1. EXPERIMENTAL EPIDEMIOLOGY AND RANDOMIZED CONTROLLED TRIALS
Dr. MUSTAQUE AHMED
MBBS,MD(COMM MEDICINE),FELLOWSHIP

2. Objective of the class Describe experimental epidemiology
Describe the Randomized control trials and its types.
Describe the steps in conducting RCT

3. Epidemiological design
TYPES OF EPIDEMIOLOGICAL STUDY
UNIT OF STUDY
OBSERVATION STUDY
A-DESCRIPTIVE STUDIES( HYPOTHESIS FORMULATION)
B- ANALYTICAL STUDIES(HYPOTHESIS TESTING)- CAUSES
1-CROSS-SECTIONAL
individual
2-CASE CONTROL
3-COHORT
4-ECOLOGICAL
population
EXPERIMENTAL STUDIES ( HYPOTHESIS CONFIRMATION)
1-RANDOMIZED CONTROLLED TRIAL
Patients
2-FIELD TRIAL
Healthy people
3-COMMUNITY TRIAL
Community
4-CLINICAL TRIAL
patients

4. Definition: EXPERIMENTAL EPIDEMIOLOGY RANDOMISED CONTROLLED TRIALS
In 1920’s it meant study of epidemics among colonies of experimental animals such as rats and mice.
In this there is an active attempt to change the disease determinant or the disease process.
Also described as a Study of effect of modification of exposure on disease .
RANDOMISED CONTROLLED TRIALS
It is a type of EXPERIMENTAL EPIDEMIOLOGY .
Those involving a process of random allocation of subject for carrying out trials.

5. JAMES LIND
James Lind performed a human experiment 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, and two oranges and one lemon daily.
All the subjects were studied for 6 days. At the end of 6 days the LIMEYS Recovered from scurvy and were found fit for duty.

6. Basic steps in conducting RCT
Drawing up a protocol
Selecting reference and experimental population
Randomization
Manipulation or intervention
Follow-up
Assessment of outcome

7. Select a 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 group
(Intervention given)
Control group
(Intervention not given)
Manipulation & follow up
Assessment

8. THE PROTOCOL It specifies: The aims and objectives of the study.
Criteria for the selection of study and control groups.
Treatments to be applied.
Standardization of working procedures.
Schedules and responsibilities of the parties involved in the trial.
It aims at preventing bias and to reduce the sources of error in the study.
It should be strictly adhered to throughout the study.

9. Selecting reference and experimental populations
Reference or target population:
It is the population to which the findings of the trial if found successful are expected to be applicable.
Experimental or study population
It is derived from the reference population.
It is the actual population that participates in the experimental study.
The participants must fulfill the following three criteria: They must give “informed consent”.They should be representative of the population to which they belong and they should be qualified or eligible for the trial.

10. Randomization
It is a statistical procedure by which the participants are allocated into groups usually called “study” and “control” groups.
It is the “heart” of the control trial.
It ensures that the investigator has no control over allocation of participants to either study or control group, thus eliminating “selection bias”.
It is crucial that both groups should be alike with regard to certain variables that might effect the outcome of the experiment (e.g., age, sex)
It is best done by using a table of random numbers.

11. RCT AND ANALYTICAL STUDY
The essential difference between a randomized control trial and an analytical study is that in the latter, there is no randomization because a differentiation into diseased and non diseased groups has already taken place.
Manipulation
This is to intervene or manipulate the study group by the deliberate application or withdrawal or reduction of the suspected causal factor.
This manipulation creates an independent variable (e.g., drug, vaccine) whose effect is then determined by measurement of the final outcome, which constitutes the dependent variable (e.g., incidence of disease, survival time)

12. Follow up
This implies examination of the experimental and control group subjects at definite intervals of time, in a standard manner.
The follow up may be short or may require many years depending upon the study undertaken.
Some losses to follow up are inevitable due to factors , such as death, migration, and loss of interest. This is known as attrition.

13. Assessment
The final step is assessment of the outcome of the trial in terms of
Positive results: benefits of the experimental measures such as reduced incidence or severity of the disease
Negative results: severity and frequency of side effects and complications ,if any ,including death
Bias may arise from errors of assessment of the outcome due to human element. They may be from three sources:
Bias on the part of participants known as “subject variations” .
“Observer bias” due to the investigator.
Bias in evaluation
In order to reduce Bias ,a technique known as “blinding” is adopted.

14. Blinding
Blinding is a procedure in which one or more parties in a trial are kept unaware of which treatment groups  participants have been assigned to. Blinding can be done in three ways –
SINGLE BLIND TRIAL: the trial is so planned that the participant is not aware whether he belongs to the study group or control group.
DOUBLE BLIND TRIAL: here neither the doctor nor the participant is aware of the group allocation and the treatment received. Patient/investigator are unaware of treatment chosen.
TRIPLE BLIND TRIAL: the participant, the investigator and the person analyzing the data are all “blind”.
Ideally ,triple blinding should be used; but the double blinding is the most frequently used method.

16. TYPES OF RANDOMIZED CONTROLLED TRIALS
1. Clinical trials:
2.Preventive trials
3.Risk factor trials
4.Cessation experiments
5.Evaluation of health services
CLINICAL TRIALS: These are concerned with evaluating therapeutic agents, mainly drugs.
Some of the recent examples include _ evaluation of beta blockers in reducing cardiovascular mortality, trials of beta carotene on cancer incidence etc.
Many ethical, administrative and technical problems are involved in the conduct of clinical trials.
dministrative

17. 2.PREVENTIVE TRIALS
These are conducted 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.
Eg. A study designed to show protective effect of a specific prophylactic measure like vaccination. The study group of 3801 children who were vaccinated and 149 developed the whooping cough and in control group of unvaccinated children, 687 developed the whooping cough. The difference is significant.
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 involves risk factor modification.
Eg. A study designed to show lesser incidence of Ischaemic Heart Disease in those who take specified exercise than in those who do not take it, by reducing obesity.

18. The study was conducted inn 3 centres in Europe.
The WHO promoted a trial on primary prevention of coronary heart disease using clofibrate to lower serum cholesterol, which was accepted as a significant risk factor for CHD.
This study is the largest preventive trial conducted , comprising of 15,000 men of whom one-third received clofibrate and two-third received olive oil as control treatment.
The study was conducted inn 3 centres in Europe.
The design was double blind and randomization was successfully achieved.
The mean observation was 9.6 years.
The trial showed a significant reduction in non fatal cardiac infarction, but unfortunately, there were 25% more deaths in the clofibrate –treated group than in the control group possibly due to long term toxic effect of the drug.

19. 4.CESSATION EXPERIMENTS
Here an attempt is made to evaluate the termination of a habit which is considered to be causally related to a disease.
The familiar example is cigarette smoking and lung cancer.
If in a RCT, one group of cigarette smokers continue to smoke and the other group has given up, the demonstration of a decrease in the incidence of lung cancer in the study group greatly strengthens the hypothesis of a causal relationship.

20. 5.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 controlled trials in the chemotherapy of tuberculosis in India, which demonstrated that “domiciliary treatment” of pulmonary TB was as effective as the more costlier “hospital or sanatorium” treatment.
The results have gained international acceptance and ushered in a new era-the era of domiciliary treatment, in the treatment of TB.

21. Community trial Is a type of experimental study .
In community trials one community is given intervention and other is kept as control and results are analysed ex.Testing the effect of defluoridization of water by supplying defluoridized water to one population and usual water(with more fluorine) to other population & observing effect is noted and analyzed(fluorosis-mottling of teeth).