The purpose of this study was to examine the relationship between the revision of the information in the “Clinically Significant Adverse Reactions” section in the package insert and the description in the RMP at the time of drug approval, to verify the usefulness of the information in the RMP and propose a direction for the utilization of RMP. The subject drugs were ones containing new active ingredients approved from April 2013 until March 2016 that were listed in National Health Insurance Drug Price Standards and marketed as of March 31, 2021. The subject revisions of the package inserts were ones in the “Clinically Significant Adverse Reactions” section which were made during the reexamination period of the drug and notified by the Ministry of Health, Labour and Welfare. Of the 116 drugs, the package inserts of 37 (31.9%) drugs were revised. 30 (81.1%) of them for which the RMPs at the time of approval were available were included in the analysis. The 30 drugs had 54 revisions. 16 (29.6%) revisions of them were listed in RMP at the time of approval, and 15 of these revisions were already listed in the “Other Adverse Reactions” section etc. in each package insert before the revision. Among the many adverse reactions listed in the “Other Adverse Reactions” section, focusing on ones that are also listed in the RMP may provide more important information. This study has shown that the RMP is a useful source in addition to the package insert. The RMPs will be useful for monitoring the safety of drugs.

In order to encourage the development of medical devices in Japan, it is important to foster the “medical-engineering collaboration.” In the insurance listing of innovative medical devices requiring new technical fees (Category C2), it is assumed that there is an organized collaboration between medical device companies and professional societies. This study aims to clarify the actual situation of such collaborations in the insurance listing process, and to understand the influence of collaboration on the determination of technical fees. Two analyses were conducted using data for Categories C1 and C2 from FY2012 to FY2021. (1) Analysis of collaboration trends in the insurance listing process. In Category C2, there was an increase in the issuance of practical guides for appropriate use. The percentage of items with collaboration in Category C1 was 20% (26/130), while that in Category C2 was significantly higher, i.e., 63% (72/114) (p<0.01). (2) The data were divided into two groups based on the presence or absence of collaboration, and a comparison of the percent discrepancy between companies’desired technical fees and the final determined technical fees in Category C2 was analyzed. The mean discrepancy was 76% in the group with collaboration (n=38) and 48% in the group without collaboration (n=10) (p=0.24). Collaboration with professional societies has progressed in Category C2 insurance listings. The practical guides for appropriate use include detailed information on intended patients and methods of use as well as training and standards for practitioners or facilities. While insurance coverage promotes high-quality medical care, training for appropriate use, and establishment of standards is important. Collaboration with professional societies is considered essential for the development of innovative medical devices and insurance coverage.

With the aim of considering improved operation of reimbursement price calculation for new drugs in Japan, the status of selection of a comparator drug in the recent price calculation process was investigated and summarized. For newly listed drugs whose price was calculated by the comparator method (Ⅰ), nearly 80% of the new drugs had different characteristics from the comparator either in the indication, mode of action, type of substance, or route of administration, which are four items to be considered in selecting a comparator. In the cases in which the indication was different between the new drug and the comparator, the two drugs had a commonality such as their target symptoms were overlapped, or their indications belonged to a same family of diseases. Also, the two drugs had a strong similarity in the mode of action, type of substance, and route of administration. In the cases in which the type of substance was different between the new drug and the comparator, their indications were identical or overlapped, although the mode of action and the route of administration were different in most cases due to the difference in the type of substance. Poor transparency in the breakdown of the price has been pointed out for products whose price was calculated by the cost accounting method, and it would be important to consider a system to extend the scope of “comparators” with a view to enhance the transparency and reasonability in price calculation. The information on the products to which the comparator method was applied in the face of the relatively low similarity with the comparator will be of help in the future discussion on extending the scope of application of the comparator method.

The Japan Pharmaceutical Manufacturers Association’s (JPMA) Regulatory Affairs Committee recently conducted a survey about differences in regulatory submissions in Japan, US and EU. Key topics addressed in the survey are as follows: ・The amount of Established Conditions considered necessary to assure product quality; ・The category of regulatory submissions in US and EU, in which past cases of regulatory submissions required in Japan; ・When US or EU submissions were required prior to approval, the time required for submission, and whether GMP inspections were conducted during the submissions.

The application of Real-World Data (RWD) can be broadly divided into two categories: those areas where the formal principles of drug development can be applied and those where they are difficult to apply, such as in the case of orphan diseases. We will discuss the latter topic in this article. In Japan, the recognition of the possibility of using RWD in pharmaceutical applications has increased in recent years. This is largely due to the efforts of Dr. Takeda’s Special Research of Health Labour Sciences Research Grant in 2015 on the use of patient registries for drug development, which was intensified under the Clinical Innovation Network initiative of the Ministry of Health, Labour and Welfare (MHLW). The MHLW’s notifications on the usage of registries in 2021 have further solidified their place in the industry. RWD utilization extends beyond just serving as the external control group in single arm clinical trials. The possibility of diversification of the composition policy of the data package and greater involvement from pharmacoepidemiologists in the development and approval review may change in the near future. These events align with previous cases of regulatory approval reviews in Japan and globally, and they are not limited to mere theoretical possibility. It is crucial to shift the discussion to addressing RWD in terms of developing and evaluating drugs in areas that tend to be neglected from therapeutic development, rather than exploiting RWD, using examples of drugs that cannot be developed with current principle. It is essential to consider measures to resolve unmet needs.

Japan Pharmaceutical Manufacturers Association (JPMA) has organized several task forces to look into utilization of Real World Data (RWD) from various aspects. One of the task forces has investigated “Pharmaceutical company’s internal process to utilize registry for filing of application for drug approval etc.” in order to facilitate the utilization of RWD for regulatory submissions (filing of application for product approval etc.). The deliverables showing the process and points to consider are aiming at encouraging pharmaceutical companies to utilize registry data. Furthermore, other stakeholders would also know the challenges for pharmaceutical companies and how they make internal decisions, expectedly leading to mutual understandings among stakeholders.

In Japan, various studies and efforts are underway to promote the use of real world data (RWD) in applications for approval and reexamination of pharmaceuticals and regenerative medical products. The Ministry of Health, Labour and Welfare (MHLW) and the Pharmaceuticals and Medical Devices Agency (PMDA) have issued a number of notifications and administrative notices on the use of RWD and ensuring its reliability, as well as disseminated information at academic conferences. In addition, from the perspective of ensuring the reliability of RWD, PMDA has established a proactive support system to promote the use of RWD through activities such as establishing a consultation framework, clarifying how the compliance assessment is conducted for the application for approval of pharmaceuticals, and disseminating information that can be generalized based on the experience of consultations. How to handle RWD from the viewpoint of ensuring its reliability was once said unclear but is now considered to be resolved through these activities. Therefore, the utilization of RWD in the application for the approval of pharmaceuticals is expected to be further promoted in Japan in the future.

Rare cancers have a challenge in establishing standard therapies compared to major cancers. Critical delays in anticancer drug development, especially for cancers defined as an annual incidence of <6 cases per 100,000 population, have been an issue. To overcome obstacles, MASTER KEY Project was launched in May 2017, which is a multicenter study based in Japan, with two main parts: prospective registry study and multiple clinical trials. Advanced rare cancers, cancers of unknown primary origin, and those with rare tissue subtypes of common cancers are targeted. The registry study accumulates highly reliable consecutive data including patients’ treatment progress and that can be used for future drug development. The multiple trials are conducted simultaneously, targeting either a specific biomarker or a rare tumor type of interest. This project is expected to accelerate development of treatments for rare cancers and show that comprehensive platform trials are an advantageous strategy.

The utilization of real-world data (RWD)/real-world evidence (RWE) in drug development is useful in designing and planning clinical trials (standard of care, competitor research, inclusion/exclusion criteria, etc.); feasibility studies for clinical trials; approval applications, including external control groups and expanded indications; and for revision of package inserts. Especially in pediatric drug development, intractable diseases, and rare diseases, there are high expectations for utilization, but including these highly expected utilizations, utilization for external control groups, etc., has not progressed due to the issues of data appropriateness and reliability. Under these circumstances, we used registry data from the Scientific Registry of Transplant Recipients (SRTR) in the United States as the main efficacy and safety data, and an additional indication for lung transplantation was approved for Tacrolimus in July 2021 in the United States. Unlike clinical trial data, the reality is that registry data includes inappropriate data from the data reliability perspective. Of course, if these inappropriate data are important data for evaluating the efficacy and safety of the drug, there is a high possibility that the data will become unusable and, as a result, affect the drug evaluation. On the other hand, the SRTR data that we have used for the application at this time had no major issues with the efficacy and safety data and the data reliability, so the U. S. Food and Drug Administration determined that the data quality was with in acceptable limits. It is important for companies to actively and flexibly consider how to utilize RWD/RWE based on an appropriate understanding of the actual situation of RWD/RWE and the appropriateness and reliability of the data to be utilized.

ICH E8 “General Considerations for Clinical Trails” is a guideline on general considerations for the conduct of both individual clinical trials and overall development strategy for new medicinal products to support approval of the product. The guideline was developed in 1997 and had never been revised ever since then. Clinical studies these days use a broader range of study designs and data sources. In addition, an opinion has been advocated recently in which quality of clinical studies should be improved proactively by designing quality into the study protocol and processes rather than by reviewing and monitoring of document and data. Based on such background, ICH E8 has been revised, and here we present an overview of the ICH E8 (R1) “General Considerations for Clinical Studies” and a development process of this guideline from the standpoint of regulatory members in the Expert Working Group in this article.