Randomised Controlled
Trials (RCTs)
Graeme MacLennan
Health Services Research Unit
University of Aberdeen
HSRU is funded by the Chief Scientist Office of the Scottish
Government Health Directorates . The author accepts full
responsibility for this talk.
James 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
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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
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The need to evaluate health
care
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Variations in health care
Unproven treatments
Inadequacies in care
Inaccurate medical models
Limitation of resources
New innovations
…
Crombie (1996)
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Evaluation process
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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
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Define research question and
what 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
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Definition of population,
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
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Measuring “outcome”
• Questionnaires, interview, medical
notes etc
• Timing of questionnaires?
– Baseline (prior to treatment)
– Short term outcomes
– Long term outcomes
• Who collects the data?
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Sources of systematic
errors
• 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
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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)
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Simple RCT model
Trial participants
RANDOMLY allocated
to experimental
or CONTROL group
EXPERIMENT
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CONTROL
What is a randomised 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
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Terminology
• Interventions are comparative regimes within
a trial
• Prophylactic, diagnostic, therapeutic e.g.
– preventative strategies
– screening programmes
– diagnostic tests
– drugs
– surgical techniques
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What is a randomised
controlled 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
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Terminology
Experimental
Group
Control Group
• can be
• receive new
intervention
– conventional
practice
• (also called
treatment group or
intervention group
interchangeably)
– no intervention
(this may be
conventional
practice)
– placebo
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What is a randomised
controlled 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
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What is a randomised
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
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Inclusion/exclusion criteria
• Decision rules applied to potential trial
participants to judge eligibility for
inclusion in trial
• See CONSORT statement
www.consort-statement.org
• Important that they are applied
identically to all groups in a trial!
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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)
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Pseudo-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 quasirandom
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Terminology
• Controlled clinical trials (CCTs) are not
the same as randomised controlled
trials
• Controlled clinical trials include nonrandomised controlled trials and
randomised controlled trials
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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 bias
Unpredictability 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
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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
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Regression 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 326:1083-4
Bland and Altman BMJ 1994 308:1499 and 309:780
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DISTRIBUTION OF RESULTS
threshold
measurement 2
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measurement 1
Hawthorne Effect
• Experimental effect in the direction
expected but not for the reason
expected
• Essentially studying/measuring
something can change what you
studying/measuring
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Placebo 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
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EFFECT OF AN
INTERVENTION
Real difference
Signal
Effect size
Therapeutic E.
Placebo E.
Noise
R. mean
Hawthorne E.
Experimental group
Control group
Minimising 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)
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Concealment 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
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Blinding, 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
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Empirical evidence of bias
Methodological Issue
Inadequate concealment
treatment allocation
Increase in treatment
effect (OR)
of
41%
Unclear method of concealment
of treatment allocation
30%
Trial not blinded (when could
have been)
17%
Schulz KF et al. JAMA 1995; 273: 408-412
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‘Explanatory’ and ‘Pragmatic’
questions
Explanatory
Pragmatic
• Can it work in an
ideal setting …..?
• Efficacy
• Hypothesis testing
• Does it work in the real
world …..?
• Effectiveness
• Choice between
alternative approaches
to health care
• Standard care
• Open
• Placebo controlled
• Double blind
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Key differences between
explanatory and pragmatic trials (1)
Explanatory
Pragmatic
Question
efficacy
effectiveness
Setting
‘laboratory’
normal practice
Participants
strictly defined
broader, clinically indicated
(uncertainty)
Interventions strictly defined
as clinical practice
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Key differences between
explanatory and pragmatic trials (2)
Explanatory
Pragmatic
Size
small (usually
single centre)
larger
(often multi-centre)
Analysis
treatment received intention to treat
Outcomes
short-term
surrogates
Relevance indirect
to practice
long-term, patientcentered and resource
orientated
direct
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Example of selection bias
for PP in an open trial White(2005)
Exp
Ctrl
None
E
None
Worse prognosis
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E
Terminology: explanatory
versus 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
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RCT 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
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RCT 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
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RCT limitations
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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!
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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.
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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)
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Parallel group (simple) RCT
design in practice
Patient eligible for either treatment
Patient gives informed consent
Yes
No
Randomise
Exclude from trial
Experimental
treatment
Standard
treatment
Standard
treatment
Summary
• “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
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Good 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
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Minimise sources of error
Systematic 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)
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Study 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
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Evaluation of health care
interventions
• 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
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Useful/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
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References
• 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
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