Points to Consider in the Development and Information Provision of Vaccines for Vaccination during Pregnancy: A Survey.

This report surveyed vaccination decisions during pregnancy based on the package inserts of vaccines approved in Japan, the USA, and Europe. Furthermore, it evaluates vaccination decision-making factors based on the characteristics of the target infections and the modality of the vaccines. Live vaccines known to cause fetal abnormalities are contraindicated for pregnant women, whereas vaccines for life-threatening infectious diseases are authorized for administration during pregnancy when the need is recognized, even for live vaccines. We compared the World Health Organization and European Medicines Agency guidelines on the development of vaccines for pregnant women and surveyed the details of the studies to collect information on SARS-CoV-2 vaccination during pregnancy. In compliance with the guidelines, for all SARS-CoV-2 vaccines, non-clinical reproductive and developmental toxicity studies and clinical trials including non-pregnant women of childbearing age were conducted prior to the vaccination of pregnant women. For all vaccines, information from registries on vaccination during pregnancy are used for post-marketing surveillance. While it is desirable to vaccinate women before pregnancy through planned immunization, whenever possible, pandemics such as H1N1 influenza and COVID-19 may require vaccination even during pregnancy. Necessary and sufficient studies for the decision of vaccination during pregnancy should be carried out promptly.

Proposal for the revision of guidelines for clinical trials of vaccines to prevent infectious diseases in Japan.

The development of vaccines against infectious diseases requires a different approach from that of therapeutics, because vaccines are inoculated into healthy individuals and have a preventive effect by activating the immunity of the inoculated human. In Japan, "The Guideline for Clinical Trials of Vaccines for the Prevention of Infectious Diseases" was published in 2010 before changes occurred in the vaccine development environment in Japan, such as the introductions of foreign vaccines and simultaneous global development. This study aimed to identify current challenges in vaccine development through a questionnaire-based survey of pharmaceutical companies in Japan and by comparing the domestic and international guidelines and surveying review reports of 35 vaccines approved in Japan between April 2010 and December 2020. Identified challenges included the requirement for protective efficacy trials, efficacy evaluation of combination vaccines, development of multiregional and foreign clinical trials, and immunization of older adults and immunocompromised patients. We propose that new vaccines against infectious diseases should be evaluated for the protective efficacy, preferably through multiregional clinical trials. Additionally, differences in the incidence of infectious diseases or in epidemic virus strains between regions may affect the trials, when multiregional clinical trials are conducted, but immunogenicity-based studies can be conducted if a correlation between protective efficacy and immunogenicity has been established. We suggest that licensed combination vaccines can be used as comparators when an antigen is added to a licensed combination vaccine. We also proposed that the efficacy of a vaccine in non-major subjects, such as older adults or immunocompromised patients could be evaluated by comparing immunogenicity in major subjects with the confirmed protective effects of the vaccine. It is expected that these revisions will lead to the rapid advancement of vaccine development, which should contribute to the improvement of public health.

Impact of the Clinical Trials Act 2018 on clinical trial activity in Japan from 2018 to 2020: a retrospective database study using new and conventional Japanese registries.

OBJECTIVE: To clarify the impact of Japan's Clinical Trials Act (CTA), which was enacted in April 2018, on subsequent clinical trial activity through an analysis of Japanese registry data. DESIGN: Retrospective database study. SETTING: We extracted information on clinical intervention studies registered between 1 April 2018 and 30 September 2020 in the conventional University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) and the new Japan Registry of Clinical Trials (jRCT). We collected and analysed information on registration dates, intervention types, funding, secondary sponsors and use of designated staff in multidisciplinary roles (research planning support, research administration, data management, statistical analysis, monitoring and auditing). The temporal trends in clinical trial activity after CTA enactment were examined. RESULTS: A total of 577 CTA-compliant specified clinical trials (ie, studies funded by pharmaceutical companies or studies evaluating the efficacy and safety of off-label drugs or devices in humans) were registered in the jRCT. During the same period, 5068 clinical trials were registered in the UMIN-CTR. The number of specific clinical trials increased immediately after the implementation of the CTA and stabilised in late 2019, whereas the number of clinical trials registered in the UMIN-CTR generally declined over time. Specified clinical trials that received industry funding and public grants were more likely to use designated staff in multidisciplinary roles. CONCLUSIONS: The implementation of the CTA has not reduced the number of specified clinical trials, but has reduced the total number of intervention trials. The use of designated staff in multidisciplinary roles is associated with funding, secondary sponsors and multicentre studies. It was inferred that funding was needed to establish research infrastructure systems that support high-quality research.

Proposal for the revision of the guidelines for Non-clinical studies of vaccines for the prevention of infectious diseases in Japan.

The efficacy and safety of vaccines for the prevention of infectious diseases are mostly evaluated based on the induction of an immune response against antigens, and do not necessarily depend on the dose administered. Therefore, there are some specific aspects that need to be considered in the development of vaccines and have been described in "The Guidelines for the non-clinical studies of vaccines for the prevention of infectious disease" in Japan. Recent changes in the vaccine development field, such as the introduction of vaccines developed overseas in Japan and vaccine development on a global scale have increased the need for revision of these guidelines. In this study, we identified the current challenges in the development of vaccines through comparison of Japanese and international guidelines. We conducted a questionnaire-based survey of pharmaceutical industries in Japan, and found issues related to non-clinical studies, such as the necessity of safety pharmacology studies and repeated-dose toxicity studies for each route of administration. We examined international guidelines on these issues as well as review reports by regulatory authorities, and determined that the results of repeated-dose toxicity studies can be used to decide whether safety pharmacology studies are required, and that studies to evaluate toxicity due to systemic effects may not be necessary for both intramuscular and subcutaneous administration. We propose revision of the guidelines for the non-clinical studies of vaccines in Japan taking international harmonizaion into account. We expected that the revised guidelines will promote smooth and rational vaccine development.