Design Diagram：A Framework for Visualizing Study Designs Using Real-world Data and Improving Study Reproducibility / 薬剤疫学

There is growing interest in generating evidence from routinely collected real-world data to support medical and regulatory decision-making. However, longitudinal study designs using real-world data are often complex, and text-only descriptions make it difficult for most readers to understand their designs. To address this issue, in 2019, experts from industry, government, and academia developed the “design diagram,” a framework for visualizing longitudinal study designs. The design diagram uses standardized terminology and a graphical structure to communicate study design details to readers, thereby improving reproducibility. Based on previous work by a joint task force between the International Society for Pharmacoepidemiology (ISPE) and the Professional Society for Health Economics and Outcomes Research (ISPOR), the diagram includes a comprehensive set of key study parameters related to reproducibility. It successfully presents study designs in an unambiguous and intuitive manner. Diagrams have been proposed for various study designs, including cohort, nested case-control, and self-controlled designs. Recently, a new diagram was developed that adds at-a-glance elements to show the observability of the source data used in the study. The use of design diagrams is recommended in both the ISPE/ISPOR-endorsed harmonized protocol template (HARPER) and in reporting guidelines for pharmacoepidemiological research, and its widespread use is expected. This paper describes the structure of the design diagram and provides examples of its use. Effective use of design diagrams is expected to improve the reproducibility and reliability of database studies.

Case-control Design and Real-world Database Studies / 薬剤疫学

A case-control design is one of common study designs in epidemiology. A case with an outcome event of interest is identified and a corresponding control without an outcome event is sampled from a study base, which give rise to the cases. Distribution of a past exposure to an agent of interest before the timing of sampling is compared between a case group and a control group, to yield an odds ratio of exposure as a risk index. A cohort design is usually costly because it requires a large sample size and a long-term follow-up period to power a study especially to detect rare outcome events. In contrast, a traditional case-control design brings efficiency in resource and time to study the association of an exposure and an outcome event by reducing a sample size to study an exposure and covariates after sampling compared with a traditional cohort design. This review article discusses whether a case-control sampling strategy in healthcare database studies, where all the data for the study variables necessary for analysis already exist and are readily available, remains advantageous over a cohort design from the viewpoints of study cost and utility.

Lifestyle behaviors associated with the initiation of renal replacement therapy in Japanese patients with chronic kidney disease: a retrospective cohort study using a claims database linked with specific health checkup results

BACKGROUND@#Chronic kidney disease (CKD) is an independent risk factor for progression to an end-stage renal disease requiring dialysis or kidney transplantation. We investigated the association of lifestyle behaviors with the initiation of renal replacement therapy (RRT) among CKD patients using an employment-based health insurance claims database linked with specific health checkup (SHC) data.@*METHODS@#This retrospective cohort study included 149,620 CKD patients aged 40-74 years who underwent a SHC between April 2008 and March 2016. CKD patients were identified using ICD-10 diagnostic codes and SHC results. We investigated lifestyle behaviors recorded at SHC. Initiation of RRT was defined by medical procedure claims. Lifestyle behaviors related to the initiation of RRT were identified using a Cox proportional hazards regression model with recency-weighted cumulative exposure as a time-dependent covariate.@*RESULTS@#During 384,042 patient-years of follow-up by the end of March 2016, 295 dialysis and no kidney transplantation cases were identified. Current smoking (hazard ratio: 1.87, 95% confidence interval, 1.04─3.36), skipping breakfast (4.80, 1.98─11.62), and taking sufficient rest along with sleep (2.09, 1.14─3.85) were associated with the initiation of RRT.@*CONCLUSIONS@#Among CKD patients, the lifestyle behaviors of smoking, skipping breakfast, and sufficient rest along with sleep were independently associated with the initiation of RRT. Our study strengthens the importance of monitoring lifestyle behaviors to delay the progression of mild CKD to RRT in the Japanese working generation. A substantial portion of subjects had missing data for eGFR and drinking frequency, warranting verification of these results in prospective studies.

Basic Dos and Don’ts in Applying Signal Detection Methods to Spontaneous Reporting Systems Databases / 医薬品情報学

“Signals are useless until they are read and possibly subjected to intensive study by appropriate investigators in WHO or in national centres”, cited from Finney’s 1974 first article on the theory of signal detection. Recently, freely available large-scale spontaneous reporting systems databases and improved computational power of personal computers have made it easier to perform signal detection in personal researches. However, adequate knowledge for the limitations of source spontaneous reports and understanding the differences with conventional clinical and epidemiological studies are imperatives for valid interpretation of signal indexes. This review describes the basic theory, aims and limitations of the signal detection method using spontaneous reporting systems databases and practical considerations.

Actual Condition Survey of Risk and Benefit Communication for Consumers and Patients on Pharmaceuticals / 医薬品情報学

Objective:It is necessary to obtain appropriate drug information (DI)so that appropriate medical care is provided for the consumers,patients. Thorough studies have not been done on institutions that offer DI for patients in Japan and the state of its dissemination. The purpose of this study is to find levels of recognition of the institutions providing medical information and the actual state of its usage.Method:In order to find the levels of recognition of the institutions that provide DI to general consumers and the state of usage of the information provided by them,we conducted questionnaire surveys using online panels. We also conducted a study to find subjective comprehension on DI by the panels. The surveys were conducted twice using the same questionnaire in order to robust the outcomes of the study.Results:We received 1,095 valid responses from the first survey and 1,086 from the second survey respectively. No significant differences were found between the two surveys. Although the levels of recognition vary for the four representative public institutions providing DI,DI provided by these institutions has been barely utilized by the respondents. As the sources of DI that have been used most,almost the same numbers of respondents replied that they used Internet search engines to access them in addition to medical doctors and pharmacists. Regarding the levels of comprehension for the provided DI,the respondents tended to have shown high levels of understanding on maintaining medication compliance,but low on safety information. There was a positive correlation between age and the understanding of the DI.Conclusion: The study implies that the environment to provide DI for patients still needs to be improved, and the respondents didnʼt understand DI enoughly. Therefore,it is necessary to study further for the creation and communication of truly user-friendly DI.

Differences on the Regulation between Foods with Health Claims and Ethical Pharmaceuticals from the Viewpoint of Regulatory Science / 日本補完代替医療学会誌

Currently, self-medication, including the use of foods with health claims (FHCs), is promoted as means of increasing our health span. However, the functional substance(s) in FHCs and its actions are diverse, and therefore it is difficult to evaluate their safety and efficacy in clinical trials. In this review article, we describe the definition and the history of regulations regarding FHCs. After discussing their types and features, we explain the differences on regulations between FHCs and ethical pharmaceuticals regarding their safety and efficacy in clinical trials, which are required to provide them with scientific evidence. Finally, we believe that transparent standards regarding the evaluation of FHCs would help increase the use of FHCs and their market value in the future.

<b>4. Lifecycle Risk Assessment: Proposals from the CIOMS Working Group VI and the PhRMA Safety Planning, Evaluation, and Reporting Team </b> / 薬剤疫学

As mentioned by the Pharmaceuticals and Medical Devices Agency, the risk management planning should start with the development phase and continue to the post-market phase throughout the lifecycle of medicinal products. The post-marketing safety risk management officially started in Japan at last, followed by the notification “On Guidance of Risk Management Plan of Pharmaceuticals” dated April 2012, and a number of the safety risk management plan documents for new medicines have become available in public domain. The evidence body of non-clinical and clinical data to determine a large portion of safety specifications of medicinal products has been derived through the safety evaluation processes of their pre-authorization development phases, however, the discussion on the approaches of developmental safety data collection and assessment has been sparse in Japan. This review outlines the systematic safety evaluation processes for development phases, in reference to the report of CIOMS VI Working Group “Management of Safety Information from Clinical Trials” and the proposal from the PhRMA Safety Planning, Evaluation, and Reporting Team.

<b>Checklist and Guidance of Scientific Approach to Developing Pharmacovigilance Plan (PVP) in Japan: A Report from a Task Force of JSPE</b> / 薬剤疫学

A Task Force team consisting of members from pharmaceutical companies --a central player to develop and implement RMP (Risk Management Plan)-- as well as health care professionals and members from academia was established in JSPE. The Task Force developed guidance for scientific approach to practical and ICH-E2E-compliant Pharmacovigilance Plan (PVP) stated in Japanese Risk Management Plan issued in April 2012 by the Ministry of Health, Labour and Welfare. The guidance contains the following topics.<br>1．Introduction: JSPE's activities and this task force's objectives for pharmacovigilance activities<br>2．How to select Safety Specification (SS) and describe its characteristics<br>・Selection of SS<br>・Characterization of SS<br>・Association with Research Questions (RQ)<br>3．How to define and describe RQ<br>・What is RQ ?<br>・RQ interpretation in other relevant guidelines<br>・Methodology to develop RQ for PVP with examples<br>・Best approach to integrating PVP for whole aspects of safety concern<br>4．How to optimize PVP for specific RQ<br>・Routine PVP or additional PVP ?<br>・Additional PVP design (RQ and study design, RQ structured with PICO or GPP's research objectives, specific aims, and rationale)<br>・Checklist to help develop PVP<br>5．Epilogue:<br>・What can/should be “Drug use investigation” in the context of ICH-E2E-compliant PVP.<br>・Significance of background incidence rate and needs for comparator group<br>・Infrastructure for the future PVP activities<br>6．Appendix: Checklist to help develop PVP activities in RMP<br>The task force team is hoping that this guidance help develop and conduct SS and PVP in accordance with ICH E2E, as stated in Japanese Risk Management Plan Guideline.

A Survey of Physicians' Understanding of the Regulatory Systems for Clinical Trials in Japan / General Medicine

<b>Background:</b> Re-revision of the Ethical Guidelines for Clinical Study (EGCS) in Japan is planned in 2013. It is important to ascertain the current situation of physicians' understanding to conduct clinical trials. It seems that the difference in regulatory processes between commercial and non-commercial clinical trials has caused significant confusion for physicians in conducting clinical trials in Japan.<br>This survey was undertaken in order to improve awareness of the differences between both types of clinical trials. Furthermore, this survey examined whether it was effective to promote about clinical trials under newly introduced regulatory guidelines and to examine the subsequent willingness of physicians to conduct such clinical trials.<br><b>Methods:</b> From 24^th March to 24^th April 2009 inclusive, a questionnaire survey was conducted targeting 286 physicians working at Shiga University of Medical Science Hospital. A follow-up survey was conducted among 109 participants at a lecture about clinical trials on 8^th July 2009.<br><b>Results:</b> Physicians who had prior knowledge of the regulations, purposes, or support systems for commercial and non-commercial clinical trials responded positively that they were more likely to conduct clinical trials, while physicians who had no prior knowledge of them responded negatively. Both groups reported that their daily working pressures and cumbersome regulatory processes prevented them from conducting clinical trials.<br><b>Conclusion:</b> Japanese physicians lack knowledge and information about clinical trials, leading to negative perceptions and reduced willingness to conduct such studies. Thus, the introduction of any strict and complex regulations should be approached carefully when the environment for clinical trials has not yet been established.