1. How I set up an RCT NW Principles of QI & Research 18 th May 2015 Dr Anton Krige

2. El Capitan – The Worlds Hardest Climb

3. 1 st Draft Protocol August 2011 The TERSC Study A Case Story NW Research Design Service. October 2011 PPI Forum December 2011 RfPB Submission May 2012 RfPB Outcome. November 2012 REC Approval November 2013

4. RN appointed November 2013 The TERSC Study A Case Story RfPB Contract Signed December 2013 Start Recruitment February 2014 Start Nested Study November 2014 End Recruitment March 2016 Publications! August 2016

5. Project Management Trial Design Co-applicants & collaborators Grant preparation Database design Appoint & train research nurse Train staff Trial Registry Site File/Archiving Portfolio Adoption TMG, TSC & DMEC IRAS completion Patient Diary, PIS, Consent form, GP letters, SOPs, Posters Annual reports: DMEC, REC & RfPB Protocol Amendments Additional nested studies

6. Objectives Clinical Research Question Literature Search Trial Design Protocol Funding Application Process & Trial Registration Conduct Reporting & Dissemination

7. UK DUETs: where Uncertainties about the Effects of Treatment are Collected & Published https://www.library.nhs.uk/duets/

8. Formulating a Clinical Research Question

9. Objectives Clinical Research Question Literature Search Trial Design Protocol Funding Application Process & Trial Registration Conduct Reporting & Dissemination

11. Objectives Clinical Research Question Literature Search Trial Design Protocol Funding Application Process & Trial Registration Conduct Reporting & Dissemination

12. Preparatory Work Systematic review Observational studies Feasibility studies Pilot studies

13. Research Design Service North West free advice on research design to researchers in the North West who are developing proposals for national, peer-reviewed funding competitions for applied health or social care research (http://www.rds-nw.nihr.ac.uk/)http://www.rds-nw.nihr.ac.uk/

14. Patient & Public Involvement (PPI)

16. Searchable database of completed & ongoing projects in core outcome set development Repository for project protocols & other documents (e.g. questionnaires), Maintenance of these resources in a publicly available searchable database Guidance on developing & reporting core outcome sets Preparing guidance on integrating patient reported outcomes into core outcome sets Guidance on obtaining funding to develop core outcome sets

17. Specifying Target Difference The difference in primary outcome value the study is designed to detect reliably. Ideally both an “Important” (MCID by stakeholder group) & “Realistic” (~current evidence) difference. Methods for specifying Important &/or Realistic Differences: 1.Anchor 2.Distribution 3.Health economic 4.Opinion-seeking 5.Pilot study 6.Review of evidence base 7.Standardised effect size

18. RCT Design Alternatives

19. Efficacy versus Effectiveness Studies

20. Superiority, Non-Inferiority & Equivalence Superiority: – Show experimental Rx better than control Rx. – However, can’t claim Rx’s equally as good when non- significant results. Equivalence: – 2 treatments could be called equivalent if observed difference & its 95% CI are completely inside the interval of clinical equivalence. – Usually bioequivalence trials. Non-inferiority: – Significant result (p < 0.025) means the experimental Rx isn’t (much) worse, i.e. non-inferior to control Rx. – Conclusion “non-inferior” depends on the chosen value for ∆NI.

21. When to use Non-Inferiority Placebo-controlled trial not ethically possible (anymore) E not expected to be better than C on primary efficacy end point, but is better on secondary end points or safer E not expected to be better than C on primary efficacy end point but is cheaper to produce or easier to administer E not expected to be better than C on primary efficacy end point in a clinical trial, but compliance & therefore efficacy will be better outside the clinical trial

23. Objectives Clinical Research Question Literature Search Trial Design Protocol Funding Application Process & Trial Registration Conduct Reporting & Dissemination

24. SPIRIT 2013 Statement: Recommendations minimum set of scientific, ethical & administrative elements that should be addressed in a clinical trial protocol. Outlines in 33-item checklist & figure. Facilitate the drafting of protocols & improve their completeness. High-quality protocols can promote proper trial implementation, reduce avoidable protocol amendments, & facilitate full appraisal of the study’s scientific & ethical considerations. http://www.spirit-statement.org

25. Objectives Clinical Research Question Literature Search Trial Design Protocol Funding Application Process & Trial Registration Conduct Reporting & Dissemination

26. Grant Applications Target appropriate Grant Where to find Grants? How much time to allow? A “Dream Team” NIHR Portfolio Adoption

27. Resources Research Design Service – North West North West Surgical Trials Centre NIHR Grant Streams Major Charities/Patient Groups Colleges (NIAA), Associations & Specialist Societies Local R&D

28. Objectives Clinical Research Question Literature Search Trial Design Protocol Funding Application Process & Trial Registration Conduct Reporting & Dissemination

31. Trials Registries

33. Objectives Clinical Research Question Literature Search Trial Design Protocol Funding Application Process & Trial Registration Conduct Reporting & Dissemination

36. Clinical Trials Units (CTU) Statistical design & analysis Data management & monitoring Trial management Information support

38. NIHR Clinical Research Networks Centralised NHS permissions – multi-centre R&D approvals Fund NHS research support posts - experienced "front-line" research staff Fund NHS support costs – Diagnostics & Pharmacy

39. Objectives Clinical Research Question Literature Search Trial Design Protocol Funding Application Process & Trial Registration Conduct Reporting & Dissemination

40. Enhancing the quality and transparency of health research Library with comprehensive searchable database of reporting guidelines & links to other resources relevant to research reporting. http://www.equator-network.org

41. Consolidated Standards of Reporting Trials: Various initiatives developed by to alleviate the problems arising from inadequate reporting of RCTs. CONSORT Statement: Evidence based minimum set of recommendations for reporting RCTs Standard way for authors to prepare reports of trial findings Facilitates complete & transparent reporting Aids critical appraisal & interpretation Comprises a 25-item checklist & flow diagram: Items focus on how the trial was designed, analysed & interpreted Flow diagram displays progress of all participants through the trial http://www.consort-statement.org