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.

We performed gamma knife treatment for multiple brain metastases including a left frontal lobe lesion in a patient in his 60s who had renal cell carcinoma. After treatment, the left frontal lobe lesion initially shrank but then began to grow again, resulting in extensive edema, right hemiparesis, impaired activities of daily living (ADL), and decreased motivation. Although the renal cell carcinoma was in the terminal stage, we judged that recovery of ADL could be expected by removing the left frontal lobe lesion and therefore performed craniotomy tumor removal. As a result, the patient’s motivation and right hemiplegia markedly improved and ADL dramatically improved. Although the period from craniotomy tumor removal to death was as short as 2 months, significant improvement of ADL during this time was achieved by removing the tumor. Tumor resection for metastatic brain tumors is rarely performed in the setting of end-stage cancer. However, this case highlights the potential of brain tumor resection as palliative treatment that can be considered for improving ADL even in patients with terminal cancer.