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Health and Disease in Populations 2002

Session 8 – 21/03/02

Randomised controlled trials 1

Dr Jenny Kurinczuk

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Lecture objectivesYou 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 studiesCase control studiesCase seriesCase reportsEcological 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

TimeObserve

Exposed

OutcomeUnexposed

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Randomised controlled trials

TimeHave control

Treatment A

OutcomeTreatment B

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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 treatmentTreatment 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 = Atails = B

• Use random number tables Odds = AEvens = 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),

blindinguse 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)