Randomised Controlled Trials RCTs

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Randomised Controlled Trials (RCTs)

• Graeme MacLennan

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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/h
  i/health/6223000.stm

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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)

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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

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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
RANDOMLY allocated to experimental or CONTROL
group
EXPERIMENT
CONTROL
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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

• 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)

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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 quasi-random

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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

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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/317/7167/1
  185

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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

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

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DISTRIBUTION OF RESULTS
threshold
measurement 1
measurement 2
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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/299/9/10
  16

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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
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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
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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

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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
• 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

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

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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
• Dont have to know everything about the
  participants

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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!

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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 20052(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
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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
  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

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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