs, 2) communication in educational settings as the means of transmitting critical information between industry-government-academia, and 3) seamless cooperation of universities and/or industry-government-academia. The education and research in regulatory science in pharmaceutics has just started in Japan. The dynamic cooperation among industry-government-academia in this area is rare. Pharmaceutics in integrated academic areas such as pharmacokinetics, drug formulation and analytical chemistry, should play an important role for expanding regulatory science. We aim to accelerate drug development within Japanese industry and regulatory bodies by expanding Japanese education and research in regulatory science by utilizing some of the US approaches.

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