If the disease is serious and there is no effective treatment option, delayed patient access to treatment leads to significant patient risk. Conditional approval regulatory frameworks have been established to accelerate the patient with serious disease and no effective therapeutic option access to innovative therapeutic options such as regenerative medical products, pharmaceuticals and medical devices. It is often difficult to conduct confirmatory clinical trials on a statistically reasonable scale for the severe disease with little effective therapeutic option. The point to be considered in the conditional approvals is how to conduct an approval condition-based post-marketing evaluation of safety and/or efficacy of the product and to ensure the product safety during the conditional approved period. However, regulatory concerns are unclear in the conditional regulatory frameworks. Here, we looked into dossiers of the conditional approved medical products. Pre-marketing clinical evidences appeared to be lower in conditional approvals than direct full approvals. In contrast, post-marketing requirements may be much more in conditional approvals than in direct full approvals. Together, the conditional approval regulatory framework may be a regulatory framework balancing between pre- and post-marketing regulatory burdens by approval requirements, leading to address a serious or life-threatening rare unmet medical need.

Rare cancers include a wide variety of malignancies and despite new target treatment focusing on their characteristics are expected, but the small number of patients often cause high price for those drugs. Number of countries introduced Health Technology Assessment (HTA), which includes cost-effectiveness, and utilized it to assess the reasonable price and reimbursement. In Japan, a cost-effectiveness evaluation regulation was also introduced to adjust drug prices. Our study investigated the cases of HTA in other countries to get the insight for future applicability of HTA to evaluate the value of rare cancer drugs. Extracted 42 rare cancer drugs approved during 2009-2019 in Japan, 2.9-12.5% were not recommended and 0-22.2% of 44 other orphan drugs in the UK, Canada and Australia. The major reason for negative recommendation was “uncertainty regarding clinical effectiveness”. Many of the “not-recommended” drugs were priced by the cost-calculation method, which means that there are no comparable drug available. Another tendency was observed that no active control was set and only small number of subjects were included in the clinical trials. In order to reduce the uncertainty in clinical effectiveness, more data collection should be attempted, such as utilizing global studies, industry-academic consortia and web recruitment. On the other hand, there is also limitation of difficulty to set control due to lack of standard treatments and/or ethical reason from insufficient efficacy of available treatments. Therefore, we should attempt to utilize real-world data to obtain control group data in the development stage and to accumulate more clinical data after marketed.

In regulatory science (RS), as proposed by Dr. Uchiyama in 1987, many instructors are engaged in education in diverse subject areas in pharmacy schools. However, since RS was incorporated into the model core curriculum of pharmacy education and its importance became recognized, various interpretations have been made, being problematic. It has recently become required in the syllabus to clarify the class subjects taught by faculty with working experience. The staff of Ministry of Health, Labor and Welfare, and Pharmaceuticals and Medical Devises Agency, move to the education site as a scholar-practitioner with working experience, and cases in which they host their own laboratory as a professor of drug evaluation, and regulatory science, have been increasing. The method of RS, in which the results are predicted from acquired data and evaluated, leading to, may be acquired by pharmacy students. Various education methods are executed by scholar-practitioners to foster their RS-related problem-solving ability by applying active learning. The adjustment and evaluation abilities acquired at university are important for not only pharmacy school graduates engaged in drug development, manufacturing, and supply, but also pharmacists. For example, pharmacy school graduates are expected to find RS-based patient-oriented solutions through learning about the substantiation of information obtained from regulatory authorities by experiencing the simulation of evaluation for new drug approval at university. It is also important to clarify the responses of the regulatory authority and provide the evidence for these to students in RS education that the evidence for the evaluation made by regulatory authority changes depending on the state of data accumulation.

The Musashino University provides regulatory science education through a wide range of subjects, such as a compulsory subject “Introduction to Pharmaceutical Sciences and Regulatory Science”, for the first semester of the first year student. In recent years, medical professionals are increasingly required to have the ability to act and solve problems independently based on scientific and logical thinking. As one of the approaches that contribute to human resource development for professionals, an active learning system has been incorporated into the education of pharmacy school. This article introduces an example of active learning in regulatory science education for pharmacy students at the Musashino University, group works utilizing new drug approval information.

In the 2013 Model Core Curriculum for Pharmaceutical Education, the content “Explain the necessity and significance of regulatory science” was newly added. This can be said to be the beginning of full-fledged regulatory science (RS) education in Japan’s six-year pharmaceutical education system. In 2016, in light of the importance of RS education, the Council on Pharmaceutical Education established a meeting of teachers in charge of subjects in the field of RS, and is promoting the exchange of information on efforts at each pharmacy school. Under such circumstances, the RS education at the Tokyo University of Pharmacy and Life Sciences is characterized by the fact that, in addition to the individual specialized education that forms the basis of RS, the university is practicing seminars that consider specific cases related to RS and distinctive education on current social topics. This practice is still in the process of trial and error, and we will continue to further enhance the education of pharmacists who can understand the concept of RS and contribute to the practical application of new drugs at pharmaceutical companies and medical facilities under the new Pharmaceutical and Medical Devices Act system.

There is a legally responsible person at pharmaceutical company named Supervisor-General which needs to be pharmacist or personnel who has pharmaceutical educational background. It is one of licensing requirements for marketing authorization holder (MAH) of pharmaceutical products to appoint a Supervisor-General based on the Pharmaceutical and Medical Devise Act. Supervisor-General for pharmaceutical products has an overall responsibility of the product which is released to market in Japan on quality management and post-marketing safety management. As eligibility requirements, Supervisor-General needs to have;

1) work experience on regulatory affairs, development, quality assurance or safety management associated with first-class marketing license of pharmaceuticals for a minimum of three years.

2) ability to comprehensively understand and make appropriate judgements on pharmaceutical regulations, product characteristics, business processes from raw material procurement to product shipment, manufacturing methods and manufacturing control, quality assurance duties and safety management duties in addition to pharmacist as of this moment.

As a Supervisor-General working at a pharmaceutical company, there are variety of things to be considered such as impact on product quality/efficacy/safety, regulatory compliance, collaboration/communication, and timely decision/action. In this manuscript, personal opinions on the requirements of Supervisor-General including regulatory science are shared by introducing specific cases.

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) -M9 guideline (Biopharmaceutics Classification System[BCS]-based biowaiver) has been implemented in Japan. This guideline proposes the concept that a bioequivalence study is waived through evaluation of drug properties (solubility and permeability) and formulation characteristics (excipients and in vitro dissolution). The BCS-based biowaiver is expected to be used for the application of formulation changes and new generic drug development. Although the M9 guideline harmonized primary requirements for BCS classification and formulation characteristics, further discussions on standardization of solubility measurement and judgment methods for dissolution similarity, and on the permitted differences in excipients are needed. In this article, we present an overview of the guidelines, the current situation in different regions worldwide, and the scientific issues to be resolved.