Title: Using re-randomisation to increase the recruitment rate in clinical trials
Funder: Department of Health and Social Care

Abstract: Background Randomised controlled trials (RCTs) are considered the gold standard for generating high quality evidence on whether new treatments are effective. However, investigators often struggle to recruit sufficient patients, with up to 45% of publically funded UK RCTs not achieving their target sample size. Poor recruitment can have adverse impacts on patient care. It can delay trial results, leading to delays of successful interventions being adopted as part of routine NHS care, or of unsuccessful or harmful treatments being discontinued. Longer recruitment periods or early discontinuation of trials can lead to higher costs and wasted research funds, resulting in fewer trials being funded overall. Finally, difficulties in recruitment can make conducting trials in rare diseases impractical.Because of these challenges, investigators sometimes allow patients who require further treatment after completion of their initial randomisation period to be enrolled again; this is called re-randomisation. One of the main advantages of this design is that in can increase the recruitment rate. Additionally, because some patients will receive both the intervention and control, a within-patient' comparison is possible (where patients act as their own controls), which can increase the power compared to parallel group trials. This design therefore has the potential to simultaneously increase the recruitment rate while reducing the required sample size compared to a parallel group trial. This could make RCTs more feasible to conduct, particularly for trials in rare diseases.However, there are a number of issues that need to be addressed before this design can be routinely used. There has been little methodological research into this design, and there is currently little guidance on how to design and analyse these trials, on how generalisable results from re-randomisation trials will be, or what the practical considerations are to conducting such trials. This project will address these issues in order to provide researchers and trialists with guidance on how best to conduct re-randomisation trials.Aims Identify optimal methods of analysis for re-randomisation trials Determine when results will differ between re-randomisation and parallel group trials, and develop design and analysis strategies to limit these differences Identify any practical limitations of conducting re-randomisation trials. Assess the quality of published re-randomisation trials, and assess whether results are different to those from similar trials using other designsPlan of investigation Work Package 1: Use analytical methods and computer simulations to develop optimal analysis methods. Work Package 2: Use analytical methods and computer simulations to identify when results from re-randomisation trials may differ to results from other trials, and to identify design and analysis techniques to limit any potential differences. Work Package 3: Conduct a case study of several recent and on-going trials which have used re-randomisation to identify any problems encountered in practice, and to assess whether the assumptions of re-randomisation have been met in these trials. Work Package 4: Conduct a systematic review and meta-epidemiological study to assess the design, analysis, and reporting of re-randomisation trials, and to compare results from re-randomisation trials to those from similar trials using other designs.Potential benefits to patients and the NHS This research will tell us how and when to use re-randomisation most effectively. Greater uptake of the re-randomisation design could provide major benefits to patients and the NHS, by: Allowing trials to be conducted more quickly, leading to successful treatments being introduced into the NHS sooner. Leading to lower trial costs, allowing more trials to be funded. Allowing trials in rare diseases to be more easily conducted, resulting in an improved evidence base for the care provided to these patients.

Lay abstract: Randomised controlled trials (RCTs) involve assigning patients at random to one of several treatments under study. Because of the random assignment, patient factors (such as age, gender, and disease stage) will, on average, be the same between treatment groups, meaning that any differences in outcomes (such as mortality, or requirement for surgery) between the groups will likely be due to the treatment. Because of this, RCTs are considered the gold standard for generating high quality evidence on whether new treatments are effective. However, finding patients to participate in trials is often difficult, and as a result many trials take longer to complete than expected, or are abandoned altogether. It is estimated that about 45% of publically funded trials in the UK are unable to recruit a sufficient number of patients, and the findings from these trials have a greatly reduced impact on clinical practice, leading to wasted opportunities to improve patient care and wasted research funds. Poor recruitment can also make conducting trials in rare disease difficult or even impossible. For example, a large number of trials in sickle cell disease (a blood disorder affecting red blood cells) have stopped early due to poor recruitment. Poor patient recruitment is a major barrier towards conducting effective trials, and methods to improve recruitment are the top research priority of the leads of UK-based Clinical Trial Units.

Research activity codes: 3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION)
Health categories: GENERIC HEALTH RELEVANCE