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What Is Known and Objective: Although there are accelerated approval pathways based on data of small populations and surrogate endpoints, the concern that these pathways authorize the use of inefficacious drugs based on limited data from earlier phase clinical trials remains. We retrospectively investigated the efficacy of anticancer drugs, which were approved or whose development was terminated in small and large clinical trials, and verified whether small clinical trials could reflect the results for efficacy in large clinical trials. Methods: All anticancer drugs approved in Japan or whose development was terminated from 2015 to 2019 were searched. The median overall survival (OS), median progression‐free survival (PFS), and overall response rates (ORR) between small clinical trials (sample size ≤100) and large clinical trials (sample size >100) with identical target populations and treatment settings were compared. Simple linear regression analysis, Spearman's correlation analysis, and paired sample t‐test were performed. Results and Discussion: A total of 61 comparable small and large clinical trials were identified. For all endpoints, statistically significant linear trends and correlation were detected (p < 0.001). There were no statistically significant differences in the median PFS and ORR between small and large clinical trials. The mean differences of both clinical trials were −0.102 months and −1.531%, respectively. What is new and Conclusion: Even when the sample size of the clinical trial was increased, the efficacy data of anticancer drugs could not be changed significantly. These results supported the accelerated approval pathway based on the promising efficacy data of small populations in anticancer drug development. [ABSTRACT FROM AUTHOR]

What is known and objective: Drug development is generally a long and expensive process. Regulatory authorities have established several expedited regulatory pathways, such as accelerated approval designation in the United States (1992) and conditional approval regulation in Japan (2017). In Japan, prior to 2017, the Pharmaceutical and Medical Device Agency (PMDA) granted marketing approval without requesting the results of confirmatory clinical trials case by case basis, and even after 2018, only three drugs have been approved via the conditional approval pathway, although many drugs without confirmatory clinical trials have been approved without this pathway; therefore, it is difficult to predict the circumstances under which confirmatory clinical trials may be waived. The aim of this study was to investigate the characteristics of drugs for which the requirement of confirmatory clinical trials for approval was waived in Japan. We also aimed to identify factors and formulae to predict a waiver of confirmatory clinical trials. Methods: Data on approved drugs and their characteristics were mainly extracted from the Japan Pharmaceuticals and Medical Device Agency database. The seriousness of the disease, existence of available treatments and number of patients were considered as candidate factors. The influence of each factor on receiving a waiver was determined using logistic regression analysis comparing drugs approved with and without confirmatory clinical trials as the binary response variable. The predictive formula was derived from the results of the logistic regression analysis. A receiver operating characteristic curve was used to evaluate the accuracy of the prediction. Results and discussion: Categorization of drugs as antineoplastic agents, use of the cost accounting method in the drug pricing system, "orphan" designation and accelerated approval designation in the United States emerged as significant factors in the logistic regression analysis, predicting a waiver for confirmatory clinical trials (p ≤ 0.05). These factors were then used to establish a predictive model to ascertain whether confirmatory clinical trials would be necessary for a new drug, exhibiting good sensitivity (0.8) and specificity (0.8) and high accuracy for newly approved drugs. What is new and conclusion: The identification of key factors that can predict waivers of confirmatory clinical trials may accelerate the development of clinically important drugs and improve patient access globally. This study investigated the characteristics of drugs that confirmatory clinical trials were waived for approval in Japan, and identified key factors and formulae to predict the waiver of confirmatory clinical trials. [ABSTRACT FROM AUTHOR]

Background: The human papillomavirus (HPV) vaccine coverage is very low in Japan since the government suspended the active encouragement of the vaccination. We aimed to conduct a benefit–risk assessment of HPV vaccination and explore different consequent scenarios to identify potential improvements to the current Japanese immunization program. Methods: To calculate social benefit–risk of HPV vaccine, we used the Markov model to represent the natural history of HPV and adverse events (AEs) using disability-adjusted life year (DALY) as the outcome. Benefits and risks were calculated as the sum of negative and positive outcomes corresponding to all preventable diseases and AEs associated with HPV vaccination, respectively. The benefit–risk balance in 2050 was estimated using published data. Results: Our model was confirmed by published cervical cancer incidence and mortality rates. The benefit–risk balance in 2050 showed that the most effective scenario was the introduction of 9-valent HPV vaccine targeting female individuals aged 10–29 years for routine vaccination starting in 2020, although there is possibility of increased risks of AEs for the vaccinated age group post resumption of recommendations. Conclusion: Our benefit–risk assessment of HPV vaccine helped estimate various scenarios pertaining to HPV vaccination and identify the best strategy regarding HPV vaccination. This benefit–risk assessment approach may be used for other vaccines and vaccination programs. [ABSTRACT FROM AUTHOR]

SK-896 [(Leu[sup 13] )motilin-Hse] is a new human motilin analogue synthesized from Escherichia coli using a biotechnological method. We investigated the gastrointestinal motor-stimulating effect of SK-896 and the mechanism of this effect using implanted force transducers in conscious dogs. Infusion of SK-896 during phase I in the interdigestive state induced interdigestive migrating contractions like motility in the gastroduodenum. The motility index (MI[sub 0–20] ) of gastric antrum motor activity induced by SK-896 was increased dose dependently (r = 0.830, p < 0.001), and the MI[sub 0–20] induced by SK-896 at a dose of 0.25 μg/kg/h for 20 min was the same as that for spontaneous phase III contractions. The SK-896-induced MI[sub 0–20] was significantly decreased by atropine, hexamethonium, dopamine, granisetron, and yohimbine. Conversely, ketanserin, phentolamine, timolol, and naloxone did not have significant effects on SK-896-induced MI[sub 0–20] . The effects of these drugs on human motilin (0.25 μg/ kg/h for 20 min) induced MI[sub 0–20] were the same as those of SK-896. These results indicate that SK-896 induces gastrointestinal motility during the interdigestive period in dogs with regulation of acetylcholine release from the cholinergic nerve terminal via the parasympathetic nervous system in the same fashion as human motilin.Copyright © 2001 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to develop and introduce new method to quantify motor functions of the upper extremity. Methods The movement was recorded using a three-dimensional motion capture system, and the movement trajectory was analyzed using newly developed two indices, which measure precise repeatability and directional smoothness. Our target task was shoulder flexion repeated ten times. We applied our method to a healthy adult without and with a weight, simulating muscle impairment. We also applied our method to assess the efficacy of a drug therapy for amelioration of motor functions in a non-ambulatory patient with spinal muscular atrophy. Movement trajectories before and after thyrotropin-releasing hormone therapy were analyzed. Results In the healthy adult, we found the values of both indices increased significantly when holding a weight so that the weight-induced deterioration in motor function was successfully detected. From the efficacy assessment of drug therapy in the patient, the directional smoothness index successfully detected improvements in motor function, which were also clinically observed by the patient’s doctors. Conclusion We have developed a new quantitative evaluation method of motor functions of the upper extremity. Clinical usability of this method is also greatly enhanced by reducing the required number of body-attached markers to only one. This simple but universal approach to quantify motor functions will provide additional insights into the clinical phenotypes of various neuromuscular diseases and developmental disorders. [ABSTRACT FROM AUTHOR]