Rethinking pragmatic randomised controlled trials: cohort multiple randomised controlled trial design

Dr Clare Relton
Sheffield School of Health and Related Research (ScHARR) Faculty of Medicine University of Sheffield

c.relton@sheffield.ac.uk

Pragmatic trials
The term pragmatic was first applied to clinical trials by Schwartz & Lellouch (1967) whose made the distinction between explanatory trials (which aim to further knowledge as to how and why) and pragmatic/practical trials (which aim to inform healthcare decisions within routine practice).

Problems with standard designs

Recruitment: 70.6% of 114 multi centre MRC & HTA funded trials failed to recruit required number within time originally specified (Campbell M., 2007) Is this important?: Failure to recruit has implications for the cost, and the validity/reliability/comparability of the results of the RCT.
21/04/2012

Problems with standard designs

Poor recruitment rates PLUS informed consent a barrier to recruitment (Ross, 1999), patient and clinician treatment experiences altered, lack of long term outcomes, unrepresentative recruited population, poor external validity....

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 some randomly selected to be offered the intervention Outcomes of randomly selected patients compared to not randomly selected. Patient information and consent replicate real world routine healthcare i.e. patients are not told about treatment that they might not receive

Cohort multiple RCT design

Relton, Torgerson, OCathain & Nicholl. BMJ 2010;340:c1066

Copyright 2010 BMJ Publishing Group Ltd.

Based on (Zelen) randomised consent design

Used to avoid Hawthorne, resentful demoralisation, avoidance of contamination, simpler IC & recruitment, avoid unnecessary distress & confusion Reviews: Schellings 2006, Adamson 2006 Similar to cluster RCT design

21/04/2012

Differences: cmRCT & Zelen

Large cohort of patients with condition of interest with capacity for multiple trials Regular outcome measurement of whole cohort Rethinking of.....
Randomisation

Informed consent procedures

Randomisation
Random allocation of all Vs

Random selection of some

Patient centred information and consent

Replicates information and consent procedures in routine healthcare where possible Patients not told about treatments that they are not then offered Patients not told prospectively that their treatment will be chosen at random

Rethinking informed consent

Two trials
CFS (Weatherley-Jones, 2004 )

FMS (Relton , 2009)

Patients behave differently Ethical issues Addressed - patient centred approach

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 of treatment eventually offered)

(II) and there is research ongoing (I) There is a treatment and the benefits are the risks are

Type and timing of information (standard RCT design)

(IV) and we are not sure which treatment is best. (V) and we are going to play a game of chance

(III) and we want to observe you.

21/04/2012

Patient centred approach

Type, timing and audience of information provided mimics routine healthcare
Separate research information from intervention information
Differentiate between treatment groups and non treatment groups - adjust information accordingly........ Patients not told about treatments they wont receive

Type and timing of information (patient centred used in cmRCT design)

(I) There is a treatment and the benefits are the risks are (IV) and we are not sure which treatment is best.

(III) and we want to observe you. (II) there is research ongoing

(V revised) and you have been selected at random to try it....

21/04/2012

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.

Examples of cmRCT
Menopausal hot flush (short term condition)

South Yorkshire Cohort (population based)

Rotherham Institute for Obesity Research Facility (long term condition and clinical population)

South Yorkshire Cohort: a cohort

trials facility study of health and weight

South Yorkshire Cohort

NIHR CLAHRC funded Obesity theme

Population based
Research Facility

http://www.biomedcentral.com/14712458/11/640

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 the benefit of health treatments Look at your health records

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

South Yorkshire Cohort (June 2011)

South Yorkshire Cohort (June 2011)

BMI category BMI Range
< 17.5

Count

Percent

Underweight

56

<1

Normal
Overweight Obese Morbidly Obese 50+

17.5<25
25<30 30<40 40<50 50+

3,856
3,334 1,634 184 13

42
37 18 2 <1

South Yorkshire Cohort (June 2011)

Self reported Long-standing conditions (n=9,532)
*P-value <0.01

Tiredness/Fatigue Pain
Insomnia Anxiety/Nerves Depression Diabetes Breathing problems

1631
2197

High blood pressure Heart disease

Osteoarthritis Stroke Cancer Other

1925*
627*

655*
998*

925*
214*

923*
667*

267
2263

1082

Rotherham Institute of Obesity

Clinical condition based cohort

Benefits of cohort multiple RCT approach

Recruitment improved quantity and more representative sample a multiple RCT facility

long term outcomes as standard

ongoing information as to the natural history of the condition and treatment as usual

increased comparability between each trial conducted within the cohort

increased efficiency, particularly for expensive or high risk interventions (unequal randomisation)

Most suited to..

Open trials with treatment as usual as comparator Research questions with easily measured & collected

outcomes
Clinical conditions where many clinical trials will be conducted Chronic conditions Highly desired treatments or expensive treatments

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

Thank you
Acknowledgements
Professor Jon Nicholl Professor Alicia OCathain Professor David Torgerson

Department of Health Fellowship University of Sheffield South Yorkshire CLAHRC

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 another way 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 literature search, Contemporary Clinical Trials, 27, 4, 330-332. Campbell, M. (2007), Recruitment to randomised trials: Strategies for trial 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.c1066 http://www.bmj.com/cgi/content/full/bmj.c1066

21/04/2012