1．Spontaneous Report Database and Case-control Studies / 薬剤疫学

In the current review, the relationship between the reporting odds ratio (ROR) and the case-control study is addressed.The proportional mortality ratio (PMR) obtained in the proportional mortality studies in the death registry cannot be regarded as the risk ratio (RR) in the cohort study, but, the mortality odds ratio (MOR) estimated by using deaths unrelated to the exposure as ‘controls’ can be regarded as the RR.In 2004, Rothman et al proposed to estimate the ROR which can be regarded as the RR by using proper ‘control events’ in the spontaneous reports database. However, in the study conducted in Japan where the RORs estimated from 20 ‘control events’ were compared with the RRs obtained from many ‘drug use investigations’, the ROR vs RR plots were so diverse.The author of the current review concludes that the study estimating the ROR in the spontaneous reports cannot be regarded as the case-control study as the case-control study should estimate the RR of the cohort study in the source population as the odds ratio (OR).The ‘disproportionality measures’ like the ROR in the spontaneous reports database should be used primarily to detect the signals of the association between a drug and an adverse outcome. However, spontaneous reports can contribute to the characterization of the adverse drug reactions and to determining the causal relationship as well. The methods of signal detection are evolving and it is hoped that Japanese researchers contribute to their further developments.

Task Force Report on the Validation of Diagnosis Codes and Other Outcome Definitions in the Japanese Receipt Data / 薬剤疫学

Although the recent revision of the ministerial ordinance on Good Post-marketing Study Practice (GPSP) included the utilization of medical information databases for post-marketing surveillance, there has been limited research on the validity of diagnosis codes and other outcome definitions in Japanese databases such as administrative claims (“receipt”) database. This task force proposed how to conduct good validations studies, based on the narrative review on around 100 published papers around the world. The established check list consists of ： (ⅰ) understanding the type of the database (e.g. administrative claims data, electronic health records, disease registry) ； (ii) understanding the setting of the validation study (e.g. “population-based” or not) ； (iii) defining the study outcome ； (iv) determining the way of linkage between databases ； (v) defining the gold standard ； (vi) selecting the sampling method (e.g. using the information of all patients in the database or a hospital, random sampling from all patients, random sampling from patients satisfying the outcome definition, random sampling from patients satisfying and not satisfying the outcome definition, “all possible cases” method) and sample size ； (vii) calculating the measures of validity (e.g. sensitivity, specificity, positive predictive value, negative predictive value) ； and (viii) discussing how to use the result for future studies. In current Japan, where the linkage between databases is logistically and legally difficult, most validation studies would to be conducted on a hospital basis. In such a situation, detailed description of hospital and patient characteristics is important to discuss the generalizability of the validation study result to the entire database. This report is expected to encourage and help to conduct appropriate validation studies.

<b>Good Pharmacovigilance Planning in Japan: Proposals from the “Task Force for Good Pharmacovigilance Planning in Japan” of Japanese Society for Pharmacoepidemiology (JSPE)</b> / 薬剤疫学

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.

<b>3. A Review of Completed Activities of “The Task Force to Make an Ideal Pharmacovigilance Plan (PVP) in Japan” : Evaluation of the Published Pharmacovigilance Plan (PVP) by JSPE's Check List and the Future Challenges&l / 薬剤疫学

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.

<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.

<b>Expectation for Development of Pharmacoepidemiology Studies in Japan with SS-MIX Standardized Storage </b> / 薬剤疫学

Resources for legitimate pharmacoepidemiology studies have been poor in Japan. One of the pivotal elements which may lead to the development of the infrastructure for legitimate pharmacoepidemiology studies in Japan is to make post-authorization studies conducted by drug companies employ more scientific pharmacoepidemiology principles. In 2012, a notice on risk management plan (RMP) was issued to require the implementation of pharmacovigilance plan (PVP)given in the ICH's E2E guidelines as well as the risk minimization action plan. The ICH's E2E guidelines require the use of pharmacoepidemiology principles in the post-authorization studies. In this article, the registry-type post-authorization study using the SS-MIX standardized storage is compared with the old Drug Utilization Investigation (DUI) conducted for several decades in Japan. A DUI has a potential to become a promotional study as the prescription of the medicine is not separated from the decision to include the patient in the study which can be avoided by the identification of study subjects by using the SS-MIX standardized storage. In addition, the standardized storage will be powerful in identifying new users of two drugs to be compared. The database study may become a component of the post-authorization studies in the future, but mainly due to the difficulty of the record linkage, the registry-type study will remain important to complement the database studies for the time being. The promotion of both of the registry-type studies and database studies using the SS-MIX standardized storage will facilitate the development of the infrastructure needed to conduct legitimate pharmacoepidemiology studies. (Jpn J Pharmacoepidemiol 2013;18(1):41-48)

<b>2. The Use of Medical Information in Foreign Countries: Examples in Pharmacoepidemiology Studies</b> / 薬剤疫学

In this manuscript, the use of medical information in foreign countries is viewed by taking pharmacoepidemiology studies conducted in US, Sweden and Taiwan as examples. The first example is the cohort study on the association between pioglitazone and bladder cancer using diabetes registry in Kaiser Permanente Northern California(KPNC) which suggested the causal relationship between pioglitazone and bladder cancer. The success of the study was due to the diabetes registry constructed taking long time in KPNC from various data sources including claims data, data of electronic health record and data in pharmacies. The second example is the study on safety of H1N1 vaccine in Sweden. In this study, the vaccine registry was newly developed on the website where almost all of the vaccinated subjects were registered as reimbursement was subject to registration. The web-based registry was linked with the existing common healthcare registers and the investigators estimated hazard ratios of rare outcomes like Bell's palsy and paraesthesia associated with vaccination. The third example is the Large Linked Database(LLDB) to monitor safety of H1N1 vaccination in Taiwan. The LLDB used the technology of IC Card Data Center and the information on diagnosis and vaccination was collected on the daily basis. The risk of various outcomes as in the second study and adverse outcomes associated with pregnancy were monitored. In all of those examples, new mechanisms such as diabetes registry, web-based vaccine registry and the LLDB were established purposefully. The record linkage is the key element to enhance the value of medical information. (Jpn J Pharmacoepidemiol 2012; 17(2): 109-116)

<b>Proposal for the Best Pharmacovigilance Plan in Japan by comparing Japan Postmarketing Studies to the U.S. Postmarketing Requirements: </b> / 薬剤疫学

<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)

A Report from Task Force on Pharmacoepidemiology and Pharmaceutical Industory / 薬剤疫学

Over 40 years, Post-maketing surveillance (PMS) studies have been conducted as a legal obligation in Japan. Though the contribution of these studies to the better use of the drug has been acknowledged, there are criticisms that these PMS studies have been stereotyped and need to be improved. The ICH-E2E guideline entitled as "Pharmcovigilance Planning", agreed in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) has been implemented in the concerned countries. The legislation of the guideline in Japan in 2005 seems to have urged drug companies and regulatory agency to review the current PMS practices in contrast with the today's highest scientific standard. We investigated the theoretical and practical aspects of pharmacoepidemiology required when the drug company evaluates safety specification prior to developing the pharmacovigilance plan and designs a PMS study along the lines stipulated in the ICH-E2E guideline. To meet this end, we evaluated the profiles of the drug, summarized "Important identified risks", "Important potential risks" and "Important missing information" to be identified and examined the pharmacovigilance plan suggested by the regulatory agency and that proposed and implemented by the drug company. We examined those aspects for 6 new products selected from 168 drugs newly approved during the period between January 2004 and October 2006. In 5 of 6 cases, we judged that the use of a comparator group would have been appropriate to asses the association between the drug and adverse events of interest. In addition, in one half (3) of 6 cases, it would have been preferable to use the database for the patient registration and/or other types of databases. The issues of relevant legislation and the infrastructure and funding for the investigations needed to develop a desirable study design and conduct a good pharmacoepidemiology study are however beyond a single company's capacity and should be set as a national strategy. The issues of post-marketing safety in the nation is becoming more and more important as the data in the countries outside Japan are being used more often for the processes of marketing authorization application of a new drug and its approval. It is urgent to secure the practice of pharmacoepidemiology to achieve the effective post-approval pharmacovigilance studies.

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.

Case-cohort Study and PMS / 薬剤疫学

Pharmacoepidemiological studies are often conducted to evaluate the association between the event with low incidence and exposure with low prevalence. To overcome the difficulty due to low event incidence and low exposure prevalence, White proposed a two-stage design in 1982 and Cain and Breslow further developed this design.<BR>In this article, the case-cohort and nested case-control designs are reviewed in contrast with the two-stage design. In addition, the usefulness of the case-cohort design in pharmacoepidmiology is assessed in comparison with that of the nested case-control design. In the nested case-control study, the control subjects are selected only after cases occur irrespective of whether the method of “risk set matching” or “unmatched density sampling” is used. Therefore, all of the events evaluated in the study must be clearly defined in advance. On the other hand, in a prospective case-cohort study, a single subcohort, selected independent of cases, is used to analyze multiple outcomes. Owing to this feature, the case-cohort design may be useful to study unknown adverse events that have not been specified as a target event prior to the study but are recognized as a problem that requires in-depth evaluation during or after the study is conducted. Weaknesses and limitations of the case-cohort design as compared to the nested case-control design are also discussed.<BR>Data yielded by simulations for hypothetical case-cohort studies are analyzed by the SAS PHREG procedure with the robust variance estimation. The program used and results of simulations are presented.<BR>The case-cohort study design may be useful for various pharmacoepidemiological studies in Japan where no large medical database is available.

Nested Case-Control Study Using Countermatching and Its Implication in PMS Studies / 薬剤疫学

According to the on-going discussion in ICH E2E, in future PMS studies, it will be necessary to specifically address the problem and the best study method for the specified problem must be properly selected. In this article, the design for a nested case-control study using countermatching is introduced as one of the best candidate methods for future PMS studies. <BR>In the method, a cohort is stratified by the exposure status and a control is selected from the stratum with the exposure status opposite to that of the “counter-matched” case. <BR>It has been shown that this method can increase the efficiency of the study. In addition, it will give those involved in the PMS studies the confidence that the use of the nested case-control study design is valid in the PMS studies where the cohort consisting of a group of patients with the study drug and another group of those with the comparator drug is observed. <BR>However, to make this method realistic in the Japanese PMS milieu, the following two conditions must be satisfied. First, those involved in the PMS studies should realize the importance of the comparison of two drugs while the comparison of two similar drugs has been to date carefully avoided in Japanese PMS studies. Secondly, a method to identify two comparable groups should become possible. The latter may be accomplished by establishing the infrastructure for the mechanism where the prescription data in hospital/community pharmacies are used to identify those who recently started either of the two drugs compared in the study.

Signal Detection from Spontaneous Reports / 薬剤疫学

Objective : To outline new methods developed in Medicines Control Agency (MCA) in the UK, Food and Drug Administration (FDA) in the USA and WHO Uppsala Monitoring Centre (UMC) to detect signals from spontaneous reports on suspected drug reactions.<BR>Methods : Presentations in the Signal Generation Symposium (Southampton, UK, June 2001) and related articles identified by hand searching were examined.<BR>Results : All of the 3 methods compare the number or probability of reports on a particular drug-event combination with the expected number or probability for the combination. For example, in the MCA's method, the expected number is estimated as (the total number of reports on a drug) × (the fraction of an event among all spontaneous reports). A signal is detected when Proportional Reporting Ratio (PRR) defined as the ratio of observed/expected numbers>2 and the corresponding chi-square value> 4. In the FDA's method, the observed number of a drug-event combination is supposed to have a Poisson distribution with a mean of μ and the signal score is defined as the expected value of a random variable λ=μ/E where E is the expected number of reports on that combination. A signal is detected when signal score>2. The “Information Component” (IC) in the UMC's methods is estimated from the ratio of posterior to prior probabilities for a particular drug-event combination. A signal is detected when the 95% confidence interval for the IC is positive and does not include 0.<BR>Conclusion : New methods outlined in this article require further theoretical development and its application to the analysis of spontaneous reports.

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.

Feasibility of Conducting Event Monitoring in Japan Similar to Prescription-Event Monitoring in England : A Report on a Health Sciences Research to Ministry of Health and Welfare Japan in 1997 / 薬剤疫学

Background : With a support from Ministry of Health and Welfare (MHW) Japan, we embarked on a pilot study for Prescription-Event Monitoring (PEM) adapted to Japanese environment. <BR>Methods : A pilot study was conducted according to the report on this subject to MHW in 1996. <BR>Results and Conclusion : PEM using monthly claims called as “Rezept” issued by individual hospitals and clinics is judged to be difficult unless the use of the claims for epidemiological studies is legally separated from the examination process of the medical cost claimed. PEM using the prescriptions dispensed by individual pharmacies is easier to conduct. Some progress has been attained by employing the latter scheme in the pilot study where approximately 1300 patients with a new antidiabetic agent, troglitazone, are compared with 1300 patients who have recently started one of “old” antidiabetics.

Methodological Issues of Pharmacoepidemiology Studies Using Hospital-based Database in Japan / 薬剤疫学

Objective : To know how to conduct good pharmacoepidemiology studies using hospital-based database in Japan.<BR>Methods : Medical records during 15 months January 1996 and March 1997 in the University of Tokyo Hospital Information System (HIS) are examined know whether it is possible to conduct pharmacoepidemiology studies similar to previous studies on asthma drugs (Spitzer et al, 1992) and calcium antagonists (Psaty et al, 1995). To know the stability of population covered by HIS, the following two intervals are calculated for ambulatory patients with asthma and hypertension ; 1) average intervals of successive two outpatient visits and 2) intervals between the last day of outpatient visit and the last day of observation.<BR>Results : The size of possible pharmacoepidemiology studies attainable using HIS is judged to be more than 5% of previous studies in Canada and America. Average intervals of successive two outpatient visits are estimated to be 30 days or less for 59% of 693 asthmatics and 77% of 2842 hypertensives. For 48% of asthmatics and 71% of hypertensives, intervals between the last day of outpatient visit and the last day of observation are estimated to be 30 days or less.<BR>Discussion : To attain a size appropriate for pharmacoepidemiology study, researchers must cooperate across hospitals. Although a patient can visit any hospital anywhere under Japanese comprehensive medical care plan, it seems that patients tend to become to visit one particular hospital. However, additional information on medical care in other hospitals is needed for each study subject.<BR>Conclusion : Japanese hospital-based database is suitable for pharmacoepidemiology studies as a record during a long time period is usually available for a large fraction of patients with a particular disease. The study may be free from some of biases closely associated with referral processes known to occur in hospital case-control studies. A design of case-control study selecting patients with long medical records across 5-10 hospitals is probably the most promising when using Japanese hospital-based databases.

Feasibility of Conducting Event Monitoring in Japan Similar to Prescription-Event Monitoring in England : A Report on a Health Sciences Research to Ministry of Health and Welfare Japan in 1996 / 薬剤疫学

Background : With a suppport from Ministry of Health and Welfare (MHW) Japan, we studied the feasibility of conducting event monitoring in Japan similar to Prescription-Event Monitoring in England. The manuscript presented is a report to MHW in 1996.<BR>Methods : Means available in Japan to identify drug, patient and doctor are examined. In addition, any modification needed to make on a questionnaire sent to doctors in PEM conducted in Japan is examined.<BR>Results and Conclusion : Monthly claims called as “Rezept” issued by individual hospitals and clinics and sent to insurers and outpatient prescriptions issued by hospitals to be dispensed by the pharmacies outside the hospitals are considered to be two available means to identify drug, patient and doctor. To have a sample representative of all drug users, the use of “Rezept” is needed as only a fraction of outpatient prescriptions are dispensed by independent pharmacies. However, the use of prescriptions dispensed by the independent pharmacies together with the cooperation of individual pharmacies is capable of finding a contemporary control which is a group of patients who have recently started “old” drugs comparable to the new “test drug”. In Japan no doctor may have a complete list of the hospitals and clinics a patient has visited and it is mandatory to ask doctors the last date when the patient visited the doctor. To clarify what problems arise when a PEM-like study is introduced to Japan, a pilot study is going to be done during 1997 and the feasibility will be examined further based on the results.

Voluntary Reporting on Suspected Drug Reactions Collected via Drug Companies in Japan : Companies' View / 薬剤疫学

Background : In Japan most (>85%) voluntary reports on suspected drug reactions are collected by drug companies.<BR>Objective : To know various aspects of case reports on suspected drug reactions collected by Japanese drug companies.<BR>Methods : Questionnaires were designed by our department and mailed to 96 major drug companies in late March 1997. They were reminded in mid-May and mid-June when not having responded.<BR>Results and Conclusion : Of 96 drug companies, 3 were found to be not eligible (e. g., selling only the OTC drugs) and excluded. Of the remaining 93 companies, 91 (98%) responded. Of all the case reports collected by drug companies (approximately 27, 000/year), 36%of serious or important cases are duly reported to Ministry of Health and Welfare (MHW) within 15 days or 30 days of receipt. In Japan individual case reports collected by drug companies and reported to MHW have been closed. Eleven companies are opposed to disclosing individual case reports while 6 agree unconditionally. Seventy companies agree to disclosing individual case reports with various conditions such as protecting patients' privacy, not disclosing the reporter's identity, and making individual case reports available to medical personnel only. Finally, 20 of 91 drug companies complained that MHW does not let them know individual case reports associated with their own products sent to MHW directly from medical doctors or via other companies. To promote pharmacoepidemiology, disclosing voluntary reports is pivotal and MHW is going to adopt this policy in two years for which however reporters and drug companies must be prepared in advance.