_______________________________ DSBS 30th May 2006, Annual Meeting _____________________________________ DMC – how and what should they evaluate? _______________________________ Bjarne Nielsen, Vice President Biometrics

DMC – Data Monitoring Committees General info Medicon is involved in DMCs for several clients and have a special group dedicated to DMC tasks. Medicon is involved either as a member of the DMC or as external statistician to perform statistical analysis for the DMC, keeping the client blinded for the trial. Medicon is at the moment involved in 12 DMC worldwide. 11-01-2019

DMC Group – staff at Medicon Bjarne Nielsen, MSc Statistics Vice President Biometrics Martin Eeg, MSc Statistics Senior Biostatistician Peter Meisels, MSc Statistics Senior Biostatistician Allan Prang, MSc Biology Senior Statistical Programmer Tony Awwad, MSc Economy Statistical Programmer Rita Schou, Executive Assistant Jesper Nelby Kristiansen, MSc Biology Senior Data Manager 11-01-2019

DMC – Data Monitoring Committees Typical Procedures An Independent experienced DMC is selected and a Charter is produced with input from DMC and protocol input is made. Open and closed sessions are prepared, a SAP is made showing deliverables (data packages) and timelines. A face-to-face meeting is held. During the trial, telecons or web-conf are held. The DMC receives data packages typically 3-5 working days after Medicon receives interim data. DMC requests additional or revised analyses or data presentations. 11-01-2019

Typical Procedures, continued DMC Data Handling Typical Procedures, continued Data sources: We receive data from various sources, e.g. Laboratories, Safety departments, Event committees, Study database, ECG readings, Fax forms. Timelines: Typically, we deliver the data package 3-5 days after receipt of (unclean) data. Web site: MUDA – Medicon Upload & Download Area. For easy exchange of information between DMC members. Personal Username and Password required in order to gain access to this site. 11-01-2019

DMC – Data Monitoring Committees What should the DMC do? – apart from recommending to either continue or stop the trial Ensure patient safety, Ensure patient safety, Ensure patient safety. Evaluate safety data and compare to control and/or expectations. Evaluate whether the conduct of the trial and the data quality are sufficient to make recommendations and ensure that ”patients are not waisted” on inconclusive trials due to sloppyness. Evaluate safety in relation to risk/benefit – requires often efficacy considerations, Ensure patient safety. 11-01-2019

DMC – Data Monitoring Committees What should the DMC do? – Evaluate safety Evaluate AEs and SAEs, critical events etc – often on a case-by-case basis. Evaluate other safety data like ECGs, laboratory data or mortality. Evaluate dose effects on the above mentioned data. How should they do that? Review data overview (descriptive summary tables and plots and stat.tests). Review case data. Use statistical stopping rules as guidance. Look for expected as well as unexpected findings. Look for trends, e.g across dose groups – even across trials!! 11-01-2019

DMC – Data Monitoring Committees What should the DMC do? – Data quality and study procedures Review data, missing data patterns and magnitude. Review study procedure appropriateness, e.g. randomisation bias, bias in censoring or sloppyness on crucial data collection points. Ensure comparabililty of data – issues relevant also in final reporting. 11-01-2019

DMC – Data Monitoring Committees What should the DMC do? – Risk / benefit evaluation Not sample size adjustment in order to reach efficacy conclusion. Basis for evaluation of risk, taking the benefit into account – requires hard endpoint data on efficacy – which may only be partly available – e.g. long time mortality measures. Often an issue for discussion. 11-01-2019

DMC – Data Monitoring Committees Conclusion A DMC must ensure patient safety Meet and discuss up front Find experienced members Plan, but be prepared for changes 11-01-2019

For further information on Medicon, please contact: Contact Details For further information on Medicon, please contact: Bjarne Nielsen, MSc Statistics Vice President, Biometrics Medicon Biometrics Datavej 24 P.O. Box 130 DK-3460 Birkerød Denmark Phone: + 45 4567 2278 Fax: + 45 7022 1571 e-mail: bn@medicon.dk www.medicon.dk 11-01-2019