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.

2．Consideration of Signal Management Process / 薬剤疫学

In the EU, signal management guideline is defined as GVP Module Ⅸ “Signal Management”, where the signal management is defined as a set of activities performed to determine whether, based on an examination individual case safety reports (ICSRs), aggregated data from active surveillance systems or studies, scientific literature information or other data sources, there are new risks associated with an active substance or a medicinal product or whether known risks have changed, as well as any related recommendations, decisions, communications and tracking. The EU signal management process includes the following activities : signal detection, signal validation, signal confirmation, signal analysis and prioritisation, signal assessment and recommendation for action.WHO and FDA have also published similar guidance in various documents. Furthermore, the social medial has become another source of signal. It is also very important to review preapproval clinical trial data. This is because, in recent years, there are increased number of drugs with a major problem due to cardiovascular risk or suicide, but such signals often appeared in clinical trial data.Traditional qualitative signal detection method is fundamental to signal detection. However, for regulators that have to monitor all drugs, statistical signal detection and its prioritization are indispensable and various methods have been implemented. For pharmaceutical companies, the need for prioritization itself is small, but the concept is very helpful in the planning of subsequent measures.In signal evaluation, post-authorization safety study in EU and postmarketing requirement in FDA are very important. For regulatory notification of recommended actions, one should consider signal prioritization elements.In Japan, the routine pharmacovigilance activities sufficient within the scope of local GVP as the enforcement regulations of the PMR Law. But for future routine pharmacovigilance activities, we must work on signal detection and evaluation of signals which are difficult to detect including cardiovascular risk, suicide, and carcinogenesis.

<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.