Vagus Nerve Stimulation (VNS) system is a fully implantable electrical stimulator, which stimulates the left vagus nerve to reduce or mitigate epileptic seizures among drug-resistant patients. Three years have passed since VNS was approved in Japan. Until now, more than 500 devices were implanted. However, changes in medical cost have not been reported yet in Japan. The aim of this study is to elucidate cost changes of VNS by comparing the direct medical cost between Pre-VNS treatment for 2 years and Post-VNS for 2 years. Seirei Hamamatsu General Hospital has experienced 87 VNS system implantations from July 2010 to November 2013. Among those, the medical costs of patients who had received the therapy for more than 2 years were surveyed in order to retrospectively compare 2-year antiepileptic drug costs pre- and post-VNS implantation. 17 patients with mean age of 28.6 years (range: 16-56) met the criterion of patients selection. Total direct medical cost in Pre-VNS for 2 years was 21,519,870 JPY and Post-VNS for 2 years was 11,597,610 JPY excluding drug cost. This change in cost was affected by reduced reimbursement codes mandated by the National Health Insurance System, including doctor's fee for diagnosis of epilepsy, EEG and image diagnosis. The 4 new antiepileptic drugs were approved after 2006 with extremely high prices, so that the cost changes occurring due to VNS implantation could not be comprehensively determined. This study may elucidate that VNS carries the changes in direct medical cost among the general epilepsy population. However, it does not mean the cost-effectiveness. Additionally the inclusion criterion for this study was that they had treatment and billing records for a period of 2 years before and after VNS implantation. Therefore the replacement cases were not included because period of the surveillance was too short. Longer term study will be required to understand the cost of VNS implantations including replacement.

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To solve the issue of the unapproved drugs and off-label drugs, since 2005, several approaches had been tried like the establishment of “Usage of Unapproved Drugs Review Conference”, “pediatric drug therapy Review Conference”, “Conference for suitable clinical trials” and “Conference for rapid delivery of the effective and safe medicines”. With these activities, we can have solved the unapproved drugs and off-labeled drugs in some degree. But the effect was restricted in the end because there were short of the financial support. In order to eliminate the lack of incentives for pharmaceutical companies, in 2009 fiscal corrective budget “support project for developing the unapproved drugs” was established as the fund for 3 years. And the new subsequent supportive drug pricing policy “incentive for acceleration to develop new drugs and off-label drugs” are now available as a trial schema from 2009 fiscal. Owing to the new these incentives, unapproved drugs and off-label drugs have been rapidly reduced and drug-lag are almost resolved now. But we are planning to improve the current system into more effective manner. As the further efforts, we are planning to establish “unapproved drugs rapid commercialization scheme”, and “expand access schema” in 2015.

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The effort to the issues of unapproved drugs and off-label use drugs has obtained a lot of results by the discussion of Review Conference on Unapproved or Off-label Use Drugs of High Therapeutic Needs and by the independent approach of pharmaceutical industries. However, not all those problems were solved. The fundamental solution of the issues of the drug lag closely related to unapproved drugs and off-label use drugs is a speedup of the new drug development and the review in Japan. Since the environment that surrounds pharmaceutical industries in Japan has changed considerably, new efforts such as the open innovation are needed. To improve the patient's access to drugs further, the Ministry of Health, Labour and Welfare tries to introduce the system of “Participation in the clinical trial from a humane viewpoint” and “Patient requested medical care system”. I describe the point that should be noted when those systems are designed and about the correspondence to off-label use drugs in the future.

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There are so many social systems and pharmaceutical jurisprudences those enable early access to drugs for unmet medical needs in the world; breakthrough therapy designation and expanded access program in the United States; early access medicines scheme and compassionate use program in the UK; fixed-term conditional approval, humane exceptional use of unapproved drugs, and patient-requested cure system in Japan etc. Patients with life-threatening and serious disease or long-suffering intractable orphan disease aspire unapproved novel drug candidates even if those efficacy/safety evidence are lacking. We, clinician, have to pay attention to those desire. Furthermore, considering the fact that Japanese universal health care's sustainability will face a crisis in 2025 when baby boomer will be elderly aged over 75 or over, industry-government-academia with patients must continue to devise an appropriate early access program in Japan.

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Eighty percent of drug administration in children is for unapproved indication and/or with unapproved dosage and administration, namely “off-label use.” In US and EU, in line with the ideas under ICH E11 guideline, developments of drugs for children have been encouraged, bringing about significant changes in environment surrounding pediatric drug products. This document intends to introduce current status of pediatric drug development in Japan and abroad and to introduce examples of efforts, which have been made for the past 15 years to promote pediatric drug development, by the Japan Pharmaceutical Manufacturers Association composed of pharmaceutical industries in collaboration with academia through Health and Labor Sciences Researches.

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Pediatric patients should be given medicines that have been appropriately evaluated for their use. However, the number of medicinal products currently labeled for pediatric use is limited. In EU and the United States, there are regulations aimed at promoting pediatric drug development, which have been significant success. In contrast, there is no specific regulation for promoting the development of medicines for pediatric use in Japan, and pediatric development is left essentially to the hands of pharmaceutical industries. Ministry of Health, Labor and Welfare (MHLW) has taken some measures to resolve this problem; such as extension of re-examination period of the drug, public knowledge-based marketing authorization application, and development promotion scheme for unapproved and off-label drugs for high medical needs. Pharmaceuticals and Medical Devices Agency (PMDA) has implemented several efforts to encourage pediatric drug development. PMDA established the pediatric working group in November 2011. In an effort to help develop medicinal products for children, the pediatric working group has, collaborated with foreign regulatory agencies for development of pediatric medicines, analyzed and clarified issues raised in the product reviews and the consultations, and exchanged views with domestic stakeholders including pharmaceutical industries, clinical investigators etc. Recently PMDA has established new strategies, Pharmaceutical Affairs Consultation on Research and Development Strategy and Advanced Review with Electronic Data Promotion. In Pharmaceutical Affairs Consultation on Research and Development Strategy, PMDA can advise academic researchers and small businesses on the development of novel drug and medical device candidates for pediatric use. PMDA believes these new strategies contribute to improve predictability of efficacy, safety and optimal dose of pediatric drugs and to accelerate efficient pediatric drug development.

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Japan's participation in global clinical trials has been steadily increasing. The ways of cooperation between Japan and foreign countries have also diversified. In the current situation of drug development, when considering whether or not Japan should participate in a global clinical trial, there are in fact many cases in which human data in a foreign population has already been obtained to some extent in drug developments lead by foreign countries. There may be cases where Japanese phase I trials are not necessarily required prior to Japan's participation in global clinical trials if safety in the Japanese population that will be included in the global clinical trial is ensured by foreign data. Based on the accumulated knowledge up to now, the “Basic Principles for Conducting Phase I Trials in the Japanese Population Prior to Global Clinical Trials” has been issued. This paper explains the necessity of phase I trials in Japanese population prior to global clinical trials, including the background of the new guidance issued and some points to consider.

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The efficacy and safety of pharmacotherapeutic agents are critical as they can spell the difference between wellness, debility, and even death. Some of the essential points to consider include how much and how often a drug is prescribed, what consequences there will be if over or under prescribed, and how it will impact on the underlying medical condition. These issues pertain not only to adult medicine, but also to pediatric medicine. At present, pediatric practice guidelines and approved pediatric product labels often vary widely, especially in Japan, in terms of dosage and administrations, and in some cases, indications. The standard drugs used worldwide for pulmonary tuberculosis in children include isoniazid, rifampicin, pyrazinamide streptomycin, and ethambutol. However, package inserts for rifampicin, pyrazinamide, and ethambutol do not provide the appropriate information for Japanese pediatric dosages. Globally and domestically, while essential drugs such as these have been used off-label successfully, it is critical to ensure they are safe and beneficial when used in children. Hence, there is a need to accommodate both the need for extemporaneous drug information and to overcome the lack of data and clinical experiences with them. In this study, we demonstrated evidence of such discrepancies and highlighted the importance of having identical information on dosing, administration, and drug indication in both products labels and practice guidelines, especially those that comply with the regulations of the Pharmaceutical Affairs Law.

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