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.

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.
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.
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.
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.

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)

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)

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.

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.
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.
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.
The case-cohort study design may be useful for various pharmacoepidemiological studies in Japan where no large medical database is available.

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.
Methods : A pilot study was conducted according to the report on this subject to MHW in 1996.
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.

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.
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.
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.
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.