Standard 3: Data Monitoring Committees DILEMMA AUTHORS: Susan Ellenberg, PhD,a Ricardo M. Fernandes, MD,b Haroon Saloojee, MD, MBBCh, FCPaed,c Dirk Bassler, Children are generally regarded as “vulnerable individuals.” There has MD, MSC,d Lisa Askie, PhD, MPH, BN, NICC, RM, RN,e Ben long been reluctance to perform research in children except in limited Vandermeer, MSc,f Martin Offringa, MD, PhD,g Ingeborg settings such as pediatric cancer and vaccine development. However, Van der Tweel, PhD,h Douglas G. Altman, DSc,i and Johanna avoidance of trials in children has resulted in uncertainty regarding H. van der Lee, MD, PhD,j for the StaR Child Health Group efficacy, safety, appropriate formulations, and dosages of treatments in aDepartment of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; 1 pediatric populations, a situation now recognized as problematic. As bDepartment of Pediatrics, Santa Maria Hospital, Laboratory more pediatric clinical trials are undertaken, it is timely to focus on of Clinical Pharmacology and Therapeutics, Faculty of Medicine, special issues in their design and conduct. One such issue is the Instituto de Medicina Molecular, Lisboa, Portugal; cDepartment monitoring of accumulating data from ongoing clinical trials. of Paediatrics and Child Health, University of the Witwatersrand, Johannesburg, South Africa; dCenter for Pediatric Clinical Studies Monitoring of safety outcomes during any trial is always required. In and Department of Neonatology, University Children’s Hospital, some trials, monitoring for efficacy is also an essential component of Tuebingen, Germany; eNHMRC Clinical Trials Centre, Sydney, f fi Australia; Department of Pediatrics, Alberta Research Centre for safety assurance, such as when ef cacy is measured based on an un- Health Evidence, University of Alberta, Edmonton, Alberta, favorable outcome or if a treatment is quickly discovered to be a major Canada; gChild Health Evaluative Sciences, Research Institute, The advance in terms of saving lives or preventing another serious outcome. Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; hJulius Center for Health Sciences and Primary Care, Inmanycases,monitoringcanbeperformedadequatelybyinvestigators University Medical Center, Utrecht, Netherlands; iCentre for and sponsors. However, for some trials, a group of independent experts, Statistics in Medicine, University of Oxford, Oxford, United typically called a data monitoring committee (DMC) or data and safety Kingdom; and jDepartment of Pediatric Clinical Epidemiology, ’ monitoring board, takes responsibility for this function. Emma Childrens Hospital, Academic Medical Centre, Amsterdam, Netherlands DMCs have been a component of certain clinical trials beginning in the KEY WORDS 1960s. Initially used in trials funded by government agencies in which the data monitoring committee, DMC charter, DMC reporting, trial objective was to decrease mortality and/or reduce major morbidity, pediatric, StaR Child Health the DMC’s tasks were to carefully monitor the accruing results to ensure ABBREVIATION — that continued enrollment remained appropriate, to consider whether DMC data monitoring committee modifications of trial conduct were needed, and to make recom- Drs Ellenberg, Van Der Tweel, and van der Lee wrote the first draft of the article; Drs Fernandes, Saloojee, Bassler, Askie, mendations to the researchers regarding continuation of the trial with Vandermeer, Offringa, and Altman contributed to the writing of or without changes.2 It was recognized that there were problems with the article; Drs Ellenberg, Fernandes, Saloojee, Bassler, Askie, having the investigators themselves perform this interim monitoring Vandermeer, Van der Tweel, and van der Lee participated in regular meetings and conference calls, identified the issues, and because their approach to recruitment and their adherence to the trial drafted the manuscript; Drs Ellenberg, Fernandes, Saloojee, protocol could be influenced by their knowledge of interim data.3,4 Bassler, Askie, Vandermeer, Van der Tweel, Altman, and van der Clearly,individualsororganizationswithfinancialintereststhatcouldbe Lee participated in identifying the evidence base for StaR Child Health standards; and Drs Ellenberg, Fernandes, Saloojee, affected by the trial results would also not be optimal overseers of the Bassler, Askie, Vandermeer, Offringa, Van der Tweel, Altman, and emergingdata. Thus, bothinvestigators andindividuals ororganizations van der Lee agree with the final version. with financial interests would have a “conflict of interest” when mon- itoring a trial. The current understanding is that a DMC is a committee (Continued on last page) of experts who are independent of the trial and who can be expected to make recommendations regarding the conduct of the trial on the basis of emerging data, while minimizing unwanted influences on their judg- ment.5 The role of the DMC is complementary to trial sponsors (ie, the company or institution that initiates the trial and is ultimately responsible for it), institutional review boards, and trial steering committees. Despite substantial attention to the operational issues for DMCs over the last 20 years5,6 and general consensus on the basic principles of monitoring, there remains variation in how these committees operate,7 and there are special issues in pediatric trials that require particular S132 ELLENBERG et al Downloaded from www.aappublications.org/news by guest on September 28, 2021 SUPPLEMENT ARTICLE consideration. The following sections of benefitsoftheexperimentalintervention TABLE 2 Trial Characteristics That Generally this standards article address princi- can be carefully balanced against po- Necessitate a DMC in Pediatric Populations ples and practices of DMCs with special tential risks. The installation of a DMC Clinical criteria attention to their application in pediatric may be particularly important when the • Trials investigating new interventions with few confirmatory (Phase III) trials. Recom- intervention is novel and previous safety safety data available mendations for practice are summarized data are limited, such as in the early • Trials addressing major morbidity or mortality end points in Table 1. trials on therapeutic cooling for ence- • High-risk populations phalopathy.8,9 Even for an intervention Methodologic criteria GUIDANCE not likely to influence mortality or seri- • Planned interim analyses with the possibility of ous morbidity, a trial conducted in a early stopping What Types of Trials Require DMCs? • Trials with a large sample size population at high risk of severe out- • Multicenter trials Not all randomized controlled trials comes during the course of the trial require a DMC. As long as safety of may benefit from a DMC. Regular review participants and trial integrity can be of comparative data may be necessary efficacy data in the separate treatment adequately assured by existing mech- to ensure that the intervention is not groups should have a DMC. The role anisms(eg,sponsor,investigators,data causing harm (eg, a trial of antiemetic of a DMC would be to review the data centers, institutional review boards, therapy in children with cancer under- and make recommendations about the regulatory agencies), a DMC is not es- going emetogenic chemotherapy). Even continuation of the trial. Such trials sential. The installation of an independent for pediatric trials, however, a large typically meet the clinical criteria cited DMC adds a level of complexity to trials proportion may be monitored accept- here. Other study factors that may in- and imparts a burden that may com- ably by investigators and sponsors. For dicate the need for a DMC are the trial promise trial efficiency. Nevertheless, example, trials not warranting DMCs size and the number of participating there are categories of trials for which include single-arm studies in which the sites.In large trials, there might bemore a DMC is essential to ensuring the safety emerging data will be known to all, so instances of rare but serious adverse of participants and the integrity of the that confidentiality of interim data is not events such that a DMC would need to trial. Both clinical and methodologic cri- an issue, or trials of short-term treatment compare rates in treatment arms to teria can be used to determine whether of a symptomatic condition in a population confirm that the benefit-to-risk ratio of a DMC is needed for a particular trial of essentially healthy children (even if the trial remains acceptable. Further- (Table 2). Because children are a vulner- randomized and controlled) so that se- more, in multicenter trials, it may be able population, it is appropriate to lean rious adverse outcomes are not expec- necessary to monitor differences in con- toward establishing the additional pro- ted (trials of a topical treatment of rash duct and outcomes to ensure that all tection of a DMC in marginal cases. or an antihistamine formulated for pe- sites are conducting study procedures diatric use). Trials that do not meet the in a similar manner. Clinical Criteria criteria shown in Table 2 generally do Who Should Serve on a DMC? Pediatric randomized controlled trials not require an independent DMC. addressing major morbidity or mor- A DMC typically comprises 1 or more Methodologic Criteria tality end points should be monitored clinicians knowledgeable in the field of for these outcomes at regular intervals Everystudydesignthat includesplanned the investigation