Leading article

Recruiting patients into randomized clinical trials in surgeryJ. M. BlazebyAcademic Unit of Surgical Research, School of Social and Community Medicine, Canynge Hall, 39 Whatley Road, Bristol BS8 2PS, UK(e-mail: j.m.blazeby@bris.ac.uk)

Published online 11 January 2012 in Wiley Online Library (www.bjs.co.uk). DOI: 10.1002/bjs.7818

Recruitment of subjects into ran-domized clinical trials (RCTs) insurgery requires communication ofthree key concepts: the need formallyto evaluate treatments because there isuncertainty about comparative effec-tiveness, the need for treatment tobe selected by randomization (ratherthan surgeon or patient preference)to combat selection bias and, finally,an understanding that the purposeof trial participation is to provideevidence to inform decision-makingfor patients in the future (altru-ism). Learning to communicate theseissues requires education and practicewith opportunities for apprenticeshipalongside experts who have a success-ful track record in enrolling patientsinto trials. Successful recruitment alsorequires strong trial leadership tomonitor the process of recruitmentand ensure collaboration with otherdisciplines, including clinical trialsmethodologists.

Undertaking RCTs to evaluatesurgical interventions is generallyuncommon worldwide, although sup-port and encouragement for partic-ipation in randomized trials in theUK can be found in recent reportsfrom the Royal College of Surgeonsof England1. There is, nevertheless, agrowing awareness, and recent exam-ples of RCTs that have successfullyrecruited using novel methods are theProstate testing for cancer and Treat-ment (ProtecT) and Reduction OfSurgical Site Infection using a NovelIntervention (ROSSINI) trials2–4.

The ProtecT three-arm RCT ran-domized men with localized prostatecancer between radical prostatec-tomy, radical conformal radiotherapy

and active prostate-specific antigenmonitoring with a 1 : 1 : 1 random-ization. The challenging recruitmentbetween surgery and radiotherapy andan active monitoring arm was at firstconsidered impossible. Similar trialshad failed to recruit and were closedearly. A fundamental aspect of Pro-tecT, therefore, was detailed record-ing of the numbers of men with local-ized prostate cancer who were eligiblefor the trial and the proportion ofeligible patients who consented torandomization, initially within a feasi-bility study and thereafter throughoutthe main trial, to allow close monitor-ing of recruitment rates. In addition,the recruitment process was embed-ded within qualitative research thatinvolved audio-recorded interviewswith surgeons to understand whatthey thought they had said to patientsabout treatment options and the trial,recordings of consultations betweensurgeons and patients to hear whatwas actually said, and interviews withpatients to understand what patientshad heard and how this was inter-preted. The recordings demonstratedthat unrecognized biases were beingcommunicated by staff and that par-ticipants were often confused aboutthe process of randomization5. Thishighlighted the need for a clearerand more consistent approach to trialrecruitment. Surgeons received indi-vidualized feedback about the contentof their consultations to ensure faircommunication of treatment options.After changing the consultations,enrolment into the trial rose from 30to 65 per cent and was maintained forthe remainder of the trial, even withexpansion into a nine-centre study.

Over 1500 men were randomized.The primary outcome of survival willbe reported in 2016.

The ROSSINI trial has alsoestablished a successful recruitmentprocess3,4. This study compares awound-edge protection device withstandard care in patients undergoingelective and emergency laparotomy.The trial was designed and led bya group of surgeons in training,the West Midlands Research Col-laborative, which includes about 70trainees, most of whom have under-gone Good Clinical Practice training.Current recruitment stands at over600 patients (target 750) achieved in18 months involving 21 sites. Recruit-ment has been integrated into thestandard clinical pathway throughpreoperative assessment clinics andsurgical teams, with clear authorshippolicies for both trainee and respon-sible consultant. There are weeklyreminders to ensure completeness ofdata, and regular newsletters withstructured educational meetings toencourage a collaborative culture oftrial participation.

Both ProtecT and ROSSINI areexcellent examples of how RCTs insurgery can be conducted successfullywithin the complexity of the surgicalpractice, involving surgeons them-selves and overcoming challengessuch as randomization between sur-gical and non-surgical interventions,and recruiting emergency patientsacross many centres. The low costs ofundertaking trials by working closelywith surgical trainees should not beoverlooked. Randomized trials have

2012 British Journal of Surgery Society Ltd British Journal of Surgery 2012; 99: 307–308Published by John Wiley & Sons Ltd

308 J. M. Blazeby

been completed in virtually all surgi-cal disciplines in recent years. Stud-ies in coronary revascularization6,oesophageal surgery7, neurosurgery8

and hand surgery9 have comparedsurgery with non-surgical alterna-tives, examined surgical technique andquestioned the value of surgical inter-vention. However, the number ofsurgical trials remains low and recruit-ment tends to be lower than in otherspecialties.

Surgeons participating in ProtecT,ROSSINI and other well led trialswill be able to coach and educateothers in how to recruit patientseffectively. This type of surgical lead-ership is urgently needed to estab-lish an integrated culture of clinicalresearch within surgical practice. Ithas great potential to influence surgi-cal research, but, more importantly,it will demonstrate that RCTs insurgery can be conducted and com-pleted. In turn, these trials will pro-vide the high-quality evidence toinform standards of surgery world-wide, leading to better care and out-comes for the surgical patient.

Acknowledgements

The author acknowledges contri-butions to this article by DionMorton, Linda Sharples and Jenny

Donovan on behalf of the Medi-cal Research Council Hubs for Tri-als Methodology Research Network(ConDuCT Hub (J.D.) and Biostatis-tics Hub (L.S.), Cambridge) and theNational Working Party on Improv-ing Recruitment to Surgical Trials(D.M.).Disclosure: The author declares noconflict of interest.

References

1 Royal College of Surgeons of England.From Theory to Theatre: OvercomingBarriers to Innovation in Surgery.http://www.rcseng.ac.uk/publications/docs/from-theory-to-theatre-overcoming-barriers-to-innovation-in-surgery [accessed 25 September2011].

2 Lane JA, Hamdy FC, Martin RM,Turner EL, Neal DE, Donovan JL.Latest results from the UK trialsevaluating prostate cancer screeningand treatment: the CAP and ProtecTstudies. Eur J Cancer 2010; 17:3095–3101.

3 Whisker L, Pinkney T, Macleod SJ;West Midlands Research CollaborativeCommittee. Designing and running amulti-centre randomised controlledtrial (RCT) – the registrar collaborativeway. Br J Surg 2011; 98(Suppl 3): 178.

4 Pinkney TD, Bartlett DC,Hawkins W, Mak T, Youssef H,Futaba K et al. Reduction of surgicalsite infection using a novel intervention

(ROSSINI): study protocol for arandomised controlled trial. Trials2011; 12: 217.

5 Donovan J, Mills N, Smith M,Brindle L, Jacoby A, Peters T et al.Quality improvement report:improving design and conduct ofrandomised trials by embedding themin qualitative research: ProtecT(prostate testing for cancer andtreatment) study. BMJ 2002; 325:766–770.

6 Serruys PW, Morice MC,Kappetein AP, Colombo A,Holmes DR, Mack MJ et al.; SYNTAXInvestigators. Percutaneous coronaryintervention versus coronary-arterybypass grafting for severe coronaryartery disease. N Engl J Med 2009; 360:961–972.

7 Boeckxstaens GE, Annese V, desVarannes SB, Chaussade S,Costantini M et al. Pneumatic dilationversus laparoscopic Heller’s myotomyfor idiopathic achalasia. N Engl J Med2011; 364: 1807–1816.

8 Santarius T, Kirkpatrick PJ,Ganesan D, Chia HL, Jalloh I,Smielewski P et al. Use of drains versusno drains after burr-hole evacuation ofchronic subdural haematoma: arandomised controlled trial. Lancet2009; 374: 1067–1073.

9 Jarvik JG, Comstock BA, Kliot M,Turner JA, Chan L, Heagerty PJ et al.Surgery versus non-surgical therapy forcarpal tunnel syndrome: a randomisedparallel-group trial. Lancet 2009; 374:1074–1081.

If you wish to comment on this, or any other article published in the BJS, pleasevisit the on-line correspondence section of the website (www.bjs.co.uk). Electroniccommunications will be reviewed by the Correspondence Editor and a selectionwill appear in the correspondence section of the Journal. Time taken to producea thoughtful and well written letter will improve the chances of publication in theJournal.

2012 British Journal of Surgery Society Ltd www.bjs.co.uk British Journal of Surgery 2012; 99: 307–308Published by John Wiley & Sons Ltd