In a longitudinal clinical study to compare two groups, the primary end point is often the time to a specific event (eg, disease progression, death). The hazard ratio estimate is routinely used to empirically quantify the between-group difference under the assumption that the ratio of the two hazard functions is approximately constant over time. When this assumption is plausible, such a ratio estimate may capture the relative difference between two survival curves. However, the clinical meaning of such a ratio estimate is difficult, if not impossible, to interpret when the underlying proportional hazards assumption is violated (ie, the hazard ratio is not constant over time). Although this issue has been studied extensively and various alternatives to the hazard ratio estimator have been discussed in the statistical literature, such crucial information does not seem to have reached the broader community of health science researchers. In this article, we summarize several critical concerns regarding this conventional practice and discuss various well-known alternatives for quantifying the underlying differences between groups with respect to a time-to-event end point. The data from three recent cancer clinical trials, which reflect a variety of scenarios, are used throughout to illustrate our discussions. When there is not sufficient information about the profile of the between-group difference at the design stage of the study, we encourage practitioners to consider a prespecified, clinically meaningful, model-free measure for quantifying the difference and to use robust estimation procedures to draw primary inferences.

1 Effects of cyclopiazonic acid (CPA), a specific inhibitor of the Ca2+-ATPase in sarcoplasmic reticulum (SR) of skeletal and cardiac muscles, on contractile responses induced by Ca2"-release from intracellular storage sites were examined in the longitudinal smooth muscle strip of the guinea-pig ileum skinned with J3-escin.2 Ca2+-loading of storage sites (Ca2'-uptake) was performed in pCa 6.3 solution. The amount of Cat aken up was monitored by use of the amplitude of contraction following application of 25 mM caffeine or 25 gM inositol 1,4,5-trisphosphate (IP3). 3 Contractile responses to caffeine or IP3 were reduced or abolished when the preceding Ca2+-uptake was performed in the presence of 0.1-10g M CPA. The dose of CPA required to inhibit the contraction induced by caffeine or IP3 by 50% was approximately 0.6 gM. The CPA-sensitive Ca2"-uptake completely depended upon the presence of ATP in the solution during Ca2+-uptake.4 When 1 gM CPA was added after Ca2"-uptake, the subsequent caffeine-or IP3-induced contraction was not significantly affected by the presence of CPA. 5 Acetylcholine-induced contraction was also almost abolished when the preceding Ca2+-uptake was performed in the presence of 10gM CPA. 6 The relationship between pCa and contraction was not affected by the presence of 10gM CPA in skinned fibres where Ca2+ storage sites had been destroyed by treatment with A23187. The enhancement of contraction in pCa 6.0 solution by calmodulin was not affected by 1O gM CPA.7 These results suggest that CPA selectively inhibits ATP-dependent Ca2"-uptake into intracellular storage sites in skinned ileal smooth muscle strips. CPA appears to be a potent, reversible, and very specific inhibitor of the Ca2+-pump in the storage sites of smooth muscle, and is an extremely valuable pharmacological tool.

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PurposeTo establish a new medical information database network (designated MID‐NET®) to provide real‐world data for drug safety assessments in Japan.MethodsThis network was designed and developed by the Ministry of Health, Labour and Welfare and the Pharmaceuticals and Medical Devices Agency in collaboration with 23 hospitals from 10 healthcare organizations across Japan. MID‐NET® is a distributed and closed network system that connects all collaborative organizations through a central data center. A wide variety of data are available for analyses, including clinical and administrative information. Several coding standards are used to standardize the data stored in MID‐NET® to allow the integration of information originating from different hospitals. A rigorous and consistent quality management system was implemented to ensure that MID‐NET® data are of high quality and meet Japanese regulatory standards (good post‐marketing study practice and related guidelines).ResultsMID‐NET® was successfully established as a reliable and valuable medical information database and was officially launched in April 2018. High data quality with almost 100% consistency was confirmed between original data in hospitals and the data stored in MID‐NET®. A major advantage is that approximately 260 clinical laboratory test results are available for analysis.ConclusionsMID‐NET® is expected to be a major data source for drug safety assessments in Japan. Experiences and best practices established in MID‐NET® may provide a model for the future development of similar database networks.

Although the number of global clinical trials (GCTs) conducted in multiple countries including Japan has increased recently, it is not clear how much these GCTs help in reducing the lag in drug development (LDD: difference between the submission dates for new drug applications (NDAs) in the United States and Japan). We examined the effects of various clinical development strategies on LDD because the development period depends on what types of clinical trials were conducted for the Japanese NDA. Although various drug development strategies are available, deciding early on an appropriate strategy is a key to minimizing the LDD in Japan. The inclusion of GCTs in the clinical development strategy is also important; simultaneously, the smaller sample size of the Japanese population should be taken into consideration. Furthermore, reinforcement of Japan's capability to lead drug development may also be important in providing innovative drugs to Japanese patients without any significant LDD.