Regional differences in multinational clinical trials: anticipating chance variation

Abstract

Background Multinational clinical trials efficiently pool resources and provide treatment comparisons across diverse populations. However, they may be difficult to interpret when there are larger than expected differences in region-specific treatment effects, such as a positive study that includes regions favoring the control arm.

Purpose This article investigates the extent of chance variation that can be expected in regional treatment effects from multinational studies. It advocates studying this expected variation during the design stage, hence limiting the potential for surprises and misinterpretations at the end of the study.

Methods The theory of order statistics was used to quantify chance variation between regions, assuming a homogeneous treatment effect. The expected values of the smallest and largest treatment difference were used to calculate the expected range of regional effects. This range was supplemented by the probability of observing at least one regional effect favoring the control arm.

Results Chance variation led to a wide range of expected regional effects. For a study with five regions and 80% power, the expected regional treatment effects ranged from no difference to double the true difference, while the probability of observing a region favoring the control was approximately 50%. With 10 regions this probability exceeded 85% and the expected range of regional effects extended to values substantially favoring the control. Increasing the power of the study to 90% or more offered little protection against wide variation in regional effects.

Limitations The proposed approach does not replace heterogeneity testing at the end of the study, but provides useful supporting information for interpreting such tests.

Conclusions Large differences between regions should be anticipated in multinational studies. The expected range of treatment effects should be assessed during study design in order to inform stakeholders and calibrate expectations. Clinical Trials 2010; 7: 147—156. http://ctj.sagepub.com

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References

Snappin SM. Multinational (Global) trial. In D’Agostino R , Sullivan J , Massaro L. (eds). Wiley Encyclopedia of Clinical Trials. Wiley, New York, 2007, dx.doi.org/10.1002/9780471462422.eoct318.

Pocock S. Clinical Trials : A Practical Approach. Wiley, New York, 1983, pp. 134-5.

Wedel H. , DeMets D. , Deedwania P. , et al. Challenges of subgroup analyses in multinational clinical trials: experience from the MERIT-HF trial. Am Heart J 2001; 142: 502-11.

Chen F. , Chen Q. , Chen J. , Hsu J. Current statistical requirements for pharmaceutical clinical trials in China . Drug Inform J 2008; 42: 321-30.

Rothwell P. Subgroup analysis in randomised controlled trials: importance, indications and interpretation. Lancet 2005; 365: 176-86.

Cook I. , Gebski V. , Keech A. Subgroup analysis in clinical trials. In Keech A , Gebski V , Pike R. (eds). Interpreting and Reporting Clinical Trials. Australasian Medical Publishing Company, Sydney, 2007, pp. 105-113.

Wang R. , Lagakos S. , Ware J. , et al. Statistics in medicine - reporting of subgroup analyses in clinical trials. New Engl J Med 2007; 357: 2189-94.

Arnold B. , Balakrishnan N. , Nagaraja H. A First Course in Order Statistics. Wiley, New York, 1992.

R Development Core Team. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna. Available at: www.R-project.org

10.

MERIT-HF StudyGroup. Effect of metroprolol CR/XL in chronic heart failure: metroprolol CR/XL randomised intervention trial in congestive heart failure (MERIT-HF). Lancet 1999; 353: 2001-7.

11.

Marshall S. Power for tests of interaction: effects of increasing type I error rate. Epidem Persp Innov 2007 ; 4: 4-10.

12.

HERO-2 Trial Investigators. Thrombin-specific anticoagulation with bivalirudin versus heparin in patients receiving fibrinolytic therapy for acute myocardial infarction: the HERO-2 randomised trial. Lancet 2001; 358: 1855-63.

13.

Simes J. , White H. , Marschner I. , et al. International differences in patients care, and outcomes associated with acute myocardial infarction: the HERO-2 trial. J Am Coll Cardiol 2002; 39: 280A.