Collective Uncertainty Project: Hope for Randomised Clinical Trials in Trauma and Orthopaedics

1. Collective Uncertainty Project: Hope for Randomised Clinical Trials in Trauma and Orthopaedics Glossary • Collective equipoise (Freedman, 1987) • justifiable uncertainty within the medical profession about which treatment is most effective for a particular condition • implies that there is no (rational) preference whatever • Collective uncertainty • in reality collective equipoise is rarely exactly evenly balanced, but uncertainty remains about the best treatment option • though individuals may have a preference for one treatment, they are balanced by the others with the opposite view • required before any clinical trial can be approved by ethics committee • Prior probability • Prior sense of the effects of treatment(s) • Can be based entirely on expert opinion Kulikov Y1, Brydges S2, Girling A3, Lilford R3, Griffin D1 1Warwick Medical School, UK 2eLab, University of Warwick, UK 3Public Health & Epidemiology, University of Birmingham, UK yuri.kulikov@warwickorthopaedics.org

2. Randomised controlled clinical trials (RCTs) in Trauma & Orthopaedics • produce the most reliable evidence about the effects of clinical care but • are (very) expensive and (very) difficult for a number of reasons (McCulloch et al, 2002) in particular because • lack of surgeons’ individual equipoise in a specific clinical situation, which is often rational, has been shown to be a major obstacle in participant recruitment Collective Uncertainty Project • to apply Collective Uncertainty to individual clinicalscenarios • to assess degree to which uncertainty must be present as the fundamental criterion for eligibility for a trial yuri.kulikov@warwickorthopaedics.org

3. Design (materials and methods) • Secure website • Clinical images • Clinical data • Interactive Voting Scale yuri.kulikov@warwickorthopaedics.org

4. Design (materials and methods) • Integrated into the UK Heel Fracture Trial (UK HeFT) – conservative versus operative treatment for displaced fractures of calcaneum • Expert panel of 10 Consultant Trauma Surgeons from 8 hospitals across the UK • Consequent potentially eligible for randomisation clinical cases identified via the UK HeFT published via secure online forum after consent being obtained in 6 weeks follow up clinic or later • Surgeons alerted about new cases via email and SMS (optional) and express their opinion online • Level of uncertainty assessed by application of 80:20 ethical uncertainty distribution limit (Johnson et al, 1991), by accounting all votes in favour of operative treatment (a bit better + significantly better + much better) • “strong votes” (significantly better + much better) were accounted separately to demonstrate support or otherwise for recommendation yuri.kulikov@warwickorthopaedics.org

5. Results • 30 eligible cases, of those 17 (56.7%) not randomised for HeFT • 4 bilateral injuries • 11 declined participation • 4 did not want to have surgery • 5 wanted to have surgery • 1 wanted to be treated privately • 1 did not want to be randomised • 1 randomised in error • 1 had previously infected tibial plate same side (removed) • Of 13 randomised 2 (15.4%) declined intended treatment (surgery) • On average 5 surgeons voted per case (min 3, max 8) • 26 cases incl. all bilateral injuries could be recommended for randomisation Legend • chXXX – case number • Grey bars – votes by individual surgeons • Burgundy bars – cumulative average votes yuri.kulikov@warwickorthopaedics.org

6. Results • 3 cases the panel recommended for non-operative treatment • CH007 – 8.4% for surgery (1.2% strong votes) • CH027 – 13.7% for surgery(1.7% strong votes) • CH014 – 15% for surgery (4% strong votes) • 1 case the panel recommended for operative treatment • CH015 – 87% for surgery (72% strong votes) • UK HeFT: CH007 – randomised to non-operative treatment; CH015 – randomised to operative treatment; CH014 – declined to take part (did not want surgery);CH027 – declined randomisation (treated non-operatively) yuri.kulikov@warwickorthopaedics.org

7. Pitfalls Surgeons’ reluctance to vote (maybe overcome if votes will be more relevant) Technical (PACS required in hospitals involved; very few glitches so far, overall simple cheap and stable system) Strengths Ease of use (3-5 min to vote per case) No geographical boundaries Instant application in real time (48 hours required to obtain votes) Ethical value (randomisation only when the panel feels appropriate; individual, personal approach ) Discussion • Measuring Collective Uncertainty in our study showed potential to DOUBLE (from 43.3% to 86.7%) patient recruitment for the UK HeFT • At the same time patients would not have been offered randomisation where current specialist opinion (prior probability) is strongly in favour of one or another treatment • Broader inclusion criteria possible, because every patient is assessed for randomisation individually • Both surgeon and patient are supported in their decision by an expert panel • The Uncertainty Measurement is an opinion (prior probability); the final decision remains between a treating surgeon and a patient yuri.kulikov@warwickorthopaedics.org

8. Conclusion • We propose Measurement of Collective Uncertainty to be introduced into Surgical RCTs where decision about randomisation is especially challenging (operative vs non-operative; standard against new but popular well-marketed treatments etc) • It is possible to set up international expert panels to suite international studies • “Empowering choice will be given precedence by those who, like me [us], think the obligation to respect individual autonomy outweighs the common good in all but the most extreme cases…” (Lilford, 2003) References • Freedman B. Equipoise and the ethics of clinical research. N Engl J Med 1987;317:141-5 • Johnson N, Lilford RJ, Brazier W. At what level of collective equipoise does a clinical trial become ethical. Journal of Medical Ethics 1991;17:30-34 • Lilford RJ. Ethics of clinical trials from a bayesian and decision analytic perspective: whose equipoise is it anyway? BMJ 2003;326:980-1 • McCulloch P, Taylor I, Sasako M, Lovett B, Griffin D. Randomised trials in surgery: problems and possible solutions. BMJ 2002;324:1448-51 yuri.kulikov@warwickorthopaedics.org

9. Warwick Medical School University Hospitals of Coventry and Warwickshire yuri.kulikov@warwickorthopaedics.org