Transcript Relationship between incidence and prevalence

Health and Disease in Populations 2002
Session 8 – 21/03/02
Randomised controlled trials 1
Dr Jenny Kurinczuk
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Lecture objectives
You should be able to:
1. Outline the steps involved in a
randomised controlled trial
2. Discuss the benefits of random
allocation, blindness and other
strategies for avoiding bias in the
estimation of treatment effects
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3. Discuss the ‘placebo effect’ and how
to deal with it
4. Describe what a ‘placebo’ is, when it
is used and be able to distinguish
the terms ‘placebo’ and ‘placebo
effect’
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What is a clinical trial ?
“Any form of planned experiment
which involves patients and is
designed to elucidate the most
appropriate method of treatment of
future patients with a given medical
condition.”
Stuart Pocock 1983
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Background
Observational -
Cohort studies
Case control studies
Case series
Case reports
Ecological studies
Experimental -
Randomised controlled
trials
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In an observational study the
researcher has no control over who
is exposed to what – we cannot
decide who smokes cigarettes and
who doesn’t – we just observe and
look for differences in outcome !
In contrast, in an experiment, the
researcher is in control of who is
exposed to what
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Cohort studies
Observe
Exposed
Unexposed
Time
Outcome
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Randomised controlled trials
Have control
Treatment A
Treatment B
Time
Outcome
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The questions that randomised
controlled trials are designed to answer
•
Is treatment A better than
treatment B?
Treatment A – usually a new treatment
Treatment B - usually the standard
(old) treatment
- there may not be an old
treatment available
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Outline of the steps involved in the
randomised controlled clinical trial
method
•
Define the disease of interest
•
Define the treatments, A & B, that
are to be tested
•
Define the patients eligible for
inclusion in the trial
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•
Identify a suitable group of patients
•
Invite them to be in the study
•
Obtain written informed consent
from those willing to participate
(but are free to drop out at any
stage)
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•
Allocate half of the patients to
receive treatment A and half to
receive treatment B
•
Perform the allocation in an
unbiased way
•
Follow the patients up in an unbiased
way, for an appropriate length of
time, to determine the outcome
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•
Compare the outcomes in the two
groups (in an unbiased way) to see:
–
If there is a difference in outcome
between the two treatments A & B
–
How big the difference is - is it a
clinically important difference?
–
Whether the difference is
attributable to the treatment
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•
Defining treatments A & B
•
Accessing patients
•
Allocating the patients to treatment
•
Assessing & comparing the outcomes
Essential feature in all the stages –
avoiding (minimising) bias
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Objective 2: Avoiding/minimising bias randomisation & blinding
•
Bias
–
–
Getting the wrong answer
Systematically favouring one group
over the other in a way that results in
a misleading answer about which
treatment is best
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Patient allocation to treatment and
avoiding bias
•
Allocate half of the patients to
receive treatment A and half to
receive treatment B
•
Perform the allocation without being
biased
•
RANDOMISE them
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Why randomise ?
•
Random allocation to the two
treatment groups performs the
allocation avoiding bias :
–
–
It avoids the clinicians’ influencing
which type of patients (eg. less sick)
receive which treatment
This is a form of selection bias
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Why randomise ?
•
In the long run randomisation leads
to a balance between the numbers
and characteristics for patients on
A&B
•
The two groups will be similar for
characteristics such as age
distribution – and other confounders
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Why randomise ?
•
Randomisation deals with confounding for
factors (such as age and sex) that we
know about
AND
factors we don’t know about, but which
may influence the prognosis
•
This is the unique benefit of RCTs and
the reason why RCTs give such strong
evidence about causality
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How to randomise ?
•
•
•
Toss of a coin – heads = A
tails = B
Use random number tables
Odds = A
Evens = B
Computer generated random
numbers
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Comparing outcomes and
avoiding/minimising bias
•
Follow the patients up, in an
unbiased way, to determine the
outcome
•
If the assessing clinician knows
which group was treated with which
drug this may influence their
assessment of the outcome
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Comparing outcomes
•
Use objective, valid, reliable and practical
outcome measures which are defined
before the start of the trial
•
Apply the outcome measures without
knowledge of which treatment the
patients’ received
•
To do this properly it is usually necessary
to be BLIND to the treatment allocation
at the start of the trial
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Blindness
•
•
•
•
•
Who should be blind ?
The allocating clinician (to avoid bias
in allocation)
The patient – may change behaviour
(& placebo effect)
The clinician assessing the effects
of treatment
DOUBLE BLIND
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How to achieve blindness
•
•
•
Make the two treatment look and
taste the same
The dosing method and regimen
should be the same
Number the bottles and only the
pharmacy will have the code to
identify which is treatment A and
which is B
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Objective 3: ‘Placebo effect’
• What if there is no standard (old)
treatment?
• Do we give one group the tablets and
the other group no tablets?
• What effect might that have?
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The effect of having only one group of
patients on treatment
• Is an improvement in the condition of
the treated group due to:
– The drug?
OR
– The act of being treated/cared for in
some way?
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‘Placebo effect’
“Even if therapy is irrelevant to the
patient’s condition the patient’s
attitude to his illness, and indeed the
illness itself, may be improved by a
feeling that something is being done
about it.”
Pocock 1983, pg 92
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‘Placebo effect’
“Many patients could be effectively
treated by placebos, inert and
preferably attractive pills, especially
if the doctor was persuasive as to
their value.”
Gribbins, 1981
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Objective 4: Placebos and their
use
• Placebo – inert substance, formulated
to look like the active drug with which
they are being compared
• Used in circumstances where there is
no standard treatment for
comparison with the new treatment
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• No standard treatment – because
there just is none and so placebo is
the only ‘treatment’ the patient
receives
• Cancer (multiple) treatment –
Drugs X + Y + Z + ‘new drug’
Drugs X + Y + Z + ‘placebo’
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• Use of placebo is a form of deception
• Therefore, it is essential that if
patients are in a trial which involves
the use of a placebo that they are
informed that they may receive a
placebo
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Summary
•
Defined what randomised controlled
trials are and the steps involved
•
Considered closely the issues of
avoiding/minimising bias:
random allocation (randomisation),
blinding
use of placebos
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Any Questions ?
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An early clinical trial
“On 20th May 1747 I took 12 patients in
the scurvy on board the ‘Salisbury’.
The cases were as similar as I could
have them. They all had putrid gums,
spots and lassitude…
They laid together… and had one diet,
common to all… two drank cider, two
others Elixir Vitriol, two others
vinegar, two sea water, two oranges
and lemons and two others nutmeg.
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The consequences was that the most
sudden and good effects were
perceived from the use of oranges
and lemons, one being at the end of
six days fit for duty… the other was
best recovered of any…”
Lind 1753
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The first clinical trial with a
randomised control group
Medical Research Council trial of the
use of steptomycin in the treatment
of tuberculosis (1948)
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