Collective Uncertainty Project: Hope for Randomised Clinical Trials in Trauma and Orthopaedics Kulikov Y 1, Brydges S 2, Girling A 3, Lilford R 3, Griffin D Warwick Medical School, UK 2 2 eLab, University of Warwick, UK 3 3 Public Health & Epidemiology, University of Birmingham, UK 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

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 clinical scenarios to assess degree to which uncertainty must be present as the fundamental criterion for eligibility for a trial

Design (materials and methods) Secure website Clinical data Clinical images Interactive Voting Scale

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 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

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

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)

Discussion 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 ) 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

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:

University Hospitals of Coventry and Warwickshire Warwick Medical School