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

Ulla Lønberg – International Safety & Pharmacovigilance – H. Lundbeck A/S 21-Feb-2007

Data Monitoring Committees


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


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


Why DMCs?

Early detection of….• Harm to trial participants• Benefit for trial participants• Futility (non-superiority)


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


What should be monitored by DMC?

• Endpoints (mortality/morbidity)• Accuracy and timelines of incoming

data• Study recruitment – adequate?• Protocol adherence


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)


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


Examples – US trial

• Newborns w. respiratory failure:Treatment: New Old p-value

Deaths: 0/9 4/10 0,09

Trial stopped


Subsequent trial - UK

Treatment: New Old p-valueDeaths: 30/93 54/92 0,0005

Ethics: individual vs. collective


Lundbeck examples

1. Drug indicated for ischaemic stroke – monitoring effect on lab values

2. Drug indicated for schizophrenia - Monitoring hepatic events


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


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


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


¿QUESTIONS ?

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

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