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How I set up an RCT
NW Principles of QI & Research18th May 2015Dr Anton Krige
El Capitan – The Worlds Hardest Climb
1st Draft Protocol
August 2011
The TERSC StudyA Case Story
NW Research Design Service.
October 2011
PPI Forum
December 2011
RfPB Submission
May 2012
RfPB Outcome.
November 2012
REC Approval
November 2013
RN appointed
November 2013
The TERSC StudyA Case Story
RfPB Contract Signed
December 2013
Start Recruitment
February 2014
Start Nested Study
November 2014
End Recruitment
March 2016
Publications!
August 2016
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
Objectives
• Clinical Research Question• Literature Search• Trial Design• Protocol• Funding• Application Process & Trial Registration• Conduct• Reporting & Dissemination
UK DUETs: where Uncertainties about the Effects of Treatment are Collected & Published
https://www.library.nhs.uk/duets/
Formulating a Clinical Research Question
Objectives
• Clinical Research Question• Literature Search• Trial Design• Protocol• Funding• Application Process & Trial Registration• Conduct• Reporting & Dissemination
Objectives
• Clinical Research Question• Literature Search• Trial Design• Protocol• Funding• Application Process & Trial Registration• Conduct• Reporting & Dissemination
Preparatory Work
• Systematic review• Observational studies• Feasibility studies• Pilot studies
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/)
Patient & Public Involvement (PPI)
• 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
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
RCT Design Alternatives
Efficacy versus Effectiveness Studies
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.
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
Objectives
• Clinical Research Question• Literature Search• Trial Design• Protocol• Funding• Application Process & Trial Registration• Conduct• Reporting & Dissemination
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
Objectives
• Clinical Research Question• Literature Search• Trial Design• Protocol• Funding• Application Process & Trial Registration• Conduct• Reporting & Dissemination
Grant Applications
• Target appropriate Grant• Where to find Grants?• How much time to allow?• A “Dream Team”• NIHR Portfolio Adoption
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
Objectives
• Clinical Research Question• Literature Search• Trial Design• Protocol• Funding• Application Process & Trial Registration• Conduct• Reporting & Dissemination
Trials Registries
Objectives
• Clinical Research Question• Literature Search• Trial Design• Protocol• Funding• Application Process & Trial Registration• Conduct• Reporting & Dissemination
Clinical Trials Units (CTU)
• Statistical design & analysis• Data management & monitoring• Trial management• Information support
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
Objectives
• Clinical Research Question• Literature Search• Trial Design• Protocol• Funding• Application Process & Trial Registration• Conduct• Reporting & Dissemination
• 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
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
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