Investigation of the Description of Important Identified Risks and Important Potential Risks in Risk Management Plan in Patient Information Materials / 医薬品情報学

Objective: The Risk Minimization Plan is developed in the Risk Management Plan (RMP), patient information materials are sometimes prepared as Additional Risk Minimization Activities (ARMA). On the other hand, there are many patient information materials that are not prepared as RMP materials, but are prepared independently by pharmaceutical companies and are actually used to provide information to patients. However, there is no detailed report on the differences between them. Therefore, in this report, we investigated for description of Important Identified Risks (IIRs) and Important Potential Risks (IPRs) in patient information materials.Methods: The previously published RMP of 588 drugs were obtained on October 1,2020, and used in analysis. We surveyed the description of IIRs and IPRs in patient information materials, and compared patient information materials based on ARMA in the RMP (patient information materials as RMP materials) and patient information materials developed independently by pharmaceutical companies that are not based on ARMA in the RMP (patient information materials as not RMP materials).Results: Of the 588 drugs, 454 drugs had patient information materials. In addition, 241 drugs had patient information materials as RMP materials. One thousand fifteen of the 1,577 IIRs were listed in the patient information materials as RMP materials (64.4%listing rate). One hundred sixty-six of the 724 IPRs were listed in the patient information materials as RMP materials (22.9%). On the other hand, 700 of the 1,131 IIRs were listed in the patient information materials as not RMP materials (61.9% listing rate). Ninty one of the 447 IPRs were listed in the patient information materials as not RMP materials (20.4%).Conclusion: It was found that there was no difference in the description of IIRs and IPRs between patient information materials as RMP materials and patient information materials as not RMP materials.

Concept of Routine Pharmacovigilance, Especially Signal Management in the US and Europe / 薬剤疫学

Monitoring of the safety profile for the approved medical products consists of routine pharmacovigilance activities for all drugs and additional pharmacovigilance activities for product-specific concerns. Signal management is an important part of routine pharmacovigilance activities, so EMA and FDA have published the guidelines for signal management in various documents. The AMED Risk Management Plan （RMP） research group, which started its activities in 2018 to enhance risk management plan in Japan, reviewed the guidelines and related articles and then put together the principles of signal management. The guidelines in EU and US describes the signal detection and evaluation methods including points to consider when conducting them, responsibilities of each action, and the procedures that the regulatory authorities disclose the outcome of their activities, in addition to the principles and procedures of signal management. Through the guidelines, they establish transparency for public including pharmaceutical industry. Our group first created the Japanese definitions of signal-related terms. Based on them, we created high-level concept for a series of activities from signal detection to risk identification and discussed the future vision of signal management in Japan.

Study on Post-marketing Drug Risk Management Plan in Japan and Its Enlightenment to China / 中国药房

OBJECTIVE：To provide reference for i mproving the post-marketing drug risk management in China by refering to the experience of post-marketing drug risk management plan （RMP）in Japan. METHODS ：The process of post-marketing drug regulation in Japan was introduced ，and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use （ICH）guidelines embodied in RMP in Japan were analyzed. The formulation and application of RMP in Japan during the post-marketing safety management were studied. And suggestions were offered for the improvement of post-marketing drug risk management in China. RESULTS & CONCLUSIONS ：The post-marketing regulation of drugs in Japan is characterized with dynamic regulation and social co-governance. ICH principle runs through the RMP management in Japan. Safety specification and risk minimization activities stipulated in RMP in Japan are consistent with ICH guidelines. RMP is defined in Pharmaceutical Affairs Law in Japan ，and is formulated and implemented under the guidance of the Good Vigilance Practice ；the changes are made under the guidance of the Good Post-marketing Study Practice. RMP is a necessary document for the registration and the re-review of new drugs in Japan ，its formulation is responsible by pharmaceutical enterprise ；RMP of new drug is available to the public through the subscription media system of Pharmaceuticals and Medical Devices Agency （PMDA）， which reflects the multi-governance of the government-pharmaceutical enterprises-the public. In China ，RMP supervision is not systematic and is inexperienced，and there is a lack of guidance documents and insufficient application of information and communication technology. It is suggested that China should strengthen post-marketing safety data management ，promote the connection between sentinel hospitals and pharmacovigilance systems of pharmaceutical enterprise ，increase the application of information and communication technology. Relevant normative documents and guidance documents of RMP should be issued by National Medical Products Administration. And the post-marketing supervision system for drugs should be clarified. Taking RMP publicity as an opportunity promote drug risk mamagement co-government ， realize sunshine and scientific supervision .

Survey on Timing Related to Preparation and Publishing of Risk Management Plans / 医薬品情報学

Objective: Risk Management Plan (RMP) is created and submitted by a pharmaceutical company while applying for new drug approval; it is published to be used by healthcare professionals. For example, healthcare professionals utilize RMP when considering whether to adopt a drug. However, there is no stipulation for the release date of RMPs; moreover, surveys regarding this are limited. We conducted a cross-sectional survey on the relationship between RMP-related timing and regulatory affairs-related timing.Methods: The surveyed drugs were those for which the first version of RMP was notified by PMDA Medinavi (mail delivery service) in FY2014 and FY2018. We examined regulatory affairs-related timing (i.e., “manufacturing and marketing approval date,” “drugprice standards listing date,” and “release date”) and RMP-related timing (i.e., “RMP creation date” and “Medinavi delivery date”).Results: For 7 of 43 items in FY2014 and 5 of 41 items in FY2018, the “RMP creation date” occurred later than the “drug-price standards listing date.” For one item in FY2014, the “RMP creation date” occurred later than the “release date.” For 12 items in FY2014 and 13 items in FY2018, the “Medinavi delivery date” occurred later than the “release date.”Conclusion: No considerable difference was confirmed between FY2014 and FY2018 regarding RMP-related timing and regulatory affairs timing. It was confirmed that there were several items for which the RMP creation occurred later than drug-price standard listing and items for which the publishing notice by Medinavi was delayed for drug marketing release. To promote the utilization of RMPs by healthcare professionals, RMPs must be created and published without delay.

Survey of the Description of “Medication Guides for Patients” and “Early Post-Marketing Phase Vigilance” on Additional Risk Minimization Activities of Risk Management Plans / 医薬品情報学

Objective: The risk management plan (RMP) is a useful information source for healthcare professionals, including pharmacists, to ensure drug safety. The “risk minimization activities” (RMA) of the RMP are especially important elements for healthcare professionals. It is known that “Medication Guides for Patients” (MGP) and “Early post-marketing phase vigilance” (EPPV) are items listed as part of the RMA. However, the creation of MGPs and the implementation of EPPVs are not performed for all medicines. In a previous study, it was difficult to evaluate this sufficiently with the safety specifications. The aim of this investigation was to evaluate RMAs, especially MGPs and EPPVs, not in terms of the safety specifications of RMP.Methods: The previously published RMPs of 177 drugs were obtained on February 22,2016, and used in the analysis. The relationship between the creation of the MGP and the description in the RMA and the relationship between the conduct described in the EPPV and the description in RMA was investigated for each medicine.Results: An MGP was created in 151 of the analyzed drugs. Of these, it was not listed in the RMA of 40 drugs. In contrast, EPPV was not listed in RMA in 2 out of 33 drugs when underway. EPPV was described in the RMA of 33 of the EPPV finished drugs. The time lag from the end of EPPV until the revision of the RMP was 4.5 month son average.Conclusion: MGPs and EPPVs are created especially for drugs requiring patient education, information provision, or safety monitoring. Therefore, for drugs for which MGPs or EPPVs are required, they should be listed in the RMA. In this study, the time lag of RMP revision was also highlighted as a problem. In order to promote the utilization of RMP by pharmacists, these issues should be resolved.

Research for Recognition of Pharmaceutical Companies toward the Effective Use of “Drug Guide for Patients” as Package Inserts for Patients / 医薬品情報学

Objective: “Drug Guide for Patients” (DGP) is a drug information tool designated as one of the routine risk minimization activities in risk management plan (RMP) developed by the Ministry of Health, Labour and Welfare. However, patients and their families hardly recognize DGP. Therefore, we administered a questionnaire on drug consultation service of pharmaceutical companies that provide DGP with an aim to collect their views, elucidate problems when they prepare DGPs and examine effective utilization of DGP in the future.Methods: We sent a questionnaire by letter for 127 drug consultation service of pharmaceutical companies, and received questionnaire results using “Questant” that is web questionnaire making software. The results were examined using Fisher’s exact test or Pearson’s chi-squared test.Results: We obtained responses from 84 (66.1%) companies out of 127. As for the question of the published situation of DGP on their website, the most companies responded “Not published” with 47.6% and subsequently 41.7% for “Published for healthcare professionals”. The combined rate of “Published for Patients (3.6%)” and “Published for both healthcare professionals and patients (7.1%)” was only 10.7%. On the other hand, regarding the burden of companies making DGP, we found that more than 60% of pharmaceutical companies (63.5%) felt burdensome, whereas only 36.5% responded “Not burdensome.” Regarding the question on the role of DGP in RMP, pharmaceutical companies answered that the role is “sufficient” 3.6%, 29.8% “not sufficient”, and 66.6% “unknown”.Conclusion: Our results suggested that it is difficult for patients to get DGP from website of pharmaceutical companies and pharmaceutical companies felt burdensome in making DGP, and they recognized that DGP was not very much utilized by patients. Therefore, it would be necessary to improve the creation criteria of DGP. Furthermore, we felt it necessary to have the DGP known and utilized widely by (consumers and) patients.

1．Evaluation of the Effectiveness of Risk Minimization Activities / 薬剤疫学

Various measures have been taken to minimize risk for individual drug products in the past. It is noteworthy that these measures are now documented and made public as a　“risk minimization plan” with the implementation of the scheme of Risk Management Plan （RMP). Risk minimization activities are conducted with the aim of securing and enhancing patients' safety, and at the same time, it places additional burdens on patients, healthcare practitioners and manufacturers/distributors. In this context, it should be assessed whether the original purpose is achieved. It is the key　for RMP to revise the plan effectively based on the assessment result. Measures to evaluate the effectiveness of risk minimization activities include analysis using medical information databases, questionnaire survey/interview to healthcare practitioner and patients. We may need to conduct prospective/retrospective surveys for some cases. There is no single method to be universally applied to different situations and we have no other way than putting our heads together and moving into action.

<b>1．Evaluation of the Effectiveness of Risk Minimization Activities </b> / 薬剤疫学

<p>Various measures have been taken to minimize risk for individual drug products in the past. It is noteworthy that these measures are now documented and made public as a　“risk minimization plan” with the implementation of the scheme of Risk Management Plan （RMP). Risk minimization activities are conducted with the aim of securing and enhancing patients' safety, and at the same time, it places additional burdens on patients, healthcare practitioners and manufacturers/distributors. In this context, it should be assessed whether the original purpose is achieved. It is the key　for RMP to revise the plan effectively based on the assessment result. Measures to evaluate the effectiveness of risk minimization activities include analysis using medical information databases, questionnaire survey/interview to healthcare practitioner and patients. We may need to conduct prospective/retrospective surveys for some cases. There is no single method to be universally applied to different situations and we have no other way than putting our heads together and moving into action.</p>

Survey of the Description of the Risk Minimization Activities in Pharmaceutical Risk Management Plans / 医薬品情報学

<b>Objective: </b>Currently, the creation of a pharmaceutical risk management plan (RMP) for new drug information is obliged to pharmaceutical companies.  The created RMP is published on the Pharmaceuticals and Medical Devices Agency (PMDA) website.  RMP is a useful information source to ensure drug safety by healthcare professionals, including pharmacists.  “Risk minimization activities” of the RMP are especially important elements for healthcare professionals because they describe measures to minimize risk to patients.  We conducted a cross-sectional survey of the description of the contents of “risk minimization activities” in the RMP.<br><b>Methods: </b>The RMP of 177 drugs that had been published in February 22, 2016 were investigated.<br><b>Results: </b>Total risks enumerated for the study drugs were 1,678.  “Routine risk minimization activities” constituted 92.0% of total risks.  The most listed item on “routine risk minimization activities” was “attention on the product labeling of the drug package insert” (91.3%).  Differences in the expression level on “attention on the product labeling” were observed.  On the other hand, the most listed item of “additional risk minimization activities” was “the creation of documents for healthcare professionals” (38.3%) and “implementation of Early Post-marketing Phase Vigilance” (27.1%).<br><b>Conclusion: </b>A clear understanding of RMP by healthcare professionals is important.  In the RMP, “risk minimization activities” (especially “additional risk minimization activities”) are the most important contents for healthcare professionals, because they include information of documents created by the pharmaceutical company for patient safety.  The level of description of the contents of RMP varies between drugs.  It is essential that these descriptions be uniform the expression level to be easily and accurately utilized by healthcare professionals.

Description of Important Potential Risks of Japanese Risk Management Plan on Each Package Insert / 医薬品情報学

<b>Objective: </b>The Japanese risk management plan (RMP) contains the risk minimization action plans for important potential risks of drugs.  One of the basic risk minimization action plans is reminding on package insert; however, we found that some potential risks were not described in package inserts.  In this study, we investigated the description of potential risks on package inserts.<br><b>Design: </b>Document analysis.<br><b>Methods: </b>We collected all posted RMP documents and the package inserts of corresponding products from the Pharmaceutical and Medical Devices Agency website on January 31, 2015 and investigated the risk minimization action plans of important potential risk items and whether the items had been described in each package insert.<br><b>Results: </b>Of 268 important potential risk items in 81 products, 56 items were not described on package insert.  The major reason for not including the risk items on the package insert was “causality was not indicated sufficiently” and some items had no written reason.<br><b>Conclusion: </b>About 20% of important potential risks are not described in package inserts.  Because most post-marketing pharmacovigilance plans depend on spontaneous reporting by healthcare personnel, description on package insert, the most frequently referred drug information resource, should be considered.

Comparison between Risks Listed in the Risk Management Plan and the Product Labeling of the Drug Package Insert / 医薬品情報学

<b>Objective: </b>Currently, Risk Management Plans (RMPs), plan that provide new risk information about drugs, are published on the Pharmaceutical and Medical Devices Agency (PMDA) website.  The aim of this study was to compare enumerated risks in RMPs to the product labeling (PL) of the drug package insert.<br><b>Methods: </b>The risks listed in RMPs on the PMDA website were assessed on February 10, 2014.  We investigated the documentation of these risks on the PL.<br><b>Results: </b>Seven-hundred and eighty-five risks were enumerated in the RMPs of 77 drugs.  The enumerated risks were classified as “important identified risks” (66%), “important potential risks” (22%), and “important missing information” (12%).  Ninety-four percent of risks listed in RMPs were documented on the PL.  A portion of both the “important identified risks” and “important potential risks” groups were not documented on the PL.<br><b>Conclusion: </b>This study was clearly the relation between risks listed in RMPs and documents on the PL.  Because a portion of the risks listed in RMPs was not documented on the PL, RMPs provide more safety information.  It is necessary to better understanding their characteristics, considering RMPs are a new source of drug information.

<b>Good Pharmacovigilance Planning in Japan: Proposals from the “Task Force for Good Pharmacovigilance Planning in Japan” of Japanese Society for Pharmacoepidemiology (JSPE)</b> / 薬剤疫学

The reform of regulation is proposed to implement the Pharmacovigilance Planning (PVP) based on the ICH E2E guidelines as indicated in the notification of Risk Management Plan (J-RMP). Even after the J-RMP is enforced, the pharmacovigilance method still heavily depends on the traditional methods like “drug use results surveys”. The “Good Post-marketing Study Practice (GPSP)” ordinance and related notifications are the root causes of the malfunctioned operation of the system. Specifically, 1) the GPSP ordinance does not encourage the investigations according to the ICH E2E notification and 2) it is believed that the pharmacovigilance method should be limited to one of the three options only, namely, “drug use results surveys”, “specific use surveys” and “post-marketing clinical studies”. The followings are proposed: <br>• The GPSP ordinance should be revised to encourage referring the annex “pharmacovigilance methods” in “Pharmacovigilance planning”.<br>• The use of the early post-marketing phase vigilance (EPPV) should be restricted to the drugs marketed at the same time in the world or marketed for the first time in Japan.<br>• The notification connecting the “Good Vigilance Practice (GVP)” and GPSP ordinances (March 11, 2013, No 0311-7) should be revised to include a prescription that the “Safety Control Manager encourage the Post-marketing Surveillance Control Manager to develop a pharmacovigilance plan according to the ICH-E2E guidelines”.<br>• Forms attached to the individual RMP submissions should be revised according to the J-RMP notification.<br>• The notification on the RMP development (No.0426-1 and No.0426-2, on April 26, 2012) should be revised to indicate that the study design is acceptable to the health professionals.<br>• It should be clarified that the additional pharmacovigilance activities may be conducted by the divisional cooperation in the world or may be conducted as a non-clinical study, if appropriate.

Awareness Survey of Medical Representatives in Relation to Drug Information / 医薬品情報学

<b>Objective:</b> Beginning in October 2014 a drug risk management plan (RMP) will be authorized as a condition for drug approval and for this and other reasons the role the medical representatives (MRs) play regarding drug information will become even greater. We therefore decided to conduct drug information awareness surveys of the MRs who visit our hospital.<br><b>Methods:</b> We first conducted a questionnaire survey on RMP, the Pharmaceuticals and Medical Devices Agency (PMDA), and postmarketing surveillance (PMS).　Following the survey we held a seminar for MRs in relation to RMPs, after which we conducted a questionnaire again.<br><b>Results:</b> The surveys revealed that most of the MRs were not actively gathering information provided by the PMDA.　They also revealed that after the seminar their knowledge regarding RMPs had increased and their understanding of the relationship between RMPs and PMS had deepened.<br><b>Conclusion:</b> Considering that the MRs gained a significantly deeper understanding after the seminar, participation by medical institutions, which are the recipients of the information, in the education of MRs can be said to be meaningful as a means of supporting proper information‐providing activities.

<b>2．Expectations for MIHARI Project from the Perspective of Academia </b> / 薬剤疫学

Based on the history of pharmacovigilance activities in Japan, the expectations for MIHARI Project from the perspective of academia are discussed. First, drug safety and risk-benefit related activities should be enhanced from the early stage of drug development and/or in the regulatory approval stage. Second, more collaboration with regulatory authorities and academia should be promoted. Third, knowledge obtained from MIHARI Project should be published timely and continuously which contribute to related safety activities conducted by other than regulators.

<b>6. Recommendations and Results of Activities for the RMP from the Japan Pharmaceutical Manufacturers Association Data Science Expert Committee </b> / 薬剤疫学

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: <br>1. In order to clarify the research question, rationale and evidence for safety specification should be evaluated carefully. <br>2. It is essential to be considered in advance how to collect and analyze the safety data for detecting safety specification during clinical development. <br>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. <br>4. Continuous PDCA cycling is critical for RMP. The first survey or research will bring you next research question (s). <br>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.

<b>5．Practical Use of Medical Database for Risk Management Plan (RMP)</b> / 薬剤疫学

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.

<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>2. Agenda for the Sound and Effective Implementation of Risk Management Plan System </b> / 薬剤疫学

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.

Development of an Application for Using the Pharmaceuticals and Medical Devices Agency Side Effect Dataset More Effectively / 医薬品情報学

<b>Objective: </b>The Pharmaceuticals and Medical Devices Agency (PMDA) discloses reports with accumulated side effect information in comma-separated value (CSV) format.  It is difficult to use the information in this type of text file because the amount of data is large and composed of multiple fields.  Therefore, we developed an application that presents the data in a way that is easier to read and understand.<br><b>Methods: </b>The application can display the whole dataset, or the search results of certain medicines and side effects within the database in Microsoft Access 2013.  It exports data from search results into an Excel spreadsheet organized by medicine and side effect.<br><b>Results: </b>This application makes it possible to understand statistics contained in the side effect dataset, such as the number of cases, the medicines, and the side effects themselves.  Moreover, the application allows the totaled search results for the medicines and the side effects to be graphed.  It also makes it possible to understand the sex and age distribution of patients, as well as the days elapsed before developing a side effect.<br><b>Conclusions: </b>Recently, the importance of information concerning the safety of medicine has increased.  This system could facilitate the effective use of side effect information and the creation of medicine risk management plans in medical institutions.

<b>Checklist and Guidance of Scientific Approach to Developing Pharmacovigilance Plan (PVP) in Japan: A Report from a Task Force of JSPE</b> / 薬剤疫学

A Task Force team consisting of members from pharmaceutical companies --a central player to develop and implement RMP (Risk Management Plan)-- as well as health care professionals and members from academia was established in JSPE. The Task Force developed guidance for scientific approach to practical and ICH-E2E-compliant Pharmacovigilance Plan (PVP) stated in Japanese Risk Management Plan issued in April 2012 by the Ministry of Health, Labour and Welfare. The guidance contains the following topics.<br>1．Introduction: JSPE's activities and this task force's objectives for pharmacovigilance activities<br>2．How to select Safety Specification (SS) and describe its characteristics<br>・Selection of SS<br>・Characterization of SS<br>・Association with Research Questions (RQ)<br>3．How to define and describe RQ<br>・What is RQ ?<br>・RQ interpretation in other relevant guidelines<br>・Methodology to develop RQ for PVP with examples<br>・Best approach to integrating PVP for whole aspects of safety concern<br>4．How to optimize PVP for specific RQ<br>・Routine PVP or additional PVP ?<br>・Additional PVP design (RQ and study design, RQ structured with PICO or GPP's research objectives, specific aims, and rationale)<br>・Checklist to help develop PVP<br>5．Epilogue:<br>・What can/should be “Drug use investigation” in the context of ICH-E2E-compliant PVP.<br>・Significance of background incidence rate and needs for comparator group<br>・Infrastructure for the future PVP activities<br>6．Appendix: Checklist to help develop PVP activities in RMP<br>The task force team is hoping that this guidance help develop and conduct SS and PVP in accordance with ICH E2E, as stated in Japanese Risk Management Plan Guideline.