Adrian Maxwell Grant

What influences recruitment to randomised controlled trials? A review of trials funded by two UK funding agencies

BackgroundA commonly reported problem with the conduct of multicentre randomised controlled trials (RCTs) is that recruitment is often slower or more difficult than expected, with many trials failing to reach their planned sample size within the timescale and funding originally envisaged. The aim of this study was to explore factors that may have been associated with good and poor recruitment in a cohort of multicentre trials funded by two public bodies: the UK Medical Research Council (MRC) and the Health Technology Assessment (HTA) Programme.MethodsThe cohort of trials was identified from the administrative databases held by the two funding bodies. 114 trials that recruited participants between 1994 and 2002 met the inclusion criteria. The full scientific applications and subsequent trial reports submitted by the trial teams to the funders provided the principal data sources. Associations between trial characteristics and recruitment success were tested using the Chi-squared test, or Fishers exact test where appropriate.ResultsLess than a third (31%) of the trials achieved their original recruitment target and half (53%) were awarded an extension. The proportion achieving targets did not appear to improve over time. The overall start to recruitment was delayed in 47 (41%) trials and early recruitment problems were identified in 77 (63%) trials. The inter-relationship between trial features and recruitment success was complex. A variety of strategies were employed to try to increase recruitment, but their success could not be assessed.ConclusionRecruitment problems are complex and challenging. Many of the trials in the cohort experienced recruitment difficulties. Trials often required extended recruitment periods (sometimes supported by additional funds). While this is of continuing concern, success in addressing the trial question may be more important than recruitment alone.

Randomised controlled trial of conservative management of postnatal urinary and faecal incontinence: six year follow up

Abstract Objective To determine the long term effects of a conservative nurse-led intervention for postnatal urinary incontinence. Design Randomised controlled trial. Setting Community based intervention in three centres in the United Kingdom and New Zealand. Participants 747 women with urinary incontinence at three months after childbirth, of whom 516 were followed up again at 6 years (69%). Intervention Active conservative treatment (pelvic floor muscle training and bladder training) at five, seven, and nine months after delivery or standard care. Main outcome measures Urinary and faecal incontinence, performance of pelvic floor muscle training. Results Of 2632 women with urinary incontinence, 747 participated in the original trial. The significant improvements relative to controls in urinary (60% v 69%) and faecal (4% v 11%) incontinence at one year were not found at six year follow up (76% v 79% (95% confidence interval for difference in means −10.2% to 4.1%) for urinary incontinence, 12% v 13% (−6.4% to 5.1%) for faecal incontinence) irrespective of subsequent obstetric events. In the short term the intervention had motivated more women to perform pelvic floor muscle training (83% v 55%) but this fell to 50% in both groups in the long term. Both urinary and faecal incontinence increased in prevalence in both groups during the study period. Conclusions The moderate short term benefits of a brief nurse-led conservative treatment of postnatal urinary incontinence may not persist, even among women with no further deliveries. About three quarters of women with urinary incontinence three months after childbirth still have this six years later.

Laparoscopic surgery for colorectal cancer: safe and effective? – A systematic review

ObjectiveTo determine the clinical effectiveness of laparoscopic and laparoscopically assisted surgery in comparison with open surgery for the treatment of colorectal cancer.BackgroundOpen resection is the standard method for surgical removal of primary colorectal tumours. However, there is significant morbidity associated with this procedure. Laparoscopic resection (LR) is technically more difficult but may overcome problems associated with open resections (OR).MethodsSystematic review and meta-analysis of short- and long-term data from randomised controlled trials (RCTs) comparing LS with OR.ResultsHighly sensitive searches of nine databases identified 19 primary RCTs describing data from over 4,500 participants. Length of hospital stay is shorter, blood loss and pain are less, and return to usual activities is likely to be faster after LR than after OR, but duration of operation is longer. Lymph node retrieval, completeness of resection and quality of life do not appear to differ. No statistically significant differences were observed in rates of anastomotic leakage, abdominal wound breakdown, incisional hernia, wound and urinary tract infections, operative and 30-day mortality, and recurrences, nor in overall and disease-free survival up to three years.ConclusionsLR is associated with a quicker recovery in terms of return to usual activities and length of hospital stay with no evidence of a difference in complications or long-term outcomes in comparison to OR, up to three years postoperatively.

Alternative approaches to endoscopic ablation for benign enlargement of the prostate: systematic review of randomised controlled trials

Objective To compare the effectiveness and risk profile of newer methods for endoscopic ablation of the prostate against the current standard of transurethral resection. Design Systematic review and meta-analysis. Data sources Electronic and paper records in subject area up to March 2006. Review methods We searched for randomised controlled trials of endoscopic ablative interventions that included transurethral resection of prostate as one of the treatment arms. Two reviewers independently extracted data and assessed quality. Meta-analyses of prespecified outcomes were done using fixed and random effects models and reported using relative risk or weighted mean difference. Results We identified 45 randomised controlled trials meeting the inclusion criteria and reporting on 3970 participants. The reports were of moderate to poor quality, with small sample sizes. None of the newer technologies resulted in significantly greater improvement in symptoms than transurethral resection at 12 months, although a trend suggested a better outcome with holmium laser enucleation (random effects weighted mean difference −0.82, 95% confidence interval 1.76 to 0.12) and worse outcome with laser vaporisation (1.49, −0.40 to 3.39). Improvements in secondary measures, such as peak urine flow rate, were consistent with change in symptoms. Blood transfusion rates were higher for transurethral resection than for the newer methods (4.8% v 0.7%) and men undergoing laser vaporisation or diathermy vaporisation were more likely to experience urinary retention (6.7% v 2.3% and 3.6% v 1.1%). Hospital stay was up to one day shorter for the newer technologies. Conclusions Although men undergoing more modern methods of removing benign prostatic enlargement have similar outcomes to standard transurethral resection of prostate along with fewer requirements for blood transfusion and shorter hospital stay, the quality of current evidence is poor. The lack of any clearly more effective procedure suggests that transurethral resection should remain the standard approach.

Minimally invasive treatments for benign prostatic enlargement: systematic review of randomised controlled trials

Objective To compare the effectiveness and risk profile of minimally invasive interventions against the current standard of transurethral resection of the prostate. Design Systematic review and meta-analysis of randomised controlled trials. Data sources Electronic and paper records up to March 2006. Review methods We searched for all relevant randomised controlled trials. Two reviewers independently extracted data and assessed quality. Meta-analyses of prespecified outcomes were performed with fixed and random effects models and reported using relative risks or weighted mean difference. Results 3794 abstracts were identified; 22 randomised controlled trials met the inclusion criteria. These provided data on 2434 participants. The studies evaluated were of moderate to poor quality with small sample sizes. Minimally invasive interventions were less effective than transurethral resection of the prostate in terms of improvement in symptom scores and increase in urine flow rate, with most comparisons showing significance despite wide confidence intervals. Rates of reoperation were significantly higher for minimally invasive treatments. The risk profile of minimally invasive interventions was better than that of transurethral resection, with fewer adverse events. The results, however, showed significant heterogeneity. Conclusion Which minimally invasive intervention is the most promising remains unclear. Their place in the management of benign prostate enlargement will continue to remain controversial until well designed and well reported randomised controlled trials following CONSORT guidelines prove they are superior and more cost effective than drug treatment, or that strategies of sequential surgical treatments are preferred by patients and are more cost effective than the more invasive but more effective tissue ablative interventions such as transurethral resection.

Marketing and clinical trials: a case study

BackgroundPublicly funded clinical trials require a substantial commitment of time and money. To ensure that sufficient numbers of patients are recruited it is essential that they address important questions in a rigorous manner and are managed well, adopting effective marketing strategies.MethodsUsing methods of analysis drawn from management studies, this paper presents a structured assessment framework or reference model, derived from a case analysis of the MRCs CRASH trial, of 12 factors that may affect the success of the marketing and sales activities associated with clinical trials.ResultsThe case study demonstrates that trials need various categories of people to buy in – hence, to be successful, trialists must embrace marketing strategies to some extent.ConclusionThe performance of future clinical trials could be enhanced if trialists routinely considered these factors.

Resource use data by patient report or hospital records: Do they agree?

BackgroundEconomic evaluations alongside clinical trials are becoming increasingly common. Cost data are often collected through the use of postal questionnaires; however, the accuracy of this method is uncertain. We compared postal questionnaires with hospital records for collecting data on physiotherapy service use.MethodsAs part of a randomised trial of orthopaedic medicine compared with orthopaedic surgery we collected physiotherapy use data on a group of patients from retrospective postal questionnaires and from hospital records.Results315 patients were referred for physiotherapy. Hospital data on attendances was available for 30% (n = 96), compared with 48% (n = 150) of patients completing questionnaire data (95% Cl for difference = 10% to 24%); 19% (n = 59) had data available from both sources. The two methods produced an intraclass correlation coefficient of 0.54 (95% Cl 0.31 to 0.70). However, the two methods produced significantly different estimates of resource use with patient self report recalling a mean of 1.3 extra visits (95% Cl 0.4 to 2.2) compared with hospital records.ConclusionsUsing questionnaires in this study produced data on a greater number of patients compared with examination of hospital records. However, the two data sources did differ in the quantity of physiotherapy used and this should be taken into account in any analysis.

The effectiveness of metal on metal hip resurfacing: a systematic review of the available evidence published before 2002

BackgroundConventional total hip replacement (THR) may be felt to carry too high a risk of failure over a patients lifetime, especially in young people. There is increasing interest in metal on metal hip resurfacing arthroplasty (MoM) as this offers a bone-conserving option for treating those patients who are not considered eligible for THR. We aim to evaluate the effectiveness of MoM for treatment of hip disease, and compare it with alternative treatments for hip disease offered within the UK.MethodsA systematic review was carried out to identify the relevant literature on MoM published before 2002. As watchful waiting and total hip replacement are alternative methods commonly used to alleviate the symptoms of degenerative joint disease of the hip, we compared MoM with these.ResultsThe data on the effectiveness of MoM are scarce, as it is a relatively new technique and at present only short-term results are available.ConclusionIt is not possible to make any firm conclusions about the effectiveness of MoM based on these early results. While the short-term results are promising, it is unclear if such results would be replicated in more rigorous studies, and what the long-term performance might be. Further research is needed which ideally should involve long-term randomised comparisons of MoM with alternative approaches to the clinical management of hip disease.

Financial considerations in the conduct of multi-centre randomised controlled trials: evidence from a qualitative study.

BackgroundSecuring and managing finances for multicentre randomised controlled trials is a highly complex activity which is rarely considered in the research literature. This paper describes the process of financial negotiation and the impact of financial considerations in four UK multicentre trials. These trials had met, or were on schedule to meet, recruitment targets agreed with their public-sector funders. The trials were considered within a larger study examining factors which might be associated with trial recruitment (STEPS).MethodsIn-depth semi-structured telephone interviews were conducted in 2003–04 with 45 individuals with various responsibilities to one of the four trials. Interviewees were recruited through purposive and then snowball sampling. Interview transcripts were analysed with the assistance of the qualitative package Atlas-ti.ResultsThe data suggest that the UK system of dividing funds into research, treatment and NHS support costs brought the trial teams into complicated negotiations with multiple funders. The divisions were somewhat malleable and the funding system was used differently in each trial. The fact that all funders had the potential to influence and shape the trials considered here was an important issue as the perspectives of applicants and funders could diverge. The extent and range of industry involvement in non-industry-led trials was striking. Three broad periods of financial work (foundation, maintenance, and resourcing completion) were identified. From development to completion of a trial, the trialists had to be resourceful and flexible, adapting to changing internal and external circumstances. In each period, trialists and collaborators could face changing costs and challenges. Each trial extended the recruitment period; three required funding extensions from MRC or HTA.ConclusionThis study highlights complex financial aspects of planning and conducting trials, especially where multiple funders are involved. Recognition of the importance of financial stability and of the need for appropriate training in this area should be paralleled by further similar research with a broader range of trials, aimed at understanding and facilitating the conduct of clinical research.

A pragmatic multi-centre randomised controlled trial of fluid loading and level of dependency in high-risk surgical patients undergoing major elective surgery: trial protocol

BackgroundPatients undergoing major elective or urgent surgery are at high risk of death or significant morbidity. Measures to reduce this morbidity and mortality include pre-operative optimisation and use of higher levels of dependency care after surgery. We propose a pragmatic multi-centre randomised controlled trial of level of dependency and pre-operative fluid therapy in high-risk surgical patients undergoing major elective surgery.Methods/DesignA multi-centre randomised controlled trial with a 2 * 2 factorial design. The first randomisation is to pre-operative fluid therapy or standard regimen and the second randomisation is to routine intensive care versus high dependency care during the early post-operative period. We intend to recruit 204 patients undergoing major elective and urgent abdominal and thoraco-abdominal surgery who fulfil high-risk surgical criteria. The primary outcome for the comparison of level of care is cost-effectiveness at six months and for the comparison of fluid optimisation is the number of hospital days after surgery.DiscussionWe believe that the results of this study will be invaluable in determining the future care and clinical resource utilisation for this group of patients and thus will have a major impact on clinical practice.Trial RegistrationTrial registration number - ISRCTN32188676