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Adaptive designs are a class of methods for improving efficiency and patient benefit of clinical trials. Although their use has increased in recent years, research suggests they are not used in many situations where they have potential to bring benefit. One barrier to their more widespread use is a lack of understanding about how the choice to use an adaptive design, rather than a traditional design, affects resources (staff and non-staff) required to set-up, conduct and report a trial. The Costing Adaptive Trials project investigated this issue using quantitative and qualitative research amongst UK Clinical Trials Units. Here, we present guidance that is informed by our research, on considering the appropriate resourcing of adaptive trials. We outline a five-step process to estimate the resources required and provide an accompanying costing tool. The process involves understanding the tasks required to undertake a trial, and how the adaptive design affects them. We identify barriers in the publicly funded landscape and provide recommendations to trial funders that would address them. Although our guidance and recommendations are most relevant to UK non-commercial trials, many aspects are relevant more widely.

Additional file 1. Brief overview of each scenario used in the Costing Adaptive Trials mock costing exercise.

Additional file 1. Trials whose staff experiences added to this paper.

Additional file 1. Scenarios and guidance pre-revision.

BackgroundSite performance is key to the success of large multicentre randomised trials. A standardised set of clear and accessible summaries of site performance could facilitate the timely identification and resolution of potential problems, minimising their impact.The aim of this study was to identify and agree a core set of key performance metrics for managing multicentre randomised trials.MethodsWe used a mixed methods approach to identify potential metrics and to achieve consensus about the final set, adapting methods that are recommended by the COMET Initiative for developing core outcome sets in health care.We used performance metrics identified from our systematic search and focus groups to create an online Delphi survey. We invited respondents to score each metric for inclusion in the final core set, over three survey rounds. Metrics scored as critical by ?70% and unimportant by 50% of participants voting for inclusion were retained.ResultsRound 1 of the Delphi survey presented 28 performance metrics, and a further six were added in round 2. Of 294 UK-based stakeholders who registered for the Delphi survey, 211 completed all three rounds.At the consensus meeting, 17 metrics were discussed and voted on: 15 metrics were retained following survey round 3, plus two others that were preferred by consensus meeting participants. Consensus was reached on a final core set of eight performance metrics in three domains: (1) recruitment and retention, (2) data quality and (3) protocol compliance. A simple tool for visual reporting of the metrics is available from the Nottingham Clinical Trials Unit website.ConclusionsWe have established a core set of metrics for measuring the performance of sites in multicentre randomised trials. These metrics could improve trial conduct by enabling researchers to identify and address problems before trials are adversely affected. Future work could evaluate the effectiveness of using the metrics and reporting tool.

Background: The ethical basis of randomised controlled \ud trials is \ud equipoise, \ud whether \ud at the collective or individual level. Neonatal intensive \ud care \ud trials \ud are \ud therefore \ud conducted in a context of clinical uncertainty as \ud well as stress \ud and trauma. \ud The \ud theoretical literature suggests that tensions \ud exist \ud in the trials \ud situation \ud between the \ud aims of care and research. \ud Objectives: To improve understanding \ud of \ud decisions that \ud clinicians \ud and \ud parents make \ud about neonatal trial collaboration, participation \ud and \ud non-participation. \ud Methods: Semi-structured interviews were conducted \ud with \ud 30 \ud neonatologists \ud and \ud 63 \ud parents from 5 UK hospitals who \ud were \ud offered enrolment \ud in the INNOVO \ud and/or \ud CANDA trials. Qualitative analysis \ud was aided \ud by ATLAS-ti. \ud Results: The neonatologists' interviews suggested an \ud intermediate level \ud of equipoise. \ud A therapeutic orientation operated \ud for the INNOVO Trial \ud but \ud not \ud for the \ud CANDA \ud Trial. Neonatologists often did not \ud connect trial \ud participation and trial-related \ud postmortem pathology studies. Most parents made very \ud rapid \ud decisions \ud about trial \ud participation. Perception of risk was \ud independent \ud of the trial \ud under \ud consideration \ud but \ud associated with a slower decision-making process. \ud The 'therapeutic \ud misconception' \ud was present for parents in both trials. Many \ud supported \ud contributing to \ud research. \ud For \ud some of the bereaved parents, this extended \ud to \ud contribution to trial-related \ud pathology \ud studies. Parents who declined the \ud CANDA \ud Trial \ud saw \ud risks \ud in the trial \ud situation. \ud Conclusions: Decisions were complex \ud and \ud multi-tiered. \ud The \ud boundaries \ud between \ud care \ud and research were often unclear for neonatologists \ud and \ud parents. \ud Clarification \ud of the \ud nature of decisions at the heart of clinical trials is \ud needed, \ud so that those \ud associated \ud with \ud research might be willing collaborators and \ud participants, \ud fully \ud cognisant \ud of the \ud activity \ud in which they are engage

BACKGROUND: Tamoxifen, taken for five years, is the standard adjuvant treatment for postmenopausal women with primary, estrogen-receptor-positive breast cancer. Despite this treatment, however, some patients have a relapse. METHODS: We conducted a double-blind, randomized trial to test whether, after two to three years of tamoxifen therapy, switching to exemestane was more effective than continuing tamoxifen therapy for the remainder of the five years of treatment. The primary end point was disease-free survival. RESULTS: Of the 4742 patients enrolled, 2362 were randomly assigned to switch to exemestane, and 2380 to continue to receive tamoxifen. After a median follow-up of 30.6 months, 449 first events (local or metastatic recurrence, contralateral breast cancer, or death) were reported--183 in the exemestane group and 266 in the tamoxifen group. The unadjusted hazard ratio in the exemestane group as compared with the tamoxifen group was 0.68 (95 percent confidence interval, 0.56 to 0.82; P

Background Early research in adults admitted to intensive care suggested that tight control of blood glucose during acute illness can be associated with reductions in mortality, length of hospital stay and complications such as infection and renal failure. Prior to our study, it was unclear whether or not children could also benefit from tight control of blood glucose during critical illness. Objectives This study aimed to determine if controlling blood glucose using insulin in paediatric intensive care units (PICUs) reduces mortality and morbidity and is cost-effective, whether or not admission follows cardiac surgery. Design Randomised open two-arm parallel group superiority design with central randomisation with minimisation. Analysis was on an intention-to-treat basis. Following random allocation, care givers and outcome assessors were no longer blind to allocation. Setting The setting was 13 English PICUs. Participants Patients who met the following criteria were eligible for inclusion: ≥ 36 weeks corrected gestational age; ≤ 16 years; in the PICU following injury, following major surgery or with critical illness; anticipated treatment > 12 hours; arterial line; mechanical ventilation; and vasoactive drugs. Exclusion criteria were as follows: diabetes mellitus; inborn error of metabolism; treatment withdrawal considered; in the PICU > 5 consecutive days; and already in CHiP (Control of Hyperglycaemia in Paediatric intensive care). Intervention The intervention was tight glycaemic control (TGC): insulin by intravenous infusion titrated to maintain blood glucose between 4.0 and 7.0 mmol/l. Conventional management (CM) This consisted of insulin by intravenous infusion only if blood glucose exceeded 12.0 mmol/l on two samples at least 30 minutes apart; insulin was stopped when blood glucose fell below 10.0 mmol/l. Main outcome measures The primary outcome was the number of days alive and free from mechanical ventilation within 30 days of trial entry (VFD-30). The secondary outcomes comprised clinical and economic outcomes at 30 days and 12 months and lifetime cost-effectiveness, which included costs per quality-adjusted life-year. Results CHiP recruited from May 2008 to September 2011. In total, 19,924 children were screened and 1369 eligible patients were randomised (TGC, 694; CM, 675), 60% of whom were in the cardiac surgery stratum. The randomised groups were comparable at trial entry. More children in the TGC than in the CM arm received insulin (66% vs. 16%). The mean VFD-30 was 23 [mean difference 0.36; 95% confidence interval (CI) –0.42 to 1.14]. The effect did not differ among prespecified subgroups. Hypoglycaemia occurred significantly more often in the TGC than in the CM arm (moderate, 12.5% vs. 3.1%; severe, 7.3% vs. 1.5%). Mean 30-day costs were similar between arms, but mean 12-month costs were lower in the TGC than in CM arm (incremental costs –£3620, 95% CI –£7743 to £502). For the non-cardiac surgery stratum, mean costs were lower in the TGC than in the CM arm (incremental cost –£9865, 95% CI –£18,558 to –£1172), but, in the cardiac surgery stratum, the costs were similar between the arms (incremental cost £133, 95% CI –£3568 to £3833). Lifetime incremental net benefits were positive overall (£3346, 95% CI –£11,203 to £17,894), but close to zero for the cardiac surgery stratum (–£919, 95% CI –£16,661 to £14,823). For the non-cardiac surgery stratum, the incremental net benefits were high (£11,322, 95% CI –£15,791 to £38,615). The probability that TGC is cost-effective is relatively high for the non-cardiac surgery stratum, but, for the cardiac surgery subgroup, the probability that TGC is cost-effective is around 0.5. Sensitivity analyses showed that the results were robust to a range of alternative assumptions. Conclusions CHiP found no differences in the clinical or cost-effectiveness of TGC compared with CM overall, or for prespecified subgroups. A higher proportion of the TGC arm had hypoglycaemia. This study did not provide any evidence to suggest that PICUs should stop providing CM for children admitted to PICUs following cardiac surgery. For the subgroup not admitted for cardiac surgery, TGC reduced average costs at 12 months and is likely to be cost-effective. Further research is required to refine the TGC protocol to minimise the risk of hypoglycaemic episodes and assess the long-term health benefits of TGC. Trial registration Current Controlled Trials ISRCTN61735247. Funding This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 26. See the NIHR Journals Library website for further project information.