ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
<b>Objective</b>: To propose the best pharmacovigilance plan in Japan by comparing post marketing safety studies in Japan and the U.S.<br><b>Method</b>: Among all of the newly approved medicines in Japan in 2010, 12 marketed products in the U. S. are selected. First, to examine the U. S. system, post-marketing safety concerns over those drugs at the time of approval in the U. S. were collected as well as its postmarketing requirements (PMR) which are studies or clinical trials that sponsors are required to conduct under one or more statutes of regulations. Then, the same drugsʼ safety issues discussed as special cautions listed during the approval process in Japan and the corresponding postmarketing safety studies were reviewed.<br><b>Result</b>: Both countries have many safety concerns in common, however, in Japan, ongoing studies are only conventional studies, such as post-marketing surveillance studies or all-cases studies, while the U. S. conducts studies to meet each individual requirement need. Ideal post-marketing safety study designs proposed by the task force, seemed beyond sponsors capabilities, particularly with regard to conduct studies with control group, and require involvement of academia external research organizations, or establishment of the national registry system for cancer and other major diseases.<br><b>Conclusion</b>: In Japan, Risk Management Plan (RMP) will soon be implemented in 2013, and that is expected to secure patientsʼ safety by the scientific pharmacovigilance plan with the international standard. It is an urgent task to discuss what plan is feasible in Japan and how to make the corporation of industry-government-academia a reality. (Jpn J Pharmacoepidemiol 2012; 17 (1): 55-66)
ABSTRACT
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.