Randomised Controlled Trials

HSRU is funded by the Chief Scientist Office of the Scottish Government Health Directorates . The author accepts full

responsibility for this talk.

Health Services Research Unit University of Aberdeen

Randomised Controlled Randomised Controlled Trials (RCTs)Trials (RCTs)

Graeme MacLennan

Health Services Research Unit

James LindJames Lind• Born Edinburgh 1716• On HMS Salisbury in 1747 he

allocated 12 men with scurvy– Cider– Seawater– Horseradish, mustard, garlic– Nutmeg– Elixir Vitriol – Oranges and Limes


Think about… Think about… • Consider how you would go about evaluating the

following interventions– Surgical versus medical termination of pregnancy– Referral guidelines for radiographic examination– Paracetamol and/or ibuprofen for treating children

with fever– Nurse counsellors as an alternative to clinical

geneticists for genetic counselling– Single dose of chemotherapy versus radiotherapy

treating testicular cancer http://news.bbc.co.uk/1/hi/health/7647007.stm

– Cervical cancer vaccine http://news.bbc.co.uk/1/hi/health/6223000.stm

http://news.bbc.co.uk/1/hi/health/7647007.stm

http://news.bbc.co.uk/1/hi/health/6223000.stm


The need to evaluate health The need to evaluate health carecare

• Variations in health care• Unproven treatments• Inadequacies in care• Inaccurate medical models• Limitation of resources• New innovations• …

Crombie (1996)


Evaluation processEvaluation process• Define research question• What is already known?• Identify appropriate study design• Define population, intervention and criteria for

evaluation• How large a study?• Consider measurement of evaluation criteria

(“outcomes”)– How often?– Timing? Length of follow up?– To whom? Who collects the data? What format?

• Analysis of data• Dissemination and implementation


Define research question and Define research question and what is already knownwhat is already known

• Research question (PICOT)– Population– Intervention– Control/comparator – Outcome– Target

• Has the question already been answered?– Conduct review to assess what is know

about intervention


Definition of population, Definition of population, intervention and “outcomes”intervention and “outcomes”

• Population– Strict definition (explanatory) or flexible (pragmatic)

• Intervention– Dose of drug, timing etc

• “Outcomes”– Health related Quality of Life– Biochemical outcomes– Symptoms– Physical assessment– Patient satisfaction– Acceptability– Cost-effectiveness


Measuring “outcome”Measuring “outcome”• Questionnaires, interview, medical

notes etc• Timing of questionnaires?

– Baseline (prior to treatment)– Short term outcomes– Long term outcomes

• Who collects the data?


Sources of systematic Sources of systematic errorserrors

• Selection bias– can be introduced by the way in which comparison

groups are assembled • Attrition bias

– systematic differences in withdrawal/follow up• Performance bias

– Systematic differences in care provided

• Observation/detection bias– systematic differences in observation, measurement,

assessment


What is a randomised controlled trial? What is a randomised controlled trial?

Simple Definition• A study in which people are allocated at

random to receive one of several interventions

(simple but powerful research tool)


Simple RCT model Simple RCT model

Trial participantsTrial participants

RANDOMLYRANDOMLY allocated allocated to experimental to experimental or or CONTROLCONTROL group group

CONTROLCONTROLEXPERIMENTEXPERIMENT


What is a What is a randomisedrandomised controlled trial? controlled trial?

• Random allocation to intervention groups

• all participants have equal chance of being allocated to each intervention group

why RCTs are referred to as randomised controlled trials


Terminology Terminology • Interventions are comparative regimes within

a trial

• Prophylactic, diagnostic, therapeutic e.g.

– preventative strategies

– screening programmes

– diagnostic tests

– drugs

– surgical techniques


What is a randomised What is a randomised controlledcontrolled trial? trial?

• One intervention is regarded as control treatment (the group of participants who receive this are the control group)

• NOTE: Contemporaneous (not historical controls)

why RCTs are referred to as randomised controlled trials


TerminologyTerminology

Control Group

• can be

– conventional practice

– no intervention (this may be conventional practice)

– placebo

Experimental Group

• receive new intervention

• (also called treatment group or intervention group interchangeably)


What is a What is a randomised randomised controlled trialcontrolled trial??

• RCTs are

– Experiments: investigators can influence number, type, regime of interventions

– Quantitative: measure events rather than try to interpret them in their natural settings

– Comparative: compare two or more interventions


What is a randomised What is a randomised controlled trial? controlled trial? More Complex Definition

• Quantitative, comparative, controlled experiments in which a group of investigators study two or more interventions in a series of participants who are allocated randomly to each intervention group


Inclusion/exclusion criteriaInclusion/exclusion criteria

• Decision rules applied to potential trial participants to judge eligibility for inclusion in trial

• See CONSORT statementwww.consort-statement.org

• Important that they are applied identically to all groups in a trial!

http://www.consort-statement.org/


What is randomisation? What is randomisation? • Randomisation is the process of random

allocation• Allocation is not determined by investigators,

clinicians or participants• Equal chance of being assigned to each

intervention group • Individual people

– patients– caregivers (physicians, nurses etc)

• Groups of people, ‘cluster randomisation’• (Covered in more depth in later lecture)


Pseudo-randomisationPseudo-randomisation

• Other allocation methods include

– according to date of birth

– the number on hospital records

– date of invitation etc.

• These are NOT regarded as random

• These are called pseudo- or quasi-random


TerminologyTerminology• Controlled clinical trials (CCTs) are not

the same as randomised controlled trials

• Controlled clinical trials include non-randomised controlled trials and randomised controlled trials


Why use randomisation? Why use randomisation? • Characteristics similar across groups at

baseline • can isolate and quantify impact of

interventions with effects from other factors minimised

• Risk of imbalance not abolished completely even if perfect randomisation

• To combat selection biasUnpredictability paradox: review of empirical comparisons of randomised and non-randomised

clinical trials, Kunz and Oxman 1998 BMJ http://www.bmj.com/cgi/content/abstract/317/7167/1185


Why do we need a control group?Why do we need a control group?

• Don’t need a control group if completely predictable results

– Parachutes when jumping from plane

– New drug cures a few rabies cases

• But

– No intervention has 100% efficacy

– Many diseases recover spontaneously


Regression to the meanRegression to the mean• Occurs when an intervention aimed at a

group or characteristic that is very different from average

• For example selecting people because they have high blood pressure then measuring them in future will see the blood pressure measurements closer to the mean of the population

Morton and Torgerson BMJ 2003 326:1083-4Bland and Altman BMJ 1994 308:1499 and 309:780


DISTRIBUTION OF RESULTSDISTRIBUTION OF RESULTS

threshold

measurement 1measurement 2


Hawthorne EffectHawthorne Effect

• Experimental effect in the direction

expected but not for the reason

expected

• Essentially studying/measuring

something can change what you

studying/measuring


Placebo EffectPlacebo Effect• Effect (usually, but not always positive)

attributed to the expectation that a therapy will have an effect

• The effect is due to the power of suggestion

• A placebo is an inert medication or procedure

Waber et al 2008 JAMA Commercial Features of Placebo and Therapeutic Efficacy

http://jama.ama-assn.org/cgi/content/full/299/9/1016

http://jama.ama-assn.org/cgi/content/full/299/9/1016

Effect size

Experimental group Control group

Hawthorne E.

R. mean

Placebo E.

Therapeutic E.

Real difference

Noise

Signal

EFFECT OF AN EFFECT OF AN INTERVENTIONINTERVENTION


Minimising bias in RCTsMinimising bias in RCTs

• Blinding– Single blind – participants are unaware of

treatment allocation– Double blind – both participants and

investigators are unaware of treatment allocation

– Requires use of placebos in drug trials Schulz and Grimes (2002)


Concealment of random allocation listConcealment of random allocation list

• “Trials with inadequate allocation concealment have been associated with larger treatment effects compared with trials in which authors reported adequate allocation concealment”

Schulz KF (1995). Subverting randomisation in controlled trials. JAMA, 274, 1456-8


Blinding, placebosBlinding, placebos• RCTs should use the maximum degree of

blinding that is possible• Placebo is a ‘dummy’ treatment given

when there is no obvious standard treatment– needed as the act of taking a treatment

may have some effect -need to attribute– double blind treatments must be

indistinguishable to those affected


Empirical evidence of biasEmpirical evidence of bias

Methodological IssueIncrease in treatmenteffect (OR)

Inadequate concealment oftreatment allocation

41%

Unclear method of concealmentof treatment allocation

30%

Trial not blinded (when couldhave been)

17%

Schulz KF et al. JAMA 1995; 273: 408-412


‘‘Explanatory’ and ‘Pragmatic’ Explanatory’ and ‘Pragmatic’ questionsquestions

Explanatory• Can it work in an

ideal setting …..?• Efficacy• Hypothesis testing

• Placebo controlled• Double blind

Pragmatic• Does it work in the real

world …..?• Effectiveness• Choice between

alternative approaches to health care

• Standard care• Open


Key differences between Key differences between explanatory and pragmatic trials (1)explanatory and pragmatic trials (1)

Explanatory PragmaticQuestion efficacy effectiveness

Setting ‘laboratory’ normal practice

Participants strictly defined broader, clinically indicated

(uncertainty)

Interventions strictly defined as clinical practice


Key differences between Key differences between explanatory and pragmatic trials (2)explanatory and pragmatic trials (2)

Explanatory PragmaticOutcomes short-term long-term, patient-

surrogates centered and resource orientated

Size small (usually largersingle centre) (often multi-centre)

Analysis treatment received intention to treat

Relevance indirect directto practice


Example of selection bias Example of selection bias for PP in an open trialfor PP in an open trial

Worse prognosisWorse prognosis

ExpExp

CtrlCtrl

None

None

White(2005)

E

E


Terminology: explanatory Terminology: explanatory versus pragmaticversus pragmatic

• Explanatory trials

– estimates efficacy - that is the benefit the treatment produces under ideal conditions

• Pragmatic trials

– estimates effectiveness - that is the benefit the treatment produces under routine clinical practice

Roland M, Torgerson D. What are pragmatic trials? BMJ 1998;316:285


RCT as the Gold StandardRCT as the Gold Standard• The randomised controlled trial is

widely regarded as the gold standard for evaluating health care technologies because it allows us to be confident that a difference in outcome can be directly attributed to a difference in the treatments and not due to some other factor


RCT strengthsRCT strengths• Confounding variables minimised• Only research design which can in

principle yield causal relationships– can clarify the direction of cause and

effect• Accepted by EBM school• Don’t have to know everything about

the participants


RCT limitationsRCT limitations• Contamination of intervention groups • Comparable controls• Problems with blinding• What to do about attrition?• Are patients/professionals willing to be

in trial different from ‘refusers’?- external validity

• Cost!


Other issues in RCTs (1)Other issues in RCTs (1)• Ethics• Management issues• Interim analysis and ‘stopping rules’

– part of ethical concern– mechanisms to avoid patient harm– Data Monitoring and Safety

Committee required for trials

Clemens F et al Data monitoring in randomised controlled trials: surveys of recent practice and policies. Clin Trials 2005;2(1):22-33.


Other issues in RCTs (2)Other issues in RCTs (2)• A power calculation is essential for the

validity of a trial and will always be necessary for grant applications and in publications of the trial (later lecture)

• The methods of randomisation should always be reported. It is not enough to say that the patients were randomly allocated to the treatments. (see CONSORT)

Parallel group (simple) RCT Parallel group (simple) RCT design in practicedesign in practice

Patient eligible for either treatment

Patient gives informed consent

Yes No

Randomise Exclude from trial

Experimental treatment

Standard treatment

Standard treatment


SummarySummary• “Gold standard” of research designs• Individual patients are randomly allocated to receive

the experimental treatment (intervention group) or the standard treatment (control group)

• Maximises the potential for attribution• Randomisation guards against selection bias between

the two treatment groups• Standard statistical analysis • Good internal validity• May lack generalisability due to highly selected

participants• Can be costly to set up and conduct, ethical issues


Good study designGood study design

General considerations• maximise attribution

– Ensure no factor other than the intervention differs between the intervention and control group

– Random allocation, if adequately carried out, will in the long run ensure comparable groups with respect to all factors

• minimise all sources of error– systematic error (bias)– random error (chance)

• be practical and ethical


Minimise sources of errorMinimise sources of errorSystematic errors (bias)• “inaccuracy which is different in its size or direction in

one of the groups under study than the others ”• Minimise bias by ensuring that the methods used are

applied in the same manner to all subjects irrespective of which group they belong to.

Random errors (chance)• “Inaccuracy which is similar in the different groups of

subjects being compared” • Adequate sample size, accurate methods of

measurement

Elwood (1998)


Study designsStudy designs

• Experimental (Randomised controlled trial)– A new intervention is deliberately introduced and

compared with standard care • Quasi-experimental (non-randomised, controlled before

and after)– Researchers do not have full control over the

implementation of the intervention (“opportunistic research”)

• Observational (Cohort, case-control, cross-sectional)– describes current practice– observed differences cannot be attributed solely to a

“treatment” effect


Evaluation of health care Evaluation of health care interventionsinterventions

• Randomised controlled trials are considered as the “gold standard”

• However, some debate over the advantages and disadvantages of different research designs for assessing the effectiveness of healthcare interventions

• Polarised views– “observational methods provide no useful means of

assessing the value of a therapy” (Doll, 1993)– RCTs may be unnecessary, inappropriate, impossible

or inadequate (Black, 1996)• Approaches should be seen as complementary and not

as alternatives (Black, 1996)– Interpretation of RCTs in terms of generalisability


Useful/interesting linksUseful/interesting links• www.jameslindlibrary.org (History)• www.consort-statement.org (CONSORT)• www-users.york.ac.uk/~mb55/pubs/pbstnote.htm

(All the stats notes from BMJ)• www.ctu.mrc.ac.uk (MRC CTU)• www.rcrt.ox.ac.uk (under construction)• Doll R. Clinical Trials the 1948 watershe BMJ 1998;317:1217-1220

• The unpredictability paradox: review of empirical comparisons of randomised and non-randomised clinical trials Regina Kunz and Andrew D Oxman BMJ 1998 317: 1185-1190

http://www.jameslindlibrary.org/

http://www.consort-statement.org/

http://www-users.york.ac.uk/~mb55/pubs/pbstnote.htm

http://www.ctu.mrc.ac.uk/

http://www.rcrt.ox.ac.uk/


ReferencesReferences• Black. Why we need observational studies to evaluate

the effectiveness of health care. BMJ 1996: 312;1215-8• Crombie. Research in Health Care. 1996• Doll. Doing more good than harm: the evaluation of

health care interventions. Ann NY Acad Sci 1993:703;310-13

• Elwood M. Critical appraisal of epidemiological studies and clinical trials. 1998 OUP; Oxford.

• Greenhalgh T. How to read a paper. 2001 BMJ; London• Schulz and Grimes. Lancet Epidemiology series. 2002

Date post:	16-Jul-2015
Category:	Health & Medicine
Upload:	fondas-vakalis
View:	31,403 times
Download:	0 times

Randomised Controlled Trials

Health & Medicine