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Multi-regional Clinical Trials Why be concerned ? A Regulatory Perspective on Issues. Robert T. O’Neill Ph.D. Director , Office of Biostatistics Office of Translational Sciences, CDER.
Robert T. O’Neill Ph.D.
Director , Office of Biostatistics
Office of Translational Sciences, CDER
To be presented at the 17th Annual Harvard Schering-Plough Workshop: Global Trials, Challenges and Opportunities ; May 28 and 29, 2009
Sources of measurement error variability that can contribute to variability in estimates of treatment effect / response
Auditing strategy vs. quality assurance strategy
Of 1,926 clinical trials analyzed by OB during FY01-FY07:41% were domestic; 50% foreign-domestic; and 9% foreign.Of all subjects enrolled in these trials:30% were U.S.; 63% domestic-foreign; and 7% foreign.
Of 1,926 trials analyzed by OB Statisticians during FY01-FY07:Trend toward increasing numbers in participation of non-U.S. centers and subjects in trial.
Estimates and confidence intervals for difference between US and Non-US treatment effects for each study
In 13 of 16 , US log hazard above 0
The trial was terminated early for a statistically significant reduction in all-cause mortality (34%, nominal p=0.00009). The risk of all-cause mortality plus all-cause hospitalization was reduced by 19% (p=0.00012). The trial also showed improvements in heart failure-related mortality and heart failure-related hospitalizations, and NYHA functional class.
The table below shows the principal results for the overall study population. The figure below illustrates principal results for a wide variety of subgroup comparisons, including US vs. non-US populations (the latter of which was not pre-specified). The combined endpoints of all-cause mortality plus all-cause hospitalization and of mortality plus heart failure hospitalization showed consistent effects in the overall study population and the subgroups, including women and the US population. However, in the US subgroup and women, overall mortality and cardiovascular mortality appeared less affected. Analyses of female and US patients were carried out because they each represented about 25% of the overall population. Nonetheless, subgroup analyses can be difficult to interpret and it is not known whether these represent true differences or chance effects.
From the label
Wedel, DeMets, Deedwania, Fagerberg, et al. Challenges of subgroup
analyses in multinational clinical trials: Experiences from
the MERIT-HF trial. Amer. Heart J 2001; 142: 502-11
Mark Levenson, Ph.D.
Statistical Safety Reviewer
Quantitative Safety and Pharmacoepidemiology Group Division of Biometrics 6/CDER/FDA
Joint Meeting of Peripheral and Central Nervous System Drugs Advisory Committee and Psychopharmacologic Drugs Advisory Committee
July 10, 2008
Risk lower in N A
K geographical regions
nh: sample size of region h
N = nh
yh | h N( h , 2/nh )
h ( , 2 )
Effect sizes vary but are all positive
Is meaningful, i.e., interpretable
for all regions? (Interaction ?)
If not, only h is applicable to region h. Then, the study will require a sufficient sample size for each region.
If is interpretable for each region, estimate by Y rhyh , ( rh=nh/N )
If, instead, = 0 is assumed for planning sample size, then the resulting sample size N0 may be too low. How low?
=0.025, =0.1, K=5, (r1 r2 r3 r4 r5)=(.2 .1 .4 .1 .2)