Randomized Controlled Trial (RCT)

EXPERIMENTAL EPIDEMIOLOGY
(EXPERIMENTAL EPIDEMIOLOGICAL STUDIES)

• Also c/a ‘Intervention studies’.

• Some action or intervention is involved such as deliberate application (of

a drug) or withdrawal of the suspected cause in the experimental (or
study) group and no change in the control group.

• Later the outcome of the experiment is compared in both the groups.

• Thus, it differs from the observational studies in that the experiment is

directly under the control of the investigator and involves cost, ethics
and feasibility whereas in the observational studies the investigator
(epidemiologist) takes no action but only observes the outcome.
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 EXPERIMENTAL EPIDEMIOLOGY
(EXPERIMENTAL EPIDEMIOLOGICAL STUDIES )
• The aim is to provide ‘scientific proof’ of the etiological
factors. (or risk factors) and to evaluate the health services.

• There are three types of experimental studies:

A. Clinical trial (or Randomized Controlled Trial)

B. Field trial (or Community Intervention Studies)
C. Community trial with entire community as the unit of
study

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 EXPERIMENTAL EPIDEMIOLOGY
(EXPERIMENTAL EPIDEMIOLOGICAL STUDIES )
A. Clinical trial (or Randomized Controlled Trial)
- e.g. Drug trial, Trail of Surgical Procedure
- Unit of Study will be “Patients” suffering from given disease
B. Field trial (or Community Intervention Studies)
- e.g. Vaccine trail, Personal Protective Measures
- Unit of Study will be “Healthy Individuals”
C. Community trial with entire community as the unit of study
- e.g. Health education to village people regarding Hand hygiene

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 Human Experiments
Examples
• Scurvy V/S diet

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 Sailors
James Lind, 1753
c/o Bleeding tendency

Improved Returned home

Not improved
Returned to journey

Reappearance\Detoriation of S\S

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 Sailors
Descriptive
Epidemiology
Bleeding tendency

Observational Improved Returned home

& Analytical Not improved
Returned to journey

Reappearance\Detoriation of S\S

Hypothesis= Related to food habits

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 Selected 12
patients– 6 gps

1 2 3 4 5 6

Lemon/ Elixir Quarts

Venagar Nutmeg Sea water
orange Vitriol of cider

IMPROVED

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 Randomized Controlled Trial (RCT)

• (RCT) is so called because the patients who constitute

the unit of study are allocated into ‘Study group’
(experimental group) and ‘Control group’ at random,
depending upon whether they receive or do not receive
the intervention.

• Random allocation eliminates bias.

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 Randomized Controlled Trials

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 Randomized Controlled Trial (RCT)
• Aim of the study:
1. To provide scientific proof of etiological
risk factors which may permit the
modification or control of those diseases

2. Measuring the effectiveness and efficacy of

drugs and health services for prevention and
treatment of diseases
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 Randomized Controlled Trial (RCT)
• USEs of RCT:
1. To evaluating new drugs and other
treatments of disease
2. To evaluating newer tests of medical care
technology
3. To assess new programs for screening and
early detection
4. For evaluation of effectiveness and efficiency
of health services
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Randomized Controlled Trial (RCT)
• Basic Steps in RCT
1. Drawing up a protocol
2. Selecting the reference and experimental
population
3. Randomization
4. Manipulation and intervention
5. Follow up
6. Assessment of outcome
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 Design of a RCT
Select suitable population
(reference or target population)

Select suitable sample (Experiment

or study population)
Make necessary exclusion
RANDOMIZE
Those not eligible
Those who do not wish
to give consent

Experimental group Control group

Manipulation & follow-up

ASSESSMENT
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 Randomized Controlled Trial (RCT)
1. The Protocol
It specifies the
– Aim and objectives,
– Criteria for selection of study and control group,
– Size of sample,
– Procedure of allocation of subjects to study and control
group,
– Intervention and analysis
• During the study, due to some ethical reason and
unpredictable and unfavorable circumstances
protocol may be modified in between
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 Randomized Controlled Trial (RCT)

2. Selecting the reference and experimental

population
– Reference or Target population
• To which the findings of the trial will be
applicable if found successful

– The Experimental or Study population

• Derived from the reference population
• It is ideally randomly chosen from the reference
population

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 Randomized Controlled Trial (RCT)
• The participants must fulfill the following criteria

1. Must give informed consent after fully informed

about purpose, procedure and possible dangers

2. They must fulfill the eligible criteria

3. They should be representative of the population to

which they belong(i.e. reference population)

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3. Randomization

 This is the ‘Heart’ of the clinical trial.

 Every individual has an equal chance of being

selected into either study group or control
group, from the reference population.

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 Randomization(contd.)

• Selection of study group (Experimental

group):
 It is the actual population (or volunteers)
derived from the reference population
randomly, participating in the experiment, still
retaining the same characteristics as the
reference population.

 Randomization eliminates bias and allows

comparability.
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 Randomization(contd.)

• Selection of control group.

Another group of the same size as that of the

study group is selected at random from the
reference population, maintaining the similar
characteristics (e.g. age, sex, occupation,
literacy level, income, etc.) as that of the study
group but they do not receive intervention
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 Randomized Controlled Trial (RCT)
4. Manipulation

• It is the application or withdrawal or increase

or reduction of suspected causal factor

• e.g. a drug, vaccine, dietary component, a habit,

a surgery etc. as laid down in protocol

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 Randomized Controlled Trial (RCT)
5. Follow up implies
– Examination of the study and control group
– At defined interval of time
– Under same given circumstances
– In same standard manner
till final assessment of out come

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 Randomized Controlled Trial (RCT)

6. Assessment
- The final step is to asses the out come of the
trial in terms of positive result or negative
results
-The results are compared in both the groups
and the differences if any are tested for
statistical significance

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Three types of analyses are done as-

1. Intent-to-treat
Analyze all persons according to allocation group, even if
some do not receive the intervention or drop out before
completion of treatment
2. Per protocol
Analyze only those who actually complete the
intervention according to their actual allocation
3. As treated
Analyze those who got actual intervention irrespective of
their allocation group
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 • Bias that may arise
1. Subjective bias- Participants may subjectively
feel better or report improvement if they know
that they are receiving a new form of treatment

2. Observer bias- The observer measuring the out

come may be influenced if he knows beforehand
what intervention and to which subject applied

3. Evaluation bias- The investigator may

subconsciously give favorable report to out
come
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 • These bias can not be removed by
randomization
• These are removed by blinding like -
1. Single blind trial
2. Double blind trial
3. Triple blind trial

No blind trial are called Open Trials done

mainly for pilot studies and dose ranging studies

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 Blinding (Masking)
• Single blind trial
• Double blind trial
• Triple blind trial

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 Single Blind Trials
• In this type, the participants do not know whether
they belong to study group or control group.
• That means they do not know whether they are
receiving new drug or the placebo.
• However, the investigator knows who belong to
which group.
• This trial helps to overcome subject variation

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 Double Blind Trials
• In this type, neither the investigator, (Doctor) nor the
participants (patients) know the group allocation and
the treatment (new drug) received.
• However, statistician knows it.
• He assigns the code numbers and hands over the
drugs with code number to the investigator (doctor)
indicating which one to be given to whom

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 Triple blind trial
• In this type, it goes one step further.
• All the participants, doctor and the statistician are
unaware (blind) of the group allocation.
• The findings of the trial by the doctor are handed over
to the statistician, with code numbers.
• He will decode and analyse the results.

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 Phases Of Clinical Trials:
Phase I:
• Trial is done on a small group of healthy
individuals to (10 to 30) know the safety, the
efficacy and the side effects of the vaccine.
• Usually, it takes 8 to 12 months to complete
phase I trial.
• Maximum tolerated dose tested

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 Phases Of Clinical Trials:
• Phase II: Trial is carried out on a larger group
of persons (50-500), to know not only the
safety of the vaccine but also refining the
dosage schedule. This is often carried out in
multiple centres.
• Phase II trials generally take 18 to 24 months
to complete.
• Done for Efficacy and Max. Drug Failure
seen
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 Phases Of Clinical Trials:
• Phase III: In this phase, trial is carried out on
thousands of volunteers not only to know the
safety, efficacy and immune response but also
to decide whether the vaccine is fit for
manufacturing.
• Comparison with existing drug
• New drug launched in market
• RCT done

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 Phases Of Clinical Trials:
• Phase IV: This is a continuous on-going process
to know the long- term effects of the vaccine
• Done for Long term side effect
• Post marketing surveillance

• Phase 0 : Healthy human volunteers

• For Micro dosing

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 Randomized Controlled Trial (RCT)

• Types of RCT
1. Clinical trials
2. Preventive trials
3. Risk factor trials
4. Cessation experiments
5. Trial of etiological agents
6. Evaluation of health services

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 1.Clinical trials
• For evaluating therapeutic agents, mainly
drugs

• E.g. Evaluation of beta-blockers in reducing

cardiovascular mortality in patient surviving
the acute phase of MI

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 2.Preventive trials
• These trials are purported to prevent or
eliminate disease on an experimental basis

• E.g. trials of vaccines and chemo prophylactic

drugs

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 3.Risk factor trials
• Often this involves risk factor modification

• Major risk factors of CHD are elevated blood

cholesterol, smoking, hypertension and
sedentary habits

• Intervention in CHD are reducing this risk

factors
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 4.Cessation experiments
• In this type of study, an attempt is made to
evaluate the termination of a habit (or removal
of suspected agent)

• E.g. Cigarette smoking and lung cancer

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 5. Trial of etiological agents

• One of the aims of experimental epidemiology

is to confirm or refute an etiological
hypothesis

• The best known example of trial of an

etiological agent relates to retrolental
fibroplasia

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 6. Evaluation of health services
• RCT have been extended to assess the
effectiveness and efficiency of health services

• An excellent example of such an evaluation is

the controlled trials in the chemotherapy of
tuberculosis in India, which demonstrated
that “domiciliary treatment” of pulmonary
tuberculosis was as effective as the more
costlier “hospital or sanatorium” treatment
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 Limitation
• Randomization may not be appropriate or ethical
in certain settings.
• Bias could occur if the investigators are not blinded
to exposure and outcome
• Expensive, difficult to execute, requires close
monitoring.
• Appropriate sample sizes are a prerequisite or else
one may end up with false negative conclusions.

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 Problems in reporting of RCT
• Evidences showed that quality of reporting of
randomized controlled trials (RCTs) were not optimal.

• Without transparent reporting, readers cannot

judge the reliability and validity of trial findings nor
extract information for systematic reviews.

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 Problems in reporting of RCT
• Recent methodological analyses indicate that
inadequate reporting are associated with
biased estimates of treatment effects.
• Such systematic error is seriously damaging
to RCTs, which are considered the gold
standard for evaluating interventions because
of their ability to minimize or avoid bias

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 Trial Registration
• In India registration is done under Clinical
Trial Registry in India (CTRI) hosted at
ICMR's National Institute of Medical Statistics
(NIMS), is a free and online public record
system for registration of clinical trials.
• International registration is done in ISRCTN
(International Standard Randomized Control
Trial Number) register and WHO trial registry.

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 Evidence Pyramid

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 Thank You!

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