Power Point RCT

Universitas MUHAMMADIYAH Aceh
FAKULTAS KESEHATAN MASYARAKAT

PROGRAM STUDI MAGISTER KESEHATAN MASYARAKAT
RANDOMIZED
CONTROL TRIAL
(RCT)
Contents
• Why randomized controlled trials?
• Design and conduct

– Selection of study population
– Allocation of study regimes
– Follow-up of participants
– Analysis and interpretation
– Publication
Universitas MUHAMMADIYAH ACEH

2
Question Design
• We need different studies to answer

different study questions
• The study question decides what design

3
Key questions
• How many are (becoming) ill? (occurence)
• Why do some people become ill why others stay healthy?

(etiology/causiality)
• How can we determine if somebody has a spesific health

condition? (diagnostics)
• What can we do to improve the health condition of

individuals/populations? (effect of measures)
• What will happen to those who are ill? (prognosis)
• What is it like to use the health service? (experience)

4
EBM Hierarchy

5
EXAMPLE OF A RCT
https://www.ncbi.nlm.nih.gov/pubmed/19059639

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EXAMPLE OF A RCT

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Intervention study –important
characteristic
• Case – control study

Participants enrolled on basis of disease
status
• Cohort study
Participants enrolled on basis of exposure
status
• RCT
Investigator allocates the exposure
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Intervention study characteristic
• Design Features of a simple RCT: a special form of the

standard prospective cohort study – the only difference being
that participants are allocated to the exposed and unexposed
groups at random
Universitas MUHAMMADIYAH ACEH 9 9
Randomized controlled trials (RCT)
”An epidemiological experiment in which

subjects in a population are randomly
allocated into groups, usually called
study and control groups to receive and
not receive an experimental preventive
or therapetuic procedure, maneuver, or
intervention”
John M.Last, 2001

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DEFINITION OF RCT
A randomized controlled trial (or randomized control

trial;[2] RCT) is a type of scientific (often medical) experiment,
where the people being studied are randomly allocated one or
other of the different treatments under study. The RCT is often
considered the gold standard for a clinical trial. RCTs are often
used to test the efficacy oreffectiveness of various types of
medical intervention and may provide information about adverse
effects, such asdrug reactions. Random assignment of
intervention is done after subjects have been assessed for
eligibility and recruited, but before the intervention to be studied
begins.

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Why RCT?
• ”Gold standard” in epidemiological

research
• Makes study groups comparable

– Controls for confounding (known and
unknown)
– Prevents selection bias

12
When can a RCT be used?
• Exposures modifiable by the investigator

• Primary outcomes are common and soon
• Ethical consideration : Equipoise
"clinical equipoise," there is genuine uncertainty regarding
the comparative therapeutic merits of each arm in a trial
within the expert medical community--not necessarily on the
part of the individual investigator--about the preferred
treatment.
• Expense and Feasibility

Intervention studies
Therapeutic Preventive
• Study population • Study Population
– Patients with disease – Population at risk
• Objectives • Objectives
– Cure patients – Reduce the risk of
– Diminish symptoms developing disease
– Prevent recurrence of
disease/risk of death

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STUDY DESIGN

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STUDY DESIGN

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Elements of the RCT
1. Randomisation 5. Adherence/Contamination
• Why? 6. Outcome Assessment
• How? 7. Loss to Follow up
• Who? 8. Analysis
2. Allocation concealment • Intention to treat Analysis
3. Intervention • Per Protocol Analysis
4. Blinding/Masking

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Design - conduct
Different phases
• Enrollment (selection of study population)
• Allocation of study regimes
• Follow-up
– Maintainence and assessment of adherence
– High and uniform rates of ascertainment
• Analysis and interpretation

18
Selection of study population 1
• Reference (source) population

– The population to whom the results of the trial is
applicable
– Generalizability
• Experimental population
– The actual group in which the trial is conducted
– Sample size
– Sufficient number of outcome (endpoints)
– Possibility for accurate follow up of information
during the trial

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• Participants must be fully informed

– Risks
– Benefits
– Blinding/placebo
• Willing to participate
– Informed consent
• Screened for eligibility

– Inclusion criteria
– Exclusion criteria

20
Population hierarchy for intervention study
Reference population
Experimental population
Exclusion criteria Excluded
Informed consent Refused
Study population
Random allocation
Intervention group Control group

Losses to follow-up Losses to follow-up
Outcome

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• The actual study population = selected

subgroup of the experimental population
– Generalizability
– Volunteerism
• Obtain baseline data and/or ascertain

outcome for subjects eligible, but
unwilling to participate
Study results generizable beyond trial group

22
Allocation of study regimes 1
• After eligible and willing
• Different comparisons:
– Another dosage of same drug
– Another therapy or program
– Continuation of standard medical practise
– Placebo
– Nothing …….
• Allocation by randomization

23
-randomization
• Random = governed by chance
• Randomization = allocation of individuals to groups by chance
• Each sampling unit has the same chance of selection
• Makes intervention and control group comparable at the start

of the investigation
• Favourable effect on those reading the published result

24
-randomization
• Simple randomization
– First option
• Stratified randomization
– Classified into subgroups before randomization
– Randomize within subgroups
– (if sample size is limited)
> blocking
• Methods:
– Table of random numbers
– Computer generated randomization-list
– Sealed envelopes
– Telephone lists
– ………..

25
-potential bias
• Knowledge on study regimes might influence

the evaluation of the outcome
• Blinding
– Hiding information about the allocated study
regimes from key participants in a trial
– Depending on outcome of interest
– Ethics, feasibility, compromise
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2947122/

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-potential bias
• Randomization minimizes differences between

treatment groups at the outset of the trial not differential
treatment later in the trial/assessment of outcomes.
• Note that allocation concealment is completely
different from blinding
• Who? participants, clinicians (surgeons), data
collectors, and data analysts.
• Challenges  Surgeon, surgical procedure vs other
therapy

- potential bias
• Placebo
– Inert medication or procedure, i.e
– No effect
– Intended to give the patient the perception they are
receiving treatment
• Single – blind
– Observer or subject are kept ignorant about allocated
study regime
• Double blind
– Both observer and the subject are kept ignorant about
allocated study regime

28
Follow-up of participants 1
- adherence
• Adherence = Health related behaviour that abides by

the recommendations from the investigator
• Possible reasons for non-adherence

– Developing side effects
– Forgetting to take medication
– Withdrawing consent
– Decide alternative treatment
– Health issues: treatment contraindicated
• Extent of non-adherence is related to length of study

time

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-adherence
• Non-adherence will decrease the statistical power to

detect the true effect of the study intervention
• Strategies to enhance adherence

– Selection of interested/reliable study population
(generelizability)
– Frequent contact with participants
• Monitoring adherence (difficult to measure)

– Self report
– Pill counts
– Biochemical parameters

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ascertainment of outcome of interest
• Uniform ascertainment – all study groups
• Complete follow-up of all study participants
• Keep number of individuals lost to

follow-up an absolute minimun

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Factorial design
• Advantage
– Answer two or more questions in a single
trial for only a marginal increase in cost
• Should not
– Complicate trial operation
– Affect eligibility reqirements
– Cause side effects – poor adherence
– Interaction between study regimes

32
Early termination of a trial
- stopping rules
• Possible reasons for early

termination/modifcation
– Data indicates clear benefit from intervention
– Intervention is harmful
• Develop guidelines before trial begins

– Statistical tests
– Interim data
• Interim results to be modified by

independent body

33
Analysis and interpretation
• Compare baseline characteristics in study groups to

assess balance
– If imbalance, control for known confounding factors
• Inclusion or exclusion of non-adherent participants in
analysis?
– Randomization is done on the basis of OFFERING
intervention
> analysis on the same basis
– Non-adherence may be related to factors that also affect
the risk of outcome under study
– Failure to include all subjects allocated to one study
regime will lead to biased results
• Intention to treat analysis
– All subjects allocated to one study regime are analyzed
together
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Analysis and Interpretation
• Intention to Treat Analysis

comparison of the treatment groups that includes all patients
as originally allocated after randomization. This is the
recommended method in superiority trials to avoid any bias.
For missing observations, “last value carried forward” is the
recommended method.
• Per Protocol Analysis
comparison of treatment groups that includes only those
patients who completed the treatment originally allocated. If
done alone, this analysis leads to bias.

Reporting Results of Trial
• Introduction
Background/Justification, Research Question, Aim, Hypothesis
• Methods
Study Design, study sample, exposure and outcome measurement,
analysis planning
• Analysis
• Results
Primary & Secondary results (tables, graphs)
• Discussion
What results mean, comparison with previous results, what went wrong in
the study, what are the implications

Reporting Results of Trial
• The CONSORT Statement

(For intervention Study)
http://www.consort-statement.org
• The STROBE Statement
(For observational Study)

CONSORT Statement 2010

CONSORT Statement 2010

Population hierarchy for intervention study
Reference population
Experimental population
Exclusion criteria Excluded
Informed consent Refused
Study population
Random allocation
Intervention group Control group
Losses to follow-up Losses to follow-up
Outcome

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Unique problems of intervention studies
• Ethics
– Sufficients doubts to withold from half the population
– Sufficient believes to expose half the population
– Requires high scientific standards
– Nuremberg Code, 1947
– Human Research Ethics Committee/Institutional Review
Board
• Feasibility
– Widespread adaption of measures by community
– Problems of finding sufficiently large eligible sample size
• Costs
– Expensive

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Summary
• Gold standard in epidemiological

research
• Makes study groups comparable
– Random allocation
– Sufficient sample size
• Unique problems of ethics, feasibility
and costs
• Ensure transparancy of all trials

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• Problem with cost

Questions

Clinical Scenario
to illustrate the importance of matching the study design to

the research question domain while using clinical scenarios
as an example..
A 37-year-old pregnant woman comes to the clinic for a routine

checkup. This is her second pregnancy. She had her first child when
she was 35 years old and had an amniocentesis at 18 weeks to test for
Down syndrome. The amniocentesis was negative. She is currently 8
weeks pregnant and would like to know as soon as possible of any
abnormalities. An ultrasound can be done in the first trimester for
diagnosing Down syndrome, but it is unknown if the results are as
reliable as the conventional test of amniocentesis.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3326852/

45
Clinical Scenario
Q: Among pregnant women over the age of 35 (patient/problem), what is

the accuracy of ultrasound (intervention/experimental test) compared to
amniocentesis (control/conventional test) in detecting Down syndrome in
fetus (outcome)?
RCT  Eliminated, ethically challenging

Case control studies  Eliminated, outcome unknown
Cohort Study  Eliminated, exposure unknown, not to calculate incidence
Cross – sectional study  allow two observations from the same group
Design: Pregnant women over the age over the age of 35 would be given
both an ultrasound and amniocentesis. The results of the tests would be
recorded and the number of true positives and negatives versus the false
positives and negatives would be calculated

46

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Universitas MUHAMMADIYAH Aceh

FAKULTAS KESEHATAN MASYARAKAT

• Why randomized controlled trials?

• Design and conduct

Universitas MUHAMMADIYAH ACEH

• We need different studies to answer

• The study question decides what design

Universitas MUHAMMADIYAH ACEH

• How many are (becoming) ill? (occurence)

• Why do some people become ill why others stay healthy?

• How can we determine if somebody has a spesific health

• What can we do to improve the health condition of

• What will happen to those who are ill? (prognosis)

• What is it like to use the health service? (experience)

Universitas MUHAMMADIYAH ACEH

Universitas MUHAMMADIYAH ACEH

Universitas MUHAMMADIYAH ACEH

Universitas MUHAMMADIYAH ACEH

• Case – control study

• Design Features of a simple RCT: a special form of the

”An epidemiological experiment in which

John M.Last, 2001

A randomized controlled trial (or randomized control

Universitas MUHAMMADIYAH ACEH

• ”Gold standard” in epidemiological

• Makes study groups comparable

Universitas MUHAMMADIYAH ACEH

• Exposures modifiable by the investigator

Universitas MUHAMMADIYAH ACEH 13 13

Universitas MUHAMMADIYAH ACEH

Universitas MUHAMMADIYAH ACEH

Universitas MUHAMMADIYAH ACEH

Universitas MUHAMMADIYAH ACEH

• Enrollment (selection of study population)

• Allocation of study regimes

• Analysis and interpretation

Universitas MUHAMMADIYAH ACEH

• Reference (source) population

Universitas MUHAMMADIYAH ACEH

• Participants must be fully informed

• Screened for eligibility

Universitas MUHAMMADIYAH ACEH

Intervention group Control group

Universitas MUHAMMADIYAH ACEH

• The actual study population = selected

• Obtain baseline data and/or ascertain

Universitas MUHAMMADIYAH ACEH

• After eligible and willing

Universitas MUHAMMADIYAH ACEH

• Random = governed by chance

• Randomization = allocation of individuals to groups by chance

• Each sampling unit has the same chance of selection

• Makes intervention and control group comparable at the start

• Favourable effect on those reading the published result

Universitas MUHAMMADIYAH ACEH

Universitas MUHAMMADIYAH ACEH

• Knowledge on study regimes might influence

Universitas MUHAMMADIYAH ACEH

• Randomization minimizes differences between

Universitas MUHAMMADIYAH ACEH 27 27

Universitas MUHAMMADIYAH ACEH

• Adherence = Health related behaviour that abides by

• Possible reasons for non-adherence

• Extent of non-adherence is related to length of study