Planning and monitoring of placebo-controlled survival trials: comparison of the triangular test with usual interim analyses methods.
OBJECTIVE
For ethical and economic reasons, interim analysis of phase III clinical trials is essential. This study was conducted to compare the efficiency of two interim analysis procedures, which could be used to allow early termination of a clinical trial.


METHODS
We made a post hoc application of two interim analysis methods (Lan & DeMets with O'Brien-Flemming modification, and the triangular test according to Whitehead) by using individual patient data from four published placebo-controlled survival trials. We determined the date the trial would have been stopped had each method been used, and we estimated consequent results in terms of events and patient numbers included in the trial, the duration of the trial, and on treatment effect.


RESULTS
The triangular test provided the lowest number of events required to reach a conclusion of the trials while providing an accurate estimate of experimental treatment effects. The triangular test thus indicated the smallest number of patients that would have been enrolled, and the shortest trial duration. The difference between the methods was most important with a detrimental effect of experimental treatment: the number of required events was reduced by 75% and the trial duration was shortened by 48% with the triangular test compared to the Lan & DeMets method.


CONCLUSIONS
Stopping a trial early must depend on the clinical context. It is most important to stop a placebo-controlled trial as soon as possible when the experimental treatment can be shown deleterious. In such a situation the triangular test is more appropriate than the Lan & DeMets method. When a treatment effect is no different from, or better than, placebo the triangular test is also superior but the importance of premature termination of the trial in such cases has to be balanced against the inevitable reduction of information that the trial can provide.
Hulot
Jean-Sébastien
JS
Pharmacology Department, Pitié-Salpêtrière Hospital, Paris, France, Clinical Pharmacology Unit, Lyon Hospitals, Lyons, France. jean-sebastien.hulot@psl.ap-hop-paris.fr
Cucherat
Michel
M
Charlesworth
Andrew
A
Van Veldhuisen
Dirk J
DJ
Corvol
Jean-Christophe
JC
Mallet
Alain
A
Boissel
Jean-Pierre
JP
Hampton
John
J
Lechat
Philippe
P
D017326:Clinical Trials, Phase III as Topic / Q000379:methods*; D018849:Controlled Clinical Trials as Topic / Q000379:methods*; D003627:Data Interpretation, Statistical; D015201:Meta-Analysis as Topic