2．Points for Evaluation of the Revised Risk Minimization Plans on Thalidomide and its Derivatives / 薬剤疫学

Thalidomide and the derivatives, lenalidomide and pomalidomide, are the most potent teratogenic medicines. Thalidomide Education and Risk Management System （TERMS®）and RevMate® for lenalidomide and pomalidomide have been operated with a goal of no exposed embryo to the drugs. The TERMS®and the RevMate®, a centralized management system, were revised in 2016 according to a request by a patient group. After the revision, the patient self-check sheet on adherence to conception prevention is primarily confirmed by his/her doctor, and the content of the completed sheet is sent to the management center in the pharmaceutical company after dispensing of the drug. The points for evaluation of the revised system will be as follows. (1) Has an appropriate procedure in accordance with the revised system been established in respective hospitals? (2) The rate of non-compliance with the procedure by the doctors or pharmacists, (3) Effect on awareness and behavior of the patients. Questionnaire studies of the patients, doctors, and pharmacists have been performed by the third-party committees.

Development of a Clinical Practice Guideline Utilization System to Support Pharmacist Prescription Proposals: / 医薬品情報学

<b>Objective: </b>Pharmacists need to know at what positioning a drug is recommended in clinical practice guidelines when they make prescription proposals.  However, the format of guidelines and the definition of recommendation grades differ between academic societies, making it difficult to comprehensively extract only the information one needs.  Therefore, we developed a guideline utilization system to support prescription proposals by pharmacists.<br><b>Methods: </b>We built a database comprised of clinical practice guidelines on pharmacological therapy for breast cancer and breast cancer-related conditions.  FileMaker®was used in the development of the system.<br><b>Result: </b>This system allows the comprehensive extraction of clinical questions and recommendations from multiple guidelines by means of standardized keywords.<br><b>Conclusion: </b>This system supports prescription proposals by pharmacists when generating pharmacological therapy protocols or when in discussions with healthcare professionals as information on the positioning of therapeutic agents in different guidelines and recommended drugs is readily available.

<b>2．Points for Evaluation of the Revised Risk Minimization Plans on Thalidomide and its </b><b>Derivatives </b> / 薬剤疫学

<p>Thalidomide and the derivatives, lenalidomide and pomalidomide, are the most potent teratogenic medicines. Thalidomide Education and Risk Management System （TERMS^®）and RevMate^® for lenalidomide and pomalidomide have been operated with a goal of no exposed embryo to the drugs. The TERMS^®and the RevMate^®, a centralized management system, were revised in 2016 according to a request by a patient group. After the revision, the patient self-check sheet on adherence to conception prevention is primarily confirmed by his/her doctor, and the content of the completed sheet is sent to the management center in the pharmaceutical company after dispensing of the drug. The points for evaluation of the revised system will be as follows. (1) Has an appropriate procedure in accordance with the revised system been established in respective hospitals? (2) The rate of non-compliance with the procedure by the doctors or pharmacists, (3) Effect on awareness and behavior of the patients. Questionnaire studies of the patients, doctors, and pharmacists have been performed by the third-party committees.</p><p></p>

<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.

<b>Information: Recommendations for developing postmarketing surveys and clinical investigations using SS-MIX standardized storage </b> / 薬剤疫学

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.

The Use of Computerized Prescription Data in Hospitals and Community Pharmacies to Identify the Drug User Cohort for Comparative Observational Studies / 薬剤疫学

<B>Background :</B>There have been only a few comparative observational studies on the safety and effectiveness of drugs in Japan. Comparative observational studies would provide important information to address these issues and thus we need to establish a means to facilitate such studies. In comparative studies, it is important to prevent the distortion of results due to selection bias. Though we do not yet have a claims database for use in pharmacoepidemiological studies, recently many hospitals and pharmacies have computerized prescription data which may be used to minimize selection bias. Good standardized procedures for the identification of patients prescribed one of two or more drugs to compare in a study using computerized prescription data would serve as a basis for a variety of pharmacoepidemiological studies in Japan.<Br><B>Methods :</B>We carried out a questionnaire survey in 2753 hospitals and 909 community pharmacies to estimate the fraction of hospitals where computerized data can be used to identify all eligible patients who used a specific drug.<Br><B>Results :</B>Questionnaires were returned by 1942 (71%) of 2753 hospitals and 632 (70%) of 909 pharmacies. From among those which responded, patients were identified, the patient list was printed, and the electronic file of the patient list was generated in 75%, 64% and 36% of the 1942 hospitals and in 100%, 93% and 49% of the 632 pharmacies respectively.<Br><B>Conclusion :</B>With procedures using computerized prescription data, the cohort for observational comparative studies may be identified with a minimal selection bias in a majority of hospitals and pharmacies.

How to Minimize ‘Lost to Follow-up’ in a Cohort Study in Pharmacoepidemiology? : / 薬剤疫学

<b>Objective</b> : To find methods to minimize ‘lost to follow-up’ in the long-term follow-up in a pilot study of Prescription-Event Monitoring in Japan (J-PEM) where hypertensive subjects who took losartan or a control drug and gave informed consent to the study were directly followed by researcher for years.<br><b>Design</b> : Cohort Study<br><b>Methods</b> : We conducted the follow-up survey twice, in which questionnaires were sent to hypertensive patients who had consented to being involved in the survey and returned it by mail. In the questionnaire, we asked about the use of the monitoring drug, change of medical institutions for the treatment of hypertension, significant health-related events. In the second survey, we reminded the non-responders by a letter of reminder and by telephone. When no information was obtained from the subject, we sent a letter, together with a copy of the informed consent given by the subject, to the municipal office where the subject's home was registered to inquire about the subject's current address and related information including the vital status. We calculated Standardized Mortality Ratio (SMR) using the information on death obtained from the mailed questionnaires, telephone and information in the municipal office.<br><b>Results</b> : In a pilot study of J-PEM on losartan, 4344 and 3517 questionnaires were sent to pharmacists and doctors, respectively. The doctors handed the informed consent form to the patients and 422 patients agreed to participate the study and sent back the signed form to the study office. In the first and second surveys, a questionnaire was mailed to the subject approximately 1 and 5 years after the first prescription of losartan or a control drug, respectively. The response rate was 73 and 60% in the 1 st and 2 nd survey, respectively. In the manuscript, the results of the 2 nd survey were mainly presented. The reminders by mail and telephone increased the response rate from 60 to 81% and provided the information on the vital status for 86% of the subjects. The response rate was further increased to 84% and the vital status was known for 99% when the information in the municipal office was used. SMR was estimated to be 0.59 (95% CI : 0.34-1.01) before reminding subjects, 0.78 (0.52-1.17) after reminding subjects by a letter and telephone and 0.92 (0.65-1.31) after further addition of the information from the municipal office. During the 5 years of the observation, 21% of 343 subjects who sent back a filled questionnaire did and 70% did not change the clinic/hospital where they received the care for hypertension, while 9% did not answer the relevant question.<br><b>Conclusion</b> : The method of the systematic survey may be useful in minimizing the ‘lost to follow-up’ subjects in the long-term pharmacoepidemiology studies in Japan where a patient can change the clinic/hospital for his/her own health care without any letter of reference. In the systematic survey, the researchers may try to follow the subjects by using several methods including reminders like a letter or telephone as well as the use of the information in the municipal office. To facilitate better follow-up, a careful design of the study including the proper design of the informed consent form is essential to maximize the amount and quality of the available information, particularly when the subject has a serious event or dies in a hospital or institution apart from that where the patient has been registered.

How was the “Case-control Study on the Association of Upper Gastrointestinal Bleeding and Nonsteroidal Anti-inflammatory Drugs in Japan” Conducted ? / 薬剤疫学

Some case-control studies have been conducted to study the relationship between a drug and adverse events in Japan. However, most such studies adopted hospital controls and rarely adopted community controls. Here, we describe the methodological issues of performing a case-control study using Japanese community controls to illustrate the association between upper gastrointestinal bleeding and nonsteroidal anti-inflammatory drugs.<BR>To ensure efficient and accurate case identification, all candidate patients admitted to the participating hospitals with target conditions (upper gastrointestinal bleeding etc.) were listed by doctors/research coordinators. Summary tables with the candidates information on eligibility and whether or not the patient gave informed consent were reported back to the study office weekly. Using the summary tables, the fraction eligible and the participation rate for cases were estimated as 24% and 76%, respectively.<BR>To select controls, residents matched with each case according to age, gender and district of residence were randomly sampled from the population registries in the municipal office. To achieve a satisfactory participation rate for residents (47%), we used envelopes with prestigious university letterhead and made phone calls in a timely manner rather than waiting for their replies, both of which yielded favorable results.<BR>By telephone interview, a large amount of information was obtained in approximately 30 minutes. To help subjects' recall, a brochure displaying pictures of analgesics and a calendar for recent 4 weeks were sent in advance, and in the interview, questions using 6 kinds of “prompts” that might enhance recall were employed.

The Need to Complement the Information Obtained from Pharmacists in the Community Pharmacy by That in the Hospital Pharmacy in Prescription-Event Monitoring in Japan (J-PEM) / 薬剤疫学

Objective : To evaluate the necessity to complement the information obtained from pharmacists in the community pharmacy by that from the hospital pharmacy in Prescription-Event Monitoring in Japan (J-PEM) by using data in a J-PEM pilot study.<BR>Methods : For each patient, two questionnaires were sent to the prescribing doctor and the pharmacist who registered the patient ID code in the pilot study. If the patient ID code was registered by the pharmacist in the community pharmacy and if a pharmacist inside the hospital where the prescription was issued was willing to co-operate, a third questionnaire for the same patient was sent to the pharmacist in the hospital pharmacy. The information given by pharmacists was analyzed for 150 pairs of questionnaires (on 150 patients) sent back from pharmacists in both community and hospital pharmacies. The questions in the questionnaire were categorized into [1] those on drugs used by patients (concurrent drugs, daily dose of the drug monitored, and compliance), [2] those on events which the patient had experienced after the prescription of the drug monitored, [3] those on patients (the first date of prescription, reason of prescribing the drug monitored, initial date when the disease developed, underlying diseases or complications and whether and when the patient was lost to follow-up). The questionnaires were examined to determine whether the answer was given to each question. When the answer was given, its quality and quantity were then assessed. The answer to each question given by the pharmacist in the community pharmacy (C) and that by the pharmacist in the hospital pharmacy (H) were compared by the McNemar test after the pairs of answers were classified into the following categories : [1] C is better than H, [2] H is better than C, [3] C and H are similar to each other, and [4] impossible to classify. The difference was considered to be significant where p<0.05.<BR>Results and conclusion : For the initial date when the disease developed and 'underlying diseases or complications', H was significantly better than C. However, for concurrent drugs, compliance and events, C was significantly better than H. Otherwise, the difference was not statistically significant. Being compatible with the superiority of C over H in regard to concurrent drugs and events, the fraction of patients lost to follow-up during the observation period was small not only in H but also in C. This observation may be associated with the fact that almost all prescriptions were issued by a single hospital in more than 60% of community pharmacies in the pilot study, and most patients identified in the study were probably a regular visitor to one of such community pharmacies. The most important information to be provided by the pharmacists in J-PEM is that on events and drugs used by patients. It is thought to be not necessary to complement the information obtained from the community pharmacy by that from the hospital pharmacy.