Clinical Trials

Clinical Trials: A Practical Guide ■❚❙❘assurance purposes. It depends on the degree of severity of the condition beingtreated, the toxicity level of the investigational intervention, and the duration ofthe enrollment and follow-up periods. If the enrollment and follow-up periods aretoo short, then interim monitoring for efficacy endpoints will not be usefulbecause the study will be completed before any decisions are made on the basis ofthis monitoring.For every trial, the amount of interim monitoring should be determined as a resultof discussions between the investigators, the sponsors, and the regulatory bodies.Monitoring may occur at regular time periods during the recruitment and followupstages, or during enrollment on reaching certain proportions of targetrecruitment (eg, 25% of target, 50% of target). These discussions should alsofocus on whether an independent data and safety monitoring board (DSMB)needs to be formed. The US Food and Drug Administration is currently draftingDSMB guidelines, and these have been discussed previously.What procedures are used for interim monitoring?The first step is to determine the level of monitoring – that is, in addition tomonitoring for safety, deciding whether to monitor for efficacy, futility, orsecondary endpoints. The second step is to decide whether the monitoring will bedone by the trial investigators or by an independent DSMB. The monitoringgroup then decides how frequently to meet and what data should be collectedfor discussion.The DSMB can be treatment-blinded or be made aware of treatment allocation,but always has to maintain complete confidentiality. Ususally, only the statisticianworking with the DSMB has access to the treatment codes.As an example, consider a pivotal trial that is designed to compare a new drugtherapy with placebo and that has an accrual period of 3 years, a follow-up periodof 5 years, and survival as the primary endpoint. Due to the length and pivotalnature of the trial, an independent DSMB would be involved. The DSMB mightdecide to monitor laboratory measurements and adverse event reports to gaugesafety, and monitor survival rates in order to gauge efficacy and futility. TheDSMB might then decide to meet every 6 months from the start of accrual tomonitor for safety, and once every year to monitor for efficacy and futility.355