Epidemiological Studies

Randomised Controlled
Trial RCT
Dr Nahlah Alsaidi
MBBS, MPH, PhD
Community Medicine Department
Faculty of Medicine
MAHSAH UNIVERSITY
 Learning Objectives
Upon finishing this class you will be able to:
1. Define and describe RCT
2. Discuss its concept
a. Randomization
b. Blinding
c. Use of placebos
3. Design, conduct and analyse RCT
4. Discuss the strengths and weaknesses of
cohort studies and RCT.

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 INTRODUCTION

› Intervention studies are considered to provide the most

reliable evidence in epidemiological research.

› The randomized controlled trial (RCT) is regarded as

one of the most valued research methodologies for
examining the efficacy or effectiveness of interventions.

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Evidence Pyramid

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 Experimental Studies in History

• In 1747: One of the most famous clinical trials was James Lind's
demonstration that citrus fruits cure scurvy

• He compares the effects of various acidic substances, ranging

from vinegar to cider, on groups of afflicted sailors
• His study concluded that within six days, the group who were
given oranges and lemons had largely recovered from scurvy.

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contd.

› Randomization for experimental studies was established

by R.A. Fisher in 1923

› The first modern randomized clinical trial in medicine is

usually considered to be the trial of streptomycin for
treating tuberculosis

› Itwas conducted by the British Medical Research

Council in 1946 and reported in 1948

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 What Is A Randomised Controlled Trial?
› A trial is an experiment

› A clinical trial is a controlled experiment that studies new tests and

treatments and evaluates their effects on human health outcomes

› A randomized clinical trial RCT is a clinical trial in which participants are

randomly assigned to separate groups that compare different treatments.

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› Randomized trials are gold standard of study
designs because the potential for bias (selection
into treatment groups) is avoided

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The most powerful tool in modern clinical research
 Prospective
 Controlled
 Unbiased

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RCT DESIGN

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 Goals of RCT

Primary goal
To test whether an intervention works by comparing it to a control
condition, usually either no intervention or an alternative
intervention (placebo).
Secondary goals
• Identify factors that influence the effects of the intervention
(i.e., Moderators)
• Understand the processes through which an intervention
influences change (i.e., Mediators or change mechanisms
that bring about the intervention effect)

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 Basic steps of Randomized Controlled Trials
1. The protocol
2. Selecting reference and experimental
populations
3. Randomization
4. Manipulation
5. Follow up
6. Assessment

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 1. The Protocol
General outline of a protocol for clinical trial

The plan of a clinical trial is formally stated in a “protocol”

• Rationale and background of the study
• Specific objectives for the study
• Concise statement of the study design (masking, randomization schemes, types and
duration of treatments, number of patients)
• Criteria for including or excluding patients
• Outline of treatment procedures
• Definition of all clinical, laboratory and other methods
• Methods of assuring integrity of the data
• Major and minor outcomes
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contd.
• Provisions for observing and recording side-effects
• Procedures for handling problem cases
• Procedures for obtaining informed consent forms from the concerned
subjects
• Procedures for periodic review of the trial
• Procedures for termination of the trial
• Procedures for analyzing results
• Procedures for communicating results of trial to study subjects and other
interested persons

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2. Selecting reference and experimental population
a) Reference or target population:
It is the population to which the findings of the trial if found
successful are expected to be applicable.

a) Experimental or study population:

It is derived from the reference population.
It is the actual population that participates in the experimental
study.

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contd.
› The participants must fulfill following criteria

i) They must give “informed consent” , after having been informed about
the purpose, procedure and possible dangers.

ii) They should be qualified or eligible for the trial.

e.g.- if we are testing for anaemia, if the persons are not anaemic then they
are not eligible.

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 Selection of the control group
› The idea is that the control group gives the clinician something to
compare the experimental results to.
› The control must be selected with care.
› The control group might be given no treatment at all, a placebo,
or “treatment-as-usual.”

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 PLACEBO

A placebo (from the Latin for “I will please”) is anything that seems to
be a "real" medical treatment -- but isn't. It could be a pill, a shot, or
some other type of "fake" treatment.
› Placebos are used in studies in order to find out whether or not the
pharmacological effect of a drug actually includes effects produced by
the drug might be related to psychological processes that are
generically called the placebo effect.

› The "placebo effect" is often described as events that occur when

patients show improvement from treatments that contain no active
ingredients.
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 3. Randomization
› Randomizations the process by which allocation of subjects to treatment
groups is done by chance, without the ability to predict who is in what group
› It eliminates “bias” and allow for comparability, though theoretically
elimination is possible by matching.
› It can be best done using random number table.
Purpose of Randomization
Primary purpose
› Prevent bias in allocating subjects to treatment groups.
Secondary purpose
› Achieve comparability between the groups.

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 Pseudo-randomisation

Other allocation methods include

• Date of birth
• The number on hospital records
• Geographical distribution etc.

These are NOT regarded as random

These are called pseudo- or quasi- random

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 4. Manipulation

• After forming the study and control group manipulation is

done by deliberate application or withdrawal or reduction of
suspected causal factor.

• It creates an independent variable (e.g.- drug, vaccine) whose

effect is the determined by final outcome which constitute
dependent variable (e.g. incidence of disease, survival time,
recovery period)

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 5. Follow up

Examination of both the group subjects at defined intervals of time,

under the same given circumstances, in the same time frame till
final assessment of outcome.
The frequency and duration of follow up will depend on:
• Type of endpoint (e.g., response to treatment, development of
new disease, progression of disease, behavioural change,
sustainability of change)
• The level of risk (higher the risk, more frequent the follow-up)

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 6. Assessment
› It is assessment of trial in terms of positive and negative result.
a) Positive results: that is, benefits of the experimental measure such as
 Reduced incidence or severity of the disease,
 Reduced cost to the health service
 Appropriate outcome in the study and control groups.

b) b) Negative results: that is, adverse effects

 Increased severity and frequency of side effects
 Complications
 Death.

›
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Errors in assessment can lead to “Bias”
Bias may occur from three sources
› first, from the participant, if he reports that feeling better
knowing that he is getting new form of treatment. i.e. “Subject
Variation”
› Secondly, investigator measuring the outcome with influence if
he knows the result beforehand. i.e. “Observer bias”

› Thirdly, “Bias in evaluation” i.e. investigator subconsciously give

favorable result of the outcome.

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 Blinding or masking
› “Single Blind Trial” is done that the participant is not know.

› “Double Blind Trial” is done that the doctor as well as the

participant are not aware.

› “Triple Blind Trial” i.e. participant, investigator and the person

analyzing the data are not aware the fact.

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 Fundamental analysis of an RCT

 Group 1 receives current treatment (CT)

 Group 2 receives new treatment (NT)

Improved Not improved

CT

NT

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RCT ANALYSIS

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Absolute risk reductions give the actual difference in risk between
treatment group and the control group.

Relative risk reductions give a percentage reduction in one group

compared to another.

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 Strengths of RCT
• Utilizes a control group (strongest evidence)
• Bias is minimized
• Extraneous factors being responsible for
outcomes is minimized.
• Most reliable technique for evaluating treatments
• Most statistically powerful study design

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 Weaknesses of RCT

• Expensive
• Time necessary to perform study can be long.
• Patient enrolment can be difficult (time length)
• Drop out rate is higher because of long term follow-up
• Ethical problems in testing new therapies in humans
• Most complex to interpret.

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 Ethical issues in RCT
• Randomized control trials are not always practical or ethical,
and such limitations can prevent researchers from conducting
their studies.

• It can be unethical to deny a new treatment to the placebo group

• “Equipoise” a genuine uncertainty or doubt about whether one

intervention or treatment is superior to another
• Protection of the study participants (including physical, mental
and social well being) is the most important responsibility of the
researcher

• The protection of the vulnerable population (whose decision–

making capacity is impaired or diminished)
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 References

› › Aparasu, R. R., & Bentley, J. P. (2014). Principles of research design and drug
literature
evaluation. Jones & Bartlett Publishers.
› Bhide, A., Shah, P. S., & Acharya, G. (2018). A simplified guide to randomized controlled
trials. Acta obstetricia et gynecologica Scandinavica, 97(4), 380-387.
› Gordis, L. (2013). BOPOD - Epidemiology: with STUDENT CONSULT Online Access:
Elsevier Health Sciences.
› Houle, S. (2015). An Introduction to the Fundamentals of Randomized Controlled Trials in
Pharmacy Research. The Canadian journal of hospital pharmacy, 68(1), 28.

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 Quiz
1. A randomised-controlled trial:

A. Has the least ethical constraints of all epidemiological studies.

B. Is usually carried out retrospectively.
C. Is usually the cheapest epidemiological study design.
D. The best study design for assessing causation.

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 Quiz
2. What is the best design you choose to study the prevalence of a disease?

A- Cross sectional study

B- Case- control study
C- Cohort study
D- RCT

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 Quiz

3. What is the best trial design to study the incidence of a disease?

A- Cross-sectional study
B- Case-control study
C- Cohort study
D- RCT

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 Quiz

3. You want to assess the efficacy of a new anti-epileptic drug

versus an old drug? What is the best design you choose for this
purpose?

A- Cross sectional study

B- Case-control study
C- Cohort study
D- RCT

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Thankyou