This is the lecture notes for Randomized controlled trial (HFS3063)

1. 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 & DieteticsSchool of Nutrition & Dietetics
Faculty of Health SciencesFaculty of Health Sciences
UniversitiUniversiti SultanSultan ZainalZainal AbidinAbidin
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2. 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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3. 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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4. 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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6. b) Minimizing bias in RCT
1) Allocation bias
2) Performance bias
3) Assessment bias
4) Attrition bias
5) Allocation concealment
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7. 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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8. 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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9. 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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10. (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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11. 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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12. 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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13. 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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14. Important factors in RCT?
1) Sample size
2) Stratification
3) Trial design
4) Between group contamination
5) Ethical issues
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15. 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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16. 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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17. 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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18. (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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19. (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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20. 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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21. 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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22. 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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23. 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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24. 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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25. 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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26. Thank YouThank You
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