<b>Analysis for Trend in Pharmacoepidemiological Studies </b> / 薬剤疫学

Since the Vol.1 No.1 was published in March 1996, the journal of “Pharmacoepidemiology” has been published approximately two times per year. The current issue is Vol.18 No.1 in 2013. The number of original articles in total was forty-three. Based on these original articles, what type of pharmacoepidemiological studies were performed and the trend of study designs are demonstrated. The studies for database and methodology of pharmacoepidemiology have been constantly conducted. The number of the studies for evaluating drug usefulness and drug utilization is decreasing. In contrast, the studies for evaluating drug safety is increasing, especially, hybrid designs, such as a case-crossover study or nested case-control study are recently conducted.

Subgroup Analysis in Meta-Analysis: a comparison of different methods / 薬剤疫学

<b>Introduction</b> : Meta-analysis is well recognized as the most important study methodology in pharmacoepidemiology. The cause of heterogeneity of the effects among studies in the conventional meta-analyses, has been typically analyzed by meta-regression and sometimes by extracting several studies in a post hoc manner, constructing subgroups from these studies and analyzing the effect in this subgroup. However, if multiple study subgroups are produced in a post hoc manner, since the potential possible number of subgroups is very huge, the multiplicity of testing results in the inflation of the type I error rate. Therefore, even when a significant subgroup has been identified, it can represent a type I error, due to multiplicity of testing. To insist on the significance of a post hoc subgroup analysis, it is indispensable to conduct an analysis adjusted for multiplicity.<br><b>Objective</b> : The present study was undertaken to establish a method for resolving the problem for the multiplicity of subgroup analysis in meta-analysis.<br><b>Methods</b> : Performance comparisons among the Bonferroni method, the Holm method, the Scheffe type method and the closed testing procedure were conducted, assuming the actual meta-analysis of clinical studies on colon cancer.<br><b>Results</b> : In the subgroup analysis without adjustment for multiplicity, the probability of type I error was unacceptably high. On the other hand, the four methods mentioned above can control this probability to below the nominal significance level. Under many situations, the closed testing procedure showed a relatively higher power, and this method was particularly superior to the other methods when a relatively high percentage of studies revealed minor effects.

Estimating a Hazard Function for Each of Four Items of Adverse Event Induced by the Anti-cancer Drug TS-1 / 薬剤疫学

Background : The safety of newly approved drugs must be assessed using postmarketing surveillance data. One of the difficulties in assessing the hazard rates of adverse events induced by the anti-cancer drug TS-1 was that the time to event was not exactly identified due to the interval censoring. Most patients were outpatients who underwent clinical laboratory tests almost periodically at 1- or 2-week intervals and therefore, the occurrence of an adverse event was confirmed at the time of testing days after the event occurrence.<BR>Objective : The purpose of this study was to propose a new model of hazard functions for each of 4 items of adverse event induced by TS-1 using post-marketing surveillance data considering the interval censoring.<BR>Methods : The data obtained from 3, 294 patients with gastric cancer who received an initial 4-week course of therapy with TS-1 administered orally twice a day, followed by a 4-week second course with a 2-week no-treatment period after the initial course, were used to estimate hazard functions. Four items of adverse event--hemoglobin level (HB), white blood cell (WBC), neutrophil (NEUT) and platelet counts (PLT) --were graded, respectively, using the criteria established by the Japan Society of Clinical Oncology. Slip-mixed log-logistic and slip-mixed Weibull models were proposed as candidate models for estimating hazard functions. The goodness of fit of the two candidate models was evaluated by applying them to the above-mentioned data. The hazard functions for each of 4 items were assessed using the model with the better fit.<BR>Results : The initial occurrence of adverse event was shown to follow the slip-mixed log-logistic model for each of 4 items. Although most events occurred early on in the initial course of therapy, a small peak in HB was also observed in the second course, while no such peak appeared for the other items.

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.

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.

Comparative Study on Data Sources of Detecting Adverse Drug Reactions / 薬剤疫学

Objective : To find the effective means to detect adverse drug reactions (ADRs) from hospital information system, three data sources, i.e. diagnosis data (Dx), laboratory data (Lab), and prescription data (Rx), are compared in diuretics induced hyperuricemia and/or gout (H/G).<BR>Design : Retrospective cohort study.<BR>Methods : Cohort entry period was three months. Hypertensive outpatients who already had H/G prior to that period were excluded. Then, they were surveyed for 9 months. The patients using diuretics were separated into two groups, i.e. Thiazide-treated group, and Loop-treated group.<BR>Controls were randomly selected from non-diuretic-treated hypertensive outpatients matched to each diuretic group by age and sex. Signals of ADRs were the new prescription of drugs employed in the treatment of H/G from Rx, abnormal serum uric acid level from Lab, and diagnosis of H/G from Dx. The interrelationship of them were examined by the Venn diagram and scatter plot. Finally the incidence of ADRs detected by the above signals and relative risks were calculated and compared. Moreover, prevalence of renal disease in each group was surveyed to examine the possibility that renal disease caused H/G.<BR>Results : Eighteen patients in 240 outpatients treated with Thiazide diuretics and 70 patients in 523 outpatients treated with Loop diuretics were found having developed H/G from Dx, Lab, and/or Rx data sources. More than 90% of total patients were detected from Lab while, a few patients were identified from Dx and Rx. It was rare and coincidental that the three data sources agreed with one another.<BR>The risk of Loop diuretics is approximately twice that of Thiazide diuretics. The incidence and risk of H/G in diuretics estimated in the current study were compatible with the prior report. However, the prevalence of renal disease were high (though not statistically significant) in Loop-treated group so that we possibly overestimated the risk of it.<BR>Conclusion : The order of three data sources, arranged according to the number of ADR signals detected, was Lab, Rx, and Dx. It may be possible to assess the risk of ADR even by Lab only. If Lab is not available, Rx and Dx are useful provided that more subjects and longer research period are involved. However it is necessary to combine three data sources, Dx, Lab, and Rx to detect as many suspected adverse events as possible when using the present clinical database.

A 10-Year Study on Antihypertensive Drug Use Based on Prescription Data in Bohsei Pharmacy / 薬剤疫学

Objective : To examine antihypertensive drug use in major therapeutic categories and to compare with guidelines for antihypertensive therapy.<BR>Design : Cross-sectional drug utilization survey.<BR>Methods : Prescription data on antihypertensives, from 1985 to 1994, were extracted from electronic record accumulated in Bohsei Pharmacy. Repeated prescriptions were identified by patients' identification code. Patients using diuretics (DU), beta-blockers (BB), Ca-channel blockers (CCB), ACE-inhibitors (ACEI), and others were counted in each calender year. These data were compared with 1993 annual utilization data of antihypertensive drugs in Western countries obtained from a commercial database.<BR>Results : The use of CCB and ACEI increased to reach a high proportion of 43.0 % and 18.7 %, respectively, in 1994. On the other hand, the use of DU and BB showed a marked decrease and DU accounted for 16.3 %, BB for 13.5 % in 1994. The other categories were minor. These figures from Bohsei Pharmacy formed a contrast to those in Western countries. For instance, the use of DU waspredominant in the UK. In the US and Germany, CCB was widely used (≅30%) but DU was also used to a similar extent (30-40%).<BR>Conclusion : The pattern of antihypertensive drug use found in the record of Bohsei Pharmacy may be judged to be appropriate since the JNC and other guidelines recommend DU, BB, CCB, and ACEI as the first line drugs. However, the proportion of the use of CCB is an issue of concern and might be criticized to be too high in light of the fact mentioned by those guidelines that efficacy/safety of CCB's has not yet been proven sufficiently based on morbidity and mortality data.