Comments on Heterogeneity of Treatment Effects in Multinational Clinical Trials

Transcription

1 1 Kitasato-Harvard Symposium: Session 4 Discussion Comments on Heterogeneity of Treatment Effects in Multinational Clinical Trials Dr. Ian Marschner Director, Asia Biometrics Centre Pfizer, Australia

2 2 Heterogeneity of treatment effects Adaptive designs allowing the study of different treatment strategies in different countries/regions (James Hung) Analysis methodology to allow for more efficient estimation of each country s or region s individual treatment effect (Hajime Uno) New methodologies for studing non-inferiority (Daphne Lin) will be impacted by heterogeneity While methodology for dealing with differences between countries and regions is important, we also need to be careful not to over-interpret apparent differences

3 3 Chance can cause treatment differences Seemingly large variation in the observed treatment effects in different countries is expected even when there is no underlying difference in treatment effects between the countries Statistical tests of heterogeneity are crucial to a full understanding of treatment differences in multinational trials even if they are underpowered Multi-national trials can benefit from simulation of expected inter-country differences during the design stage and analysis plan preparation

4 4 Simulation study of country differences Typical Result Study simulation example 4000 patients in 20 countries with a control arm risk of 20% and an experimental arm risk of 15% (Homogenous absolute risk reduction of 5%)

5 5 Chance variation in treatment effects Smallest treatment effect (5 th 95 th percentile) Based on 10,000 simulations with no inter-country differences assuming superiority Largest treatment effect (5 th 95 th percentile) Treatment Effect (Absolute risk reduction %)

6 Chance variation in treatment effects Smallest treatment effect (5 th 95 th percentile) Based on 10,000 simulations with no inter-country differences assuming equivalence Largest treatment effect (5 th 95 th percentile) Treatment Effect (Absolute risk reduction %) 6

7 7 Key points Purely by chance, the observed experimental treatment effect in different countries can be expected to range from beneficial to apparently harmful In superiority trials it will often not be surprising if the experimental treatment does not seem to offer an advantage in some countries or regions In non-inferiority trials it will often not be surprising if the control therapy appears superior to the experimental therapy in some countries or regions Often chance will be just as likely an explanation for apparent differences between countries and regions as heterogeneity

8 8 Simulation Studies When we design studies we need to prepare ourselves for the extent of likely variation in treatment effects, rather than waiting until the end of the study and being surprised by the apparent variation New design and analysis methodologies, such as those discussed in this session, are important for accommodating heterogeneity of treatment effects in multinational trials In addition to methodologies for dealing with heterogeneity, simulation studies during the design stages of multi-national studies can be valuable for preparing investigators and regulators for the expected extent of inter-country differences in treatment effect in the absence of heterogeneity

9 Back-up slides 9

10 10 Case Study: HERO-2 Trial Thrombin-specific anticoagulation with bivalirudin versus heparin in patients receiving fibrinolytic therapy for acute myocardial infarction Lancet, 358, 2001: ,073 patients with acute MI (heart attack) 539 hospitals in 46 countries Outcomes: 30 day mortality 4 day reinfarction (second heart attack)

11 11 Treatment effect estimation: Mortality Heterogeneity P > 0.05 The most appropriate estimate of mortality treatment effect in Asia is a statistically insignificant odds ratio of 0.96 (combined analysis) not a statistically significant odds ratio of 0.54

12 12 Treatment effect estimation: Reinfarction Heterogeneity P > 0.05 The most appropriate estimate of reinfarction treatment effect in Russia is a statistically significant odds ratio of 0.70 not a statistically insignificant odds ratio of 0.85