The conscientious judgement of a DSMB--statistical stopping rules re-examined.
OBJECTIVE
In the light of the recent failure of a large cardiovascular mortality and morbidity study with torcetrapib, we have undertaken a post hoc review of the decisions taken by the Data and Safety Monitoring Board (DSMB) in that study. A number of other studies in which complex decisions were made by DSMBs are also reviewed.


RESULTS
The examples illustrate the complexities involved in the decision-making process by DSMBs and indicate that too much reliance on formal statistical stopping rules should be avoided due to a risk of delaying the identification of an unacceptable emergent safety signal.


METHODS
The review was based on information submitted by the sponsors of the studies to the Medical Products Agency.


CONCLUSIONS
Multiple approaches to assessing the efficacy and safety in clinical trials need to be considered in order to facilitate early stopping of clinical trials with a negative risk benefit balance. Such systems may, for example, include the use of p-value flags and/or a complementary statistical analysis of the likelihood of achieving the study objective based on the data obtained to date.
Hedenmalm
Karin
K
Clinical Trial Unit, Medical Products Agency, Box 26, 751 03, Uppsala, Sweden. karin.hedenmalm@mpa.se
Melander
Hans
H
Alvan
Gunnar
G
D000924:Anticholesteremic Agents / Q000009:adverse effects; D002318:Cardiovascular Diseases / Q000401:mortality; D026661:Clinical Trials Data Monitoring Committees / Q000458:organization & administration*; D003627:Data Interpretation, Statistical; D003657:Decision Making; D006801:Humans; D011804:Quinolines / Q000009:adverse effects; D016032:Randomized Controlled Trials as Topic; D018570:Risk Assessment
D000924:Anticholesteremic Agents; D011804:Quinolines; C483909:torcetrapib