Research article | Open | Open Peer Review | Published:
A systematic review of the reporting of Data Monitoring Committees' roles, interim analysis and early termination in pediatric clinical trials
BMC Pediatricsvolume 9, Article number: 77 (2009)
Decisions about interim analysis and early stopping of clinical trials, as based on recommendations of Data Monitoring Committees (DMCs), have far reaching consequences for the scientific validity and clinical impact of a trial. Our aim was to evaluate the frequency and quality of the reporting on DMC composition and roles, interim analysis and early termination in pediatric trials.
We conducted a systematic review of randomized controlled clinical trials published from 2005 to 2007 in a sample of four general and four pediatric journals. We used full-text databases to identify trials which reported on DMCs, interim analysis or early termination, and included children or adolescents. Information was extracted on general trial characteristics, risk of bias, and a set of parameters regarding DMC composition and roles, interim analysis and early termination.
110 of the 648 pediatric trials in this sample (17%) reported on DMC or interim analysis or early stopping, and were included; 68 from general and 42 from pediatric journals. The presence of DMCs was reported in 89 of the 110 included trials (81%); 62 papers, including 46 of the 89 that reported on DMCs (52%), also presented information about interim analysis. No paper adequately reported all DMC parameters, and nine (15%) reported all interim analysis details. Of 32 trials which terminated early, 22 (69%) did not report predefined stopping guidelines and 15 (47%) did not provide information on statistical monitoring methods.
Reporting on DMC composition and roles, on interim analysis results and on early termination of pediatric trials is incomplete and heterogeneous. We propose a minimal set of reporting parameters that will allow the reader to assess the validity of trial results.
Data Monitoring Committees (DMCs) are central to modern clinical trials. They play a critical role in safeguarding both the interests of study participants and the scientific integrity of randomized trials This task is performed through interim monitoring of safety and efficacy outcome data, as well as vigilance over the conduct of the study and safety aspects/adverse events. One of the key activities of DMCs is to make recommendations to the sponsor or steering committee regarding the appropriateness of trial continuation. Thus, the recommendations of a DMC can influence the conclusion and interpretation of trial results and, indirectly, their implementation in clinical practice.
Experts and regulators have recently published recommendations for the appointment and operational procedures of DMCs [1–5] The increasing use and visibility of DMCs has fostered research into their activities There is evidence of heterogeneity in their roles and policies [7–9] The wide range of interim monitoring methods that are available entails considerable variability in DMCs' risk-benefit evaluations[1, 2, 10] These issues are relevant as the analyses and decisions made by DMCs may be controversial and can influence study validity, particularly in the case of trials terminated early [11–14]
Assessing DMCs' recommendations requires adequate reporting of their activities and considerations. Previous studies have suggested that reporting is insufficient for various subsets of publications and types of trials[8, 11, 15–18] The CONSORT statement of reporting guidelines for clinical trials includes an item on interim analysis, but no details on a DMCs' activities and considerations are required
There is consensus that DMCs should be a standard requirement for trials with vulnerable populations, such as children[1, 4, 5, 7, 20–22] In a recent review of pediatric trials performed until 2002, only 2% of the trials were reported to have a safety committee Recent US and EU regulations that require research on medicines in children are expected to foster an increase in the number of pediatric drug trials in the coming years This calls for the establishment of standards for trial conduct and reporting in this field, in which the need for transparency of the roles of DMCs is an important issue
We undertook a systematic review:
to estimate the frequency of reported use of a DMC and the frequency of reported interim analysis and early stopping in a sample of recent pediatric clinical trials;
to assess the quality of the reporting on the various different DMC characteristics and on information about interim analysis and early termination in these trials.
A systematic review was conducted using a sample of four general journals (British Medical Journal, Journal of the American Medical Association, Lancet, New England Journal of Medicine) and four pediatric journals (Archives of Disease in Childhood, Archives of Pediatric and Adolescent Medicine, Journal of Pediatrics, Pediatrics), published from January 2005 to December 2007. The included journals have a relevant impact factor in their field, and are known to publish pediatric trials in a broad range of conditions and age categories.
Articles were included when they:
reported on a controlled clinical trial, randomized or quasi-randomized, investigating any type of therapeutic intervention (i.e. drug, procedure, behavioral, health strategy, or other) and including, but not necessarily confined to, participants between 0-18 years;
reported on the use of a DMC or interim analysis or early trial termination.
Literature Search and Study Selection
Two searches were performed by one of the authors (R.F.). A Medline abstract search was used to identify the total number of pediatric trials for each journal, in order to obtain a denominator for frequency calculations. We used Medline's filters publication type "randomized controlled trial" and age category "0-18 years", and limited results to the specific journals and period under study. A separate full-text search was performed of the eight journals for the designated period of time using three full-text databases (HighWire Press, OVID, ScienceDirect). The search strategy for this full text search was adopted from Sydes et al and Montori et al[11, 15] The resulting list of search terms, aimed at a high sensitivity, includes variations on terms related to DMC, interim analysis and early termination. For general journals, we added terms to identify trials with participants within the pediatric age range, from previously validated search strategies The complete list of terms and the search strategy can be obtained from the corresponding author.
Titles and abstracts of the full-text search citation results were screened by one author (R.F.) for eligibility criteria. Two reviewers (R.F. and J.L.) subsequently screened the full text articles of included citations independently to confirm inclusion appropriateness. Any discrepancies were resolved through discussion until there was consensus. Motives for exclusion were noted and all search results were kept in database form.
Information was extracted from each included study report independently by two authors (R.F., J.L.) using data collection forms that can be obtained upon request from the corresponding author. The items included general trial characteristics, i.e. trial design, funding, centres and setting, details on the disease (based on the International Classification of Diseases, 10th edition), age of participants, trial interventions, outcomes, planned and actual sample size, recruitment, intervention and follow-up time Risks of bias in terms of substandard random sequence generation, allocation concealment, blinding and completeness of outcome data were assessed using the latest Cochrane Handbook criteria (v5, 2008), and disagreements were resolved by consensus
There are currently only limited reporting standards for DMC related activities. Therefore, based on current literature, we defined a priori a set of parameters for data collection regarding DMC characteristics, interim analysis and early termination. For DMC characteristics and interim analysis, we consulted the book on Data Monitoring Committees by Ellenberg et al, and the report of the DAMOCLES group [1, 2]. The latter presents empirical evidence and a set of recommendations on various issues related to DMCs' policies, structure, decision-making and reporting arrangements We also included the CONSORT statement item on interim analysis Early termination parameters were obtained from recent reviews addressing the implications of stopping trials early[11, 13] For all three topics there appears to be consensus in the literature on best practices for some of the parameters, but many others remain controversial[2, 7, 12, 14, 29] Some items were not reported in the main report of the study, but in supplementary publications (e.g. online appendix, design/protocol papers). If these were referred to in the main paper, we included them in this review.
We performed a descriptive analysis of collected data, stratifying results by type of journal (i.e. whether general or pediatric). All data analyses were performed using SPSS (version 14; http://www.spss.com).
Search Results and Prevalence of Reporting
Our search using Medline filters identified 648 controlled trials including pediatric subjects (249 from general journals and 399 from pediatric journals). The full-text search for DMC, interim and early termination terms identified a total of 6,823 potentially relevant records, which were screened for inclusion criteria. A flow diagram showing the yield of both searches is shown in Figure 1. Overall 110/648 trials (17%) reported on either, or DMC, interim analysis, or early termination, and were included in this review (Table 1 and Figure 2) [30–139] Reporting on these topics was more frequent in general journals (27%, 68/249) than in pediatric journals (11%, 42/399). DMCs were reported in 81% (89/110) of included trials, of which 52% (46/89) also referred to interim analysis. Of 62/110 (56%) trials that explicitly mentioned interim analysis, 74% (46/62) also reported use of a DMC. Early termination of a trial was reported in 32/110 (29%) articles, of which 21 (66%) reported on a DMC and 22 (69%) referred to interim analysis.
Trial Characteristics and Risk of Bias
The main characteristics of the included trials are summarized in Table 2. Most studies were designed as parallel, superiority trials (87%, 96/110). Two-arm, drug treatment studies were predominant (85%, 93/110, and 73%, 80/110, respectively). A placebo group was included in 48% (53/110) of trials, while the others used an active comparator. The majority of trials were multicentre, and in 80/110 (73%) North American or European/Russian centres were included. Outcomes included mortality in 51% (56/110) of trials. Studies published in pediatric journals most frequently included neonates and addressed neonatal conditions (52%, 22/42), in intensive care settings (50%, 21/42). The median sample size in these journals was 136, and 60% (25/42) included less than 200 participants. The sample sizes included in trials reported in general journals were substantially larger (median 601 participants). Studies published in general journals more frequently included adolescent or adult participants (51%, 35/68, and 41%, 28/68, respectively), and the most common diseases under study were infections (44%, 30/68). Planned sample size calculations were reported in most trials (84%, 92/110). Where reported, time to primary outcome was often less than 12 months (81%, 69/85), and the overall median recruitment phase lasted 30 months.
Risk of bias assessments are shown in Table 3. We found average to high levels of adequacy in all parameters.
Reporting of DMCs and Interim Analysis
DMC nomenclature varied, and we identified 16 different expressions in use. "Data Safety Monitoring Board" (or similar, with conjunctions) was the most frequent (58%, 52/89), followed by "Data Safety Monitoring Committee" (16%, 14/89) and "Data Monitoring Committee" (7%, 6/89). The terms "external" or "independent" were added in 6% (5/89) and 30% (27/89), respectively. The remaining expressions included variations on the previously presented terms ("safety", "monitoring", "committee"), and the additional keywords "ethics" (n = 3), "monitor", and "group" (both n = 1). Authors sometimes used different expressions for DMC in the same paper[39, 90, 122, 127] In some cases, the nomenclature and lack of additional information raised doubts as to whether the group in question was a DMC, particularly when dubious terms were used (e.g. "consultant") or there was a reference to other monitoring groups ("ethics", Independent Review Board, Outcome Adjudication Committee)[40, 57, 67, 75, 107, 127] Additionally, in some papers we identified reports of an apparent role of the DMC in assessing or verifying outcome diagnoses[111, 134]
In most papers DMCs and interim analyses were reported in the Methods section of the paper (89%, 93/105), sometimes in the Results (20%, 21/105) or in the Discussion (12%, 13/105) (Table 4). In one paper, interim analyses themselves were the main results If a DMC was reported in the Acknowledgements section (66%, 69/105), the identity of the DMC members was always disclosed. In a few papers published in general journals other sources were referred to for additional details on DMC and/or interim analysis. These included appendices and online supplementary material on the journal website, trial design/protocol papers published in other journals, or trial or group dedicated websites[44, 45, 116, 117, 123, 124]
Tables 5 and 6 show the reporting of DMC and interim analysis parameters in the included papers. The most frequently reported items in each category were the identity of DMC members (75%, 67/89) and the number of interim analyses performed (84%, 52/62), respectively. The affiliation of DMC members was reported infrequently (28%, 25/89), as was their independence from industry sponsors (37%, 33/89). The least reported items in each category were vigilance of trial conduct parameters beside safety/efficacy outcome monitoring (19%, 17/89), and the adjustment of results for interim analysis (31%, 19/62).
No article adequately reported on all DMC parameters, i.e. members' identity and affiliations, independence, monitored outcomes, vigilance of other trial conduct items, blinding to outcome data and existence of predefined stopping guidelines (Table 5). Nine papers (15%) reported all interim analysis details, i.e. number of analyses planned and performed, parameter defining timing of these analyses, statistical methods used and outcomes to which they were applied, and adjustment of results (Table 6). We found two pairs of trials conducted by the same group of researchers, published in different journals, with distinct DMC nomenclature and reporting of most parameters[73, 77, 100, 119] We also identified some discrepancies between protocols published as supplementary material and the papers' reports of DMC activities and interim analysis, e.g. reporting of one but not all statistical stopping rules [117, 124].
Changes in protocol, most often sample size readjustments during the trial, were reported in 18% (20/110). The DMC was reported to have been involved in these decisions in 10 (50%) of these trials.
Reporting of Early Terminated Trials
The frequency of reported early terminated trials in this sample was 21% (14/68) in general journals and 43% (18/42) in pediatric journals. Four of these trials terminated one or more arms of the trial but proceeded enrolment for the remaining interventions. DMCs and interim analysis were mentioned in 21/32 (66%) and 22/32 (69%) of early terminated trials, respectively. Reporting of parameters related to early termination is presented in Table 7. Only 28% (9/32) papers referred to early trial termination in the Title or Abstract, and 41% (13/32) addressed the implications of early termination in the Discussion section. In five trials (16%) the reason, e.g. harm, or rationale, e.g. statistical rules, for stopping early was not clear. Planned sample size was unclear or not reported in 13% (4/32) of trials, and the majority did not state predefined stopping guidelines (69%, 22/32). Statistical monitoring methods were not reported in 47% papers (15/32), while 44% (14/32) did not state the outcomes under monitoring or analysis. Only five papers (16%) reported that the final results were adjusted because of the interim analysis, e.g. by using an alpha spending approach, four (13%) of which reported all interim analysis parameters presented in Table 6. Overall, only two trials (6%) reported all relevant methodological elements for interpretation of results from early terminated trials, i.e. planned sample size, predefined stopping guidelines, statistical monitoring methods used, rationale for early termination, timing of early stop (i.e. whether trial termination was determined by one of the interim analysis, and which parameter determined the timing of this interim), whether results were adjusted, and recommendation of DMC.
Our study shows that the reporting of parameters related to DMCs, interim analysis and early termination in pediatric trial reports is heterogeneous and incomplete. This result is consistent with recent reviews of trials from various settings outside child health[8, 11, 13, 15–18] The CONSORT statement for standards of reporting clinical trials includes an item on interim analysis, but no details on DMCs or early termination We propose a minimal set of reporting parameters that will allow the reader of a trial report to assess their implications and the validity of trial results (Table 8). Also, we propose to update the CONSORT statement accordingly. Below we discuss the various components of this minimal set of reporting parameters, as they appear - from our study - to be relevant for the correct design, conduct and reporting of pediatric trials.
Use of DMCs in Pediatric Clinical Trials
In a review of pediatric trials published until 2002, only 2% were found to refer to safety committees Reporting of DMCs was more frequent in our - more recent - sample of pediatric studies, but our results are comparable to those in other recent reviews covering all age ranges[15, 18] This suggests a recent increased use of DMCs, but other relevant factors probably account for this difference. First, bias may have arisen from using a selected sample of high-impact journals, as reporting of DMC may differ according to publication practices and trial results. Second, differences observed between general and pediatric journals in the current review may be confounded, as we can expect trials published in high-impact general medical journals to have characteristics which are more frequently associated with the use of a DMC (e.g. large samples, new interventions).
Deciding whether a clinical trial actually needs a DMC involves consideration of the safety of the interventions under study, the type of outcomes, and which population is included, among other items[1, 4, 5, 7] Regulators recommend considering DMC involvement in the presence of vulnerable participants, such as children, but these are mere recommendations without obligations and no further operational guidance is given[4, 5] We found that DMCs are being reported in trials with participants of different age ranges and a wide range of conditions. These include serious, potentially fatal diseases (e.g. leukemia, bronchopulmonary dysplasia), but also minor conditions (e.g. caries, pharyngitis). Pediatric trials most often have specific ethical, safety and design issues that make a DMC indispensible, and, therefore, various pediatric specialty committees recommend their use[24, 140–143] Given the results of this study, we feel there is a need for a standard in the field of pediatric trials, including operational criteria for the establishment, roles and conduct of DMCs. We recommend to consider DMCs at least for pediatric trials concerning serious conditions and in which the recruitment time is long compared to the follow-up time for individual participants, which makes interim decisions with consequences for further inclusion possible.
The use of different expressions to denote DMCs may be attributed to local or national preferences, as well as to discrepancies in DMC-related guidance documents from various sponsors and institutions[2, 7, 15] Standardized nomenclature is necessary in order to distinguish DMCs from on site monitoring by trial centres, and from other trial oversight groups (e.g. Institutional Review Boards, Ethics Committees) It is particularly relevant to recognize each group's distinct and non-overlapping role in ensuring the validity of the trial To avoid confusion, we recommend the use of a single expression "Data Monitoring Committee", as suggested by the DAMOCLES group (see Table 8) 
Composition of the DMC
The impact of DMCs' recommendations in trials calls for transparency and accountability of its members. In our review DMC members' identities were commonly reported, but not their affiliations, nor their independence. Independence is particularly relevant and relates to real or perceived conflicts of interest of each DMC member with regard to the sponsor, the intervention under study, and the regulator[1, 4, 5, 7]
Three main models for the composition of a DMC have been proposed previously, with varying degrees of independence from the research team and the sponsor[1, 7, 145] First, trials may have an "internal" DMC with non-independent members, e.g. the principal investigator, or they may have a monitoring plan without a formal DMC. A second option is to include only members not involved in the trial, except for the trial statistician, who acts as the DMC statistician. Third, all DMC members, including the statistician, are independent In any case, appointment and funding by sponsors may affect this independence[4, 5] Knowing how a DMC was established is paramount for accepting the integrity and for the credibility of this DMC's decisions. Trial reports therefore should identify members and their affiliations, and disclosure of conflicts of interest should be made available. They should also make a clear statement about their independence, possibly with an operational definition (see Table 8).
Tasks of the DMC, Monitoring and Interim Analysis
Our findings show inadequate reporting on which roles were taken by a DMC and how they were performed. Ellenberg et al states that monitoring safety, efficacy and other trial conduct parameters are among main DMC activities Activities should be clearly agreed upon and defined in advance by DMC members, trial sponsors and investigators, preferably using a "charter"
Outcome data may be monitored in a number of ways, particularly safety data, which can include either or both adverse events and other safety/efficacy outcomes There is controversy as to the blinding of DMCs Reporting of these procedural aspects is needed to allow clinicians to judge decision-making (see Table 8).
We found discrepancies in reporting of the statistical monitoring plan and the use of interim analysis. Ellenberg et al highlight the relevance of predefined stopping guidelines, including a prudent use of statistical boundaries Indeed, performing multiple looks at data through interim analyses without correction can lead to multiplicity problems, with increased risk of type I error A number of statistical monitoring methods have been developed to overcome this issue, among which the frequentist, Bayesian and likelihood approaches As each statistical method has different assumptions and implications, reporting should be clear and unequivocal[2, 10, 29, 148] Additionally, there are differences between analyses aimed at efficacy, harm or futility, as well as the possible use of alternative trial designs (e.g. adaptive) This is compounded by a nomenclature which is often inconsistent and overlapping (e.g. "adaptive designs" vs. "sample size reviews") Clear reporting should allow readers to identify these methods and their impact of on type I and II error risks (see Table 8).
Early Terminated Trials
We found similar deficiencies in reporting on early termination as were reported previously in other samples of trials[11, 16, 17] A significant number of early terminated trials did not report on the existence of a DMC or on its role in early stopping. This raises doubts as to which trial oversight group recommended termination, and whether this recommendation was issued independently from sponsor and principal investigators.
Understanding the rationale for early termination is paramount to a correct assessment of the validity of trial results. This implies knowing which, if any, statistical monitoring methods and stopping rules or guidelines were used, for which outcome (whether primary or secondary), and at which stage of the trial[11, 13] It may be relevant in some cases to check if the results were corrected for multiplicity The ongoing controversies regarding early termination highlight the need for transparent reporting of these items (see Table 8).
Risks of early termination for benefit include implausibly large treatment effects[11, 12, 150] Additionally, futility analyses and protocol changes, like sample size reviews and adaptive designs, may interfere with the overall power of the trial[10, 148, 149] The majority of authors did not discuss these implications of early termination in their report. Because readers often base their assessment of a trial solely on information in the abstract, this should clearly report early termination and its rationale, as recommended in the latest CONSORT statement extension for journal and conference abstracts
Strengths and Limitations of this study
Our full-text search strategy allowed a thorough review of all published content in the selected journals. This strategy was chosen since the reporting of DMCs, interim analysis and early termination is not indexed in Medline records, and it is often not reported in the abstract. We opted to use Medline's filters to identify pediatric controlled trials, although we can expect some indexing inaccuracies.
We only analyzed published reports, and we did not contact authors to evaluate whether DMC and interim analysis were used but not reported. This will likely lead to an underestimation of their actual use, as previously observed with the reporting of other trial methodology issues Reports of studies in which DMCs had an active role, particularly when early termination decisions were taken, may be also more likely to report details on their activities. A relatively large proportion of trials from general journals included adult participants. Results from these trials may not apply to studies that were designed to include children exclusively, as these trials may differ for example regarding the presence of a DMC and its tasks and procedures.
The sample of trials for our review was chosen from recent volumes to have an estimate of current practice. Most of these trials were, however, designed, conducted and published before the latest standards for DMC use (i.e. DAMOCLES) were published. We expect that DAMOCLES will have a future impact on trial design, conduct, and reporting
There was a moderate to high level of adequacy in the reporting of risk of bias parameters indicating good adherence to the CONSORT statement on these items. These results show that there is an apparent shortcoming in the reporting of DMCs, interim analyses and early termination, even in trials which appeared well designed and reported in other aspects. Until CONSORT requires more information of DMC activities, we expect that reporting will remain poor. Therefore, we propose to update the CONSORT statement according to the recommendations described below.
Recommendations for Reporting of DMC, Interim Analysis and Early Termination (Table 8)
We agree with the EQUATOR Group that continued efforts are needed to improve reporting quality, by updating and disseminating current standards With the current increase of clinical trials in child health, and given our results, we feel this has become urgent in this field. We propose a list of reporting items on DMC terminology, composition, tasks, and recommendations, on statistical monitoring methods and interim analysis, and on early termination parameters. This could be considered in the next CONSORT revision. Space limitations should not preclude transparent reporting, given the current possibilities of online publishing. Discussion should be started on the inclusion of this minimal set of parameters in design/protocol papers and trial registries[154, 155]
Reporting of DMC activities, interim analysis results and early termination of pediatric trials is incomplete and heterogeneous. New standards for the reporting of these parameters are necessary in order to evaluate their impact on the validity of trial results.
- Arch Ped Adolesc Med:
Archives of Pediatric and Adolescent Medicine
British Medical Journal
- J Pediatr:
Journal of Pediatrics
- N Engl J Med:
New England Journal of Medicine
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Geijerstam JLa, Oredsson S, Britton M, Octopus SI: Medical outcome after immediate computed tomography or admission for observation in patients with mild head injury: randomised controlled trial. BMJ. 2006, 333: 465-10.1136/bmj.38918.669317.4F.
Alderman H, Konde-Lule J, Sebuliba I, Bundy D, Hall A: Effect on weight gain of routinely giving albendazole to preschool children during child health days in Uganda: cluster randomised controlled trial. BMJ. 2006, 333: 122-10.1136/bmj.38877.393530.7C.
Zar HJ, Cotton MF, Strauss S, Karpakis J, Hussey G, Schaaf HS, Rabie H, Lombard CJ: Effect of isoniazid prophylaxis on mortality and incidence of tuberculosis in children with HIV: randomised controlled trial. BMJ. 2007, 334: 136-10.1136/bmj.39000.486400.55.
Raine TR, Harper CC, Rocca CH, Fischer R, Padian N, Klausner JD, Darney PD: Direct Access to Emergency Contraception Through Pharmacies and Effect on Unintended Pregnancy and STIs: A Randomized Controlled Trial. JAMA. 2005, 293: 54-62. 10.1001/jama.293.1.54.
Pichichero ME, Rennels MB, Edwards KM, Blatter MM, Marshall GS, Bologa M, Wang E, Mills E: Combined Tetanus, Diphtheria, and 5-Component Pertussis Vaccine for Use in Adolescents and Adults. JAMA. 2005, 293: 3003-3011. 10.1001/jama.293.24.3003.
Willson DF, Thomas NJ, Markovitz BP, Bauman LA, DiCarlo JV, Pon S, Jacobs BR, Jefferson LS, Conaway MR, Egan EA, et al: Effect of Exogenous Surfactant (Calfactant) in Pediatric Acute Lung Injury: A Randomized Controlled Trial. JAMA. 2005, 293: 470-476. 10.1001/jama.293.4.470.
Curley MAQ, Hibberd PL, Fineman LD, Wypij D, Shih MC, Thompson JE, Grant MJ, Barr FE, Cvijanovich NZ, Sorce L, et al: Effect of Prone Positioning on Clinical Outcomes in Children With Acute Lung Injury: A Randomized Controlled Trial. JAMA. 2005, 294: 229-237. 10.1001/jama.294.2.229.
DeRouen TA, Martin MD, Leroux BG, Townes BD, Woods JS, Leitao J, Castro-Caldas A, Luis H, Bernardo M, Rosenbaum G, et al: Neurobehavioral Effects of Dental Amalgam in Children: A Randomized Clinical Trial. JAMA. 2006, 295: 1784-1792. 10.1001/jama.295.15.1784.
Bellinger DC, Trachtenberg F, Barregard L, Tavares M, Cernichiari E, Daniel D, McKinlay S: Neuropsychological and Renal Effects of Dental Amalgam in Children: A Randomized Clinical Trial. JAMA. 2006, 295: 1775-1783. 10.1001/jama.295.15.1775.
Walsh BT, Kaplan AS, Attia E, Olmsted M, Parides M, Carter JC, Pike KM, Devlin MJ, Woodside B, Roberto CA, et al: Fluoxetine After Weight Restoration in Anorexia Nervosa: A Randomized Controlled Trial. JAMA. 2006, 295: 2605-2612. 10.1001/jama.295.22.2605.
Thior I, Lockman S, Smeaton LM, Shapiro RL, Wester C, Heymann SJ, Gilbert PB, Stevens L, Peter T, Kim S, et al: Breastfeeding Plus Infant Zidovudine Prophylaxis for 6 Months vs Formula Feeding Plus Infant Zidovudine for 1 Month to Reduce Mother-to-Child HIV Transmission in Botswana: A Randomized Trial: The Mashi Study. JAMA. 2006, 296: 794-805. 10.1001/jama.296.7.794.
Dorsey G, Staedke S, Clark TD, Njama-Meya D, Nzarubara B, Maiteki-Sebuguzi C, Dokomajilar C, Kamya MR, Rosenthal PJ: Combination Therapy for Uncomplicated Falciparum Malaria in Ugandan Children: A Randomized Trial. JAMA. 2007, 297: 2210-2219. 10.1001/jama.297.20.2210.
Shaddy RE, Boucek MM, Hsu DT, Boucek RJ, Canter CE, Mahony L, Ross RD, Pahl E, Blume ED, Dodd DA, et al: Carvedilol for Children and Adolescents With Heart Failure: A Randomized Controlled Trial. JAMA. 2007, 298: 1171-1179. 10.1001/jama.298.10.1171.
Leslie T, Mayan MI, Hasan MA, Safi MH, Klinkenberg E, Whitty CJM, Rowland M: Sulfadoxine-Pyrimethamine, Chlorproguanil-Dapsone, or Chloroquine for the Treatment of Plasmodium vivax Malaria in Afghanistan and Pakistan: A Randomized Controlled Trial. JAMA. 2007, 297: 2201-2209. 10.1001/jama.297.20.2201.
Moya FR, Gadzinowski J, Bancalari E, Salinas V, Kopelman B, Bancalari A, Kornacka MK, Merritt TA, Segal R, Schaber CJ, et al: A Multicenter, Randomized, Masked, Comparison Trial of Lucinactant, Colfosceril Palmitate, and Beractant for the Prevention of Respiratory Distress Syndrome Among Very Preterm Infants. Pediatrics. 2005, 115: 1018-1029. 10.1542/peds.2004-2183.
Widness JA, Madan A, Grindeanu LA, Zimmerman MB, Wong DK, Stevenson DK: Reduction in Red Blood Cell Transfusions Among Preterm Infants: Results of a Randomized Trial With an In-Line Blood Gas and Chemistry Monitor. Pediatrics. 2005, 115: 1299-1306. 10.1542/peds.2004-1680.
Field D, Elbourne D, Truesdale A, Grieve R, Hardy P, Fenton AC, Subhedar N, Ahluwalia J, Halliday HL, Stocks J, et al: Neonatal Ventilation With Inhaled Nitric Oxide Versus Ventilatory Support Without Inhaled Nitric Oxide for Preterm Infants With Severe Respiratory Failure: The INNOVO Multicentre Randomised Controlled Trial (ISRCTN 17821339). Pediatrics. 2005, 115: 926-936. 10.1542/peds.2004-1209.
Gradin M, Schollin J: The Role of Endogenous Opioids in Mediating Pain Reduction by Orally Administered Glucose Among Newborns. Pediatrics. 2005, 115: 1004-1007. 10.1542/peds.2004-1189.
Sinha SK, Lacaze-Masmonteil T, Soler A, Wiswell TE, Gadzinowski J, Hajdu J, Bernstein G, Sanchez-Luna M, Segal R, Schaber CJ, et al: A Multicenter, Randomized, Controlled Trial of Lucinactant Versus Poractant Alfa Among Very Premature Infants at High Risk for Respiratory Distress Syndrome. Pediatrics. 2005, 115: 1030-1038. 10.1542/peds.2004-2231.
Spandorfer PR, Alessandrini EA, Joffe MD, Localio R, Shaw KN: Oral Versus Intravenous Rehydration of Moderately Dehydrated Children: A Randomized, Controlled Trial. Pediatrics. 2005, 115: 295-301. 10.1542/peds.2004-0245.
Powers SW, Jones JS, Ferguson KS, Piazza-Waggoner C, Daines C, Acton JD: Randomized Clinical Trial of Behavioral and Nutrition Treatment to Improve Energy Intake and Growth in Toddlers and Preschoolers With Cystic Fibrosis. Pediatrics. 2005, 116: 1442-1450. 10.1542/peds.2004-2823.
Teitelbaum DH, Tracy TF, Aouthmany MM, Llanos A, Brown MB, Yu S, Brown MR, Shulman RJ, Hirschl RB, Derusso PA, et al: Use of Cholecystokinin-Octapeptide for the Prevention of Parenteral Nutrition-Associated Cholestasis. Pediatrics. 2005, 115: 1332-1340. 10.1542/peds.2004-1014.
Dugas MA, Nguyen D, Frenette L, Lachance C, St-Onge O, Fougeres A, Belanger S, Caouette G, Proulx E, Racine MC, et al: Fluticasone Inhalation in Moderate Cases of Bronchopulmonary Dysplasia. Pediatrics. 2005, 115: e566-e572. 10.1542/peds.2004-0951.
Bloom BT, Clark RH, for the Infasurf Survanta Clinical Trial Group: Comparison of Infasurf (Calfactant) and Survanta (Beractant) in the Prevention and Treatment of Respiratory Distress Syndrome. Pediatrics. 2005, 116: 392-399. 10.1542/peds.2004-2783.
Bell EF, Strauss RG, Widness JA, Mahoney LT, Mock DM, Seward VJ, Cress GA, Johnson KJ, Kromer IJ, Zimmerman MB: Randomized Trial of Liberal Versus Restrictive Guidelines for Red Blood Cell Transfusion in Preterm Infants. Pediatrics. 2005, 115: 1685-1691. 10.1542/peds.2004-1884.
Stacpoole PW, Kerr DS, Barnes C, Bunch ST, Carney PR, Fennell EM, Felitsyn NM, Gilmore RL, Greer M, Henderson GN, et al: Controlled Clinical Trial of Dichloroacetate for Treatment of Congenital Lactic Acidosis in Children. Pediatrics. 2006, 117: 1519-1531. 10.1542/peds.2005-1226.
Bajaj L, Turner CG, Bothner J: A Randomized Trial of Home Oxygen Therapy From the Emergency Department for Acute Bronchiolitis. Pediatrics. 2006, 117: 633-640. 10.1542/peds.2005-1322.
Lightdale JR, Goldmann DA, Feldman HA, Newburg AR, DiNardo JA, Fox VL: Microstream Capnography Improves Patient Monitoring During Moderate Sedation: A Randomized, Controlled Trial. Pediatrics. 2006, 117: e1170-e1178. 10.1542/peds.2005-1709.
Marcus CL, Rosen G, Ward SLD, Halbower AC, Sterni L, Lutz J, Stading PJ, Bolduc D, Gordon N: Adherence to and Effectiveness of Positive Airway Pressure Therapy in Children With Obstructive Sleep Apnea. Pediatrics. 2006, 117: e442-e451. 10.1542/peds.2005-1634.
Doyle LW, Davis PG, Morley CJ, McPhee A, Carlin JB, the DART Study Investigators: Low-Dose Dexamethasone Facilitates Extubation Among Chronically Ventilator-Dependent Infants: A Multicenter, International, Randomized, Controlled Trial. Pediatrics. 2006, 117: 75-83. 10.1542/peds.2004-2843.
Baquero H, Soliz A, Neira F, Venegas ME, Sola A: Oral Sildenafil in Infants With Persistent Pulmonary Hypertension of the Newborn: A Pilot Randomized Blinded Study. Pediatrics. 2006, 117: 1077-1083. 10.1542/peds.2005-0523.
Mercer JS, Vohr BR, McGrath MM, Padbury JF, Wallach M, Oh W: Delayed Cord Clamping in Very Preterm Infants Reduces the Incidence of Intraventricular Hemorrhage and Late-Onset Sepsis: A Randomized, Controlled Trial. Pediatrics. 2006, 117: 1235-1242. 10.1542/peds.2005-1706.
Butler-O'Hara M, Buzzard CJ, Reubens L, McDermott MP, DiGrazio W, D'Angio CT: A Randomized Trial Comparing Long-term and Short-term Use of Umbilical Venous Catheters in Premature Infants With Birth Weights of Less Than 1251 Grams. Pediatrics. 2006, 118: e25-e35. 10.1542/peds.2005-1880.
Pichichero ME, Blatter MM, Kennedy WA, Hedrick J, Descamps D, Friedland LR: Acellular Pertussis Vaccine Booster Combined With Diphtheria and Tetanus Toxoids for Adolescents. Pediatrics. 2006, 117: 1084-1093. 10.1542/peds.2005-1759.
Walsh M, Laptook A, Kazzi SN, Engle WA, Yao Q, Rasmussen M, Buchter S, Heldt G, Rhine W, Higgins R, et al: A Cluster-Randomized Trial of Benchmarking and Multimodal Quality Improvement to Improve Rates of Survival Free of Bronchopulmonary Dysplasia for Infants With Birth Weights of Less Than 1250 Grams. Pediatrics. 2007, 119: 876-890. 10.1542/peds.2006-2656.
Whitelaw A, Evans D, Carter M, Thoresen M, Wroblewska J, Mandera M, Swietlinski J, Simpson J, Hajivassiliou C, Hunt LP, et al: Randomized Clinical Trial of Prevention of Hydrocephalus After Intraventricular Hemorrhage in Preterm Infants: Brain-Washing Versus Tapping Fluid. Pediatrics. 2007, 119: e1071-e1078. 10.1542/peds.2006-2841.
Ruiz-Palacios GM, Guerrero ML, Bautista-Marquez A, Ortega-Gallegos H, Tuz-Dzib F, Reyes-Gonzalez L, Rosales-Pedraza G, Martinez-Lopez J, Castanon-Acosta E, Cervantes Y, et al: Dose Response and Efficacy of a Live, Attenuated Human Rotavirus Vaccine in Mexican Infants. Pediatrics. 2007, 120: e253-e261. 10.1542/peds.2006-2630.
Buckmaster AG, Arnolda G, Wright IMR, Foster JP, Henderson-Smart DJ: Continuous Positive Airway Pressure Therapy for Infants With Respiratory Distress in Non-Tertiary Care Centers: A Randomized, Controlled Trial. Pediatrics. 2007, 120: 509-518. 10.1542/peds.2007-0775.
Block SL, Vesikari T, Goveia MG, Rivers SB, Adeyi BA, Dallas MJ, Bauder J, Boslego JW, Heaton PM, for the Pentavalent Rotavirus Vaccine Dose Confirmation Efficacy Study Group: Efficacy, Immunogenicity, and Safety of a Pentavalent Human-Bovine (WC3) Reassortant Rotavirus Vaccine at the End of Shelf Life. Pediatrics. 2007, 119: 11-18. 10.1542/peds.2006-2058.
Schnabel D, Grasemann C, Staab D, Wollmann H, Ratjen F, for the German Cystic Fibrosis Growth Hormone Study Group: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Metabolic and Respiratory Effects of Growth Hormone in Children With Cystic Fibrosis. Pediatrics. 2007, 119: e1230-e1238. 10.1542/peds.2006-2783.
Tielsch JM, Darmstadt GL, Mullany LC, Khatry SK, Katz J, LeClerq SC, Shrestha S, Adhikari R: Impact of Newborn Skin-Cleansing With Chlorhexidine on Neonatal Mortality in Southern Nepal: A Community-Based, Cluster-Randomized Trial. Pediatrics. 2007, 119: e330-e340. 10.1542/peds.2006-1192.
Shah PS, Kalyn A, Satodia P, Dunn MS, Parvez B, Daneman A, Salem S, Glanc P, Ohlsson A, Shah V: A Randomized, Controlled Trial of Heparin Versus Placebo Infusion to Prolong the Usability of Peripherally Placed Percutaneous Central Venous Catheters (PCVCs) in Neonates: The HIP (Heparin Infusion for PCVC) Study. Pediatrics. 2007, 119: e284-e291. 10.1542/peds.2006-0529.
Kirpalani H, Whyte RK, Andersen C, Asztalos EV, Heddle N, Blajchman MA, Peliowski A, Rios A, LaCorte M, Connelly R, et al: The premature infants in need of transfusion (pint) study: A randomized, controlled trial of a restrictive (LOW) versus liberal (HIGH) transfusion threshold for extremely low birth weight infants. J Pediatr. 2006, 149: 301-10.1016/j.jpeds.2006.05.011.
Corvaglia L, Ferlini M, Rotatori R, Paoletti V, Alessandroni R, Cocchi G, Faldella G: Starch thickening of human milk is ineffective in reducing the gastroesophageal reflux in preterm infants: A crossover study using intraluminal impedance. J Pediatr. 2006, 148: 265-268. 10.1016/j.jpeds.2005.09.034.
Zdravkovic V, Hamilton JK, Daneman D, Cummings EA: Pioglitazone as adjunctive therapy in adolescents with type 1 diabetes. J Pediatr. 2006, 149: 845-849. 10.1016/j.jpeds.2006.08.049.
Inoue Y, Okada Y, Shinohara M, Kobayashi T, Kobayashi T, Tomomasa T, Takeuchi K, Morikawa A: A multicenter prospective randomized trial of corticosteroids in primary therapy for Kawasaki disease: Clinical course and coronary artery outcome. J Pediatr. 2006, 149: 336-10.1016/j.jpeds.2006.05.025.
Borowitz D, Goss CH, Limauro S, Konstan MW, Blake K, Casey S, Quittner AL, Murray FT: Study of a novel pancreatic enzyme replacement therapy in pancreatic insufficient subjects with cystic fibrosis. J Pediatr. 2006, 149: 658-662. 10.1016/j.jpeds.2006.07.030.
DeJonge M, Burchfield D, Bloom B, Duenas M, Walker W, Polak M, Jung E, Millard D, Schelonka R, Eyal F, et al: Clinical Trial of Safety and Efficacy of IHN-A21 for the Prevention of Nosocomial Staphylococcal Bloodstream Infection in Premature Infants. J Pediatr. 2007, 151: 260-265. 10.1016/j.jpeds.2007.04.060.
Lands LC, Milner R, Cantin AM, Manson D, Corey M: High-Dose Ibuprofen in Cystic Fibrosis: Canadian Safety and Effectiveness Trial. J Pediatr. 2007, 151: 249-254. 10.1016/j.jpeds.2007.04.009.
Cutts FT, Zaman SMA, Enwere G, Jaffar S, Levine OS, Okoko JB, Oluwalana C, Vaughan A, Obaro SK, Leach A, et al: Efficacy of nine-valent pneumococcal conjugate vaccine against pneumonia and invasive pneumococcal disease in The Gambia: randomised, double-blind, placebo-controlled trial. Lancet. 2005, 365: 1139-1146. 10.1016/S0140-6736(05)71876-6.
Darmstadt GL, Saha SK, Ahmed ANU, Chowdhury MA, Law PA, Ahmed S, Alam MA, Black RE, Santosham M: Effect of topical treatment with skin barrier-enhancing emollients on nosocomial infections in preterm infants in Bangladesh: a randomised controlled trial. Lancet. 2005, 365: 1039-1045.
Ratcliff A, Siswantoro H, Kenangalem E, Maristela R, Wuwung RM, Laihad F, Ebsworth EP, Anstey NM, Tjitra E, Price RN: Two fixed-dose artemisinin combinations for drug-resistant falciparum and vivax malaria in Papua, Indonesia: an open-label randomised comparison. Lancet. 2007, 369: 757-765. 10.1016/S0140-6736(07)60160-3.
Conter V, Valsecchi MG, Silvestri D, Campbell M, Dibar E, Magyarosy E, Gadner H, Stary J, Benoit Y, Zimmermann M, et al: Pulses of vincristine and dexamethasone in addition to intensive chemotherapy for children with intermediate-risk acute lymphoblastic leukaemia: a multicentre randomised trial. Lancet. 2007, 369: 123-131. 10.1016/S0140-6736(07)60073-7.
Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM, Polin RA, Robertson CM, Thoresen M, Whitelaw A, et al: Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet. 2005, 365: 663-670.
Gray RH, Kigozi G, Serwadda D, Makumbi F, Watya S, Nalugoda F, Kiwanuka N, Moulton LH, Chaudhary MA, Chen MZ, et al: Male circumcision for HIV prevention in men in Rakai, Uganda: a randomised trial. Lancet. 2007, 369: 657-666. 10.1016/S0140-6736(07)60313-4.
Vora A, Mitchell CD, Lennard L, Eden TOB, Kinsey SE, Lilleyman J, Richards SM: Toxicity and efficacy of 6-thioguanine versus 6-mercaptopurine in childhood lymphoblastic leukaemia: a randomised trial. Lancet. 2006, 368: 1339-1348. 10.1016/S0140-6736(06)69558-5.
Tielsch JM, Khatry SK, Stoltzfus RJ, Katz J, LeClerq SC, Adhikari R, Mullany LC, Shresta S, Black RE: Effect of routine prophylactic supplementation with iron and folic acid on preschool child mortality in southern Nepal: community-based, cluster-randomised, placebo-controlled trial. Lancet. 2006, 367: 144-152. 10.1016/S0140-6736(06)67963-4.
Smyth A, Tan KHV, Hyman-Taylor P, Mulheran M, Lewis S, Stableforth D, Knox A: Once versus three-times daily regimens of tobramycin treatment for pulmonary exacerbations of cystic fibrosis--the TOPIC study: a randomised controlled trial. Lancet. 2005, 365: 573-578.
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Thwaites CL, Yen LM, Loan HT, Thuy TTD, Thwaites GE, Stepniewska K, Soni N, White NJ, Farrar JJ: Magnesium sulphate for treatment of severe tetanus: a randomised controlled trial. Lancet. 2006, 368: 1436-1443. 10.1016/S0140-6736(06)69444-0.
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Nadel S, Goldstein B, Williams MD, Dalton H, Peters M, Macias WL, bd-Allah SA, Levy H, Angle R, Wang D, et al: Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial. Lancet. 2007, 369: 836-843. 10.1016/S0140-6736(07)60411-5.
Mullany LC, Darmstadt GL, Khatry SK, Katz J, LeClerq SC, Shrestha S, Adhikari R, Tielsch JM: Topical applications of chlorhexidine to the umbilical cord for prevention of omphalitis and neonatal mortality in southern Nepal: a community-based, cluster-randomised trial. Lancet. 2006, 367: 910-918. 10.1016/S0140-6736(06)68381-5.
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Mutabingwa TK, Anthony D, Heller A, Hallett R, Ahmed J, Drakeley C, Greenwood BM, Whitty CJ: Amodiaquine alone, amodiaquine+sulfadoxine-pyrimethamine, amodiaquine+artesunate, and artemether-lumefantrine for outpatient treatment of malaria in Tanzanian children: a four-arm randomised effectiveness trial. Lancet. 2005, 365: 1474-1480. 10.1016/S0140-6736(05)66417-3.
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South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) group: Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet. 2005, 366: 717-725. 10.1016/S0140-6736(05)67176-0.
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Paavonen J, Jenkins D, Bosch FX, Naud P, Salmerón J, Wheeler CM, Chow SN, Apter DL, Kitchener HC, Castellsague X, et al: Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial. Lancet. 2007, 369: 2161-2170. 10.1016/S0140-6736(07)60946-5.
Harvey S, Harrison DA, Singer M, Ashcroft J, Jones CM, Elbourne D, Brampton W, Williams D, Young D, Rowan K: Assessment of the clinical effectiveness of pulmonary artery catheters in management of patients in intensive care (PAC-Man): a randomised controlled trial. Lancet. 2005, 366: 472-477. 10.1016/S0140-6736(05)67061-4.
Bobat R, Coovadia H, Stephen C, Naidoo KL, McKerrow N, Black RE, Moss WJ: Safety and efficacy of zinc supplementation for children with HIV-1 infection in South Africa: a randomised double-blind placebo-controlled trial. Lancet. 2005, 366: 1862-1867. 10.1016/S0140-6736(05)67756-2.
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Cullen M, Steven N, Billingham L, Gaunt C, Hastings M, Simmonds P, Stuart N, Rea D, Bower M, Fernando I, et al: Antibacterial Prophylaxis after Chemotherapy for Solid Tumors and Lymphomas. N Engl J Med. 2005, 353: 988-998. 10.1056/NEJMoa050078.
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Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, Fanaroff AA, Poole WK, Wright LL, Higgins RD, et al: Whole-Body Hypothermia for Neonates with Hypoxic-Ischemic Encephalopathy. N Engl J Med. 2005, 353: 1574-1584. 10.1056/NEJMcps050929.
Moss RL, Dimmitt RA, Barnhart DC, Sylvester KG, Brown RL, Powell DM, Islam S, Langer JC, Sato TT, Brandt ML, et al: Laparotomy versus Peritoneal Drainage for Necrotizing Enterocolitis and Perforation. N Engl J Med. 2006, 354: 2225-2234. 10.1056/NEJMoa054605.
Vesikari T, Matson DO, Dennehy P, Van Damme P, Santosham M, Rodriguez Z, Dallas MJ, Heyse JF, Goveia MG, Black SB, et al: Safety and Efficacy of a Pentavalent Human-Bovine (WC3) Reassortant Rotavirus Vaccine. N Engl J Med. 2006, 354: 23-33. 10.1056/NEJMoa052664.
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The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2431/9/77/prepub
We would like to thank Lisa Tsjovold (Edmonton) for help with the search strategy, and Dr. M. W. Tanck (Amsterdam) for statistical advice.
Ricardo M. Fernandes is supported by the Calouste Gulbenkian Foundation (Programme for Advanced Medical Education; http://www.gulbenkian.pt.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
The authors declare that they have no competing interests.
All authors contributed towards the conception and design of the study and the interpretation of the data. They also read, edited and approved the final manuscript. RF performed the full-text search. RF and JL identified relevant studies and participated in the data extraction and data analysis. RF drafted the manuscript.