4. Outline of Talk I. Characteristics of Confirmatory Trials II. Factors Leading to Design Choice III. Examples of Confirmatory Trial Designs A. Parallel Trials B. Crossover Trials C. Dose Response Trials D. Factorial Trials E. Non-inferiority Trials F. Sequential Parallel Trial IV. Summary

5. Characteristics of Confirmatory Trials 1. Concurrent control – allows a direct comparison of a new drug. 2. Randomized – on average, ensures that groups being assessed are equal at baseline in both measured and unmeasured factors. 3. Blinded – controls bias (selection or measurement).

6. Factors Leading to Choice of a Design 1. What questions are you addressing? 2. What are the characteristics of the disease and the study population?

7. Differences in Clinical Trial Designs 1. Randomization structure (single treatment or sequence of treatments) 2. Treatment structure (dose response, factorial) 3. Hypothesis structure (superiority or non- inferiority) 4. Fixed Design versus Adaptive

8. When a patient is randomized to a one treatment from a set of treatments, the trial is said to be parallel. Placebo 6 weeks Depressed patients Drug In patients suffering from major depressive disorder, does treatment with drug significantly reduce symptoms compared to placebo?

9. ‘ Add-On’ Parallel Trial: Low Dose Aspirin + Placebo 12 months Patients w/ Acute Coronary Syndrome Low Dose Aspirin + Drug In patients suffering from acute coronary syndrome, does treatment with drug in combination with low dose aspirin significantly reduce coronary events (deaths, MI, stroke) after 12 months?

10. Randomized Withdrawal Design Depressed patients administered drug Patients still on drug after 6 months and who have responded Drug Placebo

11. Randomized Withdrawal Design In patients who have responded to drug and are still on drug after 6 months, does continuation of drug reduce the relapse rate compared to placebo? NOTE: Inference is on the population of patients who have responded to drug. Therefore, design is usually reserved for drugs which have proven acute efficacy.

12. Parallel Trials – patients randomized to a fixed treatment Another possibility is to allow patients to be randomized to a sequence of treatments. Drug -> Placebo or Placebo -> Drug This type of design is called a crossover trial. Feasible only if outcome is not irreversible.

13. Benefit of the Crossover Trial The test of the drug effect is based on within patient variability as opposed to across patient variability . The intrinsic variation within a patient is usually smaller than the variation from patient to patient Therefore Crossover trials need less patients to detect a signal than parallel trials.

14. ‘ Add-On’ Crossover Trial Placebo Drug Drug Placebo Washout Patients with epilepsy on anticonvulsant medication suffering > 2 seizures/week In this population of epileptic patients, does addition of drug significantly reduce seizure frequency compared to placebo?

15. Crossover Trials Most crossover trials are 2 x 2 (two treatments by two periods). One can have more sequences than groups (A B A, B A B)….. or one can have more treatments than sequences (incomplete block design). In all cases, the crossover design should only be implemented in diseases which are chronic and stable.

16. 2 x 2 Crossover Trials One must assume that the effect of treatment in the second period is not affected by what one received in the first period (carryover effect). Statistical tests for carryover effect are problematic Crossover trials are generally conducted only when there is considerable evidence that the drug has no carryover effect. Limited use in confirmatory trials.

17. Dose Response Trials Although dose response is examined in Phase II trials, it is usually also recommended that a range of doses be examined in confirmatory trials. Confirmatory trials usually have broader representation of patients Safety signals not apparent in smaller Phase II studies could show up in Phase III studies

18. Dose Response Trials Both crossover or parallel trials can be conducted; however crossover trials have potential issues due to longer duration and potential for carry-over effects. Parallel dose-response trials most common, usually includes a placebo in addition to multiple fixed doses. Parallel study gives population-averaged dose response.

19. Dose Response Trials Several possible questions are conceivable: 1. Is there a significant trend across doses? 2. Does the lowest dose tested have a significant effect compared to placebo? 3. Is there evidence of a significant dose response from an a priori assumed model?

20. Dose Response Curve DOSE

21. Adaptive Dose Response Trials Adaptive dose response trials are used in Phase II studies; could they also be used in confirmatory studies? The idea would be to start with a larger number of doses and adapt the allocation based on the response profile being generated from the data. Algorithm and drug dispensing would have to be totally automated.

22. Hypothetical Example of Adaptive Phase III Trial Interim Analysis Placebo Low Dose High Dose Chosen Dose Placebo

23. Adaptive Clinical Trials The class of possible adaptations must be in the protocol. Method for combining evidence across stages of the study must control Type I error. Test and estimation methods must be pre-specified. Discussion with regulatory agencies necessary. The goal of an adaptive clinical trial is to enhance the overall clinical development.

24. Factorial Clinical Trials Suppose a new drug will be used in combination with an existing drug. Factorial trials study a range of doses for each separate drug and some or all of the combinations of these doses. Simplest example: Drug 1: yes/no Drug 2: yes/no Four possible combinations of the two drugs

25. Factorial Clinical Trial Turner Syndrome girls 5-12 yrs old No Estrogen / No hGH No Estrogen / hGH Estrogen / No hGH Estrogen / hGH Final Height Interesting Fact - First Patient Visit: 1987, Last Patient Visit: 2003

27. Factorial Clinical Trial The question about consistency of hGH across estrogen/no estrogen measures what is called an interaction between the two drugs. Interaction has implications: Absence of interaction indicates the statistical significance of hGH depends on total sample sizes of hGH versus no hGH patients. Presence of interaction indicates the significance of hGH may need to be assessed at each level of estrogen.

28. Active Control Trial In previous examples, placebo was the control group. It is not possible to run a placebo controlled trial in many disease areas (e. g. oncology). Trials are run with an active compound as the control. If the goal is to demonstrate superior efficacy to the active compound, then no new philosophical issues are introduced.

29. Non-Inferiority Trial If the goal is to show is to show some efficacy (but not necessarily superiority to an active control) by observing ‘similar’ efficacy to an active control, the trial is said to be a non-inferiority trial. Failure to show superiority does NOT imply that a drug is non-inferior to an active control.

30. Non-Inferiority Trials The appropriate question for non-inferiority trials is still controversial. Most non-inferiority trials are designed on a ‘fixed margin’ approach. Is the effect of the new treatment not worse than the active treatment by more than a pre-specified margin ( Δ ).

31. Non-Inferiority Trials – Fixed Margin Approach Consider the possible 95% Confidence Intervals on Difference - Δ 0 True Difference Between Treatments Non-inferiority shown Non-inferiority not shown Superiority shown

33. Problems with Placebo Controlled Design In some diseases (depression, anxiety), the failure rate of placebo controlled trials of active drugs is alarmingly high. Usually attributed to a high placebo rate. Can we modify the standard parallel trial to try and address this issue?

34. Sequential Parallel Clinical Trial - - Phase 1: Phase 2: Randomize Active Treatment Placebo Placebo Response No Response Response No Response Response No Response Active Treatment or Discontinue Active Treatment or Placebo Active Treatment or Discontinue Active Treatment Placebo or Discontinue Placebo

35. Sequential Parallel Design The goal is to enhance a signal by including a ‘second’ parallel trial with placebo non-responders Strictly speaking, rejection of the null hypothesis implies a drug difference in at least one of the phases. Currently at least six trials using this trial – results are still pending.

37. General Friedman, L. M., Furberg, C. D., DeMets, D. L., (1998). Fundamentals of Clinical Trials. York: Springer. Lewis, J. A. (1999). Statistical Principles for Clinical Trials (ICH E9) An Introductory Note on the International Guideline. Statistics in Medicine 18, 1903-1942. Temple, R. J. (2008). Oral Presentations Given to the University of North Carolina Department of Biostatistics on March 6, 2008. www.sph.unc.edu/bios/ Adaptive Trials Bretz, F., Koenig, F., Brannath, W., Glimm, E., Posch, M. (2009). Adaptive Designs for Confirmatory Clinical Trials. Statistics in Medicine 28, 1187-1217. Cross Over Trial Senn, S. J. (1993). Cross-Over Trials in Clinical Research. New York: Wiley. Factorial Trial Simon, R., Freedman, L.S. (1997). Bayesian Design and Analysis of 2 x 2 Factorial Clinical Trials. Biometrics 53, 456-464. Non-Inferiority Trial Snapinn, S., Jiang, Q. (2008). Preservation Of Effect and the Regulatory Approval of New Treatments on the Basis of Non-Inferiority Trials. Statistics in Medicine 10, 382-391. Sequential Parallel Trial Tamura, R. N., Huang, X. (2007). An Examination of the Efficiency of the Sequential Parallel Design in Psychiatric Clinical Trials. Clinical Trials 4, 309-317.