Guidelines for the usage of psychoactive drugs for behavioral and psychological symptoms of dementia (BPSD) were issued by the Japanese Ministry of Health, Labour and Welfare in July 2013. Using the Anatomical Therapeutic Chemical (ATC) classification with prescription data, we surveyed the usage of psychotropic drugs in patients with dementia. N05C (hypnotics and sedatives) was the most frequently prescribed class of drugs [9,920 (19.7%) individuals]. In addition, there are few prescription ratios of risperidone in comparison with 5.6% and the survey in the UK. Although anti-anxiety drugs should not be used as per BPSD guidelines, etizolam was prescribed in a considerable proportion of patients (6.2%). In addition, with respect to prescription of combinations of antipsychotics in the same month, the highest rate was found for risperidone and tiapride [209 (2.4%) individuals]. In addition, 39 individuals were prescribed antipsychotics that are contraindicated for patients with diabetes. When the number of the clinical departments is as above 2, the ratios to become the contraindicated prescription, careful administration prescription of the antipsychotic increase with significant difference (p<0.01). The increased of the number of the clinical departments tended to increase the ratio of the contraindications and careful administration prescription. Thus, the need for a family doctor to prevent such situations was suggested, which was introduced by the 2014 Medical Treatment Fee Revisions.

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Health economics evaluations are affected by uncertainty when estimating their parameters. Therefore, it is important that we use a sensitivity analysis to determine the robustness of these evaluations. Most countries' guidelines recommend using a probabilistic sensitivity analysis (PSA), which enables us to evaluate the uncertainty of multiple parameters at the same time, based on a joint probability distribution. In this article, we first introduce the Monte Carlo simulation and Bootstrap method as PSA methods. Then, we review how various guidelines incorporate the PSA. Finally, we review Japanese health economics studies to determine the level of PSA use in Japan. Guidelines published before 2008 recommend conducting a sensitivity analysis, but do not specify a method. In contrast, both the French, American and English guidelines, which were published after 2011, specifically recommend using a PSA. In Japan, the “Guideline for economic evaluation of healthcare technologies in Japan” recommends conducting a PSA, “if possible”. However, PSA methods are not widely used in Japan. Of 49 Japanese health economics studies based on quality-adjusted life years, only six conducted a PSA (12.2%), although 35 (71.4%) did conduct other types of sensitivity analyses. If PSA methods are accepted as a good way to determine the robustness of an evaluation, then we need to foster their use. This, in turn, means we need specific guidelines on how best to use these methods.

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ICH-E2E guideline was published on November 18, 2004. In Japan, it has been notified on September 16, 2005 as “Pharmacovigilance Planning”. Then, in parallel with the system development of PMDA is advanced, Ministry of Health, Labour and Welfare revised the notification, it was announced the “Risk Management Plan Guideline” on April 2012. Based on this Guideline, Marketing Authorization Holder creates a whole plan of post-marketing safety measures. This plan is the Japanese RMP (J-RMP). “Risk Management Plan Guideline” are created by the reference to REMS in US and EU-RMP, and modified in consideration of the real situation in Japan. Then, GVP Ordinance and GPSP Ordinance were revised on March 11, 2013. As the result, since October 2014, implementation and creation of the RMP was mandated. At the end of November 2014, 65 RMPs has already been published on Website of PMDA. J-RMP has been positioned as an important system for strengthening of post-marketing safety measures. Published versions of J-RMPs are summarized in compact an overall picture of the post-marketing safety measuresfor respective new drugs. It is also including planned time-line of post-marketing surveillance or post-marketing clinical study. By all stakeholders get a better understanding, it is expected thatthe J-RMP is steadily perform.

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One year and a half has passed since the implementation of the guideline on drug risk management plan (RMP). Japanese RMP system practically began to work. While a post-marketing surveillance study, which has played the central role in pharmacovigilance activities in Japan, is positioned as a measure to collect information to be used in the application document for re-examination, the environment surrounding pharmacovigilance has dramatically changed, e.g. increased number of spontaneous reports, improved medical information database and expansion of its availability, compared to the situation when the reexamination scheme was incorporated into law 35 years ago. Now we need to examine diversified approaches to improve the traditional method and mindset taking advantage of the advances in information technology. In order that RMP system be implemented effectively as well as soundly, it is important to implement the PDCA (plan-do-check-act) cycle in a timely manner. Also we need to assess the overall balance between the resources for post-marketing risk management activities and the performance obtained by them from the viewpoint of ensuring patients' safety.

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Following the notice of “Guidance of Drug Risk Management Plan (RMP)” by MHLW in 2012, Japanese Society for Pharmacoepidemiology (JSPE) started. “A Task Force to make an acceptable Pharmacovigilance Plan (PVP) in Japan” from May 2013. As an outcome, the force published a check list used to evaluate individual PVP for a specific medicinal product together with the guidance for the use of the check list in “Yakuzai-ekigaku”, Journal of JSPE. During over one year since RMP was implemented, RMPs with PVP (included as a component of RMP) were published for 40 compounds and we tried to evaluate those PVPs using the check list we developed. It turns out that an answer to the first question in the check list “Is the necessity of additional PVP described?” was “No” for all 40 PVPs. More serious problem was that one of a few stereotyped study designs was selected in all of the 40 PVPs. No rationale was given to explain why the selected study design could achieve the study aim associated with the important problems specified in the section of safety specification. We conclude that although RMP has been implemented over one year ago, the conventional study design remains to be used in the actual PVP and the main messages of ICH E2E guideline have not been fully realized.

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As mentioned by the Pharmaceuticals and Medical Devices Agency, the risk management planning should start with the development phase and continue to the post-market phase throughout the lifecycle of medicinal products. The post-marketing safety risk management officially started in Japan at last, followed by the notification “On Guidance of Risk Management Plan of Pharmaceuticals” dated April 2012, and a number of the safety risk management plan documents for new medicines have become available in public domain. The evidence body of non-clinical and clinical data to determine a large portion of safety specifications of medicinal products has been derived through the safety evaluation processes of their pre-authorization development phases, however, the discussion on the approaches of developmental safety data collection and assessment has been sparse in Japan. This review outlines the systematic safety evaluation processes for development phases, in reference to the report of CIOMS VI Working Group “Management of Safety Information from Clinical Trials” and the proposal from the PhRMA Safety Planning, Evaluation, and Reporting Team.

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The notification of RMP was released in 2012 and has been adapted for new drug submission since 2013. However, most cases are usual post-marketing surveillance studies. According to the ICH E2E guideline, various risk managements could be possible, especially using medical database. Recently, large database has been developed. There are two kinds of database, hospital information system including electronic medical records, and claim data. Activities of using medical database in Japan, US, and Europe are various. Based on FDA amendment acts, FDA launched Sentinel Initiative in 2008 and REMS works effectively. The Mini-Sentinel and OMOP published Common Data Model respectively. FDA also released guidance for pharmacoepidemiologic studies using electronic health data. In Europe, RMP has been implemented in 2005 and about 36% are epidemiologic studies. ENCePP which was established in 2006 provides register of pharmacoepidemiologic and pharmacovigilance studies, checklist for protocols and guide on methodological standards in pharmacoepidemiology. In Japan, PMDA provides guideline for pharmacoepidemiologic studies using medical database. Also, “MID-NET” which is the standardized medical database has been developed. As a notable activity, PMDA has conducted pilots as MIHARI project and itʼs quite promising.

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MHLW released a guideline for Risk Management Plan (RMP) in April 2012, in order to manage the risk of pharmaceutical products from the development stage towards post marketing period. The guideline suggests to determine Safety Specification and to develop Pharmacovigilance Plan (PVP) and Risk Minimization Plan aligned to the ICH E2E guideline. However, in some of the RMPs, which had been published online (as of August 2014), conventional (Special) Drug Use Results Surveys are planned as a “universal” PVP regardless of the impact, severity and characteristics of the risks. Our JPMA taskforce (Data Science Expert Committee) summarized report and published in August 2014. In this report, we explained how to evaluate safety events based on evidence level for safety specification and how to develop PVP. Also, we would like to propose KAIZEN activities for RMP improvement as follows:
1. In order to clarify the research question, rationale and evidence for safety specification should be evaluated carefully.
2. It is essential to be considered in advance how to collect and analyze the safety data for detecting safety specification during clinical development.
3. Safety profiles should be discussed thoroughly on DSUR development among stakeholders in order to clarify safety specification at NDA. Research questions for each different risk and missing information should be established according to PECO, which will flow into appropriate PVP planning.
4. Continuous PDCA cycling is critical for RMP. The first survey or research will bring you next research question (s).
We expect all stakeholders, including clinical development specialists in industry, regulatory authorities, and academia, to have better understating of RMP principle and to manage and implement it more appropriately in a scientific manner.

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