Japanese Journal of Pharmacoepidemiology/Yakuzai ekigaku Vol. 22(2017) No. 1

Various measures have been taken to minimize risk for individual drug products in the past. It is noteworthy that these measures are now documented and made public as a　“risk minimization plan” with the implementation of the scheme of Risk Management Plan （RMP). Risk minimization activities are conducted with the aim of securing and enhancing patients' safety, and at the same time, it places additional burdens on patients, healthcare practitioners and manufacturers/distributors. In this context, it should be assessed whether the original purpose is achieved. It is the key　for RMP to revise the plan effectively based on the assessment result. Measures to evaluate the effectiveness of risk minimization activities include analysis using medical information databases, questionnaire survey/interview to healthcare practitioner and patients. We may need to conduct prospective/retrospective surveys for some cases. There is no single method to be universally applied to different situations and we have no other way than putting our heads together and moving into action.

Thalidomide and the derivatives, lenalidomide and pomalidomide, are the most potent teratogenic medicines. Thalidomide Education and Risk Management System （TERMS^®）and RevMate^® for lenalidomide and pomalidomide have been operated with a goal of no exposed embryo to the drugs. The TERMS^®and the RevMate^®, a centralized management system, were revised in 2016 according to a request by a patient group. After the revision, the patient self-check sheet on adherence to conception prevention is primarily confirmed by his/her doctor, and the content of the completed sheet is sent to the management center in the pharmaceutical company after dispensing of the drug. The points for evaluation of the revised system will be as follows. (1) Has an appropriate procedure in accordance with the revised system been established in respective hospitals? (2) The rate of non-compliance with the procedure by the doctors or pharmacists, (3) Effect on awareness and behavior of the patients. Questionnaire studies of the patients, doctors, and pharmacists have been performed by the third-party committees.

RevMate^®is one of risk minimization activities in Japanese RMPs of Revlimd^®and Pomalyst^®, of which indications are hematological malignancy including multiple myeloma. This is a proper management procedure approved by Japanese health authorities in order to prevent exposure to pregnant women because these agents are derivatives of thalidomide. RevMate^® was revised in 2015 after the discussion in MHLW's Taskforce and its operation started from April 2016. Due to this revision of version 5.0, the manufacture no longer receives the patient name, and this and other information must be managed by the hospital. In addition, with regard to the same objective in the format used in the management procedure（TERMS^®）of thalidomide drug products, unification was attempted concerning the name of the format and

the notation of confirmation items. Physician becomes to make judgment to omit explanation of some RevMate^® requirements based on the patient's level of their understandings to RevMate^®. Periodical survey sheet regarding compliance with RevMate^® requirement filled by a patient is to be submitted directly to a physician on his/her visit instead of sending it to the manufacturer by mail under previous procedures. A representative person of the manufacture is required to visit the hospital periodically and confirm filing condition of the survey sheets and compliance check lists of RevMate^® for every prescription as well appropriately at the hospital. Furthermore, RevMate^® was revised to add clear role description of relevant pharmacists and nurses for in-patients and its strict drug-handling procedures at bedside as version 5.1, as we received four reports from hospitals of medication error of our drug to the another patient in the hospital within 2016. After getting approval of additional indications for Revlimid^® from March 2017, RevMate^® of version 5.2 started. In the view of implement RevMate^® as strict “risk minimization activities” to prevent pregnant women from exposure, we will continue to solve each problem recognized from the actual operation, constantly keep basics in mind by providing necessary training to our employees about thalidomide drug problem etc. In addition, we appreciate the understanding and support from the patient, patient family, Healthcare Professional, etc. involved in this procedure without incompleteness as well as non-compliance with procedures caused by habituation. Including all these, we consider it is important to endeavor as a manufacture continuously in the future.

If mother use drugs during pregnancy, the risk to the fetus is concerned. So the management of the drug is important. Previously, we have experienced The Thalidomide Disaster, the drug has not been used for many years since then. However, since thalidomide is found to have an effect on multiple myeloma, its management method is problematic. In the patients who use thalidomide, there are few women with the possibility of pregnancy. And by strict management, it has been concerned about the problem of the things that is difficult to use in patients not related to pregnancy. Isotretinoin is currently being used in the United States as the drug for acne therapy. Although there is no adaptation in Japan, the physician personally import the drug and administer to the patients. Because a lot of childbearing women are included in the patient who use the drug, strict management is necessary. Because the drug is not marketed in Japan, the offer of the information is not enough. Valproic acid has both adaptation the prevention of the migraine headache other than epilepsy. The control of epilepsy is very important, there are patients that use the drug after consideration of risk benefit balance. On the other hand, benefit was relatively small when use it for the prevention of the migraine headache. FDA prohibited the use during pregnancy for this purpose. In Japan, it is the same regulation regardless of adaptation, and balance of the risk benefit is not clear. It was thought that different attention awakening should be carried out by adaptation in future.

Recently, medical real world data involving claims data, drug data, and electrical medical record database have been developed worldwide and can be utilized for the phrmacoepidemiology research.The results of the pharmacoepidemiology research with these database contribute not only to post-marketing safety research but also to the outcomes research and pharmacoeconomic evaluation. On the other hand, collaborating with a number of local governments, we have developed maternal and child health check-up and school health check-up database in Japan. The development of healthcare lifecourse data like this will contribute to the preventive medicine, the understanding of the rare diseases, and drug development.