1. Analysis of Clinical Trials with Multiple Outcomes Changchun Xie, PhD Assistant Professor of Biostatistics Division of Biostatistics and Bioinformatics Department of Environmental Health University of Cincinnati Phone: (513)558-0229 email: xiecn@ucmail.uc.eduxiecn@ucmail.uc.edu

2. Appetizer/Quiz: Case 1 An investigator got a P-value=0.04 from one test of treatment effect with one outcome. To support his/her original hypothesis, he/she tested the treatment effect for another related outcome and got P-value=0.03. Do we need to adjust for multiple testing?

3. Case 2 With the same data, the investigator has two hypotheses for the same two outcomes. He/she used the same two statistical tests and got the same P-values. Do we need to adjust for multiple testing?

4. Outline Introduction: clinical trials Multiple outcomes in clinical trials with different objectives Multiple testing Conclusion and discussion

5. Introduction Define target patient population by using inclusion and exclusion criteria– providing a homogeneous sample The criteria help in reducing bias and variability and increase statistical power The more criteria that are imposed, the smaller the target patient population will be---more homogeneous, but it may cause difficulties in patient recruitment and limitations in generalization of the findings of the study.

6. Phases Preclinical: testing drug in non-human subjects Phase I Phase II Phase III Phase IV

7. Phase I: Phase I trials are the first stage of testing in human subjects. Normally, a small group of 20–80 healthy volunteers will be recruited. This phase is designed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of a drug. Phase I trials also normally include dose- ranging, also called dose escalation studies, so that the best and safest dose can be found and to discover the point at which a compound is too poisonous to administer.

8. Phase II: Once a dose or range of doses is determined, the next goal is to evaluate whether the drug has any biological activity or effect. Phase II trials are performed on larger groups (100-300) and are designed to assess how well the drug works, as well as to continue Phase I safety assessments in a larger group of volunteers and patients.

9. Phase III: Phase III studies are randomized controlled multicenter trials on large patient groups (300–3,000 or more depending upon the disease/medical condition studied) and are aimed at being the definitive assessment of how effective the drug is, in comparison with current 'gold standard' treatment.

10. Phase IV: Phase IV trial is also known as postmarketing surveillance Trial. It is designed to detect any rare or long-term adverse effects over a much larger patient population and longer time period than was possible during the Phase I-III clinical trials. Harmful effects discovered by Phase IV trials may result in a drug being no longer sold, or restricted to certain uses.

11. Blinding Although the concept of randomization is to prevent bias from a statistically sound assessment of the study drug. It does not guarantee that there will be no bias caused by subjective judgment in reporting evaluation data processing and statistical analysis due to the knowledge of the identity of the treatments Blinding: no one involved with the trial knows what treatment was given to the trial participant.

12. Data and Safety Monitoring Board (DSMB) The DSMB is a group (typically 3 to 7 members) who are independent of the company sponsoring the trial. At least one DSMB member will be a statistician. The DSMB will meet at predetermined intervals (three to six months typically) and review unblinded results. The DSMB has the power to recommend termination of the study based on the evaluation of these results. There are typically three reasons a DSMB might recommend termination of the study: safety concerns, outstanding benefit, and futility.

13. Patient compliance Medication compliance is the act of taking medication on schedule or taking medication as prescribed intention-to-treat (ITT) analysis is based on the initial treatment assignment and not on the treatment eventually received. (for efficacy not safety)

14. Multiple outcomes in clinical trials with different objectives To obtain better knowledge of a treatment effect in a clinical trial, many medically related outcomes are often collected.

15. All or None Approach The primary objective is defined as the simultaneous improvement in multiple endpoints For several disorders including migraine, Alzheimer’s disease and osteoarthritis, regulatory agencies have required a treatment to demonstrate statistically significant effect on all multiple endpoints, each at level α.

16. No multiplicity adjustment is necessary (high power?) This approach is very conservative since it requires that all hypothesis must be rejected at level α.

17. Global Approach

18. Composite Outcomes Composite Outcomes/Endpoints: combine multiple events as one event using the first time of any the component event as the new event time. For example, Death/myocardial infarction(MI)/Stroke, the new event time= min(death time, MI time, Stroke time)

19. Why to use a composite endpoint Decrease in sample size required to show effects (increase the event rate) Assessment of the “net” effect of an intervention: (net benefit=benefit-harmful effect)

20. Avoid bias in the assessment of an effect in presence of competing risks: The possible of bias due to competing risks arises in situations in which the occurrence of an event decrease the probability of another event of interest occurring.

21. Problems A positive effect is found for a composite endpoint, but this effect is due mainly to a component of less clinical significance, whereas the effect of component of more clinical significance is null or even negative. The biggest risk of using the composite endpoints is that they exaggerate the real benefit of the intervention

22. Problems If the decision to stop a trial early is based on the monitoring of a composite endpoint, particularly if this is driven by the least patient-important endpoint. Such an approach may lead to overestimation of the benefit and underestimation of the risk.

23. Heterogeneity of components Relative clinical significance Size of effect Frequency of events

24. Examples

25. At-least-one Approach The primary objective is to detect at least one significant effect (the trial is declared positive if the treatment effect for at least one endpoint is significant) Multiple endpoint problem becomes multiple testing problem

26. Introduction to Multiple Testing not rejected rejected Total True H 0 UVm0m0 True H 1 TSm1m1 Totalm-RRm

27. Why do we need to adjust for multiple testing

28. Error Rate control Family-wise Error Rate FWER=P(V  1) False Discovery Rate FDR=E(V/R|R>0)P(R>0) When m0=m, FDR is equivalent to FWER When m0<m, FDR≤FWER.

29. FDR is not suitable for multiple endpoint problem in clinical trials FDR is suitable for testing a large number of hypotheses in exploratory studies, in which a less stringent error control is acceptable. But tests for multiple endpoints in clinical trial are generally confirmatory for drug approval.

30. Multiple endpoints in clinical trial might have logical restrictions and decision rules. FDR is not designed to handle such complex logical restrictions and decision rules.

31. Bonferroni Correction Adjusting individual testing significance level to be α/m ---- does not require the tests are independent ---- can be conservative if tests are correlated ---- equally weighted tests

32. Fixed Sequence (FS)

33. More Methods Weighted Bonferroni Bonferroni Fix Sequence Weighted Holm

34. WMTCc method is for multiple continuous correlated endpoints. Does it still keep its advantages when correlated binary endpoints are used?

35. Survival Data For continuous data or binary data, the correlation matrix can be directly estimated from the corresponding correlated endpoints It is challenging to directly estimate the correlation matrix from the multiple endpoints in survival data since censoring is involved

36. Accepted as a chapter by the book, Innovative Statistical Methods for Public Health Data

37. Conclusion and discussion No multiple testing adjustment is necessary if a) All or none approach b) Global approach c) Composite outcome approach Multiple testing adjustment is needed if At-least-one Approach Use FWER control instead of FDR Considering correlation among multiple endpoints might increase study power

38. Thanks