Issues in data monitoring and interim analysis of trials.

OBJECTIVES: To address issues about data monitoring committees (DMCs) for randomised controlled trials (RCTs). DATA SOURCES: Electronic databases. Handsearching of selected books. Personal contacts with experts in the field. REVIEW METHODS: Systematic literature reviews of DMCs and small group processes in decision-making; sample surveys of: reports of RCTs, recently completed and ongoing RCTs and policies of major organisations involved in RCTs; case studies of four DMCs; and interviews with experienced DMC members. All focused on 23 prestated questions. RESULTS: Although still a minority, RCTs increasingly have DMCs. There is wide agreement that nearly all trials need some form of data monitoring. Central to the role of the DMC is monitoring accumulating evidence related to benefit and toxicity; variation in emphasis has been reflected in the plethora of names. DMCs for trials performed for regulatory purposes should be aware of any special requirements and regulatory consequences. Advantages were identified for both larger and smaller DMCs. There is general agreement that a DMC should be independent and multidisciplinary. Consumer and ethicist membership is controversial. The chair is recognised as being particularly influential, and likely to be most effective if he or she is experienced, understands both statistical and clinical issues, and is facilitating in style and impartial. There is no evidence available to judge suggested approaches to training. The review suggested that costs should be covered, but other rewards must be so minimal as to not affect decision-making. It is usual to have a minimum frequency of DMC meetings, with evidence that face-to-face meetings are preferable. It is common to have open sessions and a closed session. A report to a DMC should cover benefits and risks in a balanced way, summarised in an accessible style, avoiding excessive detail, and be as current as possible. Disadvantages of blinded analyses seem to outweigh advantages. Information about comparable studies should be included, although interaction with the DMCs of similar ongoing trials is controversial. A range of formal statistical approaches can be used, although this is only one of a number of considerations. DMCs usually reach decisions by consensus, but other approaches are sometimes used. The general, but not unanimous, view is that DMCs should be advisory rather than executive on the basis that it is the trial organisers who are ultimately responsible for the conduct of the trial. CONCLUSIONS: Some form of data monitoring should be considered for all RCTs, with reasons given where there is no DMC or when any member is not independent. An early DMC meeting is helpful, determining roles and responsibilities; planned operations can be agreed with investigators and sponsors/funders. A template for a DMC charter is suggested. Competing interests should be declared. DMC size (commonly three to eight people) is chosen to optimise performance. Members are usually independent and drawn from appropriate backgrounds, and some, particularly the chair, are experienced. A minimum frequency of meetings is usually agreed, with flexibility for more if needed. The DMC should understand and agree the statistical approach (and guidelines) chosen, with both the DMC statistician and analysis statistician competent to apply the method. A DMC's primary purpose is to ensure that continuing a trial according to its protocol is ethical, taking account of both individual and collective ethics. A broader remit in respect of wider ethical issues is controversial; arguably, these are primarily the responsibility of research ethics committees, trial steering committees and investigators. The DMC should know the range of recommendations or decisions open to it, in advance. A record should be kept describing the key issues discussed and the rationale for decisions taken. Errors are likely to be reduced if a DMC makes a thorough review of the evidence and has a clear understanding of how it should function, there is active participation by all members, differences are resolved through discussion and there is systematic consideration of the various decision options. DMCs should be encouraged to comment on draft final trial reports. These should include information about the data monitoring process and detail the DMC membership. It is recommended that groups responsible for data monitoring be given the standard name 'Data Monitoring Committee' (DMC). Areas for further research include: widening DMC membership beyond clinicians, trialists and statisticians; initiatives to train DMC members; methods of DMC decision-making; 'open' data monitoring; DMCs covering a portfolio of trials rather than single trials; DMC size and membership, incorporating issues of group dynamics; empirical study of the workings of DMCs and their decision-making, and which trials should or should not have a DMC.

Perinatal pathology in the context of a clinical trial: attitudes of bereaved parents.

BACKGROUND: Interviews with neonatologists in a related study had revealed a degree of discomfort with approaching bereaved parents for postmortem examinations (PMs) and a widespread concern that parents should not be further distressed or feel under pressure to consent. OBJECTIVE: To report the attitudes of bereaved parents to trial related perinatal PMs, in the light of declining perinatal PM rates and poor levels of participation in pathology studies. METHODS: A qualitative study was carried out, using semistructured interviews. The study involved 11 interviews with 18 bereaved parents from five UK neonatal units. The parents had consented to the enrolment of their baby in one of two neonatal trials. RESULTS: The data provide support for the careful approach described by neonatologists in a related study, but also suggest that it may be possible to approach more parents without undermining their wellbeing. The interviews show the variety of reactions to PMs that one would expect, from parents who were clear that they did not want a PM to others who felt that they needed the information from the examination. Between these extremes were parents who were initially discomforted by the idea but who then made the decision to go ahead. Parents who elected to have a PM did so for their own needs, or to contribute to a trial, or for both reasons. The fact that the subject was raised was generally not seen as inappropriate, and none stated that they felt that they were actually pressured into making their decision. The data also suggest that for some parents the degree of caution and selectivity exercised by the neonatologists may not be entirely appropriate. In two cases, consent for the PM was driven by a sense of making an altruistic contribution to research, and, in another two, altruism was expressed in the context of their own desire for information from a PM. CONCLUSIONS: It is important to determine whether trial related pathology studies are considered by professionals and lay people to be worth while and feasible. If there is support for such studies, the challenge is to develop the means to approach more parents in the most sensitive way.

Perinatal pathology in the context of a clinical trial: attitudes of neonatologists and pathologists.

OBJECTIVE: To describe the attitudes of neonatologists to trial related perinatal postmortem examinations (PMs), in the light of declining perinatal PM rates and poor levels of participation in pathology studies. METHODS: A qualitative study was carried out, using semistructured interviews. Twenty six neonatologists from five UK neonatal units were interviewed; five UK perinatal pathologists also contributed to the study. The professionals involved were all linked to one or both of two neonatal trials. RESULTS: Pathologists expressed concern over the difficulties experienced in UK perinatal pathology and the impact on research of inadequate levels of samples. The interviews with neonatologists reveal discomfort over approaching bereaved parents for PMs, and a widespread concern that parents should not be further distressed or feel under pressure to consent. Although there was support for neonatal trials, the study highlights a view that PMs may be unnecessary if the cause of death seems apparent or when a baby was born prematurely, and a devaluation of PMs among some younger staff. Poor rates of participation in pathology studies may be accounted for by a notable sense of disconnection between trial interventions and pathology studies. CONCLUSIONS: Neonatologists were concerned to protect vulnerable parents and varied in whether they saw this as compatible with inclusion in trial related pathology studies. Dedicated research is needed to document and gain an understanding of the consent process and should examine the usefulness and impact of consent forms. It should assess whether professionals might benefit from training, to help parents to come to their decisions.

Perinatal pathology in the context of a clinical trial: a review of the literature.

Perinatal postmortem rates are declining world wide. In the United Kingdom, perinatal pathology has recently been seriously undermined by controversy. There are important consequences for perinatal trials that include pathology studies. This review looks at the reasons for the decline in perinatal postmortem examinations and the effects on research.

Prophylactic use of oxytocin in the third stage of labour.

BACKGROUND: Many maternal deaths across the world result from complications of the third stage of labour (when the placenta is delivered). OBJECTIVES: To examine the effect of oxytocin given prophylactically in the third stage of labour on maternal and neonatal outcomes. SEARCH STRATEGY: Relevant trials were identified in the Cochrane Collaboration Controlled Trials Register and the Pregnancy and Childbirth Review Group's Specialised Register of Controlled Trials. Date of last search: May 2001. SELECTION CRITERIA: All acceptably randomised or quasi-randomised controlled trials including pregnant women anticipating a vaginal delivery where oxytocin was given prophylactically for the third stage of labour. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed studies for relevance and methodological quality, and extracted data. Analysis was by intention to treat. Subgroup analyses were based on extent of selection bias, oxytocin in the context of active or expectant management of the third stage, and timing of administration. Results are presented as relative risks, and weighted mean difference, both with 95% confidence intervals using a fixed effects model. MAIN RESULTS: In seven trials involving over 3000 women in hospital and/or developed country settings, prophylactic oxytocin showed benefits (reduced blood loss (relative risk (RR) for blood loss > 500 ml 0.50; 95% confidence interval (CI) 0.43, 0.59) and need for therapeutic oxytocics (RR 0.50; 95% CI 0.39, 0.64).) compared to no uterotonics, although there was a non-significant trend towards more manual removal of the placenta (RR 1.17; 95% CI 0.79, 1.73) which was most marked in the expectant management subgroup, and blood transfusions (RR 1.30; 95% CI 0.50, 3.39) in the trials with more manual removals of the placenta). In six trials involving over 2800 women, there was little evidence of differential effects for oxytocin versus ergot alkaloids, except ergot alkaloids are associated with more manual removals of the placenta (RR 0.57; 95% CI 0.41, 0.79), and with the suggestion of more raised blood pressure (RR 0.53; 95% CI 0.19, 1.58) than with oxytocin. In five trials involving over 2800 women, there was little evidence of a synergistic effects of adding oxytocin to ergometrine versus ergometrine alone. For all other outcomes in the comparisons either there are no data or the number of adverse events is very small, and so definite conclusions cannot be drawn. REVIEWER'S CONCLUSIONS: There are strong suggestions of benefit for oxytocin in terms of postpartum haemorrhage, and the need for therapeutic oxytocics, but without sufficient information about other outcomes and side-effects it is difficult to be confident about the trade-offs for these benefits, especially if the risk of manual removal of the placenta may be increased. There seems little evidence in favour of ergot alkaloids alone compared to either oxytocin alone, or to Syntometrine, but the data are sparse. More trials are needed in domiciliary deliveries in developing countries, which shoulder most of the burden of third stage complications.

Extending the CONSORT statement to cluster randomized trials: for discussion.

The need for clear reporting of randomized controlled trials has been emphasized recently. The CONSORT Statement has made evidence-based suggestions for a checklist and a patient flow diagram. Adapting this for cluster randomized controlled trials presents particular challenges. Simple changes in the checklist and diagram for the completely randomized two level cluster randomized trials are suggested for discussion. An example taken from an unpublished trial demonstrates that these changes are less simple to implement, although extensions to electronic publications may be helpful. These suggestions should be formally evaluated. Further work is required to consider the cases of more levels and of stratified or pair-matched cluster randomized trials.

The Salford Third Stage Trial. Oxytocin plus ergometrine versus oxytocin alone in the active management of the third stage of labor.

OBJECTIVES: To compare oxytocin plus ergometrine against oxytocin alone, when administered as part of the active management of the 3rd stage of labor, in terms of postpartum hemorrhage and manual removal of the placenta. DESIGN: A double-blind, randomized controlled trial. SETTING: A university teaching hospital: Hope Hospital, Salford. PATIENTS: All women delivering in the hospital over the period of the trial, except those for whom a cesarean section was planned, or who had significant hypertension or cardiac disease. INTERVENTIONS: Syntometrine (5 units of oxytocin with 0.5 mg of ergometrine) versus 5 units of Syntocinon (oxytocin), both given by intramuscular injection with delivery of the anterior shoulder. MAIN OUTCOME MEASURES: Postpartum blood loss, the length of the 3rd stage of labor, and the need for manual removal of the placenta. RESULTS: Four hundred sixty-one women were recruited, 230 allocated to ergometrine plus oxytocin and 231 to oxytocin alone. The duration of the 3rd stage of labor in each group was similar (difference in means 0.2 mins; 95% confidence interval [CI], -1.0 to 1.5) and the need for manual removal of the placenta (odds ratio [OR] 1.21; 95% CI, 0.37 to 4.00). There was less postpartum blood loss in the oxytocin plus ergometrine group, reflected in the lower incidence of primary postpartum hemorrhage (> 500 mL) (OR 0.37; 95% CI, 0.16 to 0.85). CONCLUSIONS: Judged on the basis of this trial alone, oxytocin plus ergometrine is more effective than oxytocin alone in the prevention of postpartum hemorrhage. However, evidence from other trials shows that the ergometrine component not uncommonly has side effects of nausea, vomiting, and raised blood pressure. The implications for practice therefore depend on the relative weights placed on these competing risks by women and clinicians. Further research is needed to quantify these along with research into possible differential effects on longer-term outcomes and into the implications of a higher dose of oxytocin.

Views of mothers and midwives participating in the Bristol randomized, controlled trial of active management of the third stage of labor.

Mothers and midwives who had participated in the Bristol randomized controlled trial of active versus physiologic management of the Third Stage of Labor were asked for their views. One hundred ninety-one mothers (11% of the total randomized) and 49 midwives completed self-administered questionnaires. Both mothers and midwives commented adversely about the length of the third stage under physiologic management. In general, their views were in accord with the conclusions of the main trial (based on clinical data, including maternal blood loss, length of third stage, need for therapeutic oxytocic agents, and specified neonatal morbidity) in favor of continuing with the current practice of active management.

The Bristol third stage trial: active versus physiological management of third stage of labour.

OBJECTIVE: To compare the effects on fetal and maternal morbidity of routine active management of third stage of labour and expectant (physiological) management, in particular to determine whether active management reduced incidence of postpartum haemorrhage. DESIGN: Randomised trial of active versus physiological management. Women entered trial on admission to labour ward with allocation revealed just before vaginal delivery. Five months into trial high rate of postpartum haemorrhage in physiological group (16.5% v 3.8%) prompted modification of protocol to exclude more women and allow those allocated to physiological group who needed some active management to be switched to fully active management. Sample size of 3900 was planned, but even after protocol modification a planned interim analysis after first 1500 deliveries showed continuing high postpartum haemorrhage rate in physiological group and study was stopped. SETTING: Maternity hospital. PARTICIPANTS: Of 4709 women delivered from 1 January 1986 to 31 January 1987, 1695 were admitted to trial and allocated randomly to physiological (849) or active (846) management. Reasons for exclusion were: refusal, antepartum haemorrhage, cardiac disease, breech presentation, multiple pregnancy, intrauterine death, and, after May 1986, ritodrine given two hours before delivery, anticoagulant treatment, and any condition needing a particular management of third stage. INTERVENTIONS: All but six women allocated to active management actually received it, having prophylactic oxytocic, cord clamping before placental delivery, and cord traction; whereas just under half those allocated to physiological management achieved it. A fifth of physiological group received prophylactic oxytocic, two fifths underwent cord traction and just over half clamping of the cord before placental delivery. ENDPOINT: Reduction in incidence of postpartum haemorrhage from 7.5% under physiological management to 5.0% under active management. MEASUREMENTS AND MAIN RESULTS: Incidence of postpartum haemorrhage was 5.9% in active management group and 17.9% in physiological group (odds ratio 3.13; 95% confidence interval 2.3 to 4.2), a contrast reflected in other indices of blood loss. In physiological group third stage was longer (median 15 min v 5 min) and more women needed therapeutic oxytocics (29.7% v 6.4%). Apgar scores at one and five minutes and incidence of neonatal respiratory problems were not significantly different between groups. Babies in physiological group weighed mean of 85 g more than those in active group. When women allocated to and receiving active management (840) were compared with those who actually received physiological management (403) active management still produced lower rate of postpartum haemorrhage (odds ratio 2.4;95% CI1.6 to 3.7). CONCLUSIONS: Policy of active management practised in this trial reduces incidence of postpartum haemorrhage, shortens third stage, and results in reduced neonatal packed cell volume.