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Opening research sites in multicentre clinical trials within the UK: a detailed analysis of delays.

ABSTRACT: To investigate the length of time taken to open UK research sites in multicentre clinical trials and to identify reasons for any delays.A case study, recording key milestone dates from the time a site receives ethical approval through to opening to recruitment. Delay reasons were prospectively logged by trial staff at a minimum of fortnightly periods using a coding system.SANADII, a phase IV pragmatic trial, managed by the Clinical Trials Research Centre, Liverpool. The trial seeks to work with over 100 National Health Service (NHS) sites to meet its recruitment target of 1510 patients.The primary outcome was time from Multicentre Regional Ethics Committee (MREC) approval to site opening using survival analysis. Where sites took over a specified time to reach milestones (>3 months from MREC to Site Specific Information (SSI) submission, >30 days from SSI validation to local R&D approval, or >30 days from local Research and Development (R&D) approval to opening to recruitment), the longest continuous delay during that milestone was identified.The median opening time for participating sites was 9.7 months (IQR 6.2 to Not Reached). SSI submission took 7 months (IQR 4.1-12.3) from ethics approval, R&D approval took 16 days (IQR 5.0-32.0) from SSI validation and site opening took 15 days (IQR 8.5-40.0) following R&D approval. The longest delays before SSI submission resulted from negotiating excess treatment costs, finalising logistics, collecting CVs and ongoing participation discussions.While recently imposed targets are reducing the time taken for R&D departments to approve valid applications, the time taken to open UK research sites remains excessive and must be reduced. At present significant public funds are being used inefficiently in order to navigate NHS systems, challenging the resolve of trial teams and the competitiveness of the UK.

SUBMITTER: Kearney A

PROVIDER: S-EPMC4166133 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Opening research sites in multicentre clinical trials within the UK: a detailed analysis of delays.

Kearney Anna A McKay Andrew A Hickey Helen H Balabanova Silviya S Marson Anthony G AG Gamble Carrol C Williamson Paula P

BMJ open 20140916 9

<h4>Objective</h4>To investigate the length of time taken to open UK research sites in multicentre clinical trials and to identify reasons for any delays.<h4>Design</h4>A case study, recording key milestone dates from the time a site receives ethical approval through to opening to recruitment. Delay reasons were prospectively logged by trial staff at a minimum of fortnightly periods using a coding system.<h4>Setting</h4>SANADII, a phase IV pragmatic trial, managed by the Clinical Trials Research ...[more]

PMID: 25227630

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Project description:When planning a multicentre clinical trial, it can be difficult to predict the time needed to open individual sites, and this in turn impacts on the total number of sites needed, the budget and the time frame for a clinical trial to be delivered successfully. This is of particular importance for funding applications with a limited time frame and budget such as NIHR RfPB. It is more efficient and cost-effective to open the total number of sites needed at the outset of a trial, rather than to respond later to slow site opening and recruitment. Here, we share our experience of successfully delivering a multicentre clinical trial for a rare disease within a limited time frame and budget by approximately doubling the number of sites initially predicted to be needed. We initially predicted 20 sites would be needed to deliver the clinical trial, but early on in the trial, the number of sites was more than doubled to allow successful recruitment of the target sample size within the desired time frame. Of the 48 ethically approved sites, the median time from ethical approval of a site to opening for recruitment was 182?days (95% confidence interval [143 to 245?days]) and ranged from 18 to 613?days. In four (9%) of these sites, part of the delay was due to pharmacy sign off not being given when R&D had issued capacity and capability (C&C). Delays due to pharmacy sign off varied from 10?days to over 3 months delay in two sites (94?days and 102?days). A mathematical solution to the problem of planning a study with a short recruitment window has been given to support the planning and costing of grants with fixed time constraints: number of sites?=?required sample size divided by (number of eligible patients per site per month times recruitment rate times (the number of months accrual minus 6?months)). We expect these results to help others who are planning multicentre clinical trials in the UK. Ethical approval from NRES Committee South West (IRAS number 225959). TRIAL REGISTRATION: EudraCT Number 2017-001171-23 . Registered on 26 June 2017.

Project description:ObjectivesTo assess the completeness of reporting of sample size determinations in unpublished research protocols and to develop guidance for research ethics committees and for statisticians advising these committees.DesignReview of original research protocols.Study selectionUnpublished research protocols for phase IIb, III, and IV randomised clinical trials of investigational medicinal products submitted to research ethics committees in the United Kingdom during 1 January to 31 December 2009.Main outcome measuresCompleteness of reporting of the sample size determination, including the justification of design assumptions, and disagreement between reported and recalculated sample size.Results446 study protocols were reviewed. Of these, 190 (43%) justified the treatment effect and 213 (48%) justified the population variability or survival experience. Only 55 (12%) discussed the clinical importance of the treatment effect sought. Few protocols provided a reasoned explanation as to why the design assumptions were plausible for the planned study. Sensitivity analyses investigating how the sample size changed under different design assumptions were lacking; six (1%) protocols included a re-estimation of the sample size in the study design. Overall, 188 (42%) protocols reported all of the information to accurately recalculate the sample size; the assumed withdrawal or dropout rate was not given in 177 (40%) studies. Only 134 of the 446 (30%) sample size calculations could be accurately reproduced. Study size tended to be over-estimated rather than under-estimated. Studies with non-commercial sponsors justified the design assumptions used in the calculation more often than studies with commercial sponsors but less often reported all the components needed to reproduce the sample size calculation. Sample sizes for studies with non-commercial sponsors were less often reproduced.ConclusionsMost research protocols did not contain sufficient information to allow the sample size to be reproduced or the plausibility of the design assumptions to be assessed. Greater transparency in the reporting of the determination of the sample size and more focus on study design during the ethical review process would allow deficiencies to be resolved early, before the trial begins. Guidance for research ethics committees and statisticians advising these committees is needed.

Project description:BACKGROUND:Recent multisite trials reveal striking heterogeneities in results between trial sites. These may be because of population differences indicating different treatment benefits among different types of participants or site anomalies, such as failures to adhere to study protocols that could negatively affect study validity. We sought to determine whether a new data analysis strategy-transportability methods-could suggest site anomalies not readily identified through standard methods. METHODS AND RESULTS:We applied transportability methods to 2 large, multicenter cardiovascular disease treatment trials: the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist; n=3445) comparing spironolactone to placebo for heart failure (for which site anomalies were suspected) and the ACCORD BP trial (Action to Control Cardiovascular Risk in Diabetes-Blood Pressure; n=4733) comparing intensive-to-standard blood pressure treatment (for which site anomalies were not suspected). The transportability methods give expected results by standardizing from one site to another using data on participant covariates. The difference between the expected and observed results was assessed using calibration tests to identify whether treatment-effect differences between sites could be explained by participant population characteristics. Standard regression methods did not detect heterogeneities in TOPCAT between Russia/Georgia study sites suspected of study protocol violations and sites in the Americas ( P=0.12 for difference in primary cardiovascular outcome; P=0.20 for difference in total mortality). The transportability methods, however, detected the difference between Russia/Georgia sites and sites in the Americas ( P<0.001) and found that measured participant characteristics did not explain the between-site discrepancies. The transport methods found no such discrepancies between sites in ACCORD BP, suggesting participant characteristics explained between-site differences. CONCLUSIONS:Transportability methods may be superior to standard approaches for detecting anomalies within multicenter randomized trials and assist data monitoring boards to determine whether important treatment-effect heterogeneities can be attributed to participant differences or potentially to site performance differences requiring further investigation.

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Opening research sites in multicentre clinical trials within the UK: a detailed analysis of delays.

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Opening research sites in multicentre clinical trials within the UK: a detailed analysis of delays.

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