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Introduction: Over the last few decades, numerous late-phase multi-regional clinical trials have been conducted to develop a novel treatment for Alzheimer's disease (AD), with no effective results., Objective: To inform the design and interpretation of future clinical trials, the aim of this study was first to examine the current landscape of late-phase clinical trials to determine key study design characteristics, and then assess the regional variation between Japan and North America for the most utilized clinical efficacy endpoint in the most targeted stage of the disease., Methods: The study design and the mechanism of action of the interventional drugs tested in the late-phase clinical trials initiated in the last 5 years (2014-2018) were assessed based on the records in ClinicalTrials.gov database. The regional variation of the most utilized clinical efficacy endpoint in the most targeted population was assessed using data from two similarly designed observational studies conducted in Japan (Japanese Alzheimer's Disease Neuroimaging Initiative, J-ADNI) and North America (Alzheimer's Disease Neuroimaging Initiative, ADNI). For the most utilized clinical efficacy endpoint, the change from baseline (CFB) at Month 6, Year 1 and Year 2 was estimated using the growth curve model with a random intercept and slope, including gender as a fixed factor and age, apolipoprotein E ε4 genotype and years of education as covariates., Results: Of 48 Phase III trials that were initiated during the study period, 25 were disease-modifying treatment trials in which individuals with early AD were the most studied (56%) and Clinical Dementia Rating-Sum of Boxes (CDR-SB) was the most frequently utilized primary clinical efficacy endpoint (64%). The baseline characteristics of the early AD population between J-ADNI and ADNI were generally comparable, except for years of education. When comparing CDR-SB in early AD, J-ADNI had generally better baseline scores and the overall progression was similar (CFB at Year 2, ADNI 2.7 and J-ADNI 2.3, p = 0.190), despite slower progression in functional domains (CFB at Year 2, ADNI 1.4 and J-ADNI 1.0, p = 0.031)., Conclusion: Over the years, the target population has shifted toward early stage of the disease, wherein the clinical progression is slower and difficult to measure. Moreover, our results suggest that regional variation could have an impact on functional measurements due to cultural differences in pivotal clinical trials. Therefore, caution should be exercised according to the characteristics of the endpoint used.

Background and Purpose: Since the failure of a number of phase III trials of neuroprotection in ischemic stroke, the need for smaller phase II studies with MRI surrogates has emerged. There is, however, little information available about sample size requirements for such phase II trials and rarely enough patients in single studies to make robust estimates. We have formed an international collaborative group to assemble larger datasets and from these have generated sample size tables for MRI-based infarct expansion as the outcome measure., Methods: Twelve centers from Australia, Europe, and North America contributed data from patients with hemispheric ischemic stroke. Infarct expansion was defined from initial diffusion-weighted images and later fluid-attenuated inversion recover or T2 images. Sample size estimates were calculated from data on infarct expansion ratios treated as dichotomous or continuous variables. A nonparametric approach was used because the distribution of infarct expansion was resistant to all forms of transformation., Results: As an example, a 20% absolute reduction in infarct expansion ratio (< or = 1), 80% power, and alpha = 0.05 requires 99 patients in each arm. To achieve an equivalent effect size with a continuous approach requires 61 patients., Conclusions: These tables will be useful in planning phase II trials of therapy with the use of MRI outcome measures. For positive studies, biologically plausible surrogates such as these may provide a rationale for proceeding to phase III trials.

Gastric carcinoma is widespread in many South American and Asian countries but may be especially deadly in the West, due to a lack of programs for early diagnosis. Advanced gastric carcinoma is incurable, and the median survival time of patients with advanced disease is only 6 to 9 months. We sought to examine investigative trends in the utilization of new agents in the treatment of advanced gastric carcinoma in North America and Europe. Representative published reports of phase II and III clinical trials of therapies for gastric carcinoma by investigators based in North America and Europe from January 1995 through December 2001 were identified by a computerized search of the PubMed literature database. Fluorouracil, cisplatin, leucovorin, methotrexate, doxorubicin, and mitomycin were considered "conventional" agents; all other drugs were considered "new" agents. Of the 42 reports identified by the literature search, 17 were by investigators in North America and 25 were by investigators in Europe. All reports by investigators in North America were phase II trials, compared with 64% of those studies in Europe; the other studies by European investigators were phase III trials (36%). Chemotherapeutic drugs we considered "new" for the purpose of this study were investigated in 64% of all trials in North America and Europe. Eighty-one percent (22/27) of the 27 trials in which new agents were studied were phase II studies. We conclude that new agents are being widely incorporated in the investigation of advanced gastric cancer in North America and Europe. This trend is likely to be continued as more new chemotherapeutic agents are developed for clinical testing.