Clinical Trials

❘❙❚■ Chapter 1 | Randomized Clinical TrialsInterim monitoringIn the CHARM program, the assignment code of randomly assigned patientswas held at an independent statistical center and an independent data andsafety monitoring board (DSMB) was established to oversee the safety of patientsenrolled in the trial and to monitor trial progress [20]. It had access to all datathrough the independent statistical center. Predefined stopping rules for efficacyor safety concentrated on mortality from the overall trial program(see Chapter 31) [13].A pharmaceutical company that has heavily invested in a trial has a considerableinterest in ensuring that the conduct of the trial does not jeopardize the likelihoodof a positive outcome of the trial, eg, that the drug of interest is safe andefficacious. The use of an independent statistical center and a DSMB makes thewhole process more transparent as these groups have patient safety as theirprimary concern. At predefined time points the existing data are thereforeanalyzed by the independent statistical center and the results are discussed withthe DSMB.The DSMB has to make sure that the new drug that patients are taking is notharmful. If, during the course of the trial, such evidence is found then the trial hasto stop (stopping for safety). This idea can also be turned around: if there is majorevidence for a beneficial effect of the new treatment before the planned end of thetrial then the trial also has to stop. This is called stopping for efficacy because thereis evidence of conclusive benefit of the treatment. Monitoring trial results isethically challenging and has to balance individual ethics with the long-terminterest in obtaining sufficient data [21].Final data analysisIntention-to-treat analysis means that outcomes of patients who were randomizedbut who subsequently discontinued or changed treatment are taken into accountas if they had finished the trial (see Chapter 22). This is a pragmatic realization ofthe view that at the time of treatment start we will never be sure whether a patientwill continue with that treatment. Hence, the intention-to-treat analysis reflectsthe general policy of using/prescribing the treatment in a given situation(ie, inclusion criteria).All analyses in the CHARM program were done by intention-to-treat, andP-values were two-sided (see Chapter 18). All time-to-event endpoints wereanalyzed with the log-rank test, stratified by three substudies and displayed onKaplan–Meier plots by treatment. The estimated hazard ratio from the Coxproportional hazards model was used to assess the size of treatment effect(candesartan against placebo) (see Chapter 21). In addition, a covariate-adjusted10