8/4/2019 Stats and Epi 210911

1/30

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

c.relton@sheffield.ac.uk

8/4/2019 Stats and Epi 210911

2/30

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).

8/4/2019 Stats and Epi 210911

3/30

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.

8/4/2019 Stats and Epi 210911

4/30

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....

8/4/2019 Stats and Epi 210911

5/30

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

8/4/2019 Stats and Epi 210911

6/30

Copyright 2010 BMJ Publishing Group Ltd.

Relton, Torgerson, OCathain & Nicholl.

BMJ 2010;340:c1066

Cohort multiple RCT design

8/4/2019 Stats and Epi 210911

7/3021/04/2012

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

8/4/2019 Stats and Epi 210911

8/30

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

8/4/2019 Stats and Epi 210911

9/30

Randomisation

Random allocation of all

Vs

Random selection of some

8/4/2019 Stats and Epi 210911

10/30

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

8/4/2019 Stats and Epi 210911

11/30

Rethinking informed consent

Two trials

CFS (Weatherley-Jones, 2004 )

FMS (Relton , 2009)

Patients behave differently

Ethical issues

Addressed - patient centred approach

8/4/2019 Stats and Epi 210911

12/30

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)

8/4/2019 Stats and Epi 210911

13/3021/04/2012

(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)

8/4/2019 Stats and Epi 210911

14/30

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

8/4/2019 Stats and Epi 210911

15/3021/04/2012

(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)

8/4/2019 Stats and Epi 210911

16/30

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.

8/4/2019 Stats and Epi 210911

17/30

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)

8/4/2019 Stats and Epi 210911

18/30

South Yorkshire Cohort:a cohort

trials facility study of health and weight

8/4/2019 Stats and Epi 210911

19/30

NIHR CLAHRC funded

Obesity theme

Population based

Research Facility

http://www.biomedcentral.com/1471-2458/11/640

South Yorkshire Cohort

8/4/2019 Stats and Epi 210911

20/30

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

8/4/2019 Stats and Epi 210911

21/30

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

8/4/2019 Stats and Epi 210911

22/30

South Yorkshire Cohort (June 2011)

8/4/2019 Stats and Epi 210911

23/30

South Yorkshire Cohort (June 2011)BMI category BMI

Range

Count Percent

Underweight < 17.5 56

8/4/2019 Stats and Epi 210911

24/30

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

8/4/2019 Stats and Epi 210911

25/30

Rotherham Institute of Obesity

Clinical condition based cohort

8/4/2019 Stats and Epi 210911

26/30

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)

8/4/2019 Stats and Epi 210911

27/30

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

8/4/2019 Stats and Epi 210911

28/30

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

8/4/2019 Stats and Epi 210911

29/30

Thank you

Acknowledgements

Professor Jon NichollProfessor Alicia OCathainProfessor David Torgerson

Department of Health FellowshipUniversity of SheffieldSouth Yorkshire CLAHRC

8/4/2019 Stats and Epi 210911

30/30

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