Objective : To detect signals of potential drug adverse events (DAEs) through data mining of health insurance claims.
Design and Data : Retrospective observational study. The data used were the database of health insurance claims collected and maintained by the Japan Medical Data Center consisting of 312, 797 medical and pharmaceutical claims in one year (August 2003 through July 2004) linked uniquely for 35, 410 patients using an encryption technique to ensure privacy.
Methods : We counted all combinations (cross product or Cartesian product) of drugs and diagnoses appearing in the same claims and counted the number of times a given drug was prescribed preceding the suspected diagnosis in all combinations of the drug and the diagnosis appearing in a claim, i.e., the prescription date precedes the diagnosing date (the preceding number). We calculated the expected preceding number from the overall prevalence of drugs and diagnoses, and then calculated the observed and expected ratio, which was used as the signal indices. We calculated the signal indices on the health insurance claims data to detect DAEs of psychiatric drugs.
Results : Amoxapine and trazodone HCL showed high signal indices with paralytic ileus and convulsion (epilepsy) as documented in their package inserts. However, paroxetine HCL and etizolam showed high signal indices with these potential adverse events although no such DAEs are documented in their package inserts.
Conclusions : The undocumented high signal indices observed between the drugs and diagnoses indicate the potential DAEs and warrant in-depth pharmacovigilance. Given the strength of health insurance claims with a well-defined source population and accurate drug exposure, the proposed signal index will likely prove to be an effective data mining technique when combined with nested case-control analysis and counter-matching.

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To evaluate and promote the rational use of antiarrhythmic drugs, a series of pharmacoepidemiological studies were performed. First, studies on hypoglycemia induced by cibenzoline were performed. The mechanism of the hypoglycemic effect of cibenzoline is related to an increase in insulin secretion. A significantly increased risk of hypoglycemia was observed in patients treated with cibenzoline in a case-controlled study. In particular, close attention should be paid to the occurrence of cibenzoline-induced hypoglycemia in elderly patients, those receiving high doses and in those with reduced renal function. After the introduction of TDM, the risk of hypoglycemia associated with cibenzoline use decreased together with an increase of the percentage of patients whose serum concentrations of cibenzoline had been measured. Dose adjustment based on TDM was beneficial for patients treated with cibenzoline in order to prevent hypoglycemia. In general, drugs are used in accordance with an approved dosage regimen in the expectation of an appropriate balance between efficacy and toxicity. However, a difference was seen between the approved dosage and the actual dose in cibenzoline therapy. Secondly, prescription research of several antiarrhythmic drugs was performed at five national hospitals. Antiarrhythmic drugs were used in lower doses than the approved dosage in clinical practice in Japan. Differences were seen between the approved dosage and the actual dose, and remarkable variations were seen in the dose distribution among the hospitals. The discrepancy between the approved dosage and practical dosage suggests that there is doubt as to whether the approved dosing regimens for antiarrhythmic drugs are appropriate.

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The role of pharmacoepidemiology in drug surveillance is becoming more important as there has been an increasing number of social issues concerning post-marketing drug safety in accordance with the increasing number of swift approvals of innovative new drugs with high potency and efficacy due to the progress of medical and pharmaceutical sciences.
The ICH E2E guideline for pharmacovigilance planning has been finalized as Step 4 and comprehensive risk management planning is being proposed in EU and US. Pharmacoepidemiology is thus an indispensable factor in safety surveillance.
On the other hand, guidelines for conducting observational studies to investigate the potential safety issues do not exist in Japan. The guidelines for post-marketing safety surveillance observational studies presented here were drafted by referring to various observational studies and guidelines used by foreign companies for post-marketing surveillance and by taking into consideration, the feasibility of implementation in Japan.
There are two parts in this report-the first part of the report describes goal, scope and principles such as standard matters, and the latter part illustrates the details of observational cohort study and nested case control study that are likely to be conducted by companies. Relevant groups will be requested to review the draft guideline to refine the contents for implementation and it is expected that pharmacoepidemiological studies would contribute to the post-marketing safety measures to be taken.

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