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:
• The GPSP ordinance should be revised to encourage referring the annex “pharmacovigilance methods” in “Pharmacovigilance planning”.
• 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.
• 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”.
• Forms attached to the individual RMP submissions should be revised according to the J-RMP notification.
• 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.
• 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.

Treadmill exercise test and cold water face-immersion test were performed in 50 patients with tetralogy of Fallot at a mean age of 11.9 years, an average of 8.2 years after intracardiac repair. Cardiac catheterization was also performed in 45 patients 0.5-11 years after the repair.
Exercise performance and results of catheterization were compared in patients with and without ventricular premature contraction (VPC) . In 22 (44%) of the 50 patients, VPC was induced by treadmill and/or cold water face-immersion test. Compared with the other 28 patients, the patients who had VPC during the tests, 1) were older (13.6 versus 10.6 years, p< 0.05, t-test) and were tested at a longer interval after repair of tetralogy of Fallot (9.5 versus 7.3 years, p<0.05), 2) showed no difference in the results of catheterization, and 3) had lower exercise performance.
Cold water face-immersion test is therefore considered to be useful for evaluation of patients after intracardiac repair of tetralogy of Fallot.

BACKGROUND: Recently, we examined the effects of 2% lidocaine gel on the tactile sensory and pain thresholds of the face, tongue and hands of symptom-free individuals using quantitative sensory testing (QST); its effect was less on the skin of the face and hands than on the tongue. Consequently, instead of 2% lidocaine gel, we examined the effect of 8% lidocaine spray on the tactile sensory and pain thresholds of the skin of the face and hands of healthy volunteers. METHODS: Using Semmes-Weinstein monofilaments, QST of the skin of the cheek and palm (thenar skin) was performed in 20 healthy volunteers. In each participant, two topical sprays were applied. On one side, 0.2 mL of 8% lidocaine pump spray was applied, and on the other side, 0.2 mL of saline pump spray was applied as control. In each participant, QST was performed before and 15 min after each application. Pain intensity was measured using a numeric rating scale (NRS). RESULTS: Both the tactile detection threshold and filament-prick pain detection threshold of the cheek and thenar skin increased significantly after lidocaine application. A significant difference between the effect of lidocaine and saline applications was found on the filament-prick pain detection threshold only. NRS of the cheek skin and thenar skin decreased after application of lidocaine, and not after application of saline. CONCLUSION: The significant effect of applying an 8% lidocaine spray on the sensory and pain thresholds of the skin of the face and hands can be objectively scored using QST.
Cheek ; Facial Pain ; Hand ; Healthy Volunteers ; Lidocaine ; Neuralgia ; Pain Threshold ; Skin ; Tongue

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.

The Standardized Structured Medical record Information eXchange (SS-MIX) was started in 2006 as the project supported by the Ministry of Health, Labour and Welfare (MHLW) for promoting the exchange of the standardized medical information. Free soft wares developed in the project allow the storage of medical information to receive HL7 messages for prescription, laboratory test results, diagnoses and patient demographics in the hospital information system (HIS). We encourage the use of the SS-MIX standardized storage for postmarketing surveys and clinical studies. The recommendations consist of the following 7 parts. [1] In surveys and clinical studies, the information of drugs and laboratory test results in the SS-MIX standardized storage can be directly transferred to the electronic questionnaire and the investigators may obtain the information with high accuracy and granularity. [2] The SS-MIX standardized storage works as the backup system for the HIS because it can provide the minimum information essential in patient care even under the disastrous condition like earthquake or unexpected network failure. [3] The SS-MIX standardized storage may be useful to conduct a good pharmacoepidemiology study not only because it provides the information in the storage efficiently but also it can be used to identify “new users” who started the drug after some period of non-use.The “new user” design is often essential to have the unbiased results. [4] When the drug company conducts postmarketing surveys according to the current regulation, the use of the SS-MIX standardized storage will facilitate the fast and efficient collection of data to develop the timely measure to minimize the drug-related risk. With the SS-MIX standardized storage, it is also expected that many types of study design can be employed and the quality of data is improved in the survey. [5] The SS-MIX standardized storage maybe also useful to evaluate the risk minimization action plan by comparing the prescription pattern or incidence of the targeted adverse event between two periods before and after the implementation of the action plan. [6] In planning clinical trials, the SS-MIX standardized storage may be used to estimate the size of eligible patients. The storage may also allow conducting cross-sectional studies to know characteristics of diseases or drug treatment. In addition, cohorts of those who had coronary artery angiography, new users of a drug and those with a rare disease may be readily identified. Using such cohorts, investigators can initiate a case-control study nested within the cohort, pharmacogenomic studies and comparative effectiveness researches. [7] The SS-MIX standardized storage may be used as the formal data source in clinical trials in the future when some conditions are satisfied. For instance, the formal agreement should be reached between industry, government and academia on the use of standards of data structure in Clinical Data Interchange Standards Consortium (CDISC) and on the operation of computerized system validation (CSV) in the clinical trials.