Investigation of the Description of Important Identified Risks and Important Potential Risks in Risk Management Plan in Patient Information Materials / 医薬品情報学

Objective: The Risk Minimization Plan is developed in the Risk Management Plan (RMP), patient information materials are sometimes prepared as Additional Risk Minimization Activities (ARMA). On the other hand, there are many patient information materials that are not prepared as RMP materials, but are prepared independently by pharmaceutical companies and are actually used to provide information to patients. However, there is no detailed report on the differences between them. Therefore, in this report, we investigated for description of Important Identified Risks (IIRs) and Important Potential Risks (IPRs) in patient information materials.Methods: The previously published RMP of 588 drugs were obtained on October 1,2020, and used in analysis. We surveyed the description of IIRs and IPRs in patient information materials, and compared patient information materials based on ARMA in the RMP (patient information materials as RMP materials) and patient information materials developed independently by pharmaceutical companies that are not based on ARMA in the RMP (patient information materials as not RMP materials).Results: Of the 588 drugs, 454 drugs had patient information materials. In addition, 241 drugs had patient information materials as RMP materials. One thousand fifteen of the 1,577 IIRs were listed in the patient information materials as RMP materials (64.4%listing rate). One hundred sixty-six of the 724 IPRs were listed in the patient information materials as RMP materials (22.9%). On the other hand, 700 of the 1,131 IIRs were listed in the patient information materials as not RMP materials (61.9% listing rate). Ninty one of the 447 IPRs were listed in the patient information materials as not RMP materials (20.4%).Conclusion: It was found that there was no difference in the description of IIRs and IPRs between patient information materials as RMP materials and patient information materials as not RMP materials.

Survey of the Description of “Medication Guides for Patients” and “Early Post-Marketing Phase Vigilance” on Additional Risk Minimization Activities of Risk Management Plans / 医薬品情報学

Objective: The risk management plan (RMP) is a useful information source for healthcare professionals, including pharmacists, to ensure drug safety. The “risk minimization activities” (RMA) of the RMP are especially important elements for healthcare professionals. It is known that “Medication Guides for Patients” (MGP) and “Early post-marketing phase vigilance” (EPPV) are items listed as part of the RMA. However, the creation of MGPs and the implementation of EPPVs are not performed for all medicines. In a previous study, it was difficult to evaluate this sufficiently with the safety specifications. The aim of this investigation was to evaluate RMAs, especially MGPs and EPPVs, not in terms of the safety specifications of RMP.Methods: The previously published RMPs of 177 drugs were obtained on February 22,2016, and used in the analysis. The relationship between the creation of the MGP and the description in the RMA and the relationship between the conduct described in the EPPV and the description in RMA was investigated for each medicine.Results: An MGP was created in 151 of the analyzed drugs. Of these, it was not listed in the RMA of 40 drugs. In contrast, EPPV was not listed in RMA in 2 out of 33 drugs when underway. EPPV was described in the RMA of 33 of the EPPV finished drugs. The time lag from the end of EPPV until the revision of the RMP was 4.5 month son average.Conclusion: MGPs and EPPVs are created especially for drugs requiring patient education, information provision, or safety monitoring. Therefore, for drugs for which MGPs or EPPVs are required, they should be listed in the RMA. In this study, the time lag of RMP revision was also highlighted as a problem. In order to promote the utilization of RMP by pharmacists, these issues should be resolved.

Research for Recognition of Pharmaceutical Companies toward the Effective Use of “Drug Guide for Patients” as Package Inserts for Patients / 医薬品情報学

Objective: “Drug Guide for Patients” (DGP) is a drug information tool designated as one of the routine risk minimization activities in risk management plan (RMP) developed by the Ministry of Health, Labour and Welfare. However, patients and their families hardly recognize DGP. Therefore, we administered a questionnaire on drug consultation service of pharmaceutical companies that provide DGP with an aim to collect their views, elucidate problems when they prepare DGPs and examine effective utilization of DGP in the future.Methods: We sent a questionnaire by letter for 127 drug consultation service of pharmaceutical companies, and received questionnaire results using “Questant” that is web questionnaire making software. The results were examined using Fisher’s exact test or Pearson’s chi-squared test.Results: We obtained responses from 84 (66.1%) companies out of 127. As for the question of the published situation of DGP on their website, the most companies responded “Not published” with 47.6% and subsequently 41.7% for “Published for healthcare professionals”. The combined rate of “Published for Patients (3.6%)” and “Published for both healthcare professionals and patients (7.1%)” was only 10.7%. On the other hand, regarding the burden of companies making DGP, we found that more than 60% of pharmaceutical companies (63.5%) felt burdensome, whereas only 36.5% responded “Not burdensome.” Regarding the question on the role of DGP in RMP, pharmaceutical companies answered that the role is “sufficient” 3.6%, 29.8% “not sufficient”, and 66.6% “unknown”.Conclusion: Our results suggested that it is difficult for patients to get DGP from website of pharmaceutical companies and pharmaceutical companies felt burdensome in making DGP, and they recognized that DGP was not very much utilized by patients. Therefore, it would be necessary to improve the creation criteria of DGP. Furthermore, we felt it necessary to have the DGP known and utilized widely by (consumers and) patients.

Risk management of medical equipment clinical trial / 医疗卫生装备

Objective To propose a set of management methods for minimized risk and continuous improvement of medical equipment clinical trial.Methods The problems were summarized on pre-trial preparation,design and signing of informed consent,insurance-related issues,supervision and quality control,perception of adverse events,and then some countermeas-ures were put forward accordingly.Results A risk management system was established for medical equipment clinical trial whole-course management.Conclusion Planning,recognition and evaluation have to be implemented over all the links of medical equipment clinical trial risk management,and corresponding countermeasures should be carried out for minimized risk and continuous improvement.

Risk Prevention and Control of Pregnant Women in Drug Clinical Trials / 中国医学伦理学

Pregnant women drug research is quite necessary and urgent,of which human trail is an important link.Pregnant women are vulnerable subjects,but they should not be excluded from drug clinical trials because of possible special risks.The governments should refine the relevant laws and regulations to standardize the clinical trials of pregnant women and safeguard their rights and interests.In order to prevent and control the risks of human trail in pregnant women drug research,it is suggested that the subjects should be limited to the pregnant women who are ill and carry out the 0 phase clinical trial of pregnant women drug research.The ethical review of pregnant women drug research should adhere to the principle of risk minimization,informed consent and reasonable compensation.Meanwhile,the ethical review should emphasize the tracing review.Risk prevention and control of pregnant women in clinical trials should form a joint force.

3．Revision of Procedures for Appropriate Management of Revlimid® and Pomalyst® （RevMate®）and Issues for the Future / 薬剤疫学

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 andthe 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.

1．Evaluation of the Effectiveness of Risk Minimization Activities / 薬剤疫学

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.

<b>1．Evaluation of the Effectiveness of Risk Minimization Activities </b> / 薬剤疫学

<p>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.</p>

Survey of the Description of the Risk Minimization Activities in Pharmaceutical Risk Management Plans / 医薬品情報学

<b>Objective: </b>Currently, the creation of a pharmaceutical risk management plan (RMP) for new drug information is obliged to pharmaceutical companies.  The created RMP is published on the Pharmaceuticals and Medical Devices Agency (PMDA) website.  RMP is a useful information source to ensure drug safety by healthcare professionals, including pharmacists.  “Risk minimization activities” of the RMP are especially important elements for healthcare professionals because they describe measures to minimize risk to patients.  We conducted a cross-sectional survey of the description of the contents of “risk minimization activities” in the RMP.<br><b>Methods: </b>The RMP of 177 drugs that had been published in February 22, 2016 were investigated.<br><b>Results: </b>Total risks enumerated for the study drugs were 1,678.  “Routine risk minimization activities” constituted 92.0% of total risks.  The most listed item on “routine risk minimization activities” was “attention on the product labeling of the drug package insert” (91.3%).  Differences in the expression level on “attention on the product labeling” were observed.  On the other hand, the most listed item of “additional risk minimization activities” was “the creation of documents for healthcare professionals” (38.3%) and “implementation of Early Post-marketing Phase Vigilance” (27.1%).<br><b>Conclusion: </b>A clear understanding of RMP by healthcare professionals is important.  In the RMP, “risk minimization activities” (especially “additional risk minimization activities”) are the most important contents for healthcare professionals, because they include information of documents created by the pharmaceutical company for patient safety.  The level of description of the contents of RMP varies between drugs.  It is essential that these descriptions be uniform the expression level to be easily and accurately utilized by healthcare professionals.

<b>2. Agenda for the Sound and Effective Implementation of Risk Management Plan System </b> / 薬剤疫学

One year and a half has passed since the implementation of the guideline on drug risk management plan (RMP). Japanese RMP system practically began to work. While a post-marketing surveillance study, which has played the central role in pharmacovigilance activities in Japan, is positioned as a measure to collect information to be used in the application document for re-examination, the environment surrounding pharmacovigilance has dramatically changed, e.g. increased number of spontaneous reports, improved medical information database and expansion of its availability, compared to the situation when the reexamination scheme was incorporated into law 35 years ago. Now we need to examine diversified approaches to improve the traditional method and mindset taking advantage of the advances in information technology. In order that RMP system be implemented effectively as well as soundly, it is important to implement the PDCA (plan-do-check-act) cycle in a timely manner. Also we need to assess the overall balance between the resources for post-marketing risk management activities and the performance obtained by them from the viewpoint of ensuring patients' safety.

Pharmacovigilance and Risk Management / 薬剤疫学

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.

Establishment of Drug Risk Management System -the Promise of Safety Science Approaching from Non-Clinical Safety / 薬剤疫学

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.