Multiregional Clinical Trials Research Articles

Factors Associated with Inclusion of Japan in Phase I Multiregional Clinical Trials in Oncology.

Early inclusion of Japan in the global development program could be a key factor in reducing the drug lag, making participation in phase I multiregional clinical trials (Ph. I MRCTs) an important consideration for oncology drug development in Japan. We aimed to investigate the factors associated with the inclusion of Japan in Ph. I MRCTs in oncology. We compared the trial design, target population, type of primary tested drug, trial conduct profile, and sponsor profile for Ph. I MRCTs with or without Japan conducted by the top 20 companies in more than two countries and started between January 1, 2011, and December 31, 2020. One hundred and ninety-seven Ph. I MRCTs included Japan, and 697 did not. Detailed features of the Ph. I MRCTs in oncology were summarized, and several factors (trial design, target population, trial conduct profile, and sponsor profile) associated with inclusion of Japan in the Ph. I MRCTs were identified. It is important for Japanese subsidiaries within global pharmaceutical companies to closely communicate with the headquarters based on medical practice and unmet needs in Japan to join global development from an early stage. In addition, further efforts to attract emerging biopharmaceutical companies to Japan from the regulatory and/or political perspectives would be needed, thereby preventing drug lag in Japan.

Different Development Strategies Affecting Japan's Drug lag between Japan-Based and Foreign-Based Companies.

We examined the development strategies of new molecular entities approved during a 10-year period (fiscal years of 2012-2021) in Japan to determine the differences in drug lag between Japan and foreign companies. The results demonstrated a clear difference in development strategies. For example, products were usually developed through a "only-Japan" strategy by Japan companies (51.1% of products), compared to a "MRCT (multi-regional clinical trials)" strategy by foreign companies (54.9% of products). Regarding types of licenses, for Japan companies, the percentage of original products was higher in the category of less drug lag, such as "no approval in the US and EU" (59.1%), whereas the percentage of "license-in" products was markedly higher in the "drug lag ≥ 5 years" category (52.5%). Such differences were not observed for products developed by foreign companies. Of 64 license-in products developed by Japan companies with a drug lag > 5 years, 51 (79.7%) had already been approved in the US or EU at initiation of clinical development in Japan. The origin of approximately half (34) of the products was from the emerging companies (non-member foreign companies of the Japan Pharmaceutical Manufacture Association). These results suggest that more global cooperation of Japan companies, particularly with emerging foreign companies, is necessary in terms of the earlier timing of license-in and development strategies of products to promote drug development without drug lag or drug loss in Japan.

Regional consistency assessment in multiregional clinical trials

ABSTRACT Multiregional clinical trials (MRCTs) have become a favored strategy for new drug development. The accurate evaluation of treatment effects across different regions is crucial for interpreting the results of MRCTs. Consistency between regional and overall results ensures the extrapolability of the overall conclusions to individual regions. While numerous statistical methods have been proposed for consistency assessment, a notable proportion necessitate a substantial escalation in sample size, particularly in scenarios involving more than four regions within MRCTs. This, paradoxically, undermines the fundamental intent of MRCTs. In addition, standardized statistical criteria for concluding consistency are yet to be established. In this paper, we develop further consistency assessment approaches in the framework of two multivariate likelihood ratio test-based methods, namely mLRTa and mLRTb, wherein consistency is cast as the alternative and null hypotheses. Notably, our exploration unveils that qualitative methods such as the funnel approach and PMDA methods are special instances of mLRTa. Furthermore, our work underscores that these three qualitative methodologies roughly share the same level of assurance probability (AP). Intriguingly, when the number of regions in an MRCT surpasses five, even when the overall sample size guarantees a power of 90% or more and the true treatment effects remain uniform across regions, the AP remains below the 70% mark. Drawing from our meticulous examination of operational attributes, we recommend mLRTa with positive treatment effects in all regions in the alternative hypothesis with significance level 0.5 or mLRTb with all regional treatment effects being equal in the null and significance level of 0.2.

A Bayesian approach based on discounting factor for consistency assessment in multi-regional clinical trial

ABSTRACT Multi-regional clinical trial (MRCT) has become an increasing trend for its supporting simultaneous global drug development. After MRCT, consistency assessment needs to be conducted to evaluate regional efficacy. The weighted Z-test approach is a common consistency assessment approach in which the weighting parameter W does not have a good practical significance; the discounting factor approach improved from the weighted Z-test approach by converting the estimation of W in original weighted Z-test approach to the estimation of discounting factor D. However, the discounting factor approach is an approach of frequency statistics, in which D was fixed as a certain value; the variation of D was not considered, which may lead to un-reasonable results. In this paper, we proposed a Bayesian approach based on D to evaluate the treatment effect for the target region in MRCT, in which the variation of D was considered. Specifically, we first took D random instead of fixed as a certain value and specified a beta distribution for it. According to the results of simulation, we further adjusted the Bayesian approach. The application of the proposed approach was illustrated by Markov Chain Monte Carlo simulation.

The Impact of Regulatory Reforms in China on Drug Lag: The Role of Clinical Development Strategies.

In recent years, there has been significant focus on China's new drug lag, but relevant research is limited. This study explores the reasons for drug lag by assessing the impact of reforms in China's drug review system, particularly focusing on the influence of clinical development strategies. This study selected drugs first launched in the United States between 2017 and 2022, examining absolute and relative lag between China and the first-launch country (including submission and review lag). These delays with drugs approved in the European Union and Japan during the same period were compared with uncover the roots of delays in China, further identifying potential factors that could reduce these delays. The results indicate that the National Medical Products Administration (NMPA) has a longer relative lag compared with the European Medicines Agency (EMA) and the Pharmaceuticals and Medical Devices Agency (PMDA). The submission lag time of the NMPA significantly surpasses that of the EMA and PMDA, whereas the review lag time of the NMPA exceeds that of the PMDA but falls short of the EMA. Focusing on clinical trial strategies, bridging trials and multiregional clinical trials (MRCTs) are typically required by the NMPA in East Asia, resulting in longer clinical delay time. Whereas the EMA and PMDA primarily require international MRCTs in Europe and America, with a clinical delay of < 5 months. It is evident that there is a significant gap in clinical trial durations between China and other countries. Further optimization of clinical trial management is necessary to address the lag for new drugs in China.

Asia-Inclusive Global Development of Enpatoran: Results of an Ethno-Bridging Study, Intrinsic/Extrinsic Factor Assessments and Disease Trajectory Modeling to Inform Design of a Phase II Multiregional Clinical Trial.

Enpatoran is a novel, highly selective, and potent dual toll-like receptor (TLR)7 and TLR8 inhibitor currently under development for the treatment of autoimmune disorders including systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), and myositis. The ongoing phase II study (WILLOW; NCT05162586) is evaluating enpatoran for 24 weeks in patients with active SLE or CLE and is currently recruiting. To support development of WILLOW as an Asia-inclusive multiregional clinical trial (MRCT) according to International Conference on Harmonisation E5 and E17 principles, we have evaluated ethnic sensitivity to enpatoran based on clinical pharmacokinetic (PK), pharmacodynamic (PD), and safety data from an ethno-bridging study (NCT04880213), supplemented by relevant quantitative PK, PD, and disease trajectory modeling (DTM) results, and drug metabolism/disease knowledge. A single-center, open-label, sequential dose group study in White and Japanese subjects matched by body weight, height, and sex demonstrated comparable PK and PD properties for enpatoran in Asian vs. non-Asian (White and other) subjects across single 100, 200, and 300 mg orally administered doses. DTM suggested no significant differences in SLE disease trajectory for Asian vs. non-Asian individuals. Aldehyde oxidase (AOX) is considered to be a key contributor to enpatoran metabolism, and a literature review indicated no relevant ethnic differences in AOX function based on in vitro and clinical PK data from marketed drugs metabolized by AOX, supporting the conclusion of low ethnic sensitivity for enpatoran. Taken together, the inclusion of Asian patients in MRCTs including WILLOW was informed based on a Totality of Evidence approach.

Nonparametric Approach for Calculating Japanese Sample Size in Multi-regional Clinical Trials

Nonparametric Approach for Calculating Japanese Sample Size in Multi-regional Clinical Trials

Implementation status and consideration for the globalisation of decentralised clinical trials: a cross-sectional analysis of clinical trial databases

ObjectiveTo comprehensively elucidate the current landscape of decentralised clinical trials (DCTs) and identify notable aspects that can facilitate DCT implementation.DesignCross-sectional analysis.SettingData were extracted using selected DCT-specific search terms on 4...

Bayesian joint models for multi-regional clinical trials.

In recent years, multi-regional clinical trials (MRCTs) have increased in popularity in the pharmaceutical industry due to their ability to accelerate the global drug development process. To address potential challenges with MRCTs, the International Council for Harmonisation released the E17 guidance document which suggests the use of statistical methods that utilize information borrowing across regions if regional sample sizes are small. We develop an approach that allows for information borrowing via Bayesian model averaging in the context of a joint analysis of survival and longitudinal data from MRCTs. In this novel application of joint models to MRCTs, we use Laplace's method to integrate over subject-specific random effects and to approximate posterior distributions for region-specific treatment effects on the time-to-event outcome. Through simulation studies, we demonstrate that the joint modeling approach can result in an increased rejection rate when testing the global treatment effect compared with methods that analyze survival data alone. We then apply the proposed approach to data from a cardiovascular outcomes MRCT.

Using eConsent to improve patient comprehension and solving issues for introduction, with special attention to the COVID-19 pandemic: A questionnaire survey by the Japan Pharmaceutical Manufacturers Association

The environment surrounding clinical trials is evolving rapidly with the advancement of digital transformation (DX). Especially during the COVID-19 pandemic, digital methods are effective in promoting multiregional clinical trials (MRCT). eConsent is an electronic tool for obtaining informed consent that is expected as a key solution to improve patient understanding. According to the report by Pietrzykowski et al., patient understanding in clinical trials is surprisingly low, and this is a significant ethical problem. Despite the current situation, the use of eConsent has not significantly progressed at least in Japan. This study aimed to identify the current issues for eConsent and consider measures to solve them. In January 2022, an online questionnaire survey was sent to 69 member companies of the Japan Pharmaceutical Manufacturers Association (JPMA), and 52 companies (75.4%) responded. Thirteen companies (25.0%) conducted a trial using eConsent. Among the 13 companies, 17 trials were conducted by 8 companies after the COVID-19 pandemic (summer 2020), compared to 8 trials by 5 companies before the pandemic. We found that the biggest obstacles to the spread of eConsent are the lack of awareness of eConsent use and the development of provisions for treating electronic files as source records in medical institutions. In conclusion, we need to encourage medical institutions to update provisions for handling electronic source documents and to notify them of the importance of eConsent. Thus, further promotion of eConsent is needed to increase patient understanding and enable more efficient clinical trials.

Characteristics of Asian Participation in Multi-regional Clinical Trials Reviewed for Drug Approval in Japan: Opportunities for Collaboration Between South-East Asia, East Asia, and Japan.

Although the percentage of multi-regional clinical trials (MRCTs) submitted for drug approval in Japan increased significantly since the 2007 publication of the regulatory guideline, "Basic principles on global clinical trials", strategic collaborations between Asian countries will be important to promote MRCTs in accordance with the ICH E17 guideline published in 2017. In this study, characteristics of MRCTs reviewed for drug approval in Japan, especially those with participation by South-East Asia and East Asia, were investigated to explore opportunities for collaborations on global drug development in Asia. More than 90% of reviewed trials were conducted as global MRCTs. In addition to Japan, South-East Asia has participated in various types of MRCTs in terms of total numbers of subjects and countries. However, South-East Asia participation was lower in large-size MRCTs (total sample size ≥ 1000) than in middle- (500 ≤ total sample size < 1000) and small-size MRCTs (total sample size < 500). Furthermore, similar clinical trials for the same indications to the MRCTs without South-East Asia were rarely conducted separately in South-East Asia. Participation of other Asian countries did not affect the percentage of Japanese subjects enrolled in an MRCT, but did significantly increase the percentage of participating Asian subjects. These results suggest that additional opportunities for collaboration on MRCTs may be possible between Japan and other Asian countries, especially more collaborations with South-East Asia in the large-size MRCTs. More data of Asian populations from MRCTs will be useful for exploring an important ethnic factor affecting drug response, and will provide a sound scientific basis in considering the application of the pooled data concept in Asia, as described in the ICH E17 guideline.

Impact of Asian Race on Prognosis in De Novo Metastatic Prostate Cancer.

Little is known about the impact of Asian race on the long-term survival outcomes of males with de novo metastatic prostate cancer (PCa). Understanding racial disparities in survival is critical for accurate prognostic risk stratification and for informing the design of multiregional clinical trials. This multiple-cohort study included individual patient-level data for males with de novo metastatic PCa from the following 3 cohorts: LATITUDE clinical trial data (n=1,199), the SEER program (n=15,476), and the National Cancer Database (NCDB; n=10,366). Primary outcomes were overall survival (OS) in LATITUDE and NCDB and OS and cancer-specific survival in SEER. Across all 3 cohorts, Asian patients diagnosed with de novo metastatic PCa had better survival than white patients. In LATITUDE, median OS was significantly longer in Asian versus white patients in the androgen deprivation therapy (ADT) + abiraterone + prednisone group (not reached vs 43.8 months; hazard ratio [HR], 0.45; 95% CI, 0.28-0.73; P=.001) as well as in the ADT + placebo group (57.6 vs 32.7 months; HR, 0.51; 95% CI, 0.33-0.78; P=.002). In SEER, among all patients diagnosed with de novo metastatic PCa, median OS was significantly longer in Asian versus white males (49 vs 39 months; HR, 0.76; 95% CI, 0.68-0.84; P<.001). Among those who received chemotherapy, Asian patients again had longer OS (52 vs 42 months; HR, 0.71; 95% CI, 0.52-0.96; P=.025). Using data on cancer-specific survival in SEER resulted in similar conclusions. In NCDB, Asian patients also had longer OS than white patients in aggregate and in subgroups of males treated with ADT or chemotherapy (aggregate: 38 vs 26 months; HR, 0.72; 95% CI, 0.62-0.83; P<.001; ADT subgroup: 41 vs 26 months; HR, 0.71; 95% CI, 0.60-0.84; P<.001; chemotherapy subgroup: 34 vs 25 months; HR, 0.67; 95% CI, 0.57-0.78; P<.001). Asian males have better OS and cancer-specific survival than white males with metastatic PCa across different treatment regimens. This should be considered when assessing prognosis and in designing multinational clinical trials.

Disparity in regional recruitment across global cancer trials: A meta-analysis.

6636 Background: Equitable regional enrollment in clinical trials is critical to addressing global inequities in health care outcomes. Therefore, we quantified disparities in regional recruitment in global cancer trials. Methods: Phase II/III clinical trials in prostate (PC), breast (BC), colorectal (CRC) and lung cancer (LC), and reporting regional recruitment were identified from Medline. Global regions were defined as North-(NA) and South- America (SA), Europe (EU), Africa (AF), Asia (AS), and Australia (AU). For multi-regional trials, enrollment incidence ratios (EIR) which compare region-wise trial enrollment against global estimates of region-wise specific cancer incidence obtained from Global Burden of Disease 2019 database. Trial-level EIRs were pooled using random-effects meta-analysis. A pooled EIR of &lt; 1.0 indicates underrepresentation of a particular region in clinical trial enrollment compared to the actual burden of the specific cancer in that region. Statistical analyses were conducted in R v4.1.2. Results: Of the total 2125 trials identified, 1681 (79.1%) trials with 691,800 participants reported information regarding regional recruitment. Among those, only 1400 (65.9%) trials reported proportions of patients from pre-defined regions. A total of 1231 (57.9%) trials were single-regional recruiting patients from EU (589; 47.8%), NA (329; 26.7%), AS (295; 23.9%), AU (10; 0.8%), AF (4; 0.3%), and SA (4; 0.3%). There was significant underrepresentation of patients from AS (EIR: 0.47; 95% CI: 0.41-0.54) in cancer clinical trials. This was consistent across different cancers: PC (0.49; 0.35-0.71), BC (0.63; 0.43-0.94), CRC (0.63; 0.43-0.94), LC (0.39; 0.30-0.50). Similarly, there is a trend of under-representation of patients from AF (0.67; 0.43-1.04). Consistently, patients from were under-represented in PC (0.43; 0.24-0.77) and LC (0.26; 0.09-0.79) trials. Patients from NA (1.27; 1.08-1.51), EU (1.64; 1.57-1.72), and AU (5.41; 3.90-7.51) were significantly over-represented in multi-regional cancer clinical trials. The results are provided in table. Conclusions: There is suboptimal reporting of region-wise enrollment in cancer clinical trials. Representation of Africa and Asia in cancer clinical trials appears to be less than their expected share based on their burden of cancer incidence. [Table: see text]

Comparison of safety outcomes of anticancer drugs in Japanese and non-Japanese patients in multi-regional clinical trials: meta-analysis of safety profiles.

No report has assessed the differences in adverse event (AE) profiles of anticancer drugs for all types of cancers in clinical trials involving Japanese patients. This study aimed to compare the safety outcomes of anticancer drugs in Japanese and non-Japanese patients in multi-regional clinical trials (MRCTs), regardless of the type of cancer or drug. All new approvals of oncology drugs in Japan from January 2009 to December 2018 were searched through the Pharmaceuticals and Medical Devices Agency website. The odds ratio (OR) for comparing the incidence of AEs between Japanese and non-Japanese patients was estimated using the Mantel-Haenszel method with a random effect model. Sixty-six multi-regional phase 3 trials were identified involving 43,712 patients. Severe AE, AE leading to dose reduction, and AE leading to dose interruption were significantly more frequent in Japanese patients than in non-Japanese (odds ratios [ORs] were 1.32 (95% confidence interval (CI): 1.13-1.53), 1.97 (95% CI: 1.66-2.31), and 1.63 (95% CI: 1.43-1.86), respectively). Serious AEs (SAEs) and AEs leading to death were significantly less frequent in Japanese patients (OR: 0.70 (95% CI: 0.62-0.77) vs. 0.56 (95% CI: 0.44-0.67), respectively). There were no differences in AEs leading to study withdrawal. The incidence of most AEs was significantly higher in Japanese patients. In Japanese patients, the incidence of SAEs and AEs leading to death was low, but severe AEs, AEs leading to dose reductions, AEs leading to dose interruption, and individual adverse events were high.

PD21-07 RACIAL IMPACT (ASIAN VS. WHITE) ON THE PROGNOSIS OF PATIENTS WITH DE NOVO MCSPC: AN ANALYSIS ON LATITUDE, SEER AND NCDB

You have accessJournal of UrologyCME1 Apr 2023PD21-07 RACIAL IMPACT (ASIAN VS. WHITE) ON THE PROGNOSIS OF PATIENTS WITH DE NOVO MCSPC: AN ANALYSIS ON LATITUDE, SEER AND NCDB XuDong Ni, Michael Luu, Weiwei Ma, Stephen Freedland, Timothy J. Daskivich, and Yao Zhu XuDong NiXuDong Ni More articles by this author , Michael LuuMichael Luu More articles by this author , Weiwei MaWeiwei Ma More articles by this author , Stephen FreedlandStephen Freedland More articles by this author , Timothy J. DaskivichTimothy J. Daskivich More articles by this author , and Yao ZhuYao Zhu More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003287.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Little is known about the impact of race (Asian or White) on the long-term survival outcomes of men with de novo mCSPC treated with different methods. Understanding racial disparities in survival is critical for accurate prognostic risk stratification and for informing the design of multiregional clinical trials. METHODS: This multiple-cohort study included individual patient-level data of men with de novo mCSPC from the following 3 cohorts: LATITUDE clinical trial data (LATITUDE [n = 1199]); Surveillance, Epidemiology, and End Results (SEER [n = 5496]); and the National Cancer Database (NCDB [n = 10366]). Key efficacy outcomes were overall survival (OS) in LATTITUDE and NCDB as well as OS and cancer-specific survival (CSS) in SEER. Kaplan-Meier analysis with propensity score matching (PSM) was used for survival analysis. Hazard ratios were calculated using a multivariate Cox proportional-hazard model. RESULTS: Across all three cohorts, Asian patients diagnosed with de novo mCSPC had better OS and CSS than White patients. In LATITUDE, median OS was significantly longer in Asian than in White men in the ADT+Abiraterone+Prednisone group (not reached vs. 43.8 months, HR0.47, 95% CI 0.28–0.77, P = 0.003 for cox analysis) as well as in the ADT+placebo group (57.6 months vs. 32.7 months, HR0.49, 95% CI 0.32–0.75, P = 0.001 for cox analysis). In SEER, among all patients diagnosed with de novo mCSPC, median OS was significantly longer in Asian than in White men (53 months vs. 42 months, HR0.76, 95% CI 0.68–0.85, p<0.001 for cox analysis). When analyses were restricted to patients who received chemotherapy, Asian men again had longer OS (67 months vs. 41 months, HR0.70 95% CI 0.51–0.95, p=0.02 for cox analysis). Using CSS data in SEER resulted in similar conclusions as OS. In NCDB, Asians also had longer OS than White men (whole cohort: 38 months vs. 26 months, HR0.73, 95%CI 0.63–0.84, P = 0.02 for cox analysis; ADT subgroup: 41 months vs. 26 months, HR0.75, 95% CI 0.63–0.89, p<0.001 for cox analysis; Chemotherapy subgroup: 34 months vs. 27 months, HR0.80, 95% CI 0.69–0.94, p=0.005 for cox analysis). CONCLUSIONS: Asian men had better OS and CSS than White men with mCSPC across different treatment regimens in all datasets examined and should be considered as an independent prognostic factor. This racial difference should also be considered when designing multiregional clinical trials. Further studies including biological analyses are needed to understand the etiology of the apparent survival advantage for Asian men. Source of Funding: NSFC 81972375, 81802528 © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e592 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information XuDong Ni More articles by this author Michael Luu More articles by this author Weiwei Ma More articles by this author Stephen Freedland More articles by this author Timothy J. Daskivich More articles by this author Yao Zhu More articles by this author Expand All Advertisement PDF downloadLoading ...

Exploratory Analysis of Drug Lag in New Oncology Drugs Between Japan and the US.

Drug lag in Japan has greatly decreased over the past decades; however, new instances of drug lag have appeared along with changes in the circumstances of oncology drug development. We aimed to investigate the factors associated with the approval lag for new oncology drugs between Japan and the United States (US) over the past decade by comparing approval dates and modalities, lead indications, approval types, and phase I strategies for earlier approval in Japan. We descriptively evaluated the characteristics of 117 new oncology drugs approved in either Japan or the US from January 1, 2011, to December 31, 2020. Seventy-one drugs were approved in Japan, 112 in the US, five only in Japan, and 46 only in the US. Interestingly, new oncology drugs were predominantly developed by the top 20 pharmaceutical companies in Japan; however, the opposite was true for drugs that were not yet approved in Japan. However, no clear trend was observed in the relationship between drug lag and the studied factors, except for the phase I strategy. There was a numerical but clear trend in which a higher percentage of phase I multiregional clinical trials (MRCTs) in the drug development strategy was observed for drugs with earlier approval in Japan. Participation in global drug development during the early stages, such as during phase I MRCTs, is one of the keys to successfully minimizing this new instance of drug lag in Japan.

Racial impact (Asian vs. White) on the prognosis of patients with de novo mCSPC: An analysis on LATITUDE, SEER and NCDB.

27 Background: Little is known about the impact of race (Asian or White) on the long-term survival outcomes of men with de novo mCSPC treated with different methods. Understanding racial disparities in survival is critical for accurate prognostic risk stratification and for informing the design of multiregional clinical trials. Methods: This multiple-cohort study included individual patient-level data of men with de novo mCSPC from the following 3 cohorts: LATITUDE clinical trial data (LATITUDE [n=1199]); Surveillance, Epidemiology, and End Results (SEER [n=5496]); and the National Cancer Database (NCDB [n=10366]). Key efficacy outcomes were overall survival (OS) in LATTITUDE and NCDB as well as OS and cancer-specific survival (CSS) in SEER. Kaplan-Meier analysis with propensity score matching (PSM) was used for survival analysis. Hazard ratios were calculated using a multivariate Cox proportional-hazard model. Results: Across all three cohorts, Asian patients diagnosed with de novo mCSPC had better OS and CSS than White patients. In LATITUDE, median OS was significantly longer in Asian than in White men in the ADT+Abiraterone+Prednisone group (not reached vs. 43.8 months, HR 0.47, 95%CI 0.28–0.77, P=0.003 for Cox analysis) as well as in the ADT+placebo group (57.6 months vs. 32.7 months, HR 0.49, 95%CI 0.32–0.75, P=0.001 for cox analysis). In SEER, among all patients diagnosed with de novo mCSPC, median OS was significantly longer in Asian than in White men (53 months vs. 42 months, HR 0.76, 95%CI 0.68–0.85, P&lt;0.001 for Cox analysis). When analyses were restricted to patients who received chemotherapy, Asian men again had longer OS (67 months vs. 41 months, HR 0.70 95% CI 0.51–0.95, P=0.02 for Cox analysis). Using CSS data in SEER resulted in similar conclusions as OS. In NCDB, Asians also had longer OS than White men (whole cohort: 38 months vs. 26 months, HR 0.73, 95%CI 0.63–0.84, P=0.02 for Cox analysis; ADT subgroup: 41 months vs. 26 months, HR 0.75, 95%CI 0.63–0.89, P&lt;0.001 for Cox analysis; Chemotherapy subgroup: 34 months vs. 27 months, HR 0.80, 95%CI 0.69–0.94, P=0.005 for Cox analysis). Conclusions: Asian men had better OS and CSS than White men with mCSPC across different treatment regimens in all datasets examined and should be considered as an independent prognostic factor. This racial difference should also be considered when designing multiregional clinical trials. Further studies including biological analyses are needed to understand the etiology of the apparent survival advantage for Asian men. [Table: see text]

Random intercept hierarchical linear model for multi-regional clinical trials

ABSTRACT In multi-regional clinical trials, hierarchical linear models have been actively studied because they can reflect that patients in the same region share common intrinsic and extrinsic factors. In this paper, we investigate the statistical properties of the hierarchical linear model including a random effect in the intercept. The big advantage of the random intercept hierarchical linear model is that it can control the type I error rates of testing the overall treatment effect when there are no or clinically negligible regional differences in the treatment effect. Moreover, we compare the pros and cons with the hierarchical linear model in which the random effect is included in the slope. For the two hierarchical linear models, the model selection criteria are determined according to the magnitude of the difference in treatment effect across the regions, and we provide the criteria through simulation studies.

Bayesian design of multi-regional clinical trials with time-to-event endpoints.

Sponsors often rely on multi-regional clinical trials (MRCTs) to introduce new treatments more rapidly into the global market. Many commonly used statistical methods do not account for regional differences, and small regional sample sizes frequently result in lower estimation quality of region-specific treatment effects. The International Council for Harmonization E17 guidelines suggest consideration of methods that allow for information borrowing across regions to improve estimation. In response to these guidelines, we develop a novel methodology to estimate global and region-specific treatment effects from MRCTs with time-to-event endpoints using Bayesian model averaging (BMA). This approach accounts for the possibility of heterogeneous treatment effects between regions, and we discuss how to assess the consistency of these effects using posterior model probabilities. We obtain posterior samples of the treatment effects using a Laplace approximation, and we show through simulation studies that the proposed modeling approach estimates region-specific treatment effects with lower mean squared error than a Cox proportional hazards model while resulting in a similar rejection rate of the global treatment effect. We then apply the BMA approach to data from the LEADER trial, an MRCT designed to evaluate the cardiovascular safety of an anti-diabetictreatment.

Regional efficacy evaluation in multi-regional clinical trials using a discounting factor weighted Z test.

Multi-regional clinical trial (MRCT) is an efficient design to accelerate drug approval globally. Once the global efficacy of test drug is demonstrated, each local regulatory agency is required to prove effectiveness of test drug in their own population. Meanwhile, the ICH E5/E17 guideline recommends using data from other regions to help evaluate regional drug efficacy. However, one of the most challenges is how to manage to bridge data among multiple regions in an MRCT since various intrinsic and extrinsic factors exist among the participating regions. Furthermore, it is critical for a local agency to determine the proportion of information borrowing from other regions given the ethnic differences between target region and non-target regions. To address these issues, we propose a discounting factor weighted Z statistic to adaptively borrow information from non-target regions. In this weighted Z statistic, the weight is derived from a discounting factor in which the discounting factor denotes the proportion of information borrowing from non-target regions. We consider three ways to construct discounting factors based on the degree of congruency between target and non-target regions either using control group data, or treatment group data, or all data. We use the calibrated power prior to construct discounting factor based on scaled Kolmogorov-Smirnov statistic. Comprehensive simulation studies show that our method has desirable operating characteristics. Two examples are used to illustrate the applications of our proposed approach.