Experimental Studies

Experimental studies are a variety of epidemiological studies. Here is a brief presentation.

1. EXPERIMENTAL STUDIES Dr. Abhijit Das, Postgraduate Resident Moderator- Dr. Amarnath Gupta, Associate Professor Dr. Pranjal Shrivastava, Assistant Professor

2. INTRODUCTION DESCRIPTIVE STUDY (Hypothesis Formulation) ANALYTIC STUDY (Testing Hypothesis) EXPERIMENTAL STUDY (Conformation)

3. INTRODUCTION In the 1920s, "experimental epidemiology" meant the study of epidemics among colonies of experimental animals such as rats and mice. In modern usage, experimental epidemiology is often equated with RANDOMIZED CONTROLLED TRIALS.

4. AIMS To provide a scientific proof of etiological (or risk) factors which may permit the modification or control of those diseases. To provide a measuring 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.

5. Animal Studies Advantages : Experimental animals can be bred in laboratories and manipulated easily according to the wishes of the investigator. Multiply rapidly and enable the investigators to carry out certain experiments (e.g., genetic experiments) which in human population would take several years and involve many generations.

6. Limitations: Not all the diseases reproduce in animals. All the conclusions derived from animal experiments may not be strictly applicable to human beings. E.g.-WHO trial of typhoid vaccine in Yugoslavia in the mid l950s.

7. Human Experiments Human experiments will always be needed to investigate disease etiology and to evaluate the preventive and therapeutic measures. E.g.- James Lind, Edward Jenner, Goldberger’s Experiment. Although the experimental method is unquestionably the most consice approach to scientific problem; ethical and logistic considerations often prevent its application to the study of disease in humans.

8. Benefits of the experiment have to be weighed against risks involved. The volunteers should be made fully aware of all possible consequences of the EXPERIMENT. Thus when an illness is fatal (e.g. excessive haemorrhage) and the benefit of treatment (e.g. blood transfusion) is self-evident, it would be ethically unacceptable to prove or disprove the therapeutic value of blood transfusion. Experimental studies are two types Randomized Control Trial. Non-Randomized trial.

9. RANDOMIZED CONTROL TRIALS It is really an epidemiologic experiment. Planned experiment designed to assess the efficacy of prophylactic / diagnostic / therapeutic agents, devices, regimens, procedures etc. applied to human subjects. Since its introduction the RCT has questioned the validity of such widely used treatments as oral hypoglycemic agents, varicose vein stripping, tonsillectomy etc.

10. Basic steps in RCT Drawing up a protocol. Selecting reference and experimental populations. Randomization . Manipulation or intervention Follow –up Assessment of outcome

11. Design of RCT

12. PROTOCOL Aims & objectives of study. Questions to be answered. Criteria for selection of study and control groups. Size of sample. The procedures for allocation of subjects into study and control groups. Treatment to be applied. Standardization of working procedures. Schedules and responsibilities of the parties involved.

13. Aim: Prevent bias and to reduce the sources of error in the study. Preliminary test runs: To find out the feasibility or operational efficiency of certain procedures, or unknown effects, or on the acceptability of certain policies. To see whether it contains any flaws .

14. SELECTING REFERENCE & EXPERIMENTAL POPULATION Reference or target population : Population to which the findings of the trail are expected to be applicable. E.g. Specific age group people. Geographically limited. Population of school children.

15. EXPERIMENTAL OR STUDY POPULATION Derived from reference population. Those who participates in experimental studies. Participants must fulfill 3 criteria must give informed consent should be representative of the population. should be eligible for the trail.

16. RANDOMIZATION Heart of RCT Participants allocated in to study and control groups. Randomization provides the best way to prove the effectiveness of a new agent or intervention by ensuring that All groups are as similar as possible Confounding, co-interventions and bias in outcome ascertainment is minimized.

17. Randomization is done only after the participants entered the study, that is after having been qualified for the trial and has given informed consent to participate in study. Randomization best done by using a table of random numbers.(simple random sample). Random numbers are a haphazard collection of certain numbers, arranged in a cunning manner to eliminate personal selection of unconscious bias in taking out the sample.

18. MANIPULATION After selection of study & control group, intervene the study group by deliberate application or withdrawal of suspected factor (vaccine, drug) as laid down in protocol. This manipulation creates an independent variable (e.g. drug, vaccine)whose effect is then determined by measuring the dependent variable(incidence of disease, survival time.)

19. FOLLOW-UP Examination of the experimental & 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. Attrition :-some cases losses to follow-up due to death, migration, loss of interest. If the attrition is substantial, it may be difficult to generalize the results to reference population.

20. ASSESSMENT Positive Results Negative Results Incidence of positive/ negative results is rigorously compared in both the groups, and the differences, if any, are tested for statistical significance.

21. Expressing the Results of Randomized Trials Efficacy This formula tells us the extent of the reduction in disease by use of the vaccine. Risks are often calculated per person-years of observation.  

22. BIAS Bias may arise from errors of assessment of the outcome due to human element. These may be from 3 sources. First - bias from the participants; known as subjective variation. Second - Observer bias. Third- Bias in evaluation.

23. BLINDING Single blinding Double blinding Triple blinding Blinding helps to eliminate- Co-intervention : participants use other therapy or change behavior or study staff, medical providers, family or friends treat participants differently Biased outcome ascertainment: participants may report symptoms or outcomes differently or physicians or investigators may elicit symptoms or outcomes differently

24. Concurrent parallel study designs Cross-over type of study designs Each patient serves as his own control. Advantages : Limit the number of study population; Economically feasible. Disadvantages : Time consuming; unsuitable for the drug or intervention cure the disease; if the drug works during a certain stage of disease; disease changes drastically.

25. Types of RCT Clinical trials: For the most part, "clinical trials” have been concerned with evaluating therapeutic agents, mainly drugs. E.g. Trials of folate- to prevent NTD. Efficacy of tonsillectomy for recurrent throat infections. Many ethical, administrative, & technical problems are involved in the conduct of clinical trials.

26. 2.Preventive trials: It implies primary prevention. Most common trials are done vaccines & chemoprophylactic drugs. E.g.: Medical research council of UK – whooping cough Since preventive trials involve larger number of subjects and longer time span to obtain results, there may be greater number of practical problems in their organization and execution.

27. 3.Risk factor trial: A type of preventive trials in which the investigator intervenes to interrupt the usual sequence in the development of disease for those individual who has risk factor in developing the disease. Often this involves risk factor modification. “Single-factor" or "multi-factor" trials. Complementary, and both are needed. E.g. CHD- WHO study- clofibrate therapy. OSLO study & MRFIT.

28. 4.Cessation experiments: Type of preventive trial An attempt is made to evaluate the termination of a habit (or removal of suspected agent) which is considered to be causally related to a disease. If such action is followed by a significant reduction in the disease, the hypothesis of cause is greatly strengthened. E.g. Cigarette smoking and lung cancer.

29. 5.Trial of etiological agents: To confirm or refute etiological hypothesis. E.g.: RLF Since most disease are fatal, disabling, human experiments to confirm an etiological hypothesis are rarely possible.

30. 6.Evaluaton of health services: RCT have been extended to assess the effectiveness & efficiency of health services. E.g.: Domiciliary treatment- Pulmonary Tuberculosis. Health services research studies.

31. Phases in clinical trials and objectives Trial phase End-points/ objectives Sample size and participants Phase I Safety Up to 50 Acceptability Healthy volunteers Phase II Long-term safety 100 to 500 Dose and schedule Low risk Early indications of efficacy Phase III Effectiveness 1000 and more High risk Phase IV Post-marketing surveillance 1000 and more Community based

32. Non Randomized Trials Due to ethical, administrative, cost it is not always possible to resort to RCT. Approach is crude. As there is no randomization, degree of comparability will be low and chances of spurious results will be high. Nevertheless, vital decisions affecting public health and preventive medicine have been made by non-experimental studies.

33. Examples of non randomized trials 1. Uncontrolled trials: Trials with no comparison groups. Useful to known whether specific therapy is valuable for particular disease, to determine the appropriate dose, to investigate adverse reaction. E.g.: indirect epidemiological evidence that the Pap smear examinaton is effective in reducing mortality from cervical cancer.

34. 2. Natural experiments: Where experimental studies are not possible in human beings, some natural circumstances mimics as experiment. E.g.: smokers and non smokers- lung cancer. John snow discovery- cholera- water born disease.

35. 3.Before and after comparison studies: These community trials fall into 2 distinct groups. Before & after comparison studies without control. Before & after comparison studies with control.

36. References K. Park, Park's Textbook Of Preventive And Social Medicine, M/S Banarsidas Bhanot Publishers,25TH edition,2019. Gordis Epidemiology, Elsevier, 6 th edition.

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