The World Health Organization (WHO) declared COVID‒19 a pandemic in March 2020. The spread of COVID‒19 impacted the medical environment, and the clinical trial sites were likely to be affected. The International Consortium for Innovation and Quality in Pharmaceutical Development Clinical Pharmacology Leadership Group (IQ CPLG) Japan Sub-team conducted a survey to collect data from 13 IQ member companies on sponsor's experiences regarding the impact on timelines, study design and development strategy due to the COVID‒19 pandemic. This survey focused on clinical pharmacology trials in Japanese healthy subjects or patients conducted at phase 1 units planned or conducted during March to July 2020. The survey questions were designed to respond for each trial level and composed of 10 quantitative questions about the number of studies; characteristics of the study; the impact on the trial timeline; site selection; study design and one descriptive question for case studies. The survey results showed 1）most of the trials that enrolled Japanese subjects were conducted in Japan, 2）changes in study design were required,（e.g., prolonged admission period, COVID‒19 PCR test), 3）remote Source Data Verifications (SDVs) were introduced more widely and 4）limited sites were selected,（e.g., reduced capacity and available regions). Mild to moderate impacts on the study timeline prior to and during the trials indicated that it was necessary for companies to design the protocol and plan the operation to avoid anticipated risks which might have significantly impacted the study results. The impacts on program timeline and site selection were limited. Proactive planning is important in future pandemic situations. The present survey results and analyses provide useful insights, learnings and considerations that can be applied in future pandemics. The results of this survey were shared with the Japan Pharmaceuticals and Medical Devices Agency (PMDA).

Typically, to support regulatory drug approval in Japan, an appropriate justification of the dosage regimen(s) in the target indication proposed in Japanese patient population based on the overall clinical data and evidence is required. More specifically, when using foreign data and/or discussing extrapolation of data/interpretation into Japanese targeted population, it is important to understand the similarity and consistency of clinical data between Japanese and non-Japanese populations (“ethnicity”) in healthy participants and targeted patients, as well as between healthy participants and patients (“disease status“) in Japanese and non-Japanese populations. This is usually supported by pharmacokinetic, pharmacodynamic (marker of efficacy), and safety data obtained from clinical studies. In this review, the concept above is thoroughly introduced with the case example of posaconazole, a globally approved triazole antifungal drug with broad-spectrum antifungal activity including in Japan, applying a model-informed approach for the dose justification of posaconazole in Japanese population as either high-risk patients with fungal infections (prophylaxis) or patients with fungal infections (treatment) using pharmacokinetic data together with exposure-response relationships. In the case of applying for regulatory approval for posaconazole, there were difficulties in interpretating the effect of ethnicity and disease status due to potential confounding and mitigating lack of clinical data for a part of targeted patient populations. Taking that into consideration, the dosage and dosing regimen for Japanese patients with target indication were justified based on the totality of comprehensive relationships among the populations with respect to ethnicity and disease status, as well as results from model-informed approaches.

Bioequivalence studies between erlotinib tablets 25 mg/150 mg “NK” and Tarceva^® t1ablets 25 mg/150 mg were conducted in healthy male Japanese volunteers. As Tarceva^® tablets are a highly variable drug, studies had an adaptive, open-label, randomized, two drug, and two-period crossover design. As there was a lack of published pharmacokinetic information for Tarceva^® tablet 25 mg, the study was conducted after a preliminary examination. Two-stage adaptive design was included in this study, and an interim analysis for the bioequivalence assessment was performed after Study Period 1 by the Interim Analysis Decision Council, which made recommendations to the sponsor according to the interim analysis procedure. As for the continuation of the study, the number of subjects in Study Period 2 was determined based on the geometric mean ratio and intra-subject variability obtained in Study Period 1. As the test statistic calculated from AUC_t and C_max in the analysis after Study Period 1 exceeded the critical value corresponding to the significance level of the interim analysis and the null hypothesis was rejected, the bioequivalence of the two formulations was verified. There were no clear differences in the safety profile between the two formulations. Although the subject number setting of highly variable drug assessment is an important issue in generic drug development, the adaptive design seems to be a useful countermeasure to this.

Nonvalvular atrial fibrillation （NVAF） is a cause of cardioembolic stroke, and direct oral anticoagulants （DOACs） are recommended for stroke prevention in patients at risk. However, poor adherence to DOACs has been reported to increase the risk of stroke in NVAF patients. The aims of this study were to examine items identified and instructed by pharmacists during medication counseling to NVAF patients, and identify issues to improve adherence to DOACs. The subjects were 130 patients assigned to the intervention arm of the SMAAP AF trial, which evaluate the effect of an educational intervention involving motivational interviewing on medication adherence assessed by electronic monitoring in patients with NVAF who were treated with DOAC once-daily （edoxaban） or twice-daily （apixaban）. Many of the questions pharmacists asked patients were related to side effects. Pharmacist assessment of adherence had high sensitivity but low specificity （adherence rate≥80％: 0.953, 0.583; adherence rate ≥90％: 0.989, 0.478）. In the 4 patients who were poorly adherent throughout the trial（mean adherence rate 65％）, there was little discussion about stroke, the purpose of treatment, and treatment effects. Furthermore, the solutions offered to the patients were technical in nature. This study showed that pharmacists' questions about DOACs were mostly about side effects and less about the purpose of treatment. Improving adherence to DOACs requires not only technical solutions, but also patient education to raise awareness of the importance of stroke prevention.

The Clinical Trials Act regulates specified clinical trials, imposing stricter compliance details and reporting requirements than research based on ethical guidelines. The Clinical Research Center of Hamamatsu University Hospital initiated Clinical Research Coordinator （CRC） support for all specified clinical trials in October 2018. This support system began with 3 full-time CRCs, but has since expanded to 5, each overseeing an average of 17 studies. To efficiently manage a larger study pool, the support has prioritized tasks with a high-risk incidence and impact, including managing the informed consent process, confirming exclusion criteria, and verifying the presence of disease or the like. This investigation was performed to examine whether these CRC support measures have enhanced the quality of specified clinical trials. Fifty-nine studies who were transferred to specified clinical trials after implementation of the Clinical Trials Act were examined. Of these 59 studies, 16 underwent monitoring and audits. The issues and reporting contents identified in the monitoring and audit reports were evaluated before and after the initiation of CRC support. The timeframe considered before the support ranged from July 2016 to the completion of each study's relocation, and that after the initiation of support ranged from each study's relocation to June 2022. During the entire study period, 243 instances were documented in monitoring and audit reports. Among the priority support categories, "inappropriate obtaining of consent" (68/8 cases before/after), "non-compliance with selection exclusion criteria" （27/0 cases before/after), and "inappropriate reporting of disease or the like" （7/1 cases before/after） were significantly improved by the CRC intervention. This investigation indicates that CRC intervention and support in specified clinical trials, particularly for categories with high-risk frequency and impact, can reduce risk and improve overall quality.

We call cases in which clinical research coordinators (CRCs) prevented non-compliance “good practice” and have been identifying these cases since April 2022. Some instances of serious non-compliance were observed, including those related to informed consent and the eligibility of patients for research. It was therefore considered necessary to educate researchers to improve practice and support CRCs. We provided a lecture on compliance at the in-hospital session on clinical research in December 2022. We investigated the effectiveness of this session by analyzing practice among 139 study participants, including some who attended the session. We obtained attendance sheets that showed participants' high level of comprehension of the session. The period from April 2022 to December 2022 was considered pre-training, and the period from December 2022 to August 2023 post-training, with a comparison of the number of cases where intervention was necessary. Overall, there were 125 cases where intervention was necessary over the whole period, of which 29 would probably have been judged as serious non-compliance if the CRC had not been involved. This suggests that CRC support has prevented many cases of non-compliance in specified clinical trials. We found 80 cases of intervention before and 45 cases after the training, indicating a significant reduction in the need for intervention. However, many of the intervention cases involved researchers who had not attended the training session (64 before and 27 after). Study participants commented that it was difficult to attend courses unless they were on-demand, and noted that they wanted to know the details of the schedule as soon as possible. It is therefore important to establish an environment conducive to accessible training and further disseminate information.