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The Generalisabilityof Economic Evaluation

Japanese Journal of Pharmacoepidemiology.2001;6(1):69-82. doi:10.3820/jjpe1996.6.69

Objective : A major challenge to the usefulness of economic evaluation for decision-making is concern over the generalisability of the results. The purpose of this paper is to review the methodological issue of generalisability within economic evaluation and to discuss approaches for facilitating the generalisability of economic analysis to the Japanese context.
Methods : Electronic searches of key databases (MEDLINE, HEALTHSTAR, OHE, NHS EED) and handsearches of key health economics and health technology journals (ISTAHC, Pharmacoeconomics, Health Economics) in the period 1990-2000 were conducted to identify papers relating to factors affecting and methods for enhancing generalisability across three dimensions : (i) from study to practice, (ii) between location and (iii) across time. These papers were critically reviewed and the information combined into a structured commentary.
Results : Several factors can potentially limit the generalisability of results including differences in epidemiology, the availability of treatments, clinical practice patterns, relative prices and incentives to healthcare professionals and institutions. Several analytical approaches are in existence, which allow the generalisation of health economic data to any local decision-making context. These include statistical analysis of data from multinational clinical-economic trials, the use of economic modelling and the systematic review of economic data.
Conclusion : Further research in the area of generalisability will add to the credibility and usefulness of economic evaluations in general and give decision-makers confidence that the data are suitable for use as a basis for resource-allocation decisions and provide some comfort that the actions arising from their use are not misguided.

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Cardiovascular Diseases and Pharmacoepidemiology : Present and Future

Nobutaka DOBA

Japanese Journal of Pharmacoepidemiology.2001;6(1):29-36. doi:10.3820/jjpe1996.6.29

The history of pharmacoepidemiology in Japan is short, and despite its importance for physicians in prescribing medicine in daily clinical work, their interest in this evidence-based science has been far from social acceptance. Pharmacoepidemiology itself especially in Japan must be firmly established with systematically constructed harmonious features defined by pharmaceutical health promotion consisting of four independent facets ; health professionals, consumer, industry and regulatory faces. Also, pharmacoepidemiology has to be developed on a scientific basis for outcome research focusing on the clinical and economic consequences of drug therapy decisions. Persuing this aim, pharmacoepidemiology will need to simultaneously invoke principles in other scientific fields such as molecular biology, biostatistics and genetic epidemiology. Ultimately, these interdisciplinary synergies can contribute to intelligent and hopefully more efficient drug development, and a better understanding of what will happen when the drug goes to market. In the clinical field of cardiology, on the other hand, numerous facets are involved in pharmacoepidemiology ; PMDS, polypharmacy and genetic aspects in gene polymorphism with special regard to LQT syndrome and anticoagulation with warfarin. These clinical factors associated with pharmacoepidemiology are summarized and discussed in detail.

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A Survey of Pharmacoeconomic Data in Applications for NHI New Drug Price Listing in Japan

Hiroyuki SAKAMAKI ; Nobuyasu HIROMORI ; Yumiko ABURAYA ; Ken KUBOTA ; Keiko NAKAMURA

Japanese Journal of Pharmacoepidemiology.2001;6(2):83-100. doi:10.3820/jjpe1996.6.83

Objectives : Pharmaceutical companies in Japan can attach pharmacoeconomic (PE) data to their application for new drug prices covered by the National Health Insurance (NHI) system since 1992. To examine the present state of PE studies in Japan by investigating the situation of PE data attachments and their details and also to identify problems concerning how to reflect the PE information in new drug pricing, a questionnaire-based survey of pharmaceutical companies was conducted.
Method : The survey covered 115 drugs filed by the members of the Japanese Pharmaceutical Manufacturers Association (JPMA), which are among the 137 drugs listed between June 20, 1997, when the NHI drug price formula was published, and November 17, 2000. Questionnaires were returned on 114 of the 115 drugs studied and the response rate was 99%.
Results : PE data was attached to 37 of the 114 drugs (32%) at the time of application. The ratio of applications accompanied by PE data tended to be decreased from 1998. No significant relation was observed between a premium for a drug and the attachment of PE data. The most common method used in the attached PE data was cost-effective analysis (14 of 37 drugs ; 38%), followed by cost-benefit analysis (7 drugs) and cost-minimization analysis (6 drugs). Cost-utility analysis was not applied to any of the 37 drugs.
Discussion : Compared with overseas PE studies, Japanese studies were found to be less comparable with one another due to the lack of a uniform system of research and reporting results. Other problems observed included insufficient epidemiological data for analysis and difficulty in the cost data collection. The questionnaire-based survey revealed that Japan needs to set guidelines for PE studies and to establish epidemiological and cost databases for these research activities. It also suggested the necessity of reviewing the present method of clinical tests so that economic parameters for PE analysis and QOL may be obtained from these tests.

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Signal Detection from Spontaneous Reports

Kiyoshi KUBOTA

Japanese Journal of Pharmacoepidemiology.2001;6(2):101-108. doi:10.3820/jjpe1996.6.101

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.
Methods : Presentations in the Signal Generation Symposium (Southampton, UK, June 2001) and related articles identified by hand searching were examined.
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.
Conclusion : New methods outlined in this article require further theoretical development and its application to the analysis of spontaneous reports.

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Cost-Effectiveness of Interferon αcon-1 (Consensus Interferon) in Chronic Hepatitis C Patients with Genotype 1b and High-Titer in Japan

Satoshi TERAMUKAI ; Haku ISHIDA ; Yuji INOUE

Japanese Journal of Pharmacoepidemiology.2002;7(1):1-11. doi:10.3820/jjpe1996.7.1

Objective : To examine the cost-effectiveness of interferon αcon-1 [consensus interferon (CIFN)] for chronic hepatitis C patients with genotype lb and high-titer.
Design : Cost-effectiveness analysis.
Methods : Data from a randomized clinical trial comparing the efficacy of CIFN to interferon-αn 1 (IFN-αn 1) for chronic hepatitis C patients were applied to a cohort simulation by Markov model to project lifelong clinical and economic outcomes from the payer's perspective. Natural history model and decision analytical model were built based on published literature and actual healthcare reimbursement data.
Results : From the randomized trial, sustained response proportion and biochemical response proportion were 16.7%and 18.2%for patients receiving CIFN, compared with 3.3%and 18.0%for IFN-αn 1, respectively. The simulation model showed that CIFN should prolong life expectancy by 0.4 year at negative incremental costs, compared to IFN-αn 1 strategy. Compared to no IFN strategy, CIFN should prolong life expectancy by 1.2year at an incremental cost-effectiveness ratio of ¥1, 320, 000 per life year gained. The results were robust, with CIFN remaining cost-effective in sensitivity analysis compared to IFN-αn 1 and no IFN treatment.
Conclusion : For chronic hepatitis C patients with genotype 1b and high-titer, CIFN should prolong life and be cost effective in comparison with IFN-αn 1 and no IFN treatment.

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Efficacy and Safety of Denopamine in Patients with Chronic Heart Failure

Koichi MOCHIZUKI ; Tadashi KAWAKAMI ; Ryo KURAI ; Izumi YAMAGUCHI ; Toshio Hara ; Kemmi KAWABE

Japanese Journal of Pharmacoepidemiology.2002;7(1):13-20. doi:10.3820/jjpe1996.7.13

Objective : To investigate the safety and effects of long-term administration of denopamine, β-1 stimulant, on the activities of daily living in heart failure patients.
Design : Case-series.
Methods : One hundred forty patients with mild to moderate chronic heart failure were administered denopamine at dose of 5 to 10 mg three times daily for 24 weeks. Concomitant circulatory system drugs such as digitalis, diuretics, vasodilator drugs, etc., were used without changing the administration method and dose. However, the use of a concomitant β-blocker was prohibited.
Results : Following administration of denopamine, the NYHA cardiac function classification improved by one degree or more in 50 patients (35.7%). The body weight decreased significantly from 54.9± 10.2kg (mean±SD) before administration to 54.0±10.2kg after administration (P<0.05), and the cardiothoracic ratio also decreased from 58.0±7.3% to 56.6±7.2% (P<0.001). No significant changes were observed in the heart rate, systolic blood pressure, or diastolic blood pressure. The activities of daily living improved by one level or more for 49 patients (51.6%). There were 36 withdrawal or dropout cases (patients' own convenience : 12 cases ; complications/accidental symptoms : 7 cases) during the investigation period. Four patients (2.9%) exhibited adverse reactions.
Conclusion : Denopamine seemed to improve the quality of life, which is one of the therapeutic purposes for patients with chronic cardiac failure. A large-scale study including investigation of the long-term prognosis for such patients needs to be performed.

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On the Utilization of Antihypertensive and Antibacterial Agents

Koichi NOBUTOMO ; Yasuhiro KITAZOE ; Takao ORII ; Hiroyuki SATOH ; Kikuo ARAKAWA ; Tetsuro MATSUMOTO ; Joichi KUMAZAWA ; Taro SHUIN

Japanese Journal of Pharmacoepidemiology.2002;7(1):21-36. doi:10.3820/jjpe1996.7.21

Here we report the results of a long-term analytical study on the utilization of antihypertensive and antibacterial agents, which was performed using the Integrated Medical Information System (IMIS) developed by Kochi Medical School. The results indicate clear (increasing or decreasing) patterns in the numbers of patients and the dosages. Specifically, the total amount of antibacterials recently prescribed is significantly lower than in the year analysis began (1983). This reduction provides evidence of a steady improvement in the quality of medication and is particularly important for macrocosmic evaluation of the primary focus of our study, which was the “proper use of drugs”. Furthermore, the results also showed medication prescribed by non-specialists to be less inventive than that prescribed by specialists. This study highlights the importance of reforming institutions providing medical treatment from the perspective of effectively utilizing medical resources (by employing specialist personnel) and the proper use of medications. Because non-specialists prescribe medication in numerous medical facilities throughout Japan, these issues must be seriously considered.

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Pharmacovigilance in Japan and Its Trend for International Harmonization

Hiroyuki USUKI

Japanese Journal of Pharmacoepidemiology.2002;7(2):39-46. doi:10.3820/jjpe1996.7.39

Pharmacovigilance in Japan took basic shape by the revision of the Pharmaceutical Affairs Law in 1979, which consists of Re-examination, Re-evaluation, and Adverse Drug Reaction Reporting (ADR-Reporting), while Adverse Reaction/Event Reporting is dominant all over the world as a basic pharmacovigilance, and the Good Post-Marketing Surveillance Practice (GPMSP), a guideline for pharmacovigilance, was first introduced in Japan in 1993.
The GPMSP was revised at the end of 2001 to introduce the Early Post-marketing Phase Vigilance (EPPV) for the purpose of not only education for physicians but also acceleration of ADR-Reporting and to abolish the so-called “3, 000 case surveillance”, which is an obligatory observational case surveillance without comparator for new drugs.
Internationally, on the other hand, the ICH guidelines of E2A, E2B, and E2C, which were established for pre-marketing safety management, also greatly contributed to the improvement of post-marketing safety management, and new discussion in the ICH has started on such topics as Periodic Safety Update Report (V1 : PSUR), Good Case Management Practice (V2 : GCMP) and Prospective Plan of Pharmacovigilance (V3 : PPP). The pharmcovigilance system in Japan seems to be changing in the sense of international harmonization as well as for science, although further discussion is needed concerning the post-marketing studies and surveillance.

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Current Status and Future Prospects of Post-Marketing Clinical Trials

Hideaki SUZUKI

Japanese Journal of Pharmacoepidemiology.2002;7(2):47-54. doi:10.3820/jjpe1996.7.47

Good Post-Marketing Surveillance Practice (GPMSP) defines “post-marketing clinical trials” as industry-initiated studies constituting a part of Post-Marketing Surveillance (PMS). Post-marketing clinical studies play the role of gathering further information on appropriate drug use. This is why the proper conduct of medically required post-marketing clinical trials would facilitate the proposal of new treatments with improved efficacy and/or safety over existing therapies, thereby contributing to the promotion of EBM and to the advance of healthcare. In the case of anticancer drugs, in particular, post-marketing clinical trials are of great importance, because they also serve as Phase III studies. In reality, however, pharmaceutical companies are not very active in conducting these studies because of the many issues involved. To solve or alleviate these problems, the Japan Pharmaceutical Manufacturers Association and COTEC are making aggressive efforts.

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Estimation of Occurrence Peaks of Adverse Events Using Hazard Functions

Akira FUKUSHIMA ; Tadashi HIROOKA ; Wataru KASHIWAGI ; Masaki SANO ; Kunio ITOH ; Yasuo OHASHI

Japanese Journal of Pharmacoepidemiology.2003;8(1):37-44. doi:10.3820/jjpe1996.8.37

Objective : The incidence rate is used frequently in drug safety assessment. The incidence rate of adverse events is defined as the number of patients experiencing a certain adverse event divided by the number of patients administered a drug in spite of duration of administration (observation). In post-marketing surveillance, the duration of administration (observation) typically differs by patient and most of the analyses fail to take into account the differences in duration of administration (observation). Therefore, we investigated the usefulness of hazard functions in a drug safety assessment using the interim results from Clinical Experience Investigation of the oral anticancer drug, TS-1.
Methods : About three thousand patients with gastric cancer were enrolled in this Clinical Experience Investigation. TS-1 was administrated orally twice daily. One course consisted of consecutive administration for 28 days and 14 days rest. Administration was repeated in two courses. Hematological measurements, stomatitis, anorexia, nausea/vomiting, diarrhea, malaise were analyzed. Adverse events were evaluated in accordance with the criteria of the Japan Society for Cancer Therapy, which were established based on criteria established by the WHO. Time to occurrence of an adverse event was calculated from the first day of administration until the adverse event was first observed. Hazard functions were estimated by smoothing methods using kernel functions.
Results : The occurrence of adverse events using smoothed hazard functions had one peak around 10 days in the first course and decreased by administration rest. With the resumption of administration, the occurrence increased again. The occurrence in the second course were less than that of the first course.
Conclusion : The occurrence peaks of adverse events were estimated graphically by smoothed hazard functions. We conclude that hazard functions are useful as an analytical tool in drug safety assessment.

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