Natasa Rajicic, ScD July 31, 2019 Database lock to Data Safety Monitoring Board Meeting – More than a click of a button? - Adaptive Design IA Example- Natasa Rajicic, ScD July 31, 2019

Cytel’s Strategic Consulting we help solve the toughest problems Regulatory, clinical, medical & health policy experts, & quantitative strategists empower better decisions DRUG DEVELOPMENT BIOLOGICS GENERICS & BIOSIMILARS DEVICES & DIGITAL HEALTH FMCG REGULATORY, CLINICAL DEVELOPMENT STRATEGIES & PRODUCT QUALITY MARKET ACCESS & COMMERCIALIZATION QUANTITATIVE STRATEGIES PARTNERSHIPS TRAINING THOUGHT LEADERSHIP

DMC REPORTS ARE NOT STUDY REPORTS 1. Title page 2. Synopsis 3. Table of contents for the clinical study report 4. List of abbreviations and definition of terms 5. Ethics 6. Investigators and study administrative structure 7. Introduction 8. Study objectives 9. Investigational plan including Statistical Method 10. Study patients 11. Efficacy evaluation 12. Safety evaluation 13. Discussion and overall conclusions 14. Tables, Figures and Graphs Referred to but not included in the text 15. References 16. Appendices Appendix 16.1.1 Protocol and any protocol amendments Appendix 16.1.2 Sample CRF (unique pages only) Appendix 16.1.3 List of IECs/IRBs, information for volunteers, consent forms Appendix 16.1.4 List and description of investigators and other important staff, including brief (1-page) CVs Appendix 16.1.5 Signatures of the Principal Investigator and Sponsor’s medical officer Appendix 16.1.6 List of subjects receiving IMP from specific batches, if more than one batch was used Appendix 16.1.7 Randomisation scheme and codes Appendix 16.1.8 Audit certificates (if applicable) Appendix 16.1.9 Documentation of statistical methods Appendix 16.1.10 Documentation of inter-lab standardisation methods (if applicable) Appendix 16.1.11 Publications based on the study (if applicable) Appendix 16.1.12 Important publications referenced in the report (if applicable DMC REPORTS ARE NOT STUDY REPORTS JSM2019 natasa rajicic, ScD

DMC Reports Need to be COMPREHENSIVE COMPREHENSIBLE Include all potentially relevant information so that the DMC has full access to what it needs to monitor the trial Comprehensiveness not done on the expense of comprehensibility Reports should be carefully and intuitively organized, easily readable Therapeutic Innovation & Regulatory Science, 2017 JSM2019 natasa rajicic, ScD

Top Down Report Structure High-level overview Detailed summaries + Figures + Summary Tables Listings+ lengthy Tables Consider adding Executive Summary Aim at presenting data in similar formats eg. across all lab components, across all AE summaries, etc. Helps the DMC review many analyses quickly Put the lengthy tables and listings in Appendices – include references and make them easily accessible from the main text JSM2019 natasa rajicic, ScD

Interim Analysis Decision Tree JSM2019 natasa rajicic, ScD

Interim Analysis Process Flow START Cytel to validate primary analyses and unblinding CROy to generate all unblinded ADaMs p-value < 0.0046 p-value < 0.0046 CROy to generate outputs incl. primary endpt analysis Cytel to conduct SSR based on CP/PP in East and provide output to CROy CROy to prepare IA report for DMC /w support from Cytel CROy share primary endpt ADaMs w/ Cytel CROy and Cytel unblinded stats participated in DMC JSM2019 natasa rajicic, ScD

references Buhr, et al. Reports to Independent Data Monitoring Committees: An Appeal for Clarity, Completeness, and Comprehensibility. Therapeutic Innovation & Regulatory Science, 2017 ICH Harmonized Tripartite Guideline (E3). STRUCTURE AND CONTENT OF CLINICAL STUDY REPORTS. 1995 JSM2019 natasa rajicic, ScD

natasa.rajicic@cytel.com 31-Jul-2019 JSM 2019 DMC Panel