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Randomised Controlled Trials RCTs

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Title: Randomised Controlled Trials RCTs


1
Randomised Controlled Trials (RCTs)
  • Graeme MacLennan

2
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

3
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/h
    i/health/6223000.stm

4
The need to evaluate health care
  • Variations in health care
  • Unproven treatments
  • Inadequacies in care
  • Inaccurate medical models
  • Limitation of resources
  • New innovations
  • Crombie
    (1996)

5
Evaluation 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

6
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

7
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

8
Measuring outcome
  • Questionnaires, interview, medical notes etc
  • Timing of questionnaires?
  • Baseline (prior to treatment)
  • Short term outcomes
  • Long term outcomes
  • Who collects the data?

9
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

10
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)

11
Simple RCT model
RANDOMLY allocated to experimental or CONTROL
group
EXPERIMENT
CONTROL
12
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

13
Terminology
  • Interventions are comparative regimes within a
    trial
  • Prophylactic, diagnostic, therapeutic e.g.
  • preventative strategies
  • screening programmes
  • diagnostic tests
  • drugs
  • surgical techniques

14
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

15
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)

16
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

17
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

18
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!

19
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)

20
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 quasi-random

21
Terminology
  • Controlled clinical trials (CCTs) are not the
    same as randomised controlled trials
  • Controlled clinical trials include non-randomised
    controlled trials and randomised controlled
    trials

22
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/317/7167/1
    185

23
Why do we need a control group?
  • Dont 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

24
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 3261083-4
  • Bland and Altman BMJ 1994 3081499 and 309780

25
DISTRIBUTION OF RESULTS
threshold
measurement 1
measurement 2
26
Hawthorne Effect
  • Experimental effect in the direction expected but
    not for the reason expected
  • Essentially studying/measuring something can
    change what you studying/measuring

27
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/299/9/10
    16

28
EFFECT OF AN INTERVENTION
Real difference
Signal
Effect size
Therapeutic E.
Placebo E.
Noise
R. mean
Hawthorne E.
Experimental group
Control group
29
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)

30
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

31
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

32
Empirical evidence of bias
33
Explanatory and Pragmatic questions
  • 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

34
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

35
Key differences between explanatory and
pragmatic trials (2)
  • Explanatory Pragmatic
  • Outcomes short-term long-term, patient- surrogate
    s centered and resource orientated
  • Size small (usually larger
  • single centre) (often multi-centre)
  • Analysis treatment received intention to treat
  • Relevance indirect direct
  • to practice

36
Example of selection bias for PP in an open trial
White(2005)
Exp
None
E
Ctrl
None
E
37
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 1998316285

38
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

39
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
  • Dont have to know everything about the
    participants

40
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!

41
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 20052(1)22-33.

42
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)

43
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
44
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

45
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

46
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)

47
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

48
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

49
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
    19983171217-1220
  • 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

50
References
  • Black. Why we need observational studies to
    evaluate the effectiveness of health care. BMJ
    1996 3121215-8
  • Crombie. Research in Health Care. 1996
  • Doll. Doing more good than harm the evaluation
    of health care interventions. Ann NY Acad Sci
    1993703310-13
  • 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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