In order to ensure the protection of human subjects and credible clinical trial data, clinical trials are audited by the Pharmaceuticals and Medical Devices Agency (PMDA) to verify Good Clinical Practice (GCP) compliance. There are 2 kinds of GCP inspections in Japan: GCP on-site inspection and document-based inspection. The conformity between raw data and case report forms (CRFs) is assessed through a GCP on-site inspection at specified medical institutions. In pivotal clinical trials, the reliability and conformity between CRFs and product application documents are confirmed by a document-based inspection and data integrity assessment. Changes in GCP compliance were investigated by examining review reports for New Drug Applications (NDAs) between fiscal year (FY) 2010 and FY2012. At some clinical study sites in GCP on-site inspections, violations were found, and the PMDA requested the applicants to exclude some cases from efficacy evaluation and to revise the dossier. The frequency of these cases of pharmaceuticals approved in FY2010, FY2011, and FY2012 were 3.0%, 2.6%, and 2.7%, respectively. At document-based inspections and data integrity assessments, the PMDA often asked the applicants to revise the original dossier. The frequency of these cases of pharmaceuticals approved in FY2010, FY2011, and FY2012 were 0.0%, 2.5%, and 1.3%, respectively. The revised dossiers were found acceptable for evaluation. The quality of the clinical trials was high and sufficient for NDAs. In Japan, it is important to develop new promising drugs for patients who need appropriate treatment while ensuring the protection of human subjects.

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A questionnaire survey addressed to pharmaceutical companies was conducted to collect information on the situation and implications of so-called “all-case surveillance studies” (post-marketing surveillance studies of all cases the drug was used), which have been conducted in Japan. For nearly 90% of 132 drugs, all-case surveillance studies were conducted for the reason that the number of cases in the pre-market domestic clinical trials was too small. Drugs classified as “antiinfectives for systemic use” and “antineoplastic and immunomodulating agents” accounted for more than 60%. Sample size of the surveillance study was pre-planned in about half of the studies, and the number of the collected cases far exceeded the planned cases in many of the studies. While a large number of responses pointed out “catching all the safety information” as the usefulness of the all-case surveillance study, importance from the viewpoint of risk-minimization such as “providing doctors with necessary information for appropriate use of the drug” and “confirming eligibility of patients in a careful manner” was indicated in some cases. Concerning the operation of the study, a lot of comments called for simplification of the case report form and clarification of the criteria and procedure of ending the study.

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Based on the amendment of Pharmaceutical Affairs Law (PAL) which is to be implemented on 25 November 2014, the Ministry of Health, Labour and Welfare is introducing regulations taking into account characteristics of medical device, which will result in acceleration of medical device marketing under more rational regulations. The name of PAL is changed to “Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics (PMD Act)”. This change intends to clarify the scope of PMD Act includes medical device.

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In order to realize the safe and quick supply of pharmaceuticals, medical devices, etc., “the law which revises the parts of the Pharmaceutical Affairs Law etc.” was proclaimed on November 27, last year. Under the revises of the Pharmaceutical Affairs Law, the package inserts should be prepared based on the newest knowledge, and notified to the Ministry of Health, Labour and Welfare as strengthening of the safety measures concerning pharmaceuticals, medical devices, etc. The construction of the new regulation based on the characteristic about medical devices will be performed. The regenerative medicine is expected as innovative medical treatment recently. To secure prompt and safe provision of regenerative medicine, new framework is needed. In this paper, the circumstances of legal revision, the institutional contents, etc. are introduced especially focusing on the new regulatory system of the regenerative medicine.

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The new regulation of the conditional and time-limited approval system considering of the characteristics of regenerative medicinal products and the Package Insert notification to the authority, are deeply associated with clinical drug development in the revision of the Pharmaceutical Affairs Law announced in November 2013 (enforcement of the revision scheduled in November 2014). The Act of safe security for regenerative medicine will be simultaneously enforced with this revision. “The correct risk assessment and the appropriate response based of the magnitude of the risk” from research and development stage until implementation as medical practice is inferred as the fundamental concepts. However, different clinical study regulation systems can be applied to the clinical study standard in Japan between regenerative medicine and other medicinal products/medical devices, and also between clinical trials for Japanese new drug application and other clinical studies, so that it would not be preferable for the properly understanding and its excellent regulation on the Act for all stakeholders. The rigid regulation systems should be hopefully established, which can be commonly used for those, with national standards for medicinal management and clinical study conduct, which would be affected on life and health of human kinds.

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I have investigated whether the revision of the Pharmaceutical Affairs Law at this time affects the promotion of the development of medical devices in Japan. It is expected that at the same time as the law revision, review of related laws and regulations is also carried out. With the maintenance of them, I hope that the development of medical devices is promoted.

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Cell therapy products, regenerative medicines, represents a new paradigm in human health, with the possibility of treating many diseases including resolution of unmet medical uses. In order to accelerate the development of the regenerative medicines, several guidelines addressed the safety and efficacy of regenerative medicine have been published. In addition of publication of guidelines, the Act on the Safety of Regenerative Medicine and the Revised Pharmaceutical Affairs Law have recently been simultaneously passed by the Japanese Diet. According to the revised law, a conditional, time-limited marketing authorization will be applied to the regenerative medicine. In this paper, the issues concerning to new legal framework of regenerative medicine will be discussed.

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Evaluation of drug interactions (DIs) in the drug development is important for reduced incidence of adverse reactions in clinical trials and proper use of drugs in the post-marketing. The current Japanese guidance on DI was issued more than 10 years ago and during which period there were a lot of progress in the research related to DI and the clinical information is accumulated. Novel guideline and draft guidance was also publicized recently from EMA and FDA, respectively. Based on this situation, we started investigation to draft new Japanese guideline from Dec. 2012, constructing a team consisting of experts from industries, academia, and regulatory agencies. Preliminary draft was notified in Dec. 2013 for public comments. After examining comments obtained, the draft guideline was finalized in May 2014, and submitted to and publicized by Japanese Ministry of Health, Labor, and Welfare. In addition to the overall update of existing guidance, the final draft supplemented detailed explanation in every area. Followings are major part of revision. 1) transporter studies on absorption in small intestine, urinally excretion from kidney, and biliary excretion from liver; 2) stepwise examination via metabolizing enzymes and transporters using decision trees; 3) evaluation by modeling and simulation using in vitro and in vivo data; 4) lists of known inhibitors and inducers on major cytochrome P450 isoforms classified in strong-, intermediate- and weak-affecting groups based on the changes of AUC or CL/F, and a table of “drugs susceptible to DIs” and “drugs moderately susceptible to DIs”; 5) Interactions with therapeutic proteins; and 6) labeling recommendations. In this review, we introduce the novel draft guideline focusing on the above important points.

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Introduction: Health technology assessments (HTA) of medical devices require analyses of claims data to understand utilization statuses. However, these analyses are inhibited by the functional group-based reimbursement regulations applied to medical devices.
Objective: To investigate the feasibility of analyzing claims data regarding medical devices.
Methods: This study reviewed 735 insurance coverage documents regarding brand names, functional groups, and starting dates of coverage for B-class and C-class devices between April 2002 and February 2013. A “solo interval” was defined as the duration from the starting coverage date of a C-class device to that of a B-class device within one functional group. Associations between the types of devices and the solo intervals were also evaluated.
Results: There were 139 (18.9%) functional groups newly covered as C-class devices; the median (interquartile range) solo interval was 16 (5-31) months. Of these, 67 (48.2%) functional groups were also covered as B-class devices. A solo interval of 6 months or less was observed in 23 C-class devices, accounting for 34.3% of 67 functional groups. Data could not be extracted by brand name in the majority of cases (71.6%) after 2 years had elapsed from coverage commencement. There was no association between the types of devices and the solo intervals (P = 0.622).
Conclusion: The functional groupbased reimbursement regulations inhibit analysis of claims data to assess medical devices utilization. To assess the cost-effectiveness of medical devices though postmarketing surveillance, it may be necessary to apply brand name-based reimbursement regulations for HTA of medical devices.

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The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) was set up in April, 1990, with the aim of international harmonization through the bringing together of regulatory authorities and the pharmaceutical industries of Europe, Japan and the US in order to discuss the scientific and technical aspects of drug registration. Since then, approximately 80 guidelines such as technical guidelines regarding efficacy, safety and quality of drugs as well as various formats for new drug application, etc., have been harmonized. The benefits of international harmonisation for better global health can be realized worldwide and the outcomes of ICH activities have contributed to the reduction of international barriers, duplicative clinical trials, and drug development and research resources as well as information-sharing with Non-ICH countries. Recently, the circumstances surrounding drug development, manufacturing and distribution have been changed significantly, which have facilitated the transition from Europe, Japan and the US to variety of sites worldwide. The rapid changes related to drug regulation calls for worldwide cooperation. ICH, a leading organization promoting schemes for international harmonization, is in the midst of its greatest transformation. It has been encouraging to the continuation of discussions related to ICH's reform and reactivation. Through improvement work, ICH has promoted organizational reform such as the expansion of ICH members. In order to achieve the reactivation of ICH, the ICH steering committee has recently adopted the implementation of eight new topics. The ICH has intensified its global efforts in conjunction with the promotion of outreach activities through the provision of training services to Non-ICH countries.

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