Background: Non-inferiority (NI) clinical trials are designed to provide the benefits such as enhanced safety, treatment convenience, etc., by demonstrating that the experimental arm is not clinically inferior to the comparator arm statistically. In the area of oncology, the NI trials would provide better treatment options for medical doctors and patients though few anti-cancer drugs have been approved by NI trial despite no opposition in guideline to drug registration by NI. Here, we study the present status of NI trials to clarify the influence of regulation and the intention of investigators and pharmaceutical companies. Methods: We investigated published papers by using PubMed from the search term ‘(tumor OR cancer) AND (non-inferior OR non-inferiority) and (survival) and (species; human) and (published; until Dec 31, 2015)'. 115 papers passed after exclusion criteria were analyzed in terms of regions, sponsors, and drug types. Results: 70% of NI trials was solely conducted in regions, the other was globally done, and only 4% in North America. 65% was categorized as investigator initiated studies (IIS). Eighteen trials were conducted for non-approved drugs and three novel drugs were approved. Conclusions: Each regional guideline describes NI trial differently, and the same tendency of the regional difference in comparison of number of NI trial was confirmed. The majority of NI trials are regional IIS. Approval of non-approved drugs by NI trial indicates that the guidelines do not oppose the design of NI trials for registration.

 This study aimed to provide a proposal for an efficient placebo-controlled fracture study design for the testing of new drugs targeted against primary osteoporosis, which also minimize the disadvantages for patients in the placebo group. We investigated 15 randomized placebo-controlled fracture studies using 11 products marketed in the United States, Europe, or Japan, previously described in medical journals. We particularly focused on the severity of osteoporosis in our fracture study cohort; we also created a new parameter “OSPC” (osteoporosis severity of patient cohort), which was calculated by multiplying the incidence of new vertebral fractures in the placebo group by 1,000 patients for each planned administration period. When the proportion of patients having≥1 prevalent vertebral fracture at baseline increased by approximately 90%, the number of patients in the placebo group of the study reduced by≤1,005 (r²＝0.5475) and the OSPC increased by≥40, except for 1 study (r²＝0.6008). The analysis of 15 fracture studies divided into 3 OSPC ranges (<40, 40－80, and≥80) showed that the number of patients in the placebo group was small and that the planned administration period was short when the patient cohort with a relatively high severity of osteoporosis (OSPC: ≥40) was enrolled in the fracture study, which was limited to the anti-new vertebral fracture effect. In addition, the number of patients in the placebo group with new vertebral fractures during the fracture study was small due to small number of patients in the placebo group and short study period. In conclusion, the efficacy of drug candidates for primary osteoporosis can be evaluated in a small sample size at a short period compared with the current standard study design, provided the incidence of new vertebral fractures is set as the primary endpoint and patients with prevalent vertebral fractures are included in the study. This study design may minimize the disadvantages for patients in the placebo group of the study and simplify the clinical development.

 Following the fraudulent incident of data manipulation and conflicts of interest arising in clinical research, compulsory legal regulation was introduced from April 1 in 2018 in place of conventional research ethics guidelines. Taking into consideration the balance with promoting clinical research, the Clinical Trials Act set minimum rules on the relationship between the four action entities (authorities, researchers, certified review boards, marketing authorization holders of medicines etc.) and planned to clarify the procedure of clinical research and improve the quality. The implementation of high quality clinical research depends on the performance of the certified review board. In order to utilize the results of high-quality clinical research, we would like to advance the environment to raise the reliability of clinical trials and carry out with the patients and society.

 The Clinical Trials Act in Japan has been enforced in April 2018. Since clinical research plan would be confirmed objectively by certified review board, atmosphere to conduct high quality clinical research would be cultivated, which will result in activation of clinical studies finally. Therefore, pharmaceutical industries expect the Act quite positively based on the following perspectives. i) The Act will induce to improve quality of clinical research, which must be a trigger to activate whole of clinical studies. ii) Result of specified clinical research would be utilize for regulatory submission data package. iii) The Clinical Trials Act and new regulations such as conditional early approval system would synergistically accelerate to make answer for a research question. iv) Both value and innovation of new medicine would be evaluated by proper clinical research. To activate whole clinical studies and to maximize objective of the Act, effective collaboration between clinical site and company should be established under sharing of role and responsibility.