Our study investigated recent strategies for proof of clinical efficacy for drugs designated as particularly high medical necessities in Japan. In this study, we focused on the 129 designated drugs with small patient number approved over 6 years from 2015 to 2020 for analyzing the characteristics of proof of clinical efficacy based on the drug background, pivotal study design, and approval condition information. All pivotal studies were classified as level 1（randomized controlled trials） to level 3（single-arm studies） and analyzed by each classification. For level 3 studies, we scrutinized the types of comparators and data sources. Characteristically, cancer drug thresholds were used as comparators for efficacy explanation. 85％ cancer drug and 48％ non-cancer drugs used thresholds as comparator. Setting a threshold as a comparator is considered an effective strategy, but the data source of the threshold is the most important issue. For cancer drugs, the study results of existing drugs were mainly used as data sources, but for non-cancer drugs, it was considered necessary to promote the use of real-world data. Post-marketing clinical efficacy data were required as an approval condition for five drugs. In this strategy, a post-marketing study plan should be included from the early development stage, and close consultation with The Pharmaceuticals and Medical Devices Agency is important.

In conclusion, a hybrid strategy, such as a single-arm pivotal study with thresholds plus a post-marketing clinical plan, may facilitate drug development. To apply the hybrid strategy, preparing external control data from the early basic research stage and the post-marketing plans to accumulate clinical efficacy data in the medical practice are essential.

In clinical trials, the need for an audit should be determined using a risk-based approach as part of a quality assurance process. However, it is difficult to define clear evaluation criteria because various risks are associated with investigator-initiated clinical trials. For example, while several Japanese standards for the conduct of clinical trials suggest that an audit should be performed “as needed,” the exact meaning of “needed ” is unclear. Therefore, this study aimed to define indications that can be used by a principal investigator to determine the need for an audit.

We first examined prerequisites to simplify our risk evaluation. They were, 1）it is to be performed for individual clinical trials, rather than to act as a systems audit to examine facilities or functionalities, and 2）it is to be performed for clinical trials that satisfy quality control measures above a certain level. Based on these prerequisites, we then examined the risk factors that are generally considered in investigator-initiated clinical trials. The results revealed that the need for an audit increases when the outcomes of the trial can be biased by conflicts of interest, and when the study intervention is highly invasive, posing a safety concern to the participants. Other situations, such as the study design and quality management level, affect the need for an audit to a lesser extent. It should be noted that the need for an audit shall be appropriately determined for each actual particular trial with reference to these ideas.

In recent years, the use of health foods has grown, and along with this, health hazards associated with the consumption of health foods have been reported. To collect the relevant information and use it to prevent the spread of health hazards, it is necessary to establish a unified collecting system that picks up adverse events from the stage when the causal relationship is not clear and to establish a causal relationship evaluation method. We have already developed a unified standardized reporting format and causal-relation estimation algorithm for the collection of information on the adverse events associated with the consumption of health foods and evaluated the feasibility of its use by medical staff. In this study, we explored the practicality of the partially modified standardized reporting format and algorithm for health food manufacturers and sellers, who are likely to receive consumption claims on adverse events as well as medical staff, using fictitious cases. The match rate for each item by the raters and the match rate between the estimates by specialists and the raters were calculated.

Evaluations were requested from 90 companies belonging to the Japan Health and Nutrition Food Association, which deals with health foods, and were obtained from 33 companies（37％）and 59 raters. The rate of agreement among the raters was generally high for many items in the reporting format and the algorithm sheet（6 items: More than 70％), but a low agreement was observed for some items. There was a possibility of having a certain level of reliability and validity for the causal relationship in the algorithm. In this study, for health food manufacturers and sellers, as for the medical staff, the potential for practicality in the collection of adverse events information was suggested, but some items had issues and needed to be improved.

The “appropriateness” and “transparency” of clinical trial costs in Japan need to be ensured based on the concept of fair market value (FMV). Here, we clarify the mechanism underlying benchmark-based costs and examine the issues that need to be addressed when introducing such a system to sponsors and medical institutions to promote its widespread use. We collected information from IQVIA Services Japan K.K. and Medidata Solutions Inc., the two main global providers of clinical trial cost benchmarking data, regarding the mechanism underlying the collection of cost data, which is the basis of benchmark data, for the provision of services, and provide an overview of the calculation method for clinical trial costs based on benchmark data. Both systems extract and store task-specific cost data for medical examinations, tests, and other tasks in clinical trials. Information is collected from a large number of clinical trial sponsors, and the data are updated periodically to reflect the latest prevailing prices, including the increases in prices and labor costs in each country. Some issues exist in the benchmark data, such as a lack of data on the cost of each service at medical institutions, and differences in the treatment of tests and diagnostic imaging related to expenses not covered by the uninsured combined medical care cost system. As clinical trials using benchmarked costs become more widespread, the reliability of the benchmark data on which the compensation for individual clinical trial tasks is based can be expected to improve.

The number of cases with heart failure (HF) is increasing with the progress of aging in Japan. Lethal arrhythmias such as sustained ventricular tachycardia or ventricular fibrillation are the primary causes of sudden cardiac death (SCD). Therefore, the use of an implantable cardioverter-defibrillator as a treatment is recommended for reducing the incidence of SCD among HF patients with a high risk of SCD. However, an effective approach to predict SCD has not been fully elucidated for treating dilated cardiomyopathy (DCM）―the main cause of heart disease in heart transplant recipients in Japan. Here, we determine the genetic variants and electrocardiographic parameters using 187-channel repolarization interval-difference mapping electrocardiography (187-ch RIDM-ECG) in patients with DCM. The group of patients with any genetic variants did not exhibit a significant difference in the rates of patients with antiarrhythmic drug (amiodarone) and prognosis than the group of patients without any genetic variants. However, in cases with specific genetic variants such as lamin A/C（LMNA）and titin（TTN）mutations, the RT dispersion and Tp-e dispersion were associated with the effect of drug treatment and prognosis. Additionally, in cases without the genetic variant, the RT dispersion and Tp-e dispersion were significantly associated with prognosis. For the appropriate drug treatment for HF, in addition to genetic testing, it is necessary to establish a prediction method using effective diagnostic techniques such as 187-ch RIDM-ECG.