1. Ulla Lønberg – International Safety & Pharmacovigilance – H. Lundbeck A/S21-Feb-2007 Data Monitoring Committees

2. Ulla Lønberg – International Safety & Pharmacovigilance – H. Lundbeck A/S21-Feb-2007 What is it? =DSMB, IDMC, DRB, etc. EMEA guideline, Jan 2006 A group of independent experts external to a study assessing the progress, safety data and, if needed, critical endpoints of a clinical trials

3. Ulla Lønberg – International Safety & Pharmacovigilance – H. Lundbeck A/S21-Feb-2007 Power of DMC Contain experts (clinicians) in the therapeutic area in addition to research generalists + statistician Independent of sponsor Can unblind and analyse ALL data A DMC charter defines –Data to be looked at Recommendations to Sponsor on future conduct of the trial

4. Ulla Lønberg – International Safety & Pharmacovigilance – H. Lundbeck A/S21-Feb-2007 Why DMCs? Early detection of…. Harm to trial participants Benefit for trial participants Futility (non-superiority)

5. Ulla Lønberg – International Safety & Pharmacovigilance – H. Lundbeck A/S21-Feb-2007 How? Planned interim analyses for outcome variables: –Mortality –Morbidity –Effect / lack of effect Safety parameters –SAEs – but not necessarily each and every one –clinically significant trends in AEs

6. Ulla Lønberg – International Safety & Pharmacovigilance – H. Lundbeck A/S21-Feb-2007 What should be monitored by DMC? Endpoints (mortality/morbidity) Accuracy and timelines of incoming data Study recruitment – adequate? Protocol adherence

7. Ulla Lønberg – International Safety & Pharmacovigilance – H. Lundbeck A/S21-Feb-2007 Which sort of studies? Not all trials need DMCs! Any controlled trial that compare rates of mortality and major morbidity Studies in emergency situations where informed consent is waivered (coma) Studies in vulnerable populations (mental handicap, children) Risk of severe side-effects are high (chemo)

8. Ulla Lønberg – International Safety & Pharmacovigilance – H. Lundbeck A/S21-Feb-2007 Terms of reference and procedures (cioms VI) Confidentiality + communication Blinding /unblinding Presence/absence of sponsor Members should be independent of sponsor NB: Rules (charter) for monitoring the study should be made before the study starts

9. Ulla Lønberg – International Safety & Pharmacovigilance – H. Lundbeck A/S21-Feb-2007 Examples – US trial Newborns w. respiratory failure: Treatment: New Old p-value Deaths: 0/9 4/10 0,09 Trial stopped

10. Ulla Lønberg – International Safety & Pharmacovigilance – H. Lundbeck A/S21-Feb-2007 Subsequent trial - UK Treatment: New Old p-value Deaths: 30/93 54/92 0,0005 Ethics: individual vs. collective

11. Ulla Lønberg – International Safety & Pharmacovigilance – H. Lundbeck A/S21-Feb-2007 Lundbeck examples 1.Drug indicated for ischaemic stroke – monitoring effect on lab values 2.Drug indicated for schizophrenia - Monitoring hepatic events

12. Ulla Lønberg – International Safety & Pharmacovigilance – H. Lundbeck A/S21-Feb-2007 When to stop? Single primary outcome The more you look, the higher risk of false-positive result (type I error) (that new treatment is better) Sequence of planned interim analyses Pre-defined stopping rules based on p- values for treatment difference I.e: STOP trial at nth analysis if p< x Only DMC aware of interim results

13. Ulla Lønberg – International Safety & Pharmacovigilance – H. Lundbeck A/S21-Feb-2007 Stopping at which p-value? (cont’d) Premature stop: –Inadequate treatment may enter clinical practice –Insufficient evidence collected on effective treatments DMC can only advise sponsor to stop

14. Ulla Lønberg – International Safety & Pharmacovigilance – H. Lundbeck A/S21-Feb-2007 Summary DMCs useful and required in i.e. high- mortality studies Composed of qualified clinicians, research people, statistician Need to be independent of sponsor Predefined: what to monitor, when to monitor, stopping rules

15. Ulla Lønberg – International Safety & Pharmacovigilance – H. Lundbeck A/S21-Feb-2007 ¿QUESTIONS ? ?