KNOWLEDGE FOR THE BENEFIT OF HUMANITYKNOWLEDGE FOR THE BENEFIT OF HUMANITY

PUBLIC HEALTH AND EPIDEMIOLOGY (HFS3063) Epidemiological Study Designs:

RANDOMISED CONTROLLED TRIALS

Dr. Dr. MohdMohd RazifRazif ShahrilShahril

School of Nutrition & Dietetics School of Nutrition & Dietetics

Faculty of Health SciencesFaculty of Health Sciences

UniversitiUniversiti Sultan Sultan ZainalZainal AbidinAbidin

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Topic Learning Outcomes

By the end of this lecture, students should be able to;

• describe randomised controlled trial design.

• explain the advantages and disadvantages of randomised controlled trial design.

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Randomized controlled trials (RCT)

• RCT or randomized clinical trials are experimental

studies where the effect of an intervention is assessed

by collecting data before and after an intervention.

• Used to compare an intervention with one or more other

intervention or with no intervention.

• Intervention are often clinical treatments but may also be

educational interventions (e.g. health promotion leaflets).

• Two main features of the RCT;

a) They are comparative

b) They are designed to minimize bias

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a) Comparative

• In RCT, an intervention is investigated by comparing one

group of people who receive the intervention with a

control group or control arm who do not.

• Control group receives usual or no treatment and their

outcome measure (or the change in measure from the

baseline) is compared with that of the intervention group.

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b) Minimizing bias in RCT

1) Allocation bias

2) Performance bias

3) Assessment bias

4) Attrition bias

5) Allocation concealment

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1) Allocation bias

• Occurs when the measured treatment effect differs from

the true treatment effect because of how participants

were selected into the intervention or control group.

• In RCT, participants will be randomized to either an

intervention or control group at study entry.

• Randomization ensures that characteristics that might

affect the relationship between intervention and outcome

measures will be roughly equal across all arms of the

study

– minimizing potential bias

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2) Performance bias

• Occurs when participants’ response to the treatment is

affected by knowledge of the group to which they are

assigned.

– They know which group they belongs to either intervention or

control.

• Performance bias might also occur when health

professionals administer treatment differently

between treatment arms.

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3) Assessment bias

• Health professionals assessing the outcome of treatment

relative to alternative or placebo interventions may

record outcome measures biased by the knowledge of

the group assignments.

• Overestimation or underestimation of the effects on

an intervention is known as assessment bias.

• There might be a systematic difference in measuring

the outcomes between the two groups because of the

method of recording used

– E.g. control group is assigned to one practitioner and the

intervention group to another, or groups are assessed at different

times of the day.

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(cont.) 3) Assessment bias

• How to minimize the assessment bias?

– Use a standardized method of evaluation across both groups.

– Avoid using subjective measures to assess the effectiveness

of a treatment which are more prone to bias.

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4) Attrition bias

• Also called as loss-to-follow-up bias.

• Occurs when patients drop out of the study from their

respective study group.

• If halfway through a study the treatment has been

successful, participants may drop out and information

about the success of the treatment is then lost.

• Participants in the control group might be unhappy with

their lack of progress and may drop out of the study in

order to seek alternative help.

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5) Allocation concealment

• Bias will be minimized where the allocation schedule is concealed of whom is assigned to which group.

• Blinding (or masking) helps prevent systematic differences between comparison groups in prognosis or responsiveness to treatments (allocation bias).

• Blinding of both participants and practitioners prevents performance and assessment bias by ensuring everybody (participants, treatment admin, those measuring outcomes) do not know which treatment was given.

• It is recommended RCT participants are blind to the treatment they receive. – Control group receives placebo

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Why carry out RCT?

• RCT are prospective longitudinal studies

– Allowing causal association between intervention and outcomes.

• The random selection of participants into each arm and

the controlled way in which trial is carried out mean that

all factors are considered equal.

• Other study design cannot infer causality.

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Important factors in RCT?

1) Sample size

2) Stratification

3) Trial design

4) Between group contamination

5) Ethical issues

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1) Sample size

• Sample size dependent upon

– the power of the test

– what size of intervention impact is considered meaningful

– type of hypothesis the RCT is testing

• The smaller magnitude of difference between groups

that is to be detected and the greater the variability in

outcomes, the larger the sample size that will be

required.

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2) Stratification

• Very large trials are likely to have a good balance of

patients within each arm.

• When samples are small, however, treatment groups

may be chance end up with different characteristics

– May affect the outcome trial

• Stratification is a way of ensuring the treatment groups

are balanced on characteristics that are likely to alter the

relationship between treatment and outcome.

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3) Trial design

• There are two commonly used trial design to allocate

treatment and control regimens in RCT;

– Parallel design

– Crossover design

• In parallel design, different patients will be randomized in

each treatment group.

– There will be differences in characteristics of participants

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(cont.) 3) Trial design

• Crossover trials are another way of overcoming

differences in groups by keeping the patients as

matched as possible.

• Instead of having different patients in each treatment

group, patients receive first one treatment and then the

other, in random order, with a wash out period in

between.

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(cont.) 3) Trial design

• Within-patient differences are then compared in

crossover design.

• Each patient effectively becomes their own ‘test’ and

‘control’.

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4) Between group contamination

• Educational interventions are prone to contamination

e.g. a member of the control arm is a friend of a patient

receiving the low fat diet advice intervention.

– Information will be passed between the two arms of trial and thus

alter results.

• Use cluster sampling so natural cluster such as

geographic areas are randomized rather than

individuals.

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5) Ethical issues

• RCT is not always possible because of ethical issues

when assigning patients to study arms.

• If one group of patients receives treatment thought to be

effective, while another group does not, the ethics of a

trial may be brought into question.

• Similarly, there are some trials that cannot be carried out

because they may actively encourage unhealthy

practices e.g. smoking.

– People cannot be randomized into smoking and non-smoking

group.

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Analysis of data

• RCT are experiments set up to test hypotheses.

• Null hypotheses – the intervention will have no impact on

the outcome measure

– Outcome will be similar in both the test and control groups

• Alternative hypotheses – intervention will have

meaningful effect and statistically significant

• Statistical method (e.g.);

– Pre and post intervention differences = paired t-test

– Mean differences pre and post between two group =

independent t-test

– Mean differences pre and post between more than two groups =

ANOVA

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Advantages of RCT

• Ability to make causal inferences mean that RCT provide

the strongest empirical evidence of a treatment’s

efficacy.

• Randomization of participants to the test and control

arms and concealment of their allocation ensures that

allocation bias and confounding or unknown variables

are minimized.

• The study can be tailored to answer a specific question.

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Disadvantages of RCT

• High dropout when the intervention has undesirable

side-effects or there is little incentive to stay in the

control arm.

• Ethical consideration may mean that a research question

cannot be investigated using RCT design

• For a descriptive overview it may be cheaper and easier

to use an observational design.

• Prior knowledge is required for sample size calculation;

– the level of improvement that is clinically meaningful

– expected variation of improvement in the sample

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Recapitulate In this lecture, you have been exposed to;

• definition of RCT

• how biases is minimized in RCT

• factors to be considered when carrying out RCT

• analysis of data for RCT

• advantages and disadvantages of RCT

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Thank YouThank You

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