1. Data Monitoring Models and Adaptive Designs: Some Regulatory Experiences Sue-Jane Wang, Ph.D. Associate Director for Adaptive Design and Pharmacogenomics, Office of Biostatistics Office of Translational Sciences, CDER, U.S. Food and Drug Administration Presented at DIA China in Data Monitoring and Adaptive Designs: Is China Ready? May 17, 2011 | Beijin, China

2. Wang SJ, May 17, 2011, DIAChina2 The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to Drug Information Association, Inc. (“DIA”), its directors, officers, employees, volunteers, members, chapters, councils, Special Interest Area Communities or affiliates, or any organization with which the presenter is employed or affiliated. These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws of the United States of America and other countries. Used by permission only. All rights reserved. The professional views presented here are those of the author and not necessarily those of the U.S. Food and Drug Administration. Drug Information Association, DIA and DIA logo are registered trademarks or trademarks of Drug Information Association Inc. All other trademarks are the property of their respective owners. Disclaimers

3. Wang SJ, May 17, 2011, DIAChina3 OUTLINE 3 Adaptive Design Consideration Monitoring trial conduct / trial integrity Monitoring adaptive process Concluding Remarks

4. Wang SJ, May 17, 2011, DIAChina4 Adaptive Design Prospectively planned opportunity for modification of one or more specified aspects of the study design and hypotheses based on analysis of data (usually interim data) from subjects in the study Analysis of the accumulating study data are performed at prospectively planned time-points within the study Analyses can be performed in a fully blinded manner or in an unblinded manner, and can occur with or without formal statistical hypothesis testing

5. Wang SJ, May 17, 2011, DIAChina5 Adaptive Designed Clinical Trials 5 Early Stages Early tolerability Early drug activity Early safety/tolerability signal

6. Wang SJ, May 17, 2011, DIAChina6 Adaptive Designed Clinical Trials 6 Mid to Later Stages Dose response Short term trial Long term trial

7. Wang SJ, May 17, 2011, DIAChina7 Over-arching principles “The well-being of trial participants takes precedence over societal interests” – The World Medical Association Declaration of Helsinki

8. Wang SJ, May 17, 2011, DIAChina8 Adaptive Designed Clinical Trials 8 How to maintain Validity of the trial results Integrity of the trial being implemented Applicable to both fixed design trial and adaptive design trial More complex with adaptive design trial

9. Wang SJ, May 17, 2011, DIAChina9 Adaptive Design – Validity – Pre-specification of possible modification of design elements – Statistical methods that yield a valid false positive error control for regulatory consideration (ICH E9) – A valid point estimate and CI that is consistent with the proposed test method in assessment of treatment effect Some principles

10. Wang SJ, May 17, 2011, DIAChina10 In addition to overall false positive-error control, for scientifically interpretable AD results, potential sources of bias need to be minimized by maintaining trial integrity on – Trial conduct – Trial logistics – Trial operation * May consider sub-structure of DMC for AD * Plan double-blinded study whenever possible Adaptive Design – Integrity

11. Wang SJ, May 17, 2011, DIAChina11 Data Monitoring Committee (DMC) Current Practice: A Formal Committee in GSD u Safety monitoring required by a formal committee WHEN u Safety concerns are unusually high u In general, study is large, of long duration, multi-center u Is DMC review practical in small trials, short term trials ? u Will a DMC help assure the scientific validity of trial ? u Who are unblinded parties u Who makes changes in an ongoing trial if there is a need u Will changes impair the credibility of study results?

12. Wang SJ, May 17, 2011, DIAChina12 u External changes may prompt an interest in modifying some aspects of the trial as it progresses u Sometimes accumulating data from within the trial may suggest the need for modification u Recommendations to change the inclusion criteria, the trial endpoints, or the size of the trial are best made by those w/o knowledge of the accumulating data u Even aggregate data on safety and efficacy may be informative, these data may be needed for some trial management functions The DMC Has Been a GSD Framework “Possibility of Adaptations” by Blinded Party

13. Wang SJ, May 17, 2011, DIAChina13 u Setup firewalls to ensure those proposing interim protocol changes based on external data are insulated from knowledge of interim comparative results u Regulatory staff generally remain blinded to interim unblined results Unblinded interim data Interim Protocol Changes

14. Wang SJ, May 17, 2011, DIAChina14 Adaptive Design of Wider Interests u Study hypotheses may be a moving target u May use biomarker for adaptive selection u Interim analysis may be blinded or unblinded u Adapt mainly from internal accumulating study data that are pre-specified u Often safety at DMC’s discretion u May drop for partial futility or terminate for full futility u Seamless between stages

15. Wang SJ, May 17, 2011, DIAChina15 Objectivity Independence Wang et al. (2011, European Neuropsychopharmacology Journal)

16. Wang SJ, May 17, 2011, DIAChina16 Key components for a successful Adaptive Design Trial

17. Wang SJ, May 17, 2011, DIAChina17 Challenges with Adaptive Monitoring u Balancing Adaptive Rules Against Safety Monitoring u Adaptive Rules u Allocation, sampling, stopping, decision u Pre-specified with limited flexibility in confirmatory trials u Chosen rules may not be ‘medically or scientifically sound’ u This is of less concern in exploratory trials u Safety Monitoring u Control of objectivity with adapting multiple (global) nulls to just a few or single nulls for final analysis u When DMC overrules

18. Concluding Remarks u Prospective adaptive scenario planning to mimic the possible adaptive monitoring scenarios u An established infrastructure for adaptive monitoring and/or adaptive decision making u Documentation on “How adaptive designs were implemented in real time including the resulting trial conduct, interim analyses, changes, etc.” could help address the issues on biases due to adaptation u Legal consequence of confidentiality agreement ? u More research and experiences are needed Wang SJ, May 17, 2011, DIAChina18