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 , 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, 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 (eg, condition under during the trial so that the potential interim analyses of the accumulating study, expected adverse effects of the intervention) and a statistician or clini- TABLE 1 Recommendations for Practice cal trial methodologist. The clinicians • DMCs should be established for all pediatric trials: (1) addressing major morbidity or mortality end points; could be a physician, nurse, or other (2) with preplanned interim analyses and the possibility of early stopping; (3) in populations with a high allied health specialist. Other specialists risk of severe outcomes; and (4) investigating new interventions with few safety data available that may be valuable for some trials • fl Criteria for con icts of interest should be established by the trial sponsor. Sponsors should avoid including include clinical pharmacologists, bio- persons with major conflicts of interest on the DMC to maximize independent decision-making • A charter describing DMC operational procedures, including assessment of conflicts of interest, should be ethicists, and public health practitioners. established and agreed on by the trial sponsor, steering group (if any), and the DMC before opening the A consumer/community advocate (often trial to accrual aparentofachildwiththediseaseor • The final report of a trial should describe the key aspects of DMC activities, including conduct of interim analyses, whether they were planned or ad hoc, their timing, what triggered them, and which statistical condition under study) may also pro- methods were used; it should also state whether the trial stopped early, for what reason, and whether the vide a helpful perspective.10 For inter- decision was based on a recommendation from the DMC national trials, the DMC should ideally

PEDIATRICS Volume 129, Supplement 3, June 2012 S133 Downloaded from www.aappublications.org/news by guest on September 28, 2021 include members from all participating a multicenter trial). In some cases, for early stopping involves a difficult regions. nonpediatric clinicians, or pediatricians balance between protecting trial par- An essential requirement for all DMC from other countries, might be included. ticipants and assuring the value and members is the absence of major con- For trials in resource-poor countries, credibility of the trial results; the ac- flict of interest to ensure the inde- however, it is important that DMC mem- ceptable balance is likely to vary among pendence of the committee. Financial bers have sufficient knowledge of the trials. For example, in a trial evaluating conflicts (eg, employment by a for-profit local issues at the trial sites. Although a new childhood vaccine, there will be sponsor, substantial stock holdings in conflict of interest concerns are im- great emphasis on collecting enough or yearly income from such a sponsor) portant, expertise in the subject matter data to ensure that the vaccine can be have been given most attention, but and experience in clinical trials are given safely to millions of healthy chil- other types of conflicts (eg, personal paramount. dren, and therefore only extreme effi- relationships, strong intellectual invest- cacy results might allow consideration ment) can also be important. For exam- Scope of Responsibilities of early termination. In a trial evaluating ple, an individual responsible for the The overarching purpose of a DMC is to a potentially life-saving treatment of initial concept being tested in the trial, or protect the safety of study participants seriously ill children, a somewhat less for early work in establishing the ratio- and the ability of the trial to yield reli- restrictive criterion might be set to al- nale for the treatment being studied, able results. Thus, the 1 responsibility low a superior treatment to be made might be more reluctant to consider common to all DMCs is regular review available more rapidly. Because is not stopping a trial for futility (or even safety) of study data and developing recom- unusual for experts to have varying than someone without such a history mendations regarding the continuation views on the optimal criteria for early because that person’s career could be of the study and/or any modifications termination,12,13 DMC members must substantially enhanced if the original that might be needed. A DMC may, for make certain they are comfortable with research concept was validated in a example, recommend that a dose level the monitoring plan proposed by the clinical study. should be reduced, that a subgroup of sponsor. A general principle is that a DMC should participants seeming to be at unac- Another common charge to DMCs is to be as small as possible while encom- ceptably high risk of adverse outcomes review and make recommendations passing all relevant expertise. Some be excluded from further enrollment, regarding the quality of study conduct. advocate that DMCs should include or if interim data clearly demonstrate When site data are not reported in a an odd number of participants to avoid that 1 treatment produces superior out- timely manner to the study data center, tie votes11; however, recommendations comes, that the study be terminated be- or the data reported include many in- should optimally be developed by con- fore reaching its original recruitment accuracies, the DMC’s ability to make sensus rather than by voting.5 The DMC goal. They may also consider the likeli- useful interim recommendations is di- chairperson should have substantial hood of the trial eventually producing minished, and the discovery of impor- experience in clinical trials and at least results that would lead to useful infor- tant safety issues could be delayed. If some experience on previous DMCs. mation for clinical practice or as a basis recruitment lags such that the feasi- Interpersonal and organizational capa- for further research, and should con- bility of successful completion of the bilities are important issues to consider sider any newly available external evi- trial is in question, participants may be when selecting the chairperson. dence when making recommendations put at risk without expectation of any A special challenge in pediatric trials is regarding study continuation. useful result. DMC recommendations balancing expertise against conflict of Many DMCs are charged with broader may ensure that such deviances be interest concerns for DMC members. responsibilities. It is common for DMCs addressed rapidly.14 The pediatric research community is to be asked to review and approve the DMCs may on occasion be asked by relatively small, especially when the study protocol before initiation. This sponsors or investigators to release focus is on less common diseases. The practice is desirable because it is certain interim data. Reasons for such pool of potentialDMC memberswith the essential for DMC members to be in requests could include the need for requisite expertise and lacking con- agreement with the study sponsors and this information in planning future stud- flicts of interest may thus be limited, investigators about the acceptability of ies, evaluating safety concerns arising particularly when many knowledgeable the study design, particularly the sta- in other studies of the investigational investigators are themselves involved tistical monitoring plan and any criteria treatment, or requests by regulatory in the trial (as would be the case for for early termination.5 Selecting criteria authorities.BecausetheDMCprotects

S134 ELLENBERG et al Downloaded from www.aappublications.org/news by guest on September 28, 2021 SUPPLEMENT ARTICLE

the confidentiality of the interim data, data.5,15 This document outlines roles is here that the confidential study efficacy it will determine whether such requests and responsibilities of the DMC and in- and safety data, split according to treat- can be granted without undermining the cludes details of membership, meeting ment arm, are fully interrogated and integrity of the trial on a case-by-case formats, reporting procedures, conflict recommendations drafted. basis. of interest criteria, taking and archiving Open and closed data reports are ide- Insometrials,DMCsareaskedtoreview of meeting minutes, and statistical moni- ally prepared by a statistician other and approve manuscripts and presen- toring plans. It is increasingly recognized than the primary study statistician to tations reporting trial results. In general, that sponsors should provide DMC mem- preserve the latter’s ability to collabo- it is good practice to offer a DMC the bers with protection from liability16 and rate with other investigators on study opportunity to review and comment on such arrangements should be docu- conduct issues without being influenced such data presentations because their mented in the charter. by knowledge of interim results.17,18 The open report is available to all meeting particular insights are likely to be valu- The conduct and frequency of DMC attendees; closed reports are provided to able, especially when the DMC has had an meetings will depend on the size of the the DMC only. Minutes are maintained for important role in the conduct of the trial. study, the expected rates of accrual and open and closed sessions. Open session Under the rubric of these general re- occurrence of study outcomes, and the meeting minutes, including DMC recom- sponsibilities, there are some specific perceived risks of the study interven- mendations, are shared with the study issues that DMCs for trials in children tions.MostDMCsmeet1to3timesayear. team, sponsors, and regulatory authori- should routinely consider. First, be- In some cases, when there is particular ties if warranted and may then be shared cause the data for planning pediatric concern about safety, the DMC or a with institutional review boards of par- trials are frequently limited, a DMC subset of members may receive reports ticipating sites. Closed session minutes should assess the validity of the design of adverse events more frequently and capture the DMC deliberations and are assumptions regarding the expected meet as necessary. Although in-person kept confidential until study termination, event rates or other data on which the meetings allow for optimal interaction, when they can then be shared. The DMC is sample size and trial duration specifi- telephone or Internet-based discussions cationswerebased.Thisshouldbedone can be effectively undertaken and are responsible for making recommenda- in the early phase (before interim an- more conserving of study resources and tions about trial conduct and continuation alyses) because the DMC may need to time of DMC members. Such meetings, but in most cases does not make binding recommend changes in the projected however, require special care to protect decisions. These remain the responsibility trial size and duration if the original the confidentiality of DMC proceedings. of the study leadership, usually the study sponsor (a funding agency or product assumptions seem substantially in- The conduct of DMC meetings usually manufacturer). In some cases, authority appropriate. Second, it may be impor- involves “open” and “closed” sessions. for such decisions is invested in a trial tant to give particular attention to Participants in open sessions may in- steering committee, which includes rep- results in different age groups, as small clude study investigators, monitors, resentatives of trial investigators and the age differences in children may have sponsors, and regulators. Open ses- study funder(s). a much stronger effect on response to sions allow the DMC to engage with the treatment, either positive or adverse, study team and to raise issues related An area of continuing controversy is than in adults. Finally, when there is the to the trial’s conduct. They also afford whether DMC members should review fi potential for delayed treatment effects an opportunity for sponsors and others interim data on ef cacy in a fully un- (eg,effectsongrowth,cognitivefunction, to inform the DMC of emerging data blinded way or according to coded arm fertility) the DMC may need to ensure external to the trial and to raise any only. Some DMC members prefer to that a plan is in place for long-term concerns they want the DMC to give view coded data initially but reserve the monitoring of outcomes in study par- special attention to. Only data on base- right to unblind themselves if felt to be ’ ticipants even beyond the formal study line characteristics, and in some cases in the participants best interest. Many completion date. aggregate outcome data, are discussed have argued that it is scientifically and at this session. The closed session typi- ethically problematic to withhold fully Operation of DMCs cally includes only DMC members and the unblinded data from the DMC.19,20 All DMCs should be governed by a DMC statistician reporting to the DMC (al- DMC members should declare any con- charter, which is typically prepared though in cases of government-sponsored flict(s) of interest at the beginning of the by the sponsor and approved by the trials, a representative of the sponsoring study. Potential conflicts newly arising DMC before their review of any interim program also attends closed sessions). It during the study should be considered

PEDIATRICS Volume 129, Supplement 3, June 2012 S135 Downloaded from www.aappublications.org/news by guest on September 28, 2021 by the sponsoraswell as by the full DMC. any interim recommendations made of individuals serving on DMCs to im- Adeterminationofunacceptableconflict by the DMC (eg, change in recruitment prove the quality of pediatric research may result in withdrawal of the member protocol or safety monitoring plan) while ensuring the safety of patients from the DMC. Finally, because of the should also be reported,21,22 either in participating in these trials. smaller pool of potential DMC members the article or in on-line supplements. in pediatrics, especially in rare disease The DMC might have a role in ensuring areas, the training of individuals for that adequate information on its activi- CONCLUSIONS future DMCs is a challenge. It is impor- ties is easily accessible to the reader of Numerous issues surrounding the prin- tant to have a sufficient number of the final trial report by requesting that ciples and practices of DMCs, with special trained potential DMC members in the this be addressed in their charter. attention to their application in pediatric pediatric research community. Some DMCs have prepared confirmatory (Phase III) trials, are cur- reports detailing decision-making pro- rently under discussion. This standards Reporting on DMC Involvement and cesses in certain trials.23–27 These can article defines a set of minimum re- Activities be informative as to the dilemmas in- quirements to which DMCs should ad- Adequate reporting of DMC activities volved in balancing harms and benefits here tobest serve pediatric researchers allows readers to evaluate the com- when difficult or unexpected situations as well as trialparticipants. Bothclinical mittee’s impact on the validity of trial emerge as trial data accumulate. We andmethodologiccriteriacanbeusedto results. Reporting of DMC roles, interim strongly encourage members of DMCs determinewhetheraDMCisrequiredfor analysis results, and early termination for pediatric trials to publish their ex- a particular study. Because pediatric has been incomplete and heteroge- periences so that they may provide research is an area in which partic- neous in published pediatric trials.21 valuable lessons for the design and ipants are often considered vulnerable, The 2010 Consolidated Standards of Re- monitoring of future trials in children. itmaybeappropriatetoincludeaDMCin porting Trials Statement recommends some cases for which the criteria de- that authors should describe the con- scribed earlier are not fully met. DMC duct of interim analyses (eg, how many RESEARCH AGENDA membership should be broad enough were performed, whether they were Five key areas for future research have to include individuals with clinical and planned or ad hoc, their timing, what been identified to date. These include the methodologic expertise and knowledge triggered them, which statistical methods following: (1) understanding the benefits of local context. The pediatric clinical were used) and any stopping guidelines and harms of having a DMC, particularly research community is relatively small, or rules defined a priori, and should in cases in which it is not clear whether however, and conflicts of interest must state whether the trial stopped early, a DMC is needed; (2) determining the be thoroughly assessed and avoided. for what reason, and whether the de- criteria for “few safety data,”“major Due to the large scope of DMCs and cision was based on a recommendation morbidity,” and “high-risk populations” potential impact on the validity of trial from a DMC.22 Names of DMC members with respect to research in pediatrics; results, the operations of these com- with their affiliations and areas of ex- (3) evaluating the effects of the use of mittees should be guided by a detailed pertise should be listed along with coded or unblinded information by DMCs charter. Including a brief description of other key trial committee member- on their recommendations; (4) defining the DMC and its operations in manu- ships. However, co-authorship for DMC the DMC role in the oversight of adaptive scripts clarifies the study monitoring members on articles reporting trial re- trials; and (5) developing effective and processes and will inform the reader in sults is inappropriate because it would appropriate training programs for nov- interpreting trial results. Finally, by create a conflict of interest (ie, DMC ice as well as experienced DMC mem- systematically addressing the research members would then also be inves- bers. Developing our understanding and agenda outlined in this article, un- tigators). Other aspects of the DMC’s evidence in these areas will not only necessary variation in DMC function and operational procedures and actions (eg, better definetheroleandtheimpactof practice can be reduced and optimal coded versus fully unblinded review) and DMCs but will also enhance the capacity practices can be advanced.

REFERENCES

1. Klassen TP, Hartling L, Craig JC, Offringa M. urgent need for high-quality trial evidence 2. Organization, review, and administration of Children are not just small adults: the in children. PLoS Med. 2008;5(8):e172 cooperative studies (Greenberg Report):

S136 ELLENBERG et al Downloaded from www.aappublications.org/news by guest on September 28, 2021 SUPPLEMENT ARTICLE

a report from the Heart Special Project Institute. J Clin Oncol. 1997;15(7):2736– 20. Meinert CL. Masked monitoring in clinical Committee to the National Advisory Heart 2743 trials—blind stupidity? N Engl J Med. 1998; Council, May 1967. Control Clin Trials. 1988; 11. Cairns JA, Hallstrom A, Held P. Should all 338(19):1381–1382 9(2):137–148 trials have a data safety and monitoring 21. Fernandes RM, van der Lee JH, Offringa M. 3. Shaw LW, Chalmers TC. Ethics in cooperative committee? Am Heart J. 2001;141(1):156–163 A of the reporting of clinical trials. Ann N Y Acad Sci. 1970;169(2): 12. Bassler D, Montori VM, Briel M, Glasziou P, Data Monitoring Committees’ roles, interim 487–495 Guyatt G. Early stopping of randomized analysis and early termination in pediatric 4. Wittes J. Behind closed doors: the data clinical trials for overt efficacy is problem- clinical trials. BMC Pediatr. 2009;9:77 monitoringboardinrandomizedclinical atic. J Clin Epidemiol. 2008;61(3):241–246 22. Moher D, Hopewell S, Schulz KF, et al; – – trials. Stat Med. 1993;12(5 6):419 424 13. Goodman SN. Stopping at nothing? Some Consolidated Standards of Reporting Trials 5. Ellenberg SS, Fleming TR, DeMets TL. Data dilemmas of data monitoring in clinical tri- Group. CONSORT 2010 explanation and elab- Monitoring Committees in Clinical Trials: als. Ann Intern Med. 2007;146(12):882–887 oration: updated guidelines for reporting A Practical Perspective. Chichester, West 14. Baigent C, Harrell FE, Buyse M, Emberson parallel group randomised trials. J Clin Sussex, United Kingdom: John Wiley & JR, Altman DG. Ensuring trial validity by Epidemiol. 2010;63(8):e1–e37 Sons, Ltd; 2002 data quality assurance and diversification 23. Ankum WM, Reitsma JB, Offringa M; Hippo- 6. Grant AM, Altman DG, Babiker AB, et al; of monitoring methods. Clin Trials. 2008;5 cratic role of Data Monitoring Committees. DAMOCLES Study Group. Issues in data (1):49–55 IVF with preimplantation genetic screening, monitoring and interim analysis of trials. 15. DAMOCLES Study Group, NHS Health Tech- a promising new treatment with unex- Health Technol Assess. 2005;9(7):1–238, nology Assessment Programme. A proposed pectedly negative health outcomes: the iii–iv charter for data monitoring Hippocratic role of Data Monitoring Com- 7. Clemens F, Elbourne D, Darbyshire J, Pocock S; committees: helping them to do their job mittees. Hum Reprod. 2008;23(1):1–3 DAMOCLES Group. Data monitoring in ran- well. Lancet. 2005;365(9460):711–722 24. DeMets DL, Furberg CD, Friedman LM. Data domized controlled trials: surveys of recent Monitoring in Clinical Trials: A Case Studies practice and policies. Clin Trials. 2005;2(1): 16. DeMets DL, Fleming TR, Rockhold F, et al. Approach. New York, NY: Springer; 2006 22–33 Liability issues for data monitoring com- mittee members. Clin Trials. 2004;1(6):525– 25. Fleming TR, Neaton JD, Goldman A, et al; 8. Gluckman PD, Wyatt JS, Azzopardi D, et al. 531 Terry Beirn Community Programs for Clinical Selective head cooling with mild systemic hypothermia after neonatal encephalopa- 17. Guidance for Clinical Trial Sponsors. Estab- Research on AIDS. Insights from moni- thy: multicentre randomised trial. Lancet. lishment and operation of clinical trial data toring the CPCRA didanosine/zalcitabine fi 2005;365(9460):663–670 monitoring committees. Available at: www. trial. J Acquir Immune De c Syndr Hum – 9. Shankaran S, Laptook AR, Ehrenkranz RA, fda.gov/downloads/RegulatoryInformation/ Retrovirol. 1995;10(suppl 2):S9 S18 et al; National Institute of Child Health and Guidances/ucm127073.pdf. Accessed Sep- 26. The Coronary Drug Project Research Group. Human Development Neonatal Research tember 6, 2011 Practical aspects of decision making in Network. Whole-body hypothermia for neo- 18. DeMets DL, Fleming TR. The independent clinical trials: the coronary drug project as nates with hypoxic-ischemic encephalopa- statistician for data monitoring commit- a case study. Control Clin Trials. 1981;1(4): thy. N Engl J Med. 2005;353(15):1574–1584 tees. Stat Med. 2004;23(10):1513–1517 363–376 10. Smith MA, Ungerleider RS, Korn EL, Rubinstein 19. Fleming TR, Ellenberg S, DeMets DL. Moni- 27. Wheatley K, Clayton D. Be skeptical about L, Simon R. Role of independent data- toring clinical trials: issues and contro- unexpected large apparent treatment effects: monitoring committees in randomized clini- versies regarding confidentiality. Stat Med. thecaseofanMRCAML12randomization. cal trials sponsored by the National Cancer 2002;21(19):2843–2851 Control Clin Trials. 2003;24(1):66–70

(Continued from first page) This is the third in a series of standard articles resulting from an ongoing process in which a group of invited experts called a Standard Development Group from StaR Child Health assembles and exchanges information about methods for pediatric trial design, conduct, and reporting. More detailed information about this topic can be found in the introductory article of this supplement or at the StaR Child Health Web site (www.starchildhealth.org). www.pediatrics.org/cgi/doi/10.1542/peds.2012-0055F doi:10.1542/peds.2012-0055F Accepted for publication Mar 23, 2012 Address correspondence to Martin Offringa, MD, PhD, Senior Scientist and Program Head, Child Health Evaluative Sciences, Research Institute, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada M5G 1X8. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2012 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: Dr Altman is supported by Cancer Research UK programme grant C5529.

PEDIATRICS Volume 129, Supplement 3, June 2012 S137 Downloaded from www.aappublications.org/news by guest on September 28, 2021 Standard 3: Data Monitoring Committees Susan Ellenberg, Ricardo M. Fernandes, Haroon Saloojee, Dirk Bassler, Lisa Askie, Ben Vandermeer, Martin Offringa, Ingeborg Van der Tweel, Douglas G. Altman, Johanna H. van der Lee and for the StaR Child Health Group Pediatrics 2012;129;S132 DOI: 10.1542/peds.2012-0055F

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/129/Supplement_3/S132 References This article cites 24 articles, 1 of which you can access for free at: http://pediatrics.aappublications.org/content/129/Supplement_3/S132 #BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Medical Education http://www.aappublications.org/cgi/collection/medical_education_su b Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 28, 2021 Standard 3: Data Monitoring Committees Susan Ellenberg, Ricardo M. Fernandes, Haroon Saloojee, Dirk Bassler, Lisa Askie, Ben Vandermeer, Martin Offringa, Ingeborg Van der Tweel, Douglas G. Altman, Johanna H. van der Lee and for the StaR Child Health Group Pediatrics 2012;129;S132 DOI: 10.1542/peds.2012-0055F

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/129/Supplement_3/S132

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2012 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

Downloaded from www.aappublications.org/news by guest on September 28, 2021