The document discusses experimental epidemiology and randomized controlled trials. It begins by defining experimental epidemiology as involving experimentation through intervention in groups to measure effects. It describes the basic steps of RCTs as drawing up a protocol, randomization, intervention/manipulation, follow-up, and outcome assessment. It provides details on sample size estimation, selection of reference and experimental populations, randomization techniques, blinding, analysis approaches, and types of RCTs including clinical trials.

1. EXPERIMENTAL EPIDEMIOLOGY
WITH SPECIAL REFERENCE TO
RANDOMIZED CONTROLLED
TRIAL
HARIMU BARGAYARY
POST GRADUATE RESIDENT
DEPARTMENT OF COMMUNITY
MEDICINE

2. CONTENTS
1. Epidemiological study designs
2. Experimental epidemiology
3. Randomized controlled trial
4. Field trials and Community trials
5. Ethical considerations
6. Summary
7. References
2

3. Epidemiologi
cal Study
Designs
Observation
al studies
Descriptive
studies
Analytical
studies
Ecologica
l
Cross-
sectional
Case
control
Cohort
Experiment
al/
Intervention
studies
Randomized
Controlled
Trials
Field trials
Community
trails
3

4. EXPERIMENTAL EPIDEMIOLOGY
A.k.a Intervention epidemiology.
 Involves experimentation in the groups/ community and the effects of
intervention are measured in two groups viz. experiment group and
control group.
 3 designs:
1. Randomized controlled trials (RCTs)
2. Field trials
3. Community trials
4

5. RANDOMIZED CONTROLLED TRIALS
5
 A.k.a Randomized clinical trial.
 Objective: To study the effectiveness of a new drug or a regimen
in ‘patients’.

6. BASIC STEPS:
1. Drawing up a protocol
2. Selecting reference and experimental populations
3. Randomization
4. Manipulation or intervention
5. Follow – up
6. Assessment of outcome
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7. 7
DESIGN OFA RANDOMIZED CONTROLLED TRIAL

8. 1.DRAWING UP THE PROTOCOL:
 It is the “blueprint” of an RCT and must specify:
• Title of the study and registration number (DCGI approval)
• Background information, rationale, aims and objectives of the study
• Selecting suitable population and reference population including sample size
• Duration of the study and roles and responsibilities of the study group
• Selection criteria for eligibility and description of interventional materials
• Informed consent process and randomization
• Intervention procedure and assessment of the intervention
• Follow-up, end-points, evaluation, reporting, closure and archiving
• Statistical considerations and quality control and assurance, monitoring and audits. 8

9. SAMPLE SIZE
PREREQUISITES TO ESTIMATE THE SAMPLE SIZE
NEEDED IN RCT
1. The difference in response rates to be detected.
2. An estimate of the response rate in one of the groups.
3. Level of statistical significance(α).
4. The value of power desired(1-β).
5. Whether the test should be one-sided or two-sided.
9

10. SAMPLE SIZE
ESTIMATION:
10
Let’s say, we are
conducting trial of 2
therapies:
• Current Therapy = 40%
cure rate
• New Therapy = 60%
cure rate
• Difference in Cure rates
= 20%
• α = 0.05; 1-β = 80%
• Lower of 2 cure rates =
40%
• Sample size for:
- Two-sided Test = 97

11. 2. SELECTION OF REFERENCE AND
EXPERIMENTAL POPULATIONS:
A. Reference / Target population:
The population to which the
findings of the trial, if found to
be successful, are expected to
be applicable.
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B. Experimental / Study population:
Derived from the reference population.
It is the actual population that
participates in the experimental study.

12. Experimental
/
study
population
Derived from the
reference population
Should be randomly
chosen
Should have same
characteristics as
reference population
Must fulfil the
following criteria
Should be eligible for
the trial
Must give informed
consent
12
Contd…

13. 3.RANDOMIZATION:
It is a statistical procedure by which the participants are
allocated into intervention and control groups.
It attempts to eliminate “bias” and allow comparability.
It ensures no control over allocation of participants to either of
the group.
13

14. BIAS
• Bias may arise from errors of assessment of the outcome due
to human element.
• Three sources:
1) “SUBJECT VARIATION - Bias on the part of the participants.
2) “OBSERVER BIAS” - Bias on the part of the Investigator
measuring the outcome of a therapeutic trial.
3) “BIAS IN EVALUATION” - the investigator may sub-
consciously give a favourable report to the outcome of the trial.
14

15. BLINDING
Blinding refers to the “ concealment of group allocation from one or
more individuals involved in a clinical research study”.
Blinding can be done in 3 ways:-
1. Single Blind Trial
2. Double Blind Trial
3.Triple Blind Trial
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16. 16

17. • Random sequence generation such as Random Number Table.
• Allocation concealment.
• Example:-
17
 How is Randomization
accomplished?
Table of Random Number

18. • If done properly, we achieve non-predictability of the next
assignment.
• Less chance for subjective biases
• If the study is large enough, randomization increases the
likelihood that the groups will be comparable to each other
in regards to characteristics concerned with affecting the
prognosis.
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 What do we hope to accomplish by
Randomization?

19. 19

20. TYPES OF RANDOMIZATION
1. Simple Randomization
- eg. Coin tossing
Using currency notes
Random number table
- Drawback - yield unequal sample sizes in the two groups .
20

21. 21
2. Restricted / Block randomization
- To ensure that comparison groups will be of approximately the same size.
- Recommended in small sized RCTs

22. 22
3. Stratified randomization
The study population is first
stratified by a particular
prognostic variable
and then participants are
randomized to intervention
groups within each stratum.

23. 4. MANIPULATION/INTERVENTION
• The next step is to intervene or manipulate the study group
by deliberate application or withdrawl or reduction of the
suspected causal factor as laid down in the protocol.
• Types of Interventions
• Pharmaceutical (Therapeutic or Preventive)
• Device
• Procedure
• Behaviour modification
23

24. 5. FOLLOW-UP:
• This implies examination of the experimental and the 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.
• Some losses to follow up are inevitable due to factors such as
death, migration and loss of interest. This is known as attrition.
• Every effort should be made to minimize the losses to follow up.
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25. 6. ASSESSMENT OF OUTCOME:
A. POSITIVE RESULTS: Benefits of experimental measure
such as reduced incidence or severity of the disease, cost to the
health service or other appropriate outcome in the study and
control groups.
B. NEGATIVE RESULTS: Severity and frequency of side-
effects and complications, if any, including death.
25

26. STUDY DESIGNS OF RCT
A. CONCURRENT PARALLEL STUDY DESIGN
B. CROSS-OVER TYPE STUDY DESIGN
C. FACTORIAL STUDY DESIGN
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27. 27
Sample
Random
Assignment
Exposed to
specific Rx.
Unexposed to
specific Rx.
COMPARE
OUTCOME
Time
CONCURRENT PARALLEL STUDY DESIGN
Observation
 Comparisons are made between two randomly assigned group, one is
exposed to specific treatment and other group is not-exposed.
 Patients remain in the study or the control group for the duration of
investigation.
The present The future
Population

28. The present The future
Population
74
Patients
Random
Assignment
Exposed to
specific Rx.
Unexposed to
specific Rx.
COMPARE
OUTCOME
EXPOSED &
UNEXPOSED TO
Rx.
Time
CROSS-OVER TYPE OF STUDY DESIGNS
Observation
 Each patient serves as his own control.
 The study group receives the treatment under consideration and the control
group receives alternative form/ placebo.
 Over the course, the groups are switched.

29. 29
PLANNED CROSS-OVER DESIGN

30. 30
UNPLANNED CROSS-OVER DESIGN

31.  Advantages Of Cross-over studies –
• All patients can be assured that sometime during the course of
investigation they will receive the new therapy.
• It economize the total number of patients required at the expense of the
time necessary to complete the study.
 Disadvantage –
• Not suitable if the drug of interest cures a disease,
• Not suitable if a drug is effective only during a certain stage of the disease,
• Not suitable if the disease changes radically during the period of study.
31

32.  ANALYSIS:
Intention-to-Treat Analysis
 Per Protocol (PP) Analysis
 As Treated (AT) Analysis
32

33. 33
INTENTION TO TREAT ANALYSIS
• A.k.a Randomized/Method Effectiveness analysis.
• Compare outcome according to the randomized group (Gold
Standard).
• Adherence to intervention not necessary.
Advantages:
• Randomization is maintained:
• Treatment assignment is based on chance alone.
• Randomization provides Theoretical foundation for Statistical
test of significance.

34. 34
Disadvantages:
• Doesn’t take into account Protocol violation
• Group may not be comparable at the end.
• Not adhering to treatment or vice versa.
• Eligibility for the trial was incorrect.
• Loss to follow up.
• Estimates of non – complied in the efficacy dilutes difference
between groups.
• Analysis may underestimate adverse effects.

35. 35
 PER PROTOCOL ANALYSIS:
• Analyze only those who fully complied to protocol.
• Doesn’t included cross-over in final analysis.
• Provides fair idea of efficacy for treatment.
• May be Biased (randomization compromised).
 AS TREATED ANALYSIS:
• Subject analyzed according to treatment taken or not (no relation
with randomization).
• Non compliant from treatment and vice versa analyzed
accordingly.
• AT is shown if ITT shows no effect (why trial done).

36. 36

37. 37

38. FACTORIAL STUDY DESIGN
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Enables to test outcome / effect of two or more
interventions not only simultaneously but also
in combination, against a control.

39. TYPES OF
RANDOMIZED CONTROLLED TRIALS
1. Clinical Trials
2. Preventive Trials
3. Risk Factor Trials
4. Cessation Experiments
5. Trial Of Etiological Agents
6. Evaluation Of Health Services
39

40. 1. CLINICAL TRIALS
It is done for various purposes like:-
- prophylactic trials( e.g. immunization, contraception)
- therapeutic trials (e.g. drug treatment, surgical procedure)
- safety trials (e.g. side effects of oral contraceptive and
injectable)
40

41. e.g.
1) Evaluation of beta blockers in reducing cardiovascular mortality in
patients surviving the acute phase of myocardial infarction.
2) Trial of folate treatment/supplementation before conception to prevent
recurrence of neural tube defects
3) Efficacy of tonsillectomy for recurrent throat infection
- Many ethical, administrative and technical problems are associated with
clinical trials.
41

42. TYPES
OF
CLINICAL
TRIALS
 BASED ON NUMBER OF
CENTRES
SINGLE CENTRE
MULTI CENTRE
 BASED ON TRIAL DESIGN
PARALLEL GROUP
CROSS OVER-
PLANNED/UNPLANNED
CLUSTER RANDOMIZED
FACTORIAL
ADAPTIVE
42
 BASED ON WHAT IT IS
DESIGNED TO PROVE
SUPERIORITY
NON-INFERIORITY
EQUIVALENCE
 BASED ON HOW IT IS
CONDUCTED
EFFICACY VS
EFFECTIVENESS

43. PHASES OF CLINICAL TRIALS
1. Pre-clinical Phase
2. Clinical Phases (Phase-0 To Phase 5)
43

44. Phase Unit of study Purpose
1.PRE-CLINICAL PHASE
Lab experiments Animals Pre-testing
2.CLINICAL PHASES
Phase-0 Healthy human volunteers Micro-dosing
Phase-1 Healthy human volunteers Safety and non-toxicity
profile(Maximally tolerated dose)
Phase-2 Patients Pharmacokinetics and
Pharmacodynamics
Phase-3 Patients RCT
Phase-4 Patients Rare and chronic Side-effects and
post-marketing surveillance
Phase-5 Patients Effectiveness and research.
Active surveillance of therapeutic
effects.
Done simultaneously with phase 4.
55

45. 2. PREVENTIVE TRIALS
-synonymous with “primary Prevention”.
- to prevent or eliminate disease on an experimental basis.
- the most frequently occurring type of preventive trials are the trials of vaccines
and chemo-prophylactic drugs.
- its analysis must result a clear statement like-
- how it will be benefitted for the community
- the cost and risk involved.
- since preventive trial involved larger number of subjects and sometimes a longer
time span to obtain results, there may be greater number of practical problems in
their organization and execution. 45

46. 3. RISK FACTOR TRIAL
- The investigator intervenes to interrupt the usual sequence in the
development of the disease for those who have “risk factor” for developing
disease; often this involves risk factor modification.
e.g.. Risk factors for CHD are cholesterol, smoking, hypertension and
sedentary habit. Risk factor trials can be single factor or multifactor. Both
the approaches are complementary and both are needed.
- Primary prevention of CHD using clofibrate to lower serum cholesterol
46

47. 4. CESSATION EXPERIMENT
- An attempt is made to evaluate the termination of a habit (or
removal of a suspected agent.) which is considered to be
causally related to a disease.
47

48. e.g. for Smoking and lung cancer if in a
RCT one group of cigarette smoker
continue to smoke and another has
given up, the demonstration of the
decrease in a incidence of lung cancer
in the study group strengthen the
hypothesis of a causal relationship.
48

49. 5. TRIAL OF AETIOLOGICALAGENT
- It is done to confirm or refute etiological hypotheses,
- since most diseases are fatal, disabling or unpleasant, human
experiment to confirm an etiological hypothesis are rarely
possible.
- E.g. Retrolental Fibroplasia as a cause of blindness due to
administration of oxygen as clinical emergency measure to
experimental premature babies (18 US hospitals).
49

50. 6. EVALUATION OF HEALTH SERVICES
- To asses the effectiveness and efficiency of health services.
- Often, choices have to be made between alternative policies of health
care delivery.
- The necessity of choice arises from the fact that the resources are
limited and priorities must be set for the implementation of large
number of activities which could contribute to welfare of society.
- e.g. Domiciliary treatment of pulmonary tuberculosis (India) was as
effective as more costlier hospital or sanatorium treatment.
50

51. • Scientifically ideal method.
• Gold standard for evaluating the efficacy of therapeutic, preventive and
other risk interventions in both clinical medicine and public health.
• Assess new programs for screening and early detection or new ways of
organizing and delivering health services.
• Confirming cause effect associations.
• Remove bias related to selection and measurement.
• Build up “faith” in the findings of the study.
51
ADVANTAGES of RCT

52. • Subjects are sometimes difficult to get or large numbers may be
needed.
• Long period of time is often required to reach a conclusion.
• High dropout when the intervention has undesirable side-effects or there
is little incentive to stay in the control arm.
• Loss to follow-up.
• High financial costs.
• Ethical issues. 52
DISADVANTAGES of RCT

53. FIELD TRIALS
• Focused on healthy
individuals who are
exposed to the risk of
development of disease.
• Example: Vaccine trials
conducted on healthy
children.
- Determination of 53
FIELD TRIALS COMMUNITY TRIALS
• In these trials, the
treatment groups are
communities rather than
individuals.
• Example: Supply of
iodized salt to community
and reduction of

54. ETHICAL CONSIDERATIONS
• Follow 3 basic principles-
1. Beneficence – safety of subjects : highest priority
2. Non–maleficence – “Do No Harm”
3. Respect for Autonomy – Informed consent , benefits, side effects,
expected length of study, follow-up measures should be conveyed.
 Research question – Relevant for the site.
 “Clinical equipoise” – uncertainty among knowledgeable.
54

55. • Randomized controlled trials are prospective, comparative studies
with controlled conditions and random allocation of interventions to
different groups.
• RCTs are considered the gold standard of study designs for
evaluating the efficacy of therapeutic, preventive and other measures
in both clinical medicine and public health.
• Key steps include protocol preparation, selection of populations,
randomization, intervention, follow-up and assessment.
55
SUMMARY

56. REFERENCES:
Park’s Textbook of Preventive and Social Medicine by K. Park; 27/e.
Gordis Epidemiology; 6/e.
IAPSM’s Textbook of Comprehensive Research Methodology by Sanjay Zodpey; 1/e.
IAPSM’s Textbook of Community Medicine by AM Kadri; 3/e.
Textbook of Community Medicine by Sunder Lal; 8/e.
Textbook of Community Medicine by Rajvir Bhalwar; 5/e.
Community Medicine With Recent Advances , AH Suryakantha; 6/e.
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