1. Clinical trials methodology group Simon Gates 9 February 2006

2. Warwick Emergency Care and Rehabilitation www.warwick.ac.uk/go/emergencycare Agenda Presentation Discussion –Format of meetings –Important issues in trials methodology –Actions for next meeting (if any) AOB Finish at 11am

3. Warwick Emergency Care and Rehabilitation www.warwick.ac.uk/go/emergencycare Contents RCT methodology –What is included? –Why is it important? –What are the major issues? Clinical Trials Methodology Group –What is it for? –How will it operate?

4. RCT methodology

5. Warwick Emergency Care and Rehabilitation www.warwick.ac.uk/go/emergencycare What might be included All aspects, including (not a complete list): Trial design Obtaining funding Ethics and R&D approvals Recruitment of clinicians and patients Informed consent Follow-up Outcome measurement Statistical methods Methods for economic evaluations Dissemination and impact of results on clinical practice.

6. Warwick Emergency Care and Rehabilitation www.warwick.ac.uk/go/emergencycare Why is methodology important? Should use the best methods (always room for improvement) Efficiency: trials need to be conducted by the most cost-effective methods

7. Warwick Emergency Care and Rehabilitation www.warwick.ac.uk/go/emergencycare Why is methodology important? Thousands of trials need to be conducted Increasing pressure on limited funding Improving efficiency will enable more trials to be conducted Good for triallists Good for patients

8. Warwick Emergency Care and Rehabilitation www.warwick.ac.uk/go/emergencycare Why is methodology important? Lots of problems occur during the conduct of RCTs Often we do not have evidence about how to solve them We should approach these problems in the same way as clinical questions Evidence-based approach

9. Warwick Emergency Care and Rehabilitation www.warwick.ac.uk/go/emergencycare Why is methodology important? Should aim to use high quality research evidence to solve problems in RCT conduct Where possible, we need randomised evidence and systematic reviews

10. Warwick Emergency Care and Rehabilitation www.warwick.ac.uk/go/emergencycare Major methodological issues Recruitment of patients Retention of patients Recruitment and retention of clinicians

11. Warwick Emergency Care and Rehabilitation www.warwick.ac.uk/go/emergencycare Recruitment of patients Poor recruitment very common Take longer than expected or fail to reach planned sample size Results delayed, more expensive, less useful Unlikely to get easier (in UK at least)

12. Warwick Emergency Care and Rehabilitation www.warwick.ac.uk/go/emergencycare Recruitment of patients In ISIS-2 (streptokinase and aspirin for acute MI), estimated that delays to recruitment resulted in up to 10,000 deaths. Collins R, Doll R, Peto R. Ethics in clinical trials. In: Williams CJ, editor(s). Introducing New Treatments For Cancer: Practical, Ethical and Legal Problems. Chichester: John Wiley, 1992:49-56.

13. Warwick Emergency Care and Rehabilitation www.warwick.ac.uk/go/emergencycare Recruitment of patients Not clear what is the best strategy when faced with poor recruitment Many possible interventions but little evidence about their effectiveness Likely that different strategies are needed in different situations

14. Warwick Emergency Care and Rehabilitation www.warwick.ac.uk/go/emergencycare Recruitment of patients Cochrane methodology review (Mapstone et al 2002) 15 studies, all interventions aimed at patients Some non-randomised studies or studies of “mock trials” RCTs of other interventions needed

15. Warwick Emergency Care and Rehabilitation www.warwick.ac.uk/go/emergencycare Retention of patients Losses to follow up always cause a problem Potentially introduce bias Best to prevent by achieving high follow-up rates Difficult in some populations Best ways to achieve this unknown

16. Warwick Emergency Care and Rehabilitation www.warwick.ac.uk/go/emergencycare Recruitment & retention of clinicians May have major impact on recruitment of patients Clinicians may be reluctant to participate if they perceive it will involve extra work Or they may agree to participate but fail to recruit any patients

17. Warwick Emergency Care and Rehabilitation www.warwick.ac.uk/go/emergencycare Recruitment & retention of clinicians Protocol for Cochrane methodology review (Rendell et al 2005) No randomised studies known

18. Clinical trials methodology group

19. Warwick Emergency Care and Rehabilitation www.warwick.ac.uk/go/emergencycare What is this group for? Discussion: Triallists who have particular problems – opportunity to discuss and get input from colleagues Research: identify, design and conduct research projects Contribute to setting the research agenda for RCT methodology and building up the literature

20. Warwick Emergency Care and Rehabilitation www.warwick.ac.uk/go/emergencycare What research might we do? RCTs of interventions to improve trial conduct Systematic reviews (e.g. Cochrane methodology reviews) Observational studies Surveys e.g. of triallists or published literature Testing of methods and recommendations for best practice Re-analysis of trial data sets

21. Warwick Emergency Care and Rehabilitation www.warwick.ac.uk/go/emergencycare Methodological research Potentially very influential Assmann et al. Subgroup analysis and other (mis)uses of baseline data in clinical trials Lancet 355 (9209): 1064-1069 Times Cited: 131 Hollis S, Campbell F What is meant by intention to treat analysis? Survey of published randomised controlled trials. BMJ 319 (7211): 670+ Times Cited: 174

22. Warwick Emergency Care and Rehabilitation www.warwick.ac.uk/go/emergencycare How will it work Meetings Research projects Website

23. Warwick Emergency Care and Rehabilitation www.warwick.ac.uk/go/emergencycare Meetings Opportunity to discuss particular issues At present scheduled for about once every 2 months Each meeting to have a specific topic

24. Warwick Emergency Care and Rehabilitation www.warwick.ac.uk/go/emergencycare Meetings - format Short presentation outlining the issues Discussion Action plan Feedback/results from ongoing projects

25. Warwick Emergency Care and Rehabilitation www.warwick.ac.uk/go/emergencycare Research projects Groups of interested people to develop and run research projects Seek funding if necessary Report back to the whole group

26. Warwick Emergency Care and Rehabilitation www.warwick.ac.uk/go/emergencycare Website Link from Clinical Trials Unit website Notes and slides from meetings Information and documents for future meetings Information about ongoing projects Anything else of interest – ideas?

27. Warwick Emergency Care and Rehabilitation www.warwick.ac.uk/go/emergencycare Tasks Short paragraph about any ongoing trials methodology projects Ideas for topics for next meetings and volunteers to present