Objective : To have future perspective on postmarketing surveillance (PMS) in Japan
Design and Methods : Several general principles considered of particular importance to PMS in Japan are outlined as follows ; (1) to help and encourage the voluntary cooperation with all health professionals, (2) to make data open to public but not exclusively to regulatory authority, (3) to conduct non-interventional or observational study which monitors the patients representative of the general population of users and (4) to encourage the development of multi-scheme system.
Results and Conclusion : It is concluded that existing schemes may be improved and some may be newly created as follows ; (1) as to voluntary reporting system, the reports should be collected from all health professionals in all clinics and hospitals, (2) a new system similar to Prescription-Event Monitoring (PEM) in UK may be worth trying to establish in Japan because medical costs including those of drugs are itemized in monthly claims for individual patients made by all Japanese clinics and hospitals, (3) hospital-based database may be further developed and (4) a system for case registration to conduct high-quality case-control studies to detect rare adverse reactions may be newly created.

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Objectives : To find the most important problems to be addressed by pharmacoepidemiology in Japan. My view presented in this article is personal conceived after having witnessed several drug-induced disasters (e.g., the SMON affair in 1970 and the Sorivudine case in 1993) and carried out a number of epidemiological studies while practicing as an internist.
Methods : Preventive measures taken after having experienced major drug-induced disasters as well as the relationship between these measures and pharmacoepidemiology are compared between the foreign developed countries and Japan. The comparison is conducted based on my belief that pharmacoepidemiology must examine the major epidemic drug-related diseases, and find and verify the effective measures to prevent them.
Results and Conclusion : It is found that in the USA and England, the drug-induced disasters have led the following effective countermeasures : revising the methods of approval of new drugs including the introduction of licensing for clinical trials of investigational products and improving postmarketingsurveillance according to the concept of “event monitoring”. Pharmacoepidemiology has been developed in association with those reforms. On the contrary, many measures posed after the drug disasters seen to have not worked well in Japan. Pharmacoepidemiology in Japan should have a more active role in (1) planning the measures to prevent drug disasters, (2) monitoring the methods and individual processes of approval of new drugs, (3) evaluating the investigational products particularly with respect to the safety (toxicity), and (4) carrying out orthodox pharmacoepidemiology researches including drug utilization studies, case-control studies, prescription-event monitoring, long term randomized controlled studies, pharmacoeconomic studies and so on.

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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).
Design : Retrospective cohort study.
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.
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.
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.
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.
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.

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Objective : To examine antihypertensive drug use in major therapeutic categories and to compare with guidelines for antihypertensive therapy.
Design : Cross-sectional drug utilization survey.
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.
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%).
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.

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Objective : To examine past trend and present status of polypharmacy, multiple drug therapy, which can be a cause of serious adverse events induced by drug interactions.
Design : Drug utilization survey using a database of the Kagoshima University Hospital Information System.
Methods : Data of the prescriptions issued during every May between 1985 and 1994 were extracted from the database. Monthly prescriptions were classified by the number of drugs they included.Furthermore, the data were sorted by patients' ID to obtain the age distribution of patients observed in each year and the distribution of the number of drugs per prescription was analyzed in each age group.
Results : The average number of medicines per prescription was increased from 3.07±2.16 (average±S.D.) in 1985 to 3.46±2.61 in 1994. During 10 years between 1985 and 1994, the proportion of patients receiving ten drugs or more also increased from 1.50%to 3.90%. There was a clear tendency that a large number of drugs were given to old patients and comparatively few drugs to young patients.Proportion of the old patients over 59 years of age increased linearly from 25.71%in 1985 to 35.37% in 1994.
Conclusion : The average number of medicines per prescription was increased during 10 years. This trend is considered to be attributable in part to the increase in the proportion of the old patients. The concomitant use of so many drugs is a problem and a rule for diminishing returns recently adopted as a reimbursement policy of health insurance system has been applied to prescriptions with ten drugs or more. Further studies are needed to examine possible adverse outcomes and other characteristic features of multiple therapy.

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Background : A vitamin K₂ agent has recently been approved and is going to be marketed for the treatment of osteoporosis. Since vitamin K₂ agents are known to cause rebound of blood coagulation capacity lowered by an anticoagulant warfarin, a great caution is necessary for the concomitant use of these agents.
Objective and Design : A drug utilization survey to examine the use of warfarin and drugs for osteoporosis.
Methods : Fukui Medical School Database was surveyed to identify patients who used warfarin and/or drugs for osteoporosis during the period between January 1, 1988 and July 31, 1995. Patients with a diagnosis osteoporosis made between December 1, 1983 and July 31, 1995, were also identified and their prescription data were extracted to examine the combined use of warfarin and drugs for osteoporosis. In addition, 53 outpatients with cardiovascular diseases were interviewed to know the treatments and medications given by other clinics.
Results : Concomitant drug therapy for osteoporosis was given to 6.9% (56/813) of warfarin users. The proportion of concomitant use was 15% (36/234) in women, much higher than 3.5% (20/579) in men. More than 10% of the interviewed patients were receiving some treatments in other orthopedic clinics for osteoporosis or other diseases but few patients were aware of their medication.
Conclusion : Old female users of warfarin, especially those having osteoporosis concomitantly, are likely to berome a high risk group for the possible interaction between warfarin and the vitamin K₂ agent. Useful information on the safety associated with the interaction between these two drugs should be given to this group of patients as well as to the prescribers and dispensers.

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Objective : To get first-hand information on and understand MEDWatch, a newly created program of the US FDA, on safety information reporting and management.
Design and Method : Through a visit to the FDA office by Japanese members of the ICH M1 (Medical Terminology) Expert Working Group (EWG) and other concerned experts, and discussion with relevant FDA staffs.
Results and Conclusion : (1) The MEDWatch program was introduced in June 1993, to accelerate the spontaneous reporting of adverse events (AE) to FDA by developing a single Adverse Event Reporting Form, i.e., FDA 3500, for (1) drugs, (2) biologics (except vaccine), (3) medical devices, (4) food, and (5) veterinary medicines; (2) Five responsible sectors in FDA have been working together to develop a smooth flow of information from health care professionals and industries; (3) The remarkable result from the development of this new program is the increased reporting of serious AE; (4) Much efforts have been exerted by FDA on the education of health professionals through various health societies and through publications; (5) Some of the issues which remain unresolved include database integration of NDA and PMS information; (6) Advocacy of the AE concept and importance of reporting thereof by health care professionals and the use of simple, easy-to-fill-out form is recommended in Japan.

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