The slide contains an overview of experimental studies. This presentation is solely for educational use.

1. Experimental Epidemiology
Dr. Anu Marhatta
Lecturer
Department of Community Medicine

2. Experimental Studies
Clinical Trials
 Individuals based
 More commonly used in epidemiology
Field Trials & Community Trials
 Community based
 Mainly aims to evaluate primary preventives (agents intended to
prevent disease onset in the first place)
 Are less common than clinical trials

3. How is it different from observational studies ?
 Similar to cohort but RCT is under direct control of investigator
 Experimental studies involve intervention or manipulation
 In Observational studies epidemiologist takes no action but only
observe the natural course of events or outcome

4.  Experimental studies have all the advantages and disadvantages of the
usual prospective cohort studies plus three additional problems namely
cost, ethics and feasibility.
 Experimental studies have become a major area of epidemiological studies.
 They may be conducted in animals or human beings.

5.  The aims of experimental studies may be stated as follows :
a. To provide "scientific proof" of etiological (or risk) factors which
may permit the modification or control of those diseases : and
b. To provide a method of measuring the effectiveness and efficiency
of health services for the prevention, control and treatment
of disease and improve the health of the community.

6. Animal immunology genetics, studies have contributed to our knowledge of anatomy,
physiology, pathology, microbiology, chemotherapy and so many others.
 More important application of animal experiments have been in
(a) Experimental reproduction of human disease in animals to confirm etiological
hypotheses and to study the pathogenic phenomenon or mechanisms
(b) Testing efficacy of preventive and therapeutic measures such as vaccine and drugs
(c) Completing the natural history of disease.
 The advantages are that the experimental animals can be bred in laboratories and
manipulated easily according to the wishes of the investigator.

7. Human experiments
 Human experiments will always be needed to investigate disease etiology and to
evaluate the preventive and therapeutic measures.
 Historically, in 1747, James Lind performed a human experiment (clinical trial) in
which he added different substances to diet of 12 soldiers who were suffering
from scurvy.
 He divided his patients into 6 pairs and supplemented the diets of each pair with
cider, elixir vitriol, vinegar, sea water; a mixture of nutmeg, garlic, mustard and
tamarind in barley water; and two oranges and one lemon daily.

8. Randomization Control Trial
 RCT is a planned experiment designed to asses the efficacy of an
intervention in human beings by comparing the effect of intervention in a
control/ placebo group.
 The allocation of subjects to study or control is determined purely by chance.
 It is mainly in the last 35 to 40 years, determined efforts have been made to
use scientific techniques to evaluate methods of treatment and prevention.
 An important advance in this field has been the development of an
assessment method, known as Randomized Controlled Trial
 Blinding is mainly carried out while conducting RCTs

9.  Experimental studies are of two types .
a. Randomized controlled trials
b. Non-randomized or "non-experimental" trials

10.  The basic steps in the conducting a RCT include the following:-
1. Drawing up a protocol.
2. Selecting reference and experimental populations.
3. Randomization.
4. Manipulation or intervention.
5. Follow-up.
6. Assessment of outcome.

11. 1. Protocol
 The protocol specifies the
a. aims and objectives of study
b. questions to be answered ,
c. criteria for selection of study and control groups ,
d. size of sample ,
e. Treatment to be applied , procedure of study etc.
 The protocol aims at preventing bias and to reduce the sources of error in the
study.

12. 2. Selecting reference and experimental population
a. Reference and target population is the one to which the finding of trial , if
found successful are expected to be applicable (drug, vaccine or other
procedures)
 The participants selected should fulfill the criteria:
i. The population must be stable and cooperative for follow up.
ii. They must give informed consent for the trial.
iii. They should be representative of the population to which they belong
iv. They should be qualified or eligible for the trial
 Whole population, school children , industrial workers

13. 2. Selecting reference and experimental population
b. Experimental or study group
 The study population derived from reference population.
 Chosen Randomly from reference population, so that the
characteristics are similar.

14. 3. Randomization
 Randomization is a statistical procedure by which the participants
are allocated into groups usually called "study" and "control"
groups,
 to receive or not to receive an therapeutic procedure, experimental
preventive or manoeuvre or intervention.
 Randomization is the "heart" of a control trial.
 It will give the greatest confidence that the groups are comparable
so that "like can be compared with like“.

15. 4. Manipulation or intervention
 The study/experiment group is intervened or manipulated by the
application or withdrawal or reduction of the suspected causal factor
(e.g., this may be a drug, vaccine, dietary component, a habit, etc) as
laid down in the protocol.
 This manipulation creates an independent variable (e.g., drug,
vaccine, a new procedure) whose effect is then determined by
measurement of the final outcome, in terms of dependent variable
(e.g., incidence of disease, survival time, recovery period).

16. 5. Follow up
 It refers to examination of experimental or control group subjects at
defined intervals of time to assess the outcome.
 The examination should be in standard manner , with equal
intensity ,under the same circumstances, in the same time frame for
both the groups till the final assessment of outcome.
 Every effort should me made to minimize the loses of follow up.
 Some loss to follow up are inevitable , death, migration and loss of
interest .
 This is known as attrition.

17. 6. Assessment
The final assessment in the trial is in the form of
(a) Positive results
 Benefits of the 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
 The severity and frequency of side-effects and complications, including death.
 Adverse effects may be missed if they are not sought.

18. Design of RCT

19. Some study designs
 1. Concurrent parallel study design
 2. Cross-over type of study design

20. Concurrent parallel study design
 Comparisons are made between two randomly assigned groups
 one group exposed to the specific treatment, and the other group not
exposed.
 Patients remain in this study group or a control group for the
duration of investigation.

21. Crossover studies
 Subjects randomly assigned to a sequence of treatments
 Group A: Placebo 8 weeks –> Drug 8 Weeks
 Group B: Drug 8 weeks –> Placebo 8 weeks
 Subjects serve as their own control ;carry over washout

22. Types of RCTs and uses
1. Clinical trials
 Evaluating therapeutic agents(drugs) or procedures in different
diseases e.g. evaluation of Beta-blockers in reducing cardiovascular
mortality in MI patients, evaluation of tonsillectomy for recurrent
throat infection.

23. Phases of clinical trials
Phase 1
 Small number of healthy volunteers
 Safety, toxicity, pharmacokinetics
Phase 2
 Small number of sick patients
 Efficacy, dosing, side effects
 Often placebo controlled, often blinded

24. Phase 3
 Large number of sick patients
 Many patients, many centers
 Randomized trials
 Drug efficacy determined vs. placebo or standard care
 After phase 3, drug may be approved

25. Phase 4 :
Post-marketing study
 After drug is on the market and being used
 Monitor for long term effects
 Sometimes test in different groups of patients

26. 2. Preventive trials
 Evaluation of primary preventive measures such as vaccines and chemoprophylaxis drugs in
reduction of disease incidence e.g. Trials conducted to study efficacy of vaccines.
3.Risk factor trial
 Study of impact of risk factor modification or interruption in the usual sequence of development
of the disease.
 Trials to study of utility of clobifibrate in reducing serum cholesterol , a risk factor for
cardiovascular immortality .
4.Cessation experiments
 Evaluation of termination of habit (or suspected agent) which is considered to be causally
related to disease .e.g. efficacy of giving-up cigarette –smoking in reduction of lung cancer
incidence.

27. 5.Trial of etiological agents
 To confirm or refuse an etiological hypothesis i.e. role of suspected factor in
development of disease. E.g. study of association of oxygen administration to
preterm babies and development of retrolental fibroplasis (FLP) leading to blindness
.
6.Evaluation of health services
 To asses the effectiveness and cost efficacy of health services minimizing disease
prevalence and allow proper choices between health care delivery system e.g.
evaluation of domiciliary treatment of pulmonary tuberculosis with the hospital
treatment.

28. Non Randomized Trials
 Randomized experiments are not always possible but due to ethical,
administrative and other reasons to resort to a randomized
controlled trial in human beings
 Non randomized trials are conducted to deporting from strict
randomization but in such a manner that it will have no effect on the
theoretical basis conclusion.

29. Types of Non Randomized Trials and uses
 Uncontrolled trials
These are the trials conducted without any “control” i.e comparison
group and directly studying the role of a suspected factor or efficacy of
therapeutic procedure in the incidence of disease.
e.g. when pap smear test was introduced in 1920s controlled trials
weren’t conducted; rather numerous uncontrolled trials gave evidence
that pap test is effective in early detection reduction of mortality due to
the disease.

30. Types of Non Randomized Trials and uses (continued )
 Natural experiments
When the experiments aren’t possible to conduct in the population due to ethical
reasons ,the epidemiologist seeks to identify natural circumstances mimicking an
experiment .
 e.g. A major earthquake in Athens in 1981 provided a "natural experiment" where
stress was naturally created and showed excess of deaths due to cardiac causes.
 John Snow's discovery that cholera is a water-borne disease was the outcome of a
natural experiment.

31. Types of Non Randomized Trials and uses (continued )
A. Before and after comparison studies without control
 comparison o the incidence of disease in the study population
before and after introduced of preventive measure.
 The same population prior to introduction of measures is taken
as control and thus the comparability is optimum.

32. Types of Non Randomized Trials and uses (continued )
A. Before and after comparison studies without control
 These studies center round comparing the incidence of disease before and after
introduction of a preventive measure.
 In other words, the experiment serves as its own control; this eliminates virtually
all group differences.

33.  The classic examples of "before and after comparison studies" were
a. The prevention of scurvy among sailors by James Lind in 1750 by
providing fresh fruit;
b. Studies on the transmission of cholera by John Snow in 1854;
c. Prevention of polio by Salk and Sabin vaccines.

34. B. Before and after comparison studies with control
 There is absence of a control group
 The epidemiologist tries to utilize a "natural" control group
 If preventive programme is to be applied to an entire community,
one will be select another community as similar as possible, with
respect to frequency and characteristics of the disease to be
prevented.

35. (source : Park textbook )
 In the example cited above, the existence of a control with which the results in Victoria could
be compared strengthens the conclusion that there was definite fall in the number of deaths
and injuries in occupants of cars after the introduction of compulsory seat-belt legislation.

36. e.g. before and after comparison study in road traffic accidents
Victoria (Aus) in 1971 following legislation of seatbelt.

37. B. Before and after comparison studies with control
Comparison of the change in incidence before and introduction of a
preventive measure in the study population to the change in incidence
during that period in another “control” population where the measure
hasn’t been introduced.
 The control population should be as similar as possible particularly
in respect to frequency and characteristic of disease.

38. E.g. before and after companion study in one city following seat-belt
legislation compared to other cities the legislation not introduced.

39. Reference
1. Park's textbook of preventive and social medicine(26th
edition)
2. Gordis.L., Epidemiology.(5th
edition)