Objective : To find methods to minimize ‘lost to follow-up’ in the long-term follow-up in a pilot study of Prescription-Event Monitoring in Japan (J-PEM) where hypertensive subjects who took losartan or a control drug and gave informed consent to the study were directly followed by researcher for years.
Design : Cohort Study
Methods : We conducted the follow-up survey twice, in which questionnaires were sent to hypertensive patients who had consented to being involved in the survey and returned it by mail. In the questionnaire, we asked about the use of the monitoring drug, change of medical institutions for the treatment of hypertension, significant health-related events. In the second survey, we reminded the non-responders by a letter of reminder and by telephone. When no information was obtained from the subject, we sent a letter, together with a copy of the informed consent given by the subject, to the municipal office where the subject's home was registered to inquire about the subject's current address and related information including the vital status. We calculated Standardized Mortality Ratio (SMR) using the information on death obtained from the mailed questionnaires, telephone and information in the municipal office.
Results : In a pilot study of J-PEM on losartan, 4344 and 3517 questionnaires were sent to pharmacists and doctors, respectively. The doctors handed the informed consent form to the patients and 422 patients agreed to participate the study and sent back the signed form to the study office. In the first and second surveys, a questionnaire was mailed to the subject approximately 1 and 5 years after the first prescription of losartan or a control drug, respectively. The response rate was 73 and 60% in the 1 st and 2 nd survey, respectively. In the manuscript, the results of the 2 nd survey were mainly presented. The reminders by mail and telephone increased the response rate from 60 to 81% and provided the information on the vital status for 86% of the subjects. The response rate was further increased to 84% and the vital status was known for 99% when the information in the municipal office was used. SMR was estimated to be 0.59 (95% CI : 0.34-1.01) before reminding subjects, 0.78 (0.52-1.17) after reminding subjects by a letter and telephone and 0.92 (0.65-1.31) after further addition of the information from the municipal office. During the 5 years of the observation, 21% of 343 subjects who sent back a filled questionnaire did and 70% did not change the clinic/hospital where they received the care for hypertension, while 9% did not answer the relevant question.
Conclusion : The method of the systematic survey may be useful in minimizing the ‘lost to follow-up’ subjects in the long-term pharmacoepidemiology studies in Japan where a patient can change the clinic/hospital for his/her own health care without any letter of reference. In the systematic survey, the researchers may try to follow the subjects by using several methods including reminders like a letter or telephone as well as the use of the information in the municipal office. To facilitate better follow-up, a careful design of the study including the proper design of the informed consent form is essential to maximize the amount and quality of the available information, particularly when the subject has a serious event or dies in a hospital or institution apart from that where the patient has been registered.

Background :There have been only a few comparative observational studies on the safety and effectiveness of drugs in Japan. Comparative observational studies would provide important information to address these issues and thus we need to establish a means to facilitate such studies. In comparative studies, it is important to prevent the distortion of results due to selection bias. Though we do not yet have a claims database for use in pharmacoepidemiological studies, recently many hospitals and pharmacies have computerized prescription data which may be used to minimize selection bias. Good standardized procedures for the identification of patients prescribed one of two or more drugs to compare in a study using computerized prescription data would serve as a basis for a variety of pharmacoepidemiological studies in Japan.
Methods :We carried out a questionnaire survey in 2753 hospitals and 909 community pharmacies to estimate the fraction of hospitals where computerized data can be used to identify all eligible patients who used a specific drug.
Results :Questionnaires were returned by 1942 (71%) of 2753 hospitals and 632 (70%) of 909 pharmacies. From among those which responded, patients were identified, the patient list was printed, and the electronic file of the patient list was generated in 75%, 64% and 36% of the 1942 hospitals and in 100%, 93% and 49% of the 632 pharmacies respectively.
Conclusion :With procedures using computerized prescription data, the cohort for observational comparative studies may be identified with a minimal selection bias in a majority of hospitals and pharmacies.

A questionnaire survey of risk management systems for medical products was conducted with the cooperation of domestic and foreign pharmaceutical companies. As for the foreign companies, it was revealed that specialized safety management teams and data-management committees are established to formulate risk management plans in order to create systems that assure consistent risk management for each company. In addition, it was revealed that toxicologists are incorporated in the central decision making organization. As for domestic companies, it turned out that no less than half of the respondents pay attention to consistent risk management from the development stage through the post marketing stage. From now on, it will be essential to consolidate safety data, improve the accessibility of centralized safety data from the relevant departments, and establish systems to provide consistent risk management from the development stage to the post marketing stage.

Implementation of the ICH E2E Guideline is based on the Notification dated September 16, 2005 concerning pharmacovigilance planning. The E2E Guideline requires post-marketing safety measures, observational studies, and clinical trials to be performed according to the profile of a particular drug.
Development of specific pharmacovigilance plans has remained incomplete because of the limited available experience on which planning can be based.
Examples of safety measures taken, observational studies, and clinical trials conducted with the anticancer drug TS-1 are explained from the view point of the E2E Guideline.
Important risks identified after the market launch of TS-1 include a significant difference from similar drugs in adverse drug reaction profile, contraindication of concomitant medication with 5-FU-containing drugs due to interactions, and an increase in side effects resulting from renal disorders. Examples of missing information include lack of data on concomitant medication with other anticancer drugs and on the efficacy and safety of post-operative medication. Data on long-term medication were also lacking. How these issues were addressed will be explained.
Plans for post-marketing safety measures, observational studies, and clinical trials cannot be standardized; risks and other specific factors for each particular drug need to be taken into consideration.

Therapeutic Risk Management is indispensable in accelerating the approval of new medicines and getting them successfully launched. Regulatory authorities in Europe and the United States released a series of Guidance documents on how to implement Risk Management in 2005. While in Japan, the Investigative Commission for Promptly Providing Safety and Effective Pharmaceuticals made a similar proposal in 2007. Also, since the implementation of ICH E2E Pharmacovigilance Planning in 2005, safety measures have been prepared in Japan for individual drugs. But it is now time to take comprehensive safety countermeasures from the view point of Risk Management. This paper introduces Risk Management procedures in Europe and the United States and considers imminent challenges Japan has to tackle.

Although the two regulatory bodies, Pharmaceutical and Medical Devices Agency (PMDA) and Ministry of Health, Labour & Welfare (MHLW) cooperate in pharmacovigilance in Japan, presence of clinicians in the two bodies is surprisingly limited with only about twenty medical doctors compared more than 300 in CDER/CBER. The lack of doctors in PMDA, resulting from several factors including low social status and hard work, make them to review drugs and devices in which they are not expertised at all. For example, a paediatric cardiologist is obliged to review a drug for overactive bladder because no urologist is available for drug review in PMDA. Such a case would make the reviewer guilty of professional negligence. These critical issues make a PMDA reviewer rather dangerous than unexciting job. On the other hand, most Japanese doctors, heavily dependent on PMDA and pharmaceutical companies for drug information, would not commit in the drug review or pharmacovigilance. To make Japanese doctors more committed in pharmacovigilance, there are several measures to be implemented. First, better benefit, i.e. income, working hours, holidays. Second, escape clause for the reviewers. Third, more doctors to the Office of Safety rather than the Offices of New Drug. People outside PMDA can also contribute to pharmacovigilance with better media literacy and better understanding of PMDA.

The Japanese Society of Hospital Pharmacists (JSHP) started to collect the pharmaceutical care reports from the hospital pharmacists by a name of “PreAVOID” from 1999. The report number of PreAVOID increased year by year and reached about 50,000 totals in 2006. PreAVOID reports are classified in 2. One is the prevention of the adverse reaction and the drug interaction, the other is the avoidance of progress to the adverse reaction. In the latter, the role of the adverse reaction monitoring is included. Therefore PreAVOID is able to apply in Pharmacovigilance. PreAVOID is reported to JSHP by Fax or E-mail or the homepage of JSHP and it is evaluated and classified and then are accumulated in the database. The accumulated PreAVOID reports are utilized for creation of the pharmaceutical care information, study promotion about the medical economy. Therefore PreAVOID takes an important role as a nucleus of the pharmaceutical care management system by the pharmacists.
We are convinced that PreAVOID will be able to contribute to achievement of real purpose of Pharmacovigilance that is the effective and safety drug therapy.

Over 40 years, Post-maketing surveillance (PMS) studies have been conducted as a legal obligation in Japan. Though the contribution of these studies to the better use of the drug has been acknowledged, there are criticisms that these PMS studies have been stereotyped and need to be improved. The ICH-E2E guideline entitled as "Pharmcovigilance Planning", agreed in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) has been implemented in the concerned countries. The legislation of the guideline in Japan in 2005 seems to have urged drug companies and regulatory agency to review the current PMS practices in contrast with the today's highest scientific standard. We investigated the theoretical and practical aspects of pharmacoepidemiology required when the drug company evaluates safety specification prior to developing the pharmacovigilance plan and designs a PMS study along the lines stipulated in the ICH-E2E guideline. To meet this end, we evaluated the profiles of the drug, summarized "Important identified risks", "Important potential risks" and "Important missing information" to be identified and examined the pharmacovigilance plan suggested by the regulatory agency and that proposed and implemented by the drug company. We examined those aspects for 6 new products selected from 168 drugs newly approved during the period between January 2004 and October 2006. In 5 of 6 cases, we judged that the use of a comparator group would have been appropriate to asses the association between the drug and adverse events of interest. In addition, in one half (3) of 6 cases, it would have been preferable to use the database for the patient registration and/or other types of databases. The issues of relevant legislation and the infrastructure and funding for the investigations needed to develop a desirable study design and conduct a good pharmacoepidemiology study are however beyond a single company's capacity and should be set as a national strategy. The issues of post-marketing safety in the nation is becoming more and more important as the data in the countries outside Japan are being used more often for the processes of marketing authorization application of a new drug and its approval. It is urgent to secure the practice of pharmacoepidemiology to achieve the effective post-approval pharmacovigilance studies.

For the purpose of pharmacists to be able to be more involved clinically, the pharmacy education system in Japan was revised in April 2006 and the term length of pharmacy education was extended from 4 years to 6 years.
The Japanese Society for Pharmacoepidemiology is deeply concerned about the new curriculum which will be adopted for the 6-year course, especially the handling of pharmacoepidemiology education. Two questionnaire surveys were sent to the dean of all schools of pharmacy to inquire whether they lecture pharmacoepidemiology and, if not, what study in pharmaceutical sciences would be most closely related to pharmacoepidemiology. The surveys were conducted just before and just after the introduction of the new system, in October 2005 and July 2007. The recovery of the first and second survey were 90% and 76%, respectively.
In the first survey only 17 universities (31%) had lectures on pharmacoepidemiology but in the second survey 31 universities (57%) did, and in 55% of these 31 universities the lecture was required. The result indicates that the understanding of professors of pharmacy school regarding the lecture have been gradually promoted and they feel that pharmacoepidemiology is going to be considered to be one of the essential lectures in pharmacy education in Japan. However, many responders indicated that pharmacoepidemiology was still an immature field of study and there are few appropriate textbooks and no teaching experts, and therefore, the society should take these matters into reconsideration.

During the post-approval period, hypotheses about potentially new adverse drug reactions (ADR) have traditionally emerged from passive surveillance systems that collect large volumes of spontaneous case reports of suspected adverse drug reactions. With signal detection by traditional (or conventional, or manual) methods, quantitative (or statistical, or automated) methods for spontaneous reporting system (SRS) databases were introduced in the late 1990’s in order to detect serious ADR as early as possible. Most quantitative methods rely on comparisons of relative reporting frequencies, also known as disproportionality analyses. In FY 2009, the Pharmaceuticals and Medical Device Agency (PMDA) plans to introduce the quantitative methods (data mining method) used on Japanese SRS database. This paper introduces the recent situation on signal detection and signal management of adverse drug reactions.