•Sujata Devi .

•Stuti Pritom Boruah

•Anuwarul Islam .
CONTENTS
 Introduction
 AIMS
 EXPERIMENTAL STUDIES-TYPES
 RCT-BASIC STEPS
 Uses of RCT
 REFERENCES
WHAT IS EPIDEMIOLOGY?

"The study of the distribution and determinants of

health-related states or events in specified
populations,and the application of this study to the
control of health problems’’
EPIDEMIOLOGICAL METHODS
Classification of Epidemiological
methods
• Descriptive epidemiology
• Analytical epidemiology
Observational • Case control study
studies • Cohort study

• Randomized control trials

Experimental • Community trials
• Field trials
studies
AIMS

1. To provide scientific proof of aetiological

factors which may permit the modification or
control of those disease

2. To provide a method of measuring the

effectiveness & efficiency of health services for
the prevention, control & treatment of disease
& improve the health of the community
RCT

“An epidemiological experiment in which subjects

in a specified population are randomly allocated
into groups usually called study and control
groups to receive and not receive an experimental
preventive or therapeutic procedure,
manoeuvre,or intervention.”
-John M Last
1. For evaluating new drugs & other
treatments of disease
2. For evaluating new tests of medical care
technology
3. To assess new programs for screening &
early detection
4. For evaluation of effectiveness & efficiency
of health services
WHEN IS AN RCT NOT APPROPIATE
 In knowing the etiology and natural history of the
disease.
 Unethical o randomize.
 Very rare outcomes.
 Outcomes may take a long time to develop.
 When the effect of an intervention is so powerful that
a trial is not necessary.
Steps of conducting RCT

Drawing up a protocol
Selection of reference & experimental population
Randomization
Manipulation or intervention
Follow -up
Assessment of outcome
 SELECT SUITABLE POPULATION
(REFERENCE OR TARGET POPULATION)

SELECT SUITABLE SAMPLE

(EXPERIMENTAL OR STUDY POPULATION)
THOSE NOT
ELIGIBLE
MAKE NECESSARY EXCLUSIONS
THOSE WHO DO
NOT WISH TO
GIVE CONSENT
RANDOMIZE

EXPERIMENTAL CONTROL
GROUP GROUP

MANIPULATION &
FOLLOW-UP

ASSESSMENT
 Having formed the study and control groups now the next step
is to intervene or manipulate the study (experimental group)
by the deliberate application or withdrawl or reduction of the
suspected causal factor.

 It may be drug, vaccine, dietary component etc.

 This manipulation creates an independent variable (drugs,

vaccine, a new procedure) whose effect is then determined by
measurement of the final outcome, which constitutes the
dependent variable (eg incidence of disease, survival time,
recovery period)
FOLLOW-UP
 This implies examination of the experimental and control group subjects
at:
 Defined intervals of time
 In a standard manner
 With equal intensity
 Under the same given circumstances
 In the same time frame till final assessment of outcome

 Thus the follow up may be short or may take many years depending upon
the study undertaken.
 It may be mentioned that some losses to follow up are unavoidable due to
factors such as death, migration, and loss of interest. This is known as
ATTRITION.
 If the attrition is substantial, it may be difficult to generalise the results of
the study to the reference population. So every effort should be made to
minimize the losses to follow up.
ASSESSMENT
 The final step is assessment of the outcome of the trial in
terms of
 POSITIVE RESULTS: Benefits of the experimental results
such as reduced incidence or severity of disease,
appropriate outcome in the study and control groups.
 NEGATIVE RESULTS: Severity and frequency of side effects
and complications if any including death.
The incidence of positive/negative results is rigorously
compared in both the groups, and differences, if any,
are tested for statistical significance.
 Techniques are available for the analysis of data as they are
collected , but it is more useful to analyse the results at the
end of trial.
Errors in assessment can lead to “BIAS”
Bias can arise from three sources:
SUBJECT VARIATION
OBSERVER BIAS
EVALUATION BIAS
Randomization cannot guard against these sort of bias
To avoid the above situations, BLINDING is done.
BLINDING
Blinding can be done in three ways-

a) SINGLE BLIND TRIAL: The trial is so planned that the

participant is not aware whether he belongs to the study
group or control group.
b) DOUBLE BLIND TRIAL: The trial is so planned that
neither the doctor nor the participant is aware of the
group allocation and the treatment received.
c) TRIPLE BLIND TRIAL: This goes one step further. The
participant, the investigator and the person analysing the
data are all “blind”. Ideally of course, the triple blinding
should be used; but double blinding is the most
frequently used method when a blind trial is conducted.
EXAMPLE OF RCT- whether it is worthwhile to give Isoniazid
chemoprophylaxis to children who are close contacts of open
cases of pulmonary TB
BASED ON STUDY
DESIGNS:
1. CONCURRENT PARALLEL STUDY
DESIGNS:
 In this design , comparisons are made
between two randomly assigned groups, one
group exposed to specific treatment, and the
other group not exposed.
 Patients remain in the study group or the
control group for the duration of the
investigation.
2. CROSS OVER TYPE OF STUDY DESIGNS:
 With this type of study design, each patient serves as his own control.

 As before, the patients are randomly assigned to a study group and control
group. The study group receives the treatment under consideration. The
control group receives some alternate form of active treatment or placebo.

 The two groups are observed over time. Then the patients in each group are
taken off their medication or placebo to allow for the elimination of the
medication from the body and for the possibility of any “carry over” effect.

 After this period of medication, the two groups are switched. Those who
received the treatment under study are changed to the control group
therapy or placebo, and vice versa.
CROSS OVER STUDIES OFFER A
NUMBER OF ADVANTAGES
1. All patients can be assured that sometime during the
course of investigation, they will receive the new
therapy.
2. Such studies generally economize on the total number
of patients required at the expense of the time
necessary to complete the study.
DISADVANTAGES OF CROSS OVER
STUDIES
This method of study is not suitable if the drug of interest
cures the disease, if the drug is effective only during a
certain stage of the disease or if the disease changes
radically during the period of time required for the study.
ADVANTAGES AND DISADVANTAGES OF
RANDOMIZED CONTROL TRIAL
ADVANTAGES
 It eliminates bias in treatment assignment , specially
selection bias and confounding.
 It facilitates blinding of the identity of treatments from
investigators, participants and assessors, which
decreases bias.
 Ensures that the physician running the trial is not
consciously or unconsciously allocating certain patients
to a particular group.
 Good randomization will help prevent any population
bias.
Disadvantages
 Expensive in terms of time and money.
 Volunteer biases: the population that participates may
not be representative of the whole.
 Loss to follow up attributed to treatment.
 Ethical issue
 Compliance
 Inefficient for investigating infrequent adverse effects.
 Cannot evaluate potentially harmful exposure.
a. Clinical trials
b. Preventive trials
c. Risk factor trials
d. Cessation experiments
e. Trial of aetiological experiments
f. Evaluation of health services
Clinical trials
 Clinical trials have been concerned with evaluating therapeutic
agents , mainly drugs .
 Unit of study is – ‘ patient suffering from a given disease’
 Some of the recent examples are –
 Evaluation of beta blockers in reducing cardiovascular mortality in patients
surviving myocardial infarction
 Trials of folate treatment before conception to prevent recurrence of neural
tube defects
 Trials of coronary bypass surgery for the prevention of myocardial infarction
, etc

 Not all clinical trials are susceptible to being blinded.

Preventive Trials
 The term ‘preventive trials’ implies trials of
preventive measures.
 These trials are purported to prevent or eliminate
disease on an experimental basis
 Most frequent preventive trials are – trials of
vaccines and chemo prophylactic drugs
 These are applied to groups of subjects instead of
individual subjects.
 For example-

In 1946 , the Medical research council of UK conducted an

extensive trial to test whooping cough vaccine from three
manufacturers in ten separate field trials . The study and
control groups comprised of children between 6 to 18 months
of age.
The vaccine was given in three ,monthly injections and followed
up to detect the occurrence of whooping cough.

STUDY GROUP = 3,801 vaccinated children

whooping cough developed by= 149

CONTROL GROUP=3,757 unvaccinated children

whooping cough developed by =687
 Analysis of a preventive trial must result in a clear
statement about
 the benefit the community will derive from the measure
 The risks involved
 The costs to the health service in terms of money, men and
material resources.

 Since these involve larger number of subjects and a longer

time span, there may be greater number of practical
problems in their organisation and execution
Risk factor trials
 It is a type of preventive trial , in which the investigator
intervenes to interrupt the usual sequence in the
development of disease for those individuals who have
‘risk factor’ for developing the disease ; often this
involves risk factor modification.

 Risk factor trials can be ‘single factor’ or ‘multi factor’.

 For example-

 According to the major risk factors involved in coronary heart disease, the four
main possibilities of intervention are- reduction of blood cholesterol, cessation
of smoking, control of hypertension and promotion of physical activity.
 The WHO promoted a trial on primary prevention of coronary heart disease
using clofibrate to lower serum cholesterol. This study was done on 15,000 men
of whom one third received clofibrate and two third received olive oil as a
control treatment
 After a mean observation of 9.6 years, the trial showed a significant reduction in
non fatal cardiac infarction ,but unfortunately due to long term adverse effect of
the drug , there were 25 per cent more deaths in the study group than in the
control group.

 The trial illustrates the kind of contribution that an epidemiological

approach can make to protect the public health against the possible
adverse effects of long term medication with potent drugs.
Cessation Experiments
 In this type of study, an attempt is made to evaluate the
termination of a habit which is considered to be
related to a disease.
 If such action is followed by a significant reduction in the
disease, the hypothesis of cause is greatly strengthened.
 For example- cigarette smoking and lung cancer
Trial of aetiological agents

 One of the aims of experimental epidemiology is to confirm

or refute an aetiological hypothesis.

 The best known example of this trial relates to retrolental

fibroplasia (RLF).
-Analytical studies demonstrated its close association with
administration of oxygen in premature babies
 A large randomised control trial was mounted involving 18
hospitals in the US, in which premature babies with birth weight
of 1500 gram or less were allocated into experimental and control
groups. In the experimental group, all the babies received 50 per
cent oxygen therapy and the control group oxygen was only used
in clinical emergency.
 It was later found that all cases who developed RLF had received
some oxygen. There were no cases among those who received
none, confirming the aetiological hypothesis.

since most diseases are fatal, disabling or unpleasant , human

experiments to confirm the aetiological hypothesis are rarely
possible.
Evaluation of health services
 Randomised controlled trials have been extended to assess the
effectiveness and efficiency of health services.

 This is necessary when resources are limited and a large number of

activities are to be implemented for the welfare of the society.

 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 treatment is as effective as the
more costlier ‘hospital’ treatment.
References:
 Park’s Textbook of PREVENTIVE AND SOCIAL
MEDICINE
 IAPSM’S Textbook of Community Medicine
Thank you