<b>3. A Review of Completed Activities of “The Task Force to Make an Ideal Pharmacovigilance Plan (PVP) in Japan” : Evaluation of the Published Pharmacovigilance Plan (PVP) by JSPE's Check List and the Future Challenges&l / 薬剤疫学

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.

<b>1. The Feature and Implementation Process of Japanese RMP from the Regulatory Authority's Viewpoint </b> / 薬剤疫学

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.

A Report from Task Force on Pharmacoepidemiology and Pharmaceutical Industory / 薬剤疫学

Over 40 years, Post-maketing surveillance (PMS) studies have been conducted as a legal obligation in Japan. Though the contribution of these studies to the better use of the drug has been acknowledged, there are criticisms that these PMS studies have been stereotyped and need to be improved. The ICH-E2E guideline entitled as "Pharmcovigilance Planning", agreed in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) has been implemented in the concerned countries. The legislation of the guideline in Japan in 2005 seems to have urged drug companies and regulatory agency to review the current PMS practices in contrast with the today's highest scientific standard. We investigated the theoretical and practical aspects of pharmacoepidemiology required when the drug company evaluates safety specification prior to developing the pharmacovigilance plan and designs a PMS study along the lines stipulated in the ICH-E2E guideline. To meet this end, we evaluated the profiles of the drug, summarized "Important identified risks", "Important potential risks" and "Important missing information" to be identified and examined the pharmacovigilance plan suggested by the regulatory agency and that proposed and implemented by the drug company. We examined those aspects for 6 new products selected from 168 drugs newly approved during the period between January 2004 and October 2006. In 5 of 6 cases, we judged that the use of a comparator group would have been appropriate to asses the association between the drug and adverse events of interest. In addition, in one half (3) of 6 cases, it would have been preferable to use the database for the patient registration and/or other types of databases. The issues of relevant legislation and the infrastructure and funding for the investigations needed to develop a desirable study design and conduct a good pharmacoepidemiology study are however beyond a single company's capacity and should be set as a national strategy. The issues of post-marketing safety in the nation is becoming more and more important as the data in the countries outside Japan are being used more often for the processes of marketing authorization application of a new drug and its approval. It is urgent to secure the practice of pharmacoepidemiology to achieve the effective post-approval pharmacovigilance studies.

Pharmacovigilance based on ICH E2E / 薬剤疫学

Implementation of the ICH E2E Guideline is based on the Notification dated September 16, 2005 concerning pharmacovigilance planning. The E2E Guideline requires post-marketing safety measures, observational studies, and clinical trials to be performed according to the profile of a particular drug.<br> Development of specific pharmacovigilance plans has remained incomplete because of the limited available experience on which planning can be based.<br> Examples of safety measures taken, observational studies, and clinical trials conducted with the anticancer drug TS-1 are explained from the view point of the E2E Guideline.<br> Important risks identified after the market launch of TS-1 include a significant difference from similar drugs in adverse drug reaction profile, contraindication of concomitant medication with 5-FU-containing drugs due to interactions, and an increase in side effects resulting from renal disorders. Examples of missing information include lack of data on concomitant medication with other anticancer drugs and on the efficacy and safety of post-operative medication. Data on long-term medication were also lacking. How these issues were addressed will be explained.<br> Plans for post-marketing safety measures, observational studies, and clinical trials cannot be standardized; risks and other specific factors for each particular drug need to be taken into consideration.

Nested Case-Control Study Using Countermatching and Its Implication in PMS Studies / 薬剤疫学

According to the on-going discussion in ICH E2E, in future PMS studies, it will be necessary to specifically address the problem and the best study method for the specified problem must be properly selected. In this article, the design for a nested case-control study using countermatching is introduced as one of the best candidate methods for future PMS studies. <BR>In the method, a cohort is stratified by the exposure status and a control is selected from the stratum with the exposure status opposite to that of the “counter-matched” case. <BR>It has been shown that this method can increase the efficiency of the study. In addition, it will give those involved in the PMS studies the confidence that the use of the nested case-control study design is valid in the PMS studies where the cohort consisting of a group of patients with the study drug and another group of those with the comparator drug is observed. <BR>However, to make this method realistic in the Japanese PMS milieu, the following two conditions must be satisfied. First, those involved in the PMS studies should realize the importance of the comparison of two drugs while the comparison of two similar drugs has been to date carefully avoided in Japanese PMS studies. Secondly, a method to identify two comparable groups should become possible. The latter may be accomplished by establishing the infrastructure for the mechanism where the prescription data in hospital/community pharmacies are used to identify those who recently started either of the two drugs compared in the study.