Journal of Perinatology (2010) 30, 163–169 r 2010 Nature Publishing Group All rights reserved. 0743-8346/10 $32 www.nature.com/jp ORIGINAL ARTICLE Variation among institutional review boards in evaluating the design of a multicenter randomized trial

AR Stark1, JE Tyson2 and PL Hibberd3 1Department of Pediatrics, Section of Neonatology, Baylor College of Medicine, Houston, TX, USA; 2Center for and Evidence Based Medicine, University of Texas Health Science Center at Houston Medical School, Houston, TX, USA and 3Center for Global Health Research, Tufts University School of Medicine, Boston, MA, USA

appropriate because institutional IRBs reflect local values in Objective: The objective of the study was to examine the variation among assessing potential risks and benefits. However, less desirable institutional review boards (IRBs) in evaluation of the study design of a reasons for variation may be due to the difficulty for local IRBs to multicenter trial. include the expertise needed to review the full range of research Study Design: We assessed the first written response of local IRBs to questions that might be asked or study designs that might be used. each site investigator for a multicenter trial of vitamin A supplementation Variation among IRBs is of particular concern in large in extremely low birth weight (ELBW) infants performed by the National randomized multicenter trials, especially those involving high-risk, Institute of Child Health and Human Development Neonatal Research vulnerable populations in which the assessment of the risk–benefit Network. Each author of this paper independently reviewed and ratio may be most important. To understand the causes categorized IRB concerns as major, minor or none, according to the contributing to variation in evaluating the design of such trials, we predefined criteria. systematically examined the variation in IRB review of a multicenter randomized trial performed in extremely low birth Result: Initially, 9 of 18 IRBs withheld approval because of at least one weight (ELBW) newborns by the National Institute of Child Health major concern. These concerns reflected difficulties in evaluating specific and Human Development Neonatal Research Network.13,14 scientific issues for the design of the trial, including its justification, Although this analysis was completed during the trial, we present enrollment criteria, control and experimental therapies, co-interventions, this information because of the increasing interest in promoting toxicity assessment, outcome monitoring and informed consent. rigorous testing of interventions used in high-risk populations, Conclusion: The difficulty in assessing appropriate trial design for the because of the paucity of data regarding IRB review of trial design, specific hypothesis under investigation resulted in considerable variability and also because recent publications of IRB variation in the review in the evaluation by local IRBs. of observational or minimal risk studies6–11 indicate that the type Journal of Perinatology (2010) 30, 163–169; doi:10.1038/jp.2009.157; of difficulties in the IRB review illustrated by this trial continue published online 1 October 2009 today.

Keywords: multicenter ; institutional review board; study design Methods Introduction Description of the trial evaluated by IRBs At the time the trial was proposed, vitamin A was not widely used in Local institutional review boards (IRBs) vary considerably in their 1–11 preterm infants, although a meta-analysis of several small trials review of the same proposal for a multicenter study. Variation identified an improved survival without chronic lung disease.15 The in the informed consent form has received considerable 8,12 primary hypothesis was that supplementation with vitamin A would attention. However, little information is available regarding increase survival without chronic lung disease among ELBW other differences in the review process and their importance, infants who need early respiratory support.13,14 The eligible infants especially in assessing study design. Some variation may be weighed 401 to 1000 g and required assisted ventilation or Correspondence: Professor AR Stark, Department of Pediatrics, Section of Neonatology, Baylor supplemental oxygen at 24 h of age. Exclusion criteria were major College of Medicine, Texas Children’s Hospital, 6621 Fannin, Mail code WT6-104, Houston, congenital anomaly, congenital nonbacterial infection, terminal TX 77030, USA. illness, vitamin A administration in lipid emulsion or in amounts E-mail: [email protected] Received 31 March 2009; revised 8 August 2009; accepted 13 August 2009; published online 1 exceeding that in standard doses of multivitamins or parental October 2009 refusal of consent. Infants were randomly assigned at 24 to 96 h of Institutional review board variation AR Stark et al 164 age to intervention or control groups after stratification by birth study background and rationale, study design, inclusion or weight and center. Infants in the intervention group received exclusion criteria, interventions, sample size, analysis, data safety 5000 IU (0.1 ml) vitamin A intramuscularly with a 29-gauge monitoring or other issues that required further justification or needle three times weekly for 4 weeks, a dose established by a clarification. We considered concerns about the to be preceding pilot study.15 Infants in the control group received minor if they involved questions about administrative issues or simulated injections. To maintain masking, the research nurse further clarification of the protocol. We also reviewed changes administered treatment with a screen around the bed, used a requested in the consent form. To assess concordance, a third pacifier to minimize crying and placed a band-aid over the actual reviewer (PLH), who was not associated with the network and who or simulated injection site that the research nurse removed at the was masked to the identity of the sites, evaluated the letters and time of the next dose. Measurement of serum vitamin A levels and classified responses using the same criteria. Any differences in the retinol dose-response testing were performed in the first 300 evaluation were resolved through discussion and consensus subjects, and masked investigators performed weekly physical agreement. examinations on all infants to assess potential clinical toxicity. An independent data safety and monitoring committee appointed by Results the National Institute of Child Health and Human Development In all, 7 of the 18 IRBs expressed no concerns about the study reviewed data and adverse events at specified intervals. The final results indicated that the vitamin A regimen tested had no protocol. Initially, nine raised at least one major concern that needed to be addressed by the local investigator before the trial discernible toxicity and decreased the risk of chronic lung disease ( 0.89, 95% confidence interval 0.80 to 0.99, number could be approved and initiated. Two IRBs had only minor needed to treat 14 to 15). concerns, requesting clarification about sample size or drug dosing. All except two IRBs required modifications of the consent Process of protocol review before IRB review form to address major or minor concerns. The protocol was Implementation of the trial followed a standardized process that subsequently approved at all sites without any changes in study involved a much more extensive critique of study design than for design. most studies submitted to IRBs.16 Network investigators evaluated There was complete concordance among the three reviewers the proposal and provided written critique to the study principal regarding classification of the concerns as major, minor or related investigator (PI). A subcommittee was formed to assist the PI, and to the consent form. The major IRB concerns were related to basic additional critique was obtained from the member neonatology scientific issues in the design of clinical trials (see Table 1). divisions and from external reviewers with expertise in trial design, neonatal disease and treatment and vitamin A research. Before Discussion submission to any IRB, the protocol was approved by the entire Despite extensive previous review, IRBs varied substantially in the network steering committee and an external advisory board. concerns expressed about the study. Although we cannot entirely Before implementation, site PIs at the 14 network centers exclude the possibility that lack of clarity persisted despite this submitted the protocol to 18 IRBs responsible for the research in review and contributed to variation in responses, we think that participating hospitals. The protocol included an extensive these concerns may reflect the need for additional expertise to assist discussion of the rationale for the study design related to in evaluating the trial design for the specific intervention, disorder, background information about vitamin A, the results of previous population and outcome under investigation. neonatal studies of vitamin A, the need for an effectiveness trial, the selection of the primary and secondary outcomes, the basis for What distinguishes ‘experimental’ from ‘standard’ therapies? the vitamin A regimen, the assessment of safety and the avoidance In considering whether the trial was justified, three IRBs required of caregiver and assessor bias. The study PI prepared a general the site investigator to specify whether vitamin A supplementation consent form describing the protocol and potential risks and was the standard of care for ELBW infants in that center. However, benefits, which the investigators at each site modified to meet local the central issue is the strength of the evidence supporting vitamin requirements. However, the protocol was identical at all centers. A supplementation, rather than the treatment preference of local neonatologists. As Freedman17 noted, ‘The ethics of medical Evaluation of IRB review practice grants no ethical or normative meaning to treatment The authors evaluated the first written response addressed to each preference, however powerful, that is based on a hunch or anything network site PI from their local IRB(s) after review of the protocol less than evidence publicly presented and convincing to the clinical and consent forms. Two of the researchers (ARS, JET) categorized community’. concerns raised by each IRB about the protocol a priori as major, In all areas of medicine,18,19 including neonatology,20,21 many minor or none. Major issues involved fundamental questions about commonly used therapies have been later shown to be harmful.

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Table 1 Major IRB concerns that required investigator response before approval and the associated fundamental questions in study design

Major concerns Related design question

Justification for trial Asked whether vitamin A supplementation was ‘standard of care’ in the local site (3 IRBs) What distinguishes experimental from standard therapies? Thought study should not be performed on the grounds that vitamin A supplementation When should a clinical trial be performed? has established benefit (1 IRB) Thought study should not be performed on the grounds that there was insufficient prior As above research to assure that the hazards would not far exceed any benefits (1 IRB)

Control and experimental therapies Questioned the use of sham rather than placebo injection for controls (1 IRB) When should a placebo or a sham procedure be used?

Co-interventions Recommended control of dietary intake of vitamin A (2 IRBs) What aspects of care should be controlled in effectiveness trials other than the intervention under investigation?

Enrollment criteria Requested rationale for enrollment of patients <500 g birth weight as this might encourage What population should be enrolled? What is the role of the IRB use of intensive care for infants too immature to benefit (1 IRB) in this decision?

Evaluation of toxicity Thought serial vitamin A blood levels should be measured in all subjects (2 IRBs) How should normal and abnormal values be defined and distinguished? How should toxicity be assessed?

Informed consent process and document Required detailed information on aspects such as randomization method, sample size or What information about study design and support should be withdrawal criteria (multiple IRBs); disallowed statement of potential benefit from extra provided in seeking informed consent? monitoring (multiple IRBs); disallowed statement of NIH funding (1 IRB); disallowed use of separate pamphlet describing trial (1 IRB)

Monitoring, termination of trial Wanted interim outcome data for infants in each treatment group in local site (1 IRB) What is the role of the local IRB and of the data safety monitoring committee in a multicenter trial?

Abbreviations: IRB, institutional review board; NIH, National Institutes of Health.

Accordingly, the Institutional Review Guidebook of the National and meta-analysis of previously published Institutes of Health defines experimental as a ‘term often used to trials.15,23 In contrast, a second IRB initially withheld approval denote a therapy (drug, device, procedure) that is unproven or not because the evidence supporting routine supplementation was yet scientifically validated with respect to safety and efficacy’.22 The considered too weak to justify its use in the proposed trial. This IRB Guidebook also notes that a therapy may be considered was particularly concerned about the possibility of unidentified experimental ‘without necessarily being part of a formal study toxicity. The first IRB eventually approved the protocol, in part (research) to evaluate its usefulness’. Using similar rationale, it because the dose in the proposed trial might be more effective than would be preferable to refer to commonly used but unproven in most previous trials, the results of the meta-analysis were only therapies as ‘conventional treatment’ rather than ‘standard of care’ marginally significant, no large trials had been performed and in protocols submitted to the IRB. This may avoid any suggestion small trials with negative results are less likely to be published that such treatment is necessarily beneficial or even properly tested. promptly or published at all than are trials with positive results.24 The second IRB approved the proposed trial after reconsidering the When should a clinical trial be performed? results of all previous trials. One IRB initially withheld approval because the evidence In general, a clinical trial is warranted if there is sufficient but supporting routine vitamin A supplementation was considered too not definitive evidence that the intervention to be assessed would compelling to withhold its use. This judgment was based on a have a favorable risk–benefit ratio in the population to be

Journal of Perinatology Institutional review board variation AR Stark et al 166 enrolled. Justification to perform this trial was considered in depth circumstances. Thus, other aspects of care (co-interventions) are by the Neonatal Research Network investigators during the often closely controlled. Effectiveness trials (also known as development and extensive internal and external review of the management trials), such as the vitamin A trial, are conducted to protocol before submission to the IRBs at each site. Considerable determine whether an intervention is effective under usual clinical training, skill and effort are often required to identify and evaluate circumstances (‘real-world conditions’). Such trials are needed to the best relevant evidence25,26 and to assess and balance the determine whether a therapy should be recommended for routine potential hazards and benefits27,28 of interventions proposed for clinical use. study. Routine involvement of a central body to provide an expert review of multicenter trials29–31 has been proposed to assure the Which patients should be enrolled? availability of these skills for trials being assessed at local sites. One IRB initially questioned the enrollment of infants <500 g of birth weight on the grounds that their inclusion in the trial might When should a placebo be used? prompt use of intensive care within or outside Network centers for One IRB initially suggested using intramuscular injections of infants too small or immature to benefit. We consider this concern placebo rather than the sham procedure proposed in the protocol. inappropriate for several reasons. First, many centers have provided Whether a placebo or sham procedure should be used in trials may intensive care to selected infants with a birth weight <500 g. The involve complex clinical, ethical and methodological issues.32 In majority of these infants develop chronic lung disease that might this case, reviewers with the relevant clinical and methodological be ameliorated by vitamin A supplementation. The study was expertise agreed that the sham procedure was preferred because designed to be broadly generalizable to ELBW infants, including placebo solutions previously thought to be innocuous might have the smallest patients, who were given intensive care. Second, there harmful effects in small premature infants;33 the pain resulting was little basis to believe the enrollment criteria for the proposed from intramuscular injections of placebo might have important trial would alter decisions to administer intensive care. Finally, the adverse effects in high-risk newborns;34 such injections would designated responsibilities of IRBs22 do not specify consideration of reduce the acceptability of the study to parents and caregivers; and whether the enrollment criteria or results would be misused in the sham procedure would impose minimal, if any, risk, and clinical practice. assure that unmasking would be uncommon and unlikely to affect the primary outcome under investigation.35 How should normal and abnormal values be distinguished? How should toxicity be assessed? What aspects of care (other than the intervention under Two IRBs initially recommended obtaining serial assessments of investigation) should be controlled? serum vitamin A concentrations in all patients to distinguish those Several IRBs were concerned that vitamin A provided by milk with abnormal or toxic values from those with normal values. feedings should be controlled by the study protocol. This approach Such a recommendation was problematic for several reasons. First, would have been inappropriate for several reasons. The study was the IRB did not indicate what is meant by the term ‘abnormal designed as an effectiveness trial to assess the effects of an values’. This term can have different meanings depending on intramuscular regimen of vitamin A supplementation on ELBW whether it is defined in terms of values that are unusual (for infants whose feedings were regulated by their clinical team. example, values not within 2 s.d. of the mean), values associated Enteral intake of vitamin A would be difficult to determine and with increased risk, values that cause adverse outcomes or values regulate because the concentration in human milk is variable, that warrant treatment (values for which the benefits of treatment many ELBW infants have prolonged feeding intolerance and poor exceed the hazards, a definition that may well be established only enteral absorption of vitamin A and intravenous administration is by conducting randomized trials as we proposed).38 A second unreliable (a reason that vitamin A administration was problem is that there may not be adequate research to differentiate intramuscular in the trial).13 Moreover, feeding tolerance and normal from abnormal values, regardless of the type of definition dietary intake of vitamin A and other nutrients were considered used. In premature infants, the values that would be considered outcome variables that might be influenced by the effect of abnormal by the last three definitions above are unclear, and intramuscular vitamin A administration on the development of cannot be extrapolated from term infants or older patients.13 For chronic lung disease, sepsis or necrotizing enterocolitis.13 this reason, the identification of any vitamin A toxicity in the trial Whether other aspects of clinical care should be controlled was based primarily on serial detailed assessments performed by depends upon whether the clinical trial is being conducted as an masked and experienced evaluators. In this way, values obtained in efficacy or an effectiveness trial.19,36,37 Early randomized trials of any infants with signs of toxicity could be compared with values of new therapies are usually small efficacy trials (also known as infants without signs of toxicity. The most sensitive sign of vitamin explanatory trials). These trials are conducted to determine A toxicity in infants is an increase in fontanelle tension.39–41 whether or how an intervention works under ideal or restricted Fortunately, such signs were very uncommon and no more

Journal of Perinatology Institutional review board variation AR Stark et al 167 frequent among supplemented than control infants and a lower analyses and reporting their conclusions to the site PIs and their proportion of supplemented infants had blood levels considered to local IRBs.7,49,51,52 be low at older ages. In providing data for serum retinol at the end In conclusion, we observed considerable variation among IRBs of treatment, the study helped define values that would be within in their concerns about scientific issues involved in the design of a the range of normal defined in terms of values that warrant multicenter trial. This variation might have been substantially treatment. greater had the design and description of the proposal been less thoroughly critiqued before submission or described in less detail in What information should be provided about study design the protocol provided to each IRB. With their increasing work load, during the process of seeking informed consent? IRBs face increasing difficulty in recruiting members and Modifications of the consent form to meet local institutional accomplishing timely reviews. Given the extremely wide range of requirements are always appropriate. However, IRBs varied in their clinical problems and potential interventions, the complexity of the responses to the content of the form. Some IRBs required detailed biological, clinical and design issues and the necessarily limited descriptions of the randomization procedure, withdrawal criteria or availability of expertise within any institution to address all these the criteria used to evaluate the outcome of the study. One IRB issues, the evaluation of multicenter clinical trials may be quite initially disallowed a statement that the National Institutes of challenging and burdensome for individual IRBs. Furthermore, Health provided funding for the study. Several IRBs disallowed a because large academic centers often have multiple IRBs, statement that the potential benefits to participants were the variability might worsen even within single institutions. additional examinations, monitoring and evaluation during the One potential solution applicable to multicenter trials is to neonatal period and follow-up evaluations of health and involve a central body to provide scientific, and perhaps also development through 18 to 22 months corrected age. One IRB ethical, review of the protocols.4,28,30,31,53,54 The extent to which the initially stipulated wording changes not appropriate for newborns IRB chose to rely on this review body could vary, depending on (for example, noting ‘fainting’ as a hazard of collecting blood local expertise and the specific study protocol. In this way, the local samples). IRB might more efficiently use its limited personnel, time and The value or justification for some of these requirements is resources to assure that high ethical standards were met in seeking debatable.42–45 Whatever the potential benefits of participating in consent and in performing the study while maintaining its our trial, further research is needed to determine whether or not authority.55,56 patients enrolled in clinical trials generally have better overall outcomes than otherwise similar patients not enrolled in such trials.46 At least one study has shown that outcomes of sick Conflict of interest newborns assigned to the placebo arm of a randomized trial were The authors declare no conflict of interest. better than those of eligible infants who were not randomized.47 Additional study is required to define the information that is justified, understandable and beneficial in seeking consent, Acknowledgments especially in highly stressful circumstances such as those 42,48 The National Institutes of Health and the National Institute of Child Health experienced by parents of ELBW infants. and Human Development provided grant support for recruitment and data analysis for the Neonatal Research Network’s Vitamin A Supplementation Study What is the role of the local IRB in evaluating adverse events in for 1996 and 1997. The funding agencies provided overall oversight for study a multicenter trial? conduct, but all data analyses and interpretation were independent of the funding One IRB planned to obtain interim outcome data for each agencies. We are indebted to our medical and nursing colleagues and the infants treatment group in that study center, if not all study centers. These and their parents who agreed to take part in this study. The following investigators responses indicate the ambiguity in the role of the local IRB participated in this study: NRN Steering Committee Chair: Alan Jobe, University relative to that of the data safety and monitoring committee. There of Cincinnati; Brown University Women & Infants Hospital of Rhode Island has been considerable dismay expressed about the requirement for (U10 HD27904)FWilliam Oh and Angelita Hensman; Case Western Reserve local IRBs to monitor adverse events in their center in multicenter University Rainbow Babies & Children’s Hospital (GCRC M01 RR80, U10 F trials.49,50 These IRBs are often not staffed adequately or provided HD21364) Avroy A Fanaroff, Michele C Walsh and Nancy S Newman; Emory University Children’s Healthcare of Atlanta, Grady Memorial Hospital, and Emory sufficient resources to evaluate those events. They may also lack Crawford Long Hospital (GCRC M01 RR39, U10 HD27851)FBarbara J Stoll and the information required, particularly for masked trials, such as Ellen Hale; Harvard Medical School Brigham and Women’s Hospital (GCRC M01 this one, in which the IRB does not know the treatment received by RR2172, GCRC M01 RR2635, U10 HD34167)FAnn R Stark and Kerri Fournier; 51 individual patients. These problems can be obviated if, as in this Indiana University Indiana University Hospital, Methodist Hospital, Riley trial, a central data safety and monitoring committee is responsible Hospital for Children, and Wishard Health Services (GCRC M01 RR750, U10 for evaluating adverse events across all sites, conducting interim HD27856)FJames A Lemons and Diana D Appel; National Institute of Child

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