EXPERIMENTAL STUDY DESIGN- RANDOMIZED CONTROLLED TRIAL

Randomized controlled clinical trial is a prospective experimental study.
It essentially involves comparing the outcomes in two groups of patients treated with a test treatment and a control treatment, both groups are followed over the same period of time. Prepare a plan of study or protocol
a. Define clear objectives
b. State the inclusion and exclusion criteria of case
c. Determine the sample size, place and period of study
d. Design of trial (single blind, double blind and triple blind method)
2. Define study population: Most often the patients are chosen from hospital or from the community. For example, for a study for comparison of home and sanatorium treatment, open cases of tuberculosis may be chosen.

3. Selection of participants by defined criteria as per plan:

Selection of participants should be done with precision and should be precisely stated in writing so that it can be replicated by others. For example, out of open cases of tuberculosis those who fulfill criteria for inclusion may be selected (age groups, severity of disease and treatment taken or not, etc.)
Randomization ensures that participants have an equal chance to be assigned to one of two or more groups:

One group gets the most widely accepted treatment (standard treatment/ gold standard)

The other gets the new treatment being tested, which researchers hope and have reason to believe will be better than the standard treatment
Subject variation: First, there may be bias on the part of the participants, who may subjectively feel better or report improvement if they knew they were receiving a new form of treatment.

Observer bias: The investigator measuring the outcome of a therapeutic trial may be influenced if he knows beforehand the particular procedure or therapy to which the patient has been subjected.

Evaluation bias: There may be bias in evaluation - that is, the investigator(Analyzer) may subconsciously give a favorable report of the outcome of the trial.
Co-intervention:
participants use other therapy or change behavior
Study staff, medical providers, family or friends treat participants differently.
Biased outcome ascertainment:
participants may report symptoms or outcomes differently or physicians
Investigators may elicit symptoms or outcomes differently

A technique used to prevent selection bias by concealing the allocation sequence from those assigning participants to intervention groups, until the moment of assignment.
Allocation concealment prevents researchers from influencing which participants are assigned to a given intervention group.

All clinical trials must be approved by Institutional Ethics Committee before initiation
It is mandatory to register clinical trials with Clinical Trials Registry of India
Informed consent from all study participants is mandatory.

A preclinical trial is a stage of research that begins before clinical trials, and during which important feasibility and drug safety data are collected.

Following points high.

1. EXPERIMENTAL STUDY DESIGN- RANDOMIZED CONTROLLED TRIAL Presented By- Dr. Rishank Shahi PG-1st Year, PSM NSCB Medical College

2. OBJECTIVES Experimental study designs RCT Steps and Types of RCT Randomisation Bias in RCT Blinding Co-intervention Phases in clinical trial Advantages and Disadvantages of RCT

3. Epidemiological Studies Did investigators assign exposures? YES Experimental Studies Random Allocation? YES NO Randomised Control trial Non Randomised Control trial

4. Randomized controlled clinical trials Randomized controlled clinical trial is a prospective experimental study. It essentially involves comparing the outcomes in two groups of patients treated with a test treatment and a control treatment, both groups are followed over the same period of time.

5. The objectives of clinical trials A clinical trial is a planned experiment designed to assess the efficacy of an intervention such as- New drugs/ treatment New medical / health care technology New organization/ delivery system of health care New methods of primary prevention New programs of screening or early detection

6. Steps of Conducting RCT 1. Prepare a plan of study or protocol a. Define clear objectives b. State the inclusion and exclusion criteria of case c. Determine the sample size, place and period of study d. Design of trial (single blind, double blind and triple blind method)

7. 2. Define study population : Most often the patients are chosen from hospital or from the community. For example, for a study for comparison of home and sanatorium treatment, open cases of tuberculosis may be chosen. 3. Selection of participants by defined criteria as per plan: Selection of participants should be done with precision and should be precisely stated in writing so that it can be replicated by others. For example, out of open cases of tuberculosis those who fulfill criteria for inclusion may be selected (age groups, severity of disease and treatment taken or not, etc.)

8. Randomization The most critical step in a clinical trial is what we call as randomization. The participants do not decide that he or she or they want to participant in a particular arm. Also, the investigators do not decide, whether a particular participant goes in arm A or arm B.

9. Randomization ensures that participants have an equal chance to be assigned to one of two or more groups: One group gets the most widely accepted treatment (standard treatment/ gold standard) The other gets the new treatment being tested, which researchers hope and have reason to believe will be better than the standard treatment

10. Types of RCT: Therapeutic RCT Preventive RCT

11. Schematics of a therapeutic clinical trial

12. Examples of a therapeutic trial Plasma therapy in treatment of hospitalized and sick COVID- 19 patients. Lopinavir/Ritonavir in the treatment of COVID-19 patients.

13. Schematics of a preventive clinical trial

14. Examples of a Prevention trial HPV vaccine trial in the prevention of cervical cancer Hydroxychloroquine in the prevention of COVID-19 in Health care Workers

15. BIAS IN RCT Subject variation : First, there may be bias on the part of the participants , who may subjectively feel better or report improvement if they knew they were receiving a new form of treatment. Observer bias : The investigator measuring the outcome of a therapeutic trial may be influenced if he knows beforehand the particular procedure or therapy to which the patient has been subjected. Evaluation bias : There may be bias in evaluation - that is, the investigator(Analyzer) may subconsciously give a favorable report of the outcome of the trial.

16. Blinding / Blind RCT Blinding is another quality improvement technique , often used in clinical trials

17. Blinding can be at the level of- 1. Participants

18. 2. Participants and investigators

19. 3. Participants, investigators and analysts

20. Blinding helps to eliminate- Co-intervention: participants use other therapy or change behavior Study staff, medical providers, family or friends treat participants differently. Biased outcome ascertainment: participants may report symptoms or outcomes differently or physicians Investigators may elicit symptoms or outcomes differently

21. Allocation Concealment A technique used to prevent selection bias by concealing the allocation sequence from those assigning participants to intervention groups, until the moment of assignment. Allocation concealment prevents researchers from influencing which participants are assigned to a given intervention group.

22. Human subject protection (Ethical approvals) before the trial start: All clinical trials must be approved by Institutional Ethics Committee before initiation It is mandatory to register clinical trials with Clinical Trials Registry of India Informed consent from all study participants is mandatory.

23. Human subject Protection during the trial: Adverse events reporting Serious adverse events reporting Periodic follow-up Review by Data Safety Monitoring Board

24. PRE- CLINICAL TRIAL A preclinical trial is a stage of research that begins before clinical trials, and during which important feasibility and drug safety data are collected. Preclinical trials or non clinical trials are laboratory test of a new drug substance or medical devices etc., usually done on animal subjects, to see whether the treatment really works and if it is safe to test on humans. Products may include new medical devices, drugs, gene therapy solutions, etc.

25. Following points highlight the importance of pre-clinical trials: 1. To determine the dose, toxic dose, pharmacological action, etc. 2. It is the requirement of regulatory body for performing clinical trials. 3. From ethical viewpoint, it is necessary to check safety of drug on animals before starting to check on human being.

26. PHASE 0 Micro-dosing studies Phase 0 study is an exploratory study, conducted early in the process of drug development and allows for human use of an investigational new drug (IND) with less preclinical data and in lower doses than is required for a conventional Phase I study. This study involves very limited human exposure, and has no therapeutic or diagnostic intent. This is invariably part of a regulatory study and requires approval of Drug Controller General of India.

27. Phases in clinical trials

28. Advantages of RCTs The clinical trials are the only way for making a progress in medical science because, if there are no clinical trials, no new drugs/ technologies/ vaccines/ interventions will be tested. They are considered as the methodological standard of excellence, and gold standard for scientific experiments. In terms of study designs, Randomized controlled trials (RCTs) are regarded as the gold standard of scientific evidence. The only effective method known to control selection bias.

29. Advantages Cont. In diagnostic research, the new diagnostic test is evaluated against the best available test ie. benchmark for diagnosis of a particular disease (Gold standard). Standard in research can also mean 'Standard of care' which refers to the existing treatment against which the new interventions are compared. Maintains advantages of cohort studies.

30. Disadvantages of RCTs May be complex and expensive Lack representativeness – volunteers differ from population of interest Ethical challenges are immense- Appropriate implemented informed consent procedure as well as long-term care and support to trial participants help to overcome several ethical concerns.

31. Refrences Swayam App BCBR Manual ICMR (www.nie.gov.in). Handbook of “Basic course in biomedical research” by Tanmay Mehta. IAPSM Textbook of Community Medicine by AM Kadri.

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