The purpose of this study is to identify the factors that affect doctors’ engagement in medical device innovation. While the engagement of professionals in medical innovation is essential for the growth of the medical device industry, there is little research on the factors that influence doctors’ engagement in the activities. Therefore, we designed a questionnaire based on the findings of management studies, which have focused on the factors that affect/inhibit individual engagement in innovation activities. The subjects were doctors who are members of two hospitals affiliated with Yokohama City University and their affiliated hospitals. In this survey, we investigated the characteristics and motivations of doctors engaged in medical device innovation. Also, we explored the factors that may inhibit their engagement and the conditions under which involvement is likely to occur. The sample includes 26 doctors who have engaged and 55 doctors who have not yet engaged. From t-test and correlation analysis, we found the positive relationships between engagement and five factors: colleague effect (recommendation from doctor’s organization and the colleagues who have engaged), lead-userness, intrinsic motivation, problem-solving orientation, and the motivation for resource acquisition. Furthermore, data suggested negative relationships between engagement and two factors: incompatibility with the area of expertise and cost (e. g., spending effort and time on activities). These results suggest managers and governmental policymakers need to design a system that encourages and supports medical professionals’ engagement.

It is essential during new drug development to assess the effects of food on oral drug products. The effects of food on absorption have been evaluated in the early clinical stages and a food-effect (FE) study using the final formulation has also been conducted, based on the basic principles of the regulatory document. This study systematically evaluated FE studies conducted when developing oral dose formulations containing new active pharmaceutical ingredients (APIs) that were approved in Japan between 2010 and 2019, in order to consider the designs and practical aspects of FE studies for new drug development. Most FE studies were conducted with healthy subjects in a cross-over design using a single clinical dose under a high-fat meal versus fasting conditions. We summarized cases in which FE studies were not necessary or FE studies outside the standard study design were acceptable. The FE study using the final formulation should be basically essential in the development of drug substances with properties of low-solubility and/or-permeability, other types of formulations such as extended-release, and changes in excipients with which effects on gastrointestinal absorption are expected. FE studies results under multiple test meals are useful, depending on API characteristics and indications to be developed. While, for high-solubility and -permeability APIs in immediate-release formulation, early FE studies are considered informative for product labeling because the effects of food on bioavailability is not considered to be clinically significant. The findings of this study provide specific and practical points to consider in the planning, implementation, and evaluation of FE studies in new drug development.

It is necessary to set a first-in-human dose (FHD) cautiously in the development of new drugs, but relevant information available at the time is limited. We evaluated the safety factors applied in setting the FHD for new drugs approved in Japan between 2009 and 2018 by calculating the human-equivalent-dose (HED) based on the no-observed-adverse-effect level (NOAEL) in the repeated dose toxicity study. We also calculated the HED based on the clearance (CL) and investigated the relationship between the HED and the approved dose. For most drugs investigated in this study, the safety factor was greater than 10, a figure recommended by the US Food and Drug Administration guidance document. This suggested that the starting dose had been determined very cautiously in the past first-in-human studies. In most drugs, the FHD, calculated by applying a safety factor of 10 to the HED obtained from either NOAEL or CL, was lower than the approved dose, which suggested that it was possible to set a FHD lower than the approved dose in most cases by applying a safety factor of 10 to the HED.

There are few reports summarizing the status of drug recalls. Therefore, we analyzed the voluntary product recall information published by Pharmaceuticals and Medical Devices Agency (PMDA) during the 3 years from April 1, 2017 to March 31, 2020. The number of voluntary recalls by year was 129 in fiscal year (FY) 2017, 150 in FY2018, and 156 in FY2019, for a total of 435 cases, and the total number of products collected was 701. Most of the original and generic products were voluntarily collected in class Ⅱ, and in 2019, serious class Ⅰ recalls increased due to the presence of the carcinogen N-nitrosodimethylamine in ranitidine preparations. The dosage form with the largest number of voluntary recalls was injection, followed by tablets. The reasons for recall were as follows: foreign substances in 44 items, 129 items that did not conform to the specifications, 177 items that deviated the marketing approval, 79 items that were recalled based on blood donation information, 68 items that were mislabeled, 34 items that were defective in containers, 7 items that were voluntarily recalled because of marketing approval deviation or misspecification, and 163 items for other reasons. There was correlation between the number of products handled and the number of voluntary recalls for manufacturers that mainly handle generic drug.

In recent years, the development of radiopharmaceuticals for therapy has become active globally, with the entry of major pharmaceutical companies. One of the characteristics of radiopharmaceuticals is that the ligand itself does not exhibit pharmacological effect, but indicating efficacy by the radiation emitted when a trace amount of radioisotope (RI) undergoes radioactive decay. Due to its characteristics, radiopharmaceuticals require a quality and safety evaluation method different from that of non-radioactive pharmaceuticals, and it is normally found that radiopharmaceuticals are excluded from the scope of the guidelines for non-radioactive drugs. Regarding guidelines on the development of radiopharmaceuticals in Japan, “Guidelines for clinical evaluation of diagnostic radiopharmaceuticals (June 2012)” has been issued, on the other hands, there are no guidance for the development of radiopharmaceuticals for therapy. Because the approach for drug development differ between diagnostic agents and therapeutic agents, it is hoped that guidelines for therapy will be issued. In the United States, the U. S. Food and Drug Administration (FDA) has issued “Oncology Therapeutic Radiopharmaceuticals: Nonclinical Studies and Labeling Recommendations Guidance for Industry (Guidance for Industry, FDA-2018-D-1772)” (August 2019), which is the guidance on nonclinical studies and labeling for radiopharmaceuticals used in cancer treatment. In addition, the European Medicines Agency (EMA) has issued “Guideline on the non-clinical requirements for radiopharmaceuticals” (draft stage) (November 2018). In this article, the authors created a Japanese translation of the guidance issued by the FDA, and inserted supplements where it was determined that additional explanation was necessary for a deeper understanding of the guidance. As mentioned above, no documents regarding the development of therapeutic radiopharmaceutical drugs have been issued in Japan, and it is considered that formulation of guidelines by referring to the FDA and EMA guidance documents is important for advancing the development of radiopharmaceuticals in Japan.

Model animals, artificially induced with a specific disease, are used in general non-clinical studies in the development of medical devices for human. Moreover, companion animals with spontaneous diseases such as cancer (diseased animals) are useful for more accurate evaluations on the safety and efficacy of applications in humans because they retain immune functions and may reflect pathological conditions of chronic diseases on target-affected areas and other organs. Therefore, pilot studies using diseased animals may be used as valuable test methods before First-in-Human trials for the devices with innovative techniques. However, for its implementation, it is necessary to be fully considered from the perspective of regulatory science regarding ethical basis, related laws and regulations, applicable cases, risk assessments, safety and efficacy evaluation methods, testing systems. Considering this background, and to establish a revolutionary state-of-the-art test method, we developed the basic concept of safety and efficacy assessments of the devices using diseased companion animals, with the cooperation of relevant academic societies, industry organizations, and regulatory authorities.

Almost a decade has passed since the implementation of the risk management plan system in Japan, which aims to help plan and conduct comprehensive risk management activities for pharmaceuticals in the post-marketing stage. To improve effectiveness of this system, we need to examine a mechanism that does not impose undue burden on relevant parties, along with enhancing the contents of individual risk management activities, and to maintain a fine balance. For this purpose, it is necessary to evaluate effectiveness of risk minimization activities as well as burden on relevant parties, and to optimize the activities based on the evaluation. At the same time, enhancement of routine pharmacovigilance activities is important. In this paper, we present an outline of the proposed actions for improved effectiveness and efficiency of risk management activities for pharmaceuticals, which were prepared based on the study findings by and discussions among relevant parties on each of the issues under a research grant from the Japan Agency for Medical Research and Development (AMED).

Risk management plan may require elements to assure safe use such as mandatory training for prescribing physicians, preparation of instructions for additional Risk Minimization Measures (aRMM). In order for additional Risk Minimization Measures to be effective, it is necessary for the instructions to reach, use, understand, and act on the target person. According to our research, it is possible that aRMM instructions have not been sufficiently delivered to physicians or pharmacists. Organizations such as building a risk management system by team medical care and implementing using an electronic medical record system in order to reliably and efficiently carry out the clinical examination necessary for managing identified risk described in aRMM instructions in busy medical setting. RMP Guide for Patients should be structured so that it is easy to understand the roles and actions that patients should play in order to minimize identified risk. It was found that the necessary knowledge was described in the latter half of the RMP Guide for Patients, and the situation was dominated by other information. In some cases, RMP Guide for Patients were set for potential risks. It is considered that the aRMM for potential risks may not lead to the correct understanding of physicians and pharmacists because the reason why it is necessary is not fully explained. In order to resolve these issues, it was considered necessary for stakeholders belonging to pharmaceutical companies, healthcare professionals, and regulatory agencies to work to foster mutual understanding regarding the implementation of RMP and the confirmation of its effectiveness.

The risk minimization measures, which is one of the three components of the risk management plan (RMP), is classified into two types: routine and additional. In daily medical practice, various materials for healthcare professionals and patients are distributed in addition to the materials specified in RMP. Most of these materials are well documented; however, it is unclear how effective they are in preventing the occurrence of important risks and reducing their severity at the time of occurrence, which is the original purpose of risk minimization. In Europe and the United States, it is stipulated that companies should formulate additional risk minimization measures proportionate to the risk characteristics and evaluate their effectiveness after considering the impact on the resources of healthcare workers and patients and their feasibility. In this paper, we summarize the research results regarding the optimization of risk minimization measures and the evaluation of their effectiveness conducted under a research grant from the Japan Agency for Medical Research and Development (AMED), and introduce recommendations for improvement in Japan.

The Organisation for Economic Co-operation and Development (OECD) is developing a framework for assessing the safety of chemicals based on adverse outcome pathways (AOPs). Such AOPs are expected to serve as the theoretical basis for creating integrated approaches to testing and assessment, which combine test results and information on specific toxicity endpoints to guide the safety assessment. In the midst of this international movement, Japan is actively promoting the development of AOPs for immunotoxicity and in vitro assays. After providing an overview of the basic concepts of AOPs, this paper first discusses the development of AOPs for immunotoxicity by Japan and then discusses skin sensitization as an example of how AOPs have become the theoretical basis for OECD test guidelines.