Graeme MacLennan 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 ID: 379590
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Slide1
Randomised Controlled Trials (RCTs)
Graeme MacLennanSlide2
James Lind
Born Edinburgh 1716
On HMS Salisbury in 1747 he allocated 12 men with scurvy
Cider
SeawaterHorseradish, mustard, garlicNutmegElixir Vitriol Oranges and Limes Slide3
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 feverNurse counsellors as an alternative to clinical geneticists for genetic counsellingSingle 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
Slide4
The need to evaluate health care
Variations in health care
Unproven treatments
Inadequacies in care
Inaccurate medical modelsLimitation of resourcesNew innovations… Crombie (1996)Slide5
Evaluation process
Define research question
What is already known?
Identify appropriate study design
Define population, intervention and criteria for evaluationHow 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 implementationSlide6
Define research question and what is already known
Research question (PICOT)
Population
Intervention
Control/comparator OutcomeTarget Has the question already been answered?Conduct review to assess what is know about interventionSlide7
Definition of population, intervention and “outcomes”
Population
Strict definition (explanatory) or flexible (pragmatic)
Intervention
Dose of drug, timing etc“Outcomes”Health related Quality of LifeBiochemical outcomes
Symptoms
Physical assessment
Patient satisfaction
Acceptability
Cost-effectivenessSlide8
Measuring “outcome”
Questionnaires, interview, medical notes etc
Timing of questionnaires?
Baseline (prior to treatment)
Short term outcomesLong term outcomesWho collects the data?Slide9
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 upPerformance biasSystematic differences in care providedObservation/detection bias
systematic differences in observation, measurement, assessmentSlide10
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)Slide11
Simple RCT model
Trial participants
RANDOMLY
allocated
to experimental
or
CONTROL
group
CONTROL
EXPERIMENTSlide12
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
trialsSlide13
Terminology
Interventions
are comparative regimes within a trial
Prophylactic, diagnostic, therapeutic e.g.
preventative strategiesscreening programmesdiagnostic tests
drugs
surgical techniquesSlide14
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 trialsSlide15
Terminology
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)Slide16
What is a randomised controlled trial
?
RCTs are
Experiments:
investigators can influence number, type, regime of interventionsQuantitative: measure events rather than try to interpret them in their natural settings
Comparative:
compare two or more interventionsSlide17
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 groupSlide18
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! Slide19
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 peoplepatientscaregivers (physicians, nurses etc)Groups of people, ‘cluster randomisation’
(Covered in more depth in later lecture)Slide20
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 randomThese are called pseudo- or quasi-randomSlide21
Terminology
Controlled
clinical trials (CCTs)
are not the same as randomised controlled trialsControlled clinical trials include non-randomised controlled trials and randomised controlled trialsSlide22
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/317/7167/1185Slide23
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
ButNo intervention has 100% efficacy Many diseases recover spontaneously Slide24
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 309:780Slide25
DISTRIBUTION OF RESULTS
threshold
measurement 1
measurement 2Slide26
Hawthorne Effect
Experimental effect in the direction expected but not for the reason expected
Essentially studying/measuring something can change what you studying/measuringSlide27
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/299/9/1016Slide28
Effect size
Experimental group
Control group
Hawthorne E.
R. mean
Placebo E.
Therapeutic E.
Real difference
Noise
Signal
EFFECT OF AN INTERVENTIONSlide29
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)Slide30
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, 1456-8Slide31
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 affectedSlide32
Empirical evidence of biasSlide33
‘Explanatory’ and ‘Pragmatic’ questions
Explanatory
Can
it work in an ideal setting …..?
Efficacy Hypothesis testing Placebo controlledDouble blind
Pragmatic
Does
it work in the real world …..?
Effectiveness
Choice between alternative approaches to health care
Standard care
OpenSlide34
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 practiceSlide35
Key differences between
explanatory and pragmatic trials (2)
Explanatory Pragmatic
Outcomes short-term long-term, patient- surrogates centered and resource orientated
Size small (usually larger
single centre) (often multi-centre)
Analysis treatment received intention to treat
Relevance indirect direct
to practiceSlide36
Example of selection bias for PP in an open trial
Worse prognosis
Exp
Ctrl
None
None
White(2005)
E
ESlide37
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;316:285Slide38
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 factorSlide39
RCT strengths
Confounding variables minimised
Only research design which can in principle yield causal
relationships
can clarify the direction of cause and effectAccepted by EBM schoolDon’t have to know everything about the participantsSlide40
RCT 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!Slide41
Other issues in RCTs (1)
Ethics
Management issues
Interim analysis and ‘stopping rules’
part of ethical concernmechanisms to avoid patient harmData 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.Slide42
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)Slide43
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 treatmentSlide44
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 attributionRandomisation guards against selection bias between the two treatment groupsStandard statistical analysis Good internal validityMay lack generalisability due to highly selected participantsCan be costly to set up and conduct, ethical issuesSlide45
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 factorsminimise all sources of errorsystematic error (bias)random error (chance)be practical and ethicalSlide46
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)Slide47
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” effectSlide48
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
generalisabilitySlide49
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: 1185-1190Slide50
References
Black. Why we need observational studies to evaluate the effectiveness of health care.
BMJ 1996
: 312;1215-8
Crombie. Research in Health Care. 1996Doll. Doing more good than harm: the evaluation of health care interventions. Ann NY Acad Sci 1993:703;310-13Elwood 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