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Rethinking pragmatic randomised
controlled trials: cohort multiple
randomised controlled trial design
Dr Clare ReltonSheffield School of Health and Related Research (ScHARR)Faculty of Medicine
University of Sheffield
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Pragmatic trials
The term pragmatic was first applied to
clinical trials by Schwartz & Lellouch(1967) whose made the distinctionbetween explanatory trials (which aim to
further knowledge as to how and why) andpragmatic/practical trials (which aim toinform healthcare decisions within routinepractice).
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21/04/2012
Problems with standard designs Recruitment: 70.6% of 114 multi centre
MRC & HTA funded trials failed to recruit
required number within time originallyspecified (Campbell M., 2007)
Is this important?: Failure to recruit has
implications for the cost, and thevalidity/reliability/comparability of theresults of the RCT.
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Problems with standard designs
Poor recruitment rates PLUS informed
consent a barrier to recruitment (Ross,1999), patient and clinician treatmentexperiences altered, lack of long term
outcomes, unrepresentative recruitedpopulation, poor external validity....
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cohort multiple RCT design Recruit observational cohort of patients with condition of
interest
Regular outcome measurement for the whole cohort Capacity for multiple RCTs over time
For each RCT, eligible patients identified from which somerandomly selected to be offered the intervention
Outcomes of randomly selected patients compared to notrandomly selected.
Patient information and consent replicate real world routinehealthcare i.e. patients are not told about treatment that theymight not receive
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Copyright 2010 BMJ Publishing Group Ltd.
Relton, Torgerson, OCathain & Nicholl.
BMJ 2010;340:c1066
Cohort multiple RCT design
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Based on (Zelen) randomisedconsent design
Used to avoid Hawthorne, resentful
demoralisation, avoidance of contamination,simpler IC & recruitment, avoid unnecessarydistress & confusion
Reviews: Schellings 2006, Adamson 2006
Similar to cluster RCT design
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Differences: cmRCT & Zelen Large cohort of patients with condition of
interest with capacity for multiple trials
Regular outcome measurement of wholecohort
Rethinking of..... Randomisation
Informed consent procedures
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Randomisation
Random allocation of all
Vs
Random selection of some
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Patient centredinformation and consent
Replicates information and consent
procedures in routine healthcare wherepossible
Patients not told about treatments that
they are not then offered
Patients not told prospectively that theirtreatment will be chosen at random
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Rethinking informed consent
Two trials
CFS (Weatherley-Jones, 2004 )
FMS (Relton , 2009)
Patients behave differently
Ethical issues
Addressed - patient centred approach
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Standard pragmatic RCT
Issues with the type, timing and audience
of information provided Combine multiple types of information
All at one single time point
For all trial subgroups (regardless oftreatment eventually offered)
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(II)and
there isresearchongoing
(III) and wewant to observeyou.
(IV)andwe are notsure whichtreatment
is best.
(V)andwe aregoing toplay a
game ofchance
(I) There isa treatment
and thebenefitsare the
risks are
Type and timing ofinformation
(standard RCT design)
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Patient centred approach
Type, timing and audience of information
provided mimics routine healthcare Separate research information from
intervention information
Differentiate between treatment groups andnon treatment groups - adjust informationaccordingly........ Patients not told abouttreatments they wont receive
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(II)there isresearchongoing
(III) andwe want toobserve
you.
(IV)andwe are notsure whichtreatmentis best.
(V revised)
and youhave been
selected atrandom to tryit....
(I) There isa treatmentand thebenefitsare the
risks are
Type and timing of information(patient centred used in cmRCT design)
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Information mismatches
(between pragmatic open trials and routine healthcare)
Chance
Trials: Patients are informed that their treatment will be decided by chance
Routine healthcare: this is not the case.
Unavailable treatments
Trials: Some patients provided with information about treatments not
available to them
Routine healthcare: this rarely happens.
Timing
Trials: Multiple types of information (I-VI) at single time point (prior to
randomisation)
Routine healthcare: flow of information is staged and shaped by the patients
needs at any particular time.
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Examples of cmRCT
Menopausal hot flush (short term
condition) South Yorkshire Cohort (population based)
Rotherham Institute for Obesity Research
Facility (long term condition and clinicalpopulation)
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South Yorkshire Cohort:a cohort
trials facility study of health and weight
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NIHR CLAHRC funded
Obesity theme
Population based
Research Facility
http://www.biomedcentral.com/1471-2458/11/640
South Yorkshire Cohort
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South Yorkshire Cohort Recruitment 40 GP practices, 180,000
patients mailed postal health questionnaires
NHS number
Consent to
Contact you again
Use the information you provide to look at thebenefit of health treatments
Look at your health records
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South Yorkshire Cohort
10,000 patients recruited
Full recruitment (20,000) Oct 2012
Two studies embedded (DaWM, IQuEST)
Further studies sought
Qualitative
Quantitative including pragmatic cmRCTs
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South Yorkshire Cohort (June 2011)
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South Yorkshire Cohort (June 2011)BMI category BMI
Range
Count Percent
Underweight < 17.5 56
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Self reported Long-standing conditions (n=9,532)*P-value
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Rotherham Institute of Obesity
Clinical condition based cohort
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Benefits of cohortmultiple RCT approach
Recruitment improved quantity and morerepresentative sample
a multiple RCT facility
long term outcomes as standard
ongoing information as to the natural history of thecondition and treatment as usual
increased comparability between each trial conductedwithin the cohort
increased efficiency, particularly for expensive or highrisk interventions (unequal randomisation)
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Most suited to.. Open trials with treatment as usual as comparator
Research questions with easily measured & collectedoutcomes
Clinical conditions where many clinical trials will be
conducted
Chronic conditions
Highly desired treatments or expensive treatments
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Least suited to..
Closed trial designs with masking or placebo arms
Research questions with hard to measure and hard to
collect outcomes
Acute or short term conditions
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Thank you
Acknowledgements
Professor Jon NichollProfessor Alicia OCathainProfessor David Torgerson
Department of Health FellowshipUniversity of SheffieldSouth Yorkshire CLAHRC
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References Adamson, J., Cockayne, S., Puffer, S. et al. (2006), Review of
randomised trials using the post-randomised consent (Zelens) design,Contemporary Clinical Trials, 4, 305-319.
Hewitt, C.E., Torgerson, D.J., Miles, J.V.N., (2006), Is there anotherway to take account of noncompliance in randomized controlled trials?
Canadian Medical Association Journal, 175, 347. Schellings, R., Kessels, A.G., ter Riet, G. et al. (2006), Randomized
consent designs in randomized controlled trials: Systematic literaturesearch, Contemporary Clinical Trials, 27, 4, 330-332.
Campbell, M. (2007), Recruitment to randomised trials: Strategies fortrial enrolment & participation study (STEPS)
http://www.hta.ac.uk/fullmono/mon1148.pdf Relton et al (2010) Rethinking pragmatic RCT design: the cohort
multiple RCT design. doi: 10.1136/bmj.c1066http://www.bmj.com/cgi/content/full/bmj.c1066
http://www.hta.ac.uk/fullmono/mon1148.pdfhttp://www.hta.ac.uk/fullmono/mon1148.pdf