RANDOMIZED CONTROLLED TRIAL DR. SANJAY P. ZODPEY, MD, PhD JULY 9-13, 2007 MGIMS-SEWAGRAM, IAPSM -EPIDEMIOLOGY COMMITTEE & MAHARASHTRA CHAPTER

RANDOMIZED CONTROLLED TRIAL Objectives: To understand the design issues related to RCTs To know various steps involved in conduct of RCTs To know various types of clinical trials

RANDOMIZED CONTROLLED TRIAL Earlier public health measures were introduced on the basis of assumed benefits without subjecting them to rigorous testing Last 30 to 40 years – Evolution of Randomized Controlled Trials

CLINICAL TRIALS Prospective study comparing the effect and value of one of more interventions against a control in human subjects with a given medical condition. Measures causality in terms of the effect of an intervention: If one alters the risk factor, does one alter the occurrence of the event/injury?  "...the most definitive tool for evaluation of the applicability of clinical research.“

RANDOMIZED CONTROLLED TRIAL A true experiment, in which the researcher randomly assigns some patients to at least one maneuver (treatment) and other patients to a placebo, or usual treatment. Key features the classic way to evaluate efficacy or effectiveness of drugs (or exercise, diet, counseling) patients are followed over time (prospective) Properly done, an RCT can be used to determine cause and effect.

The ideal clinical trial is one that is randomized and double-blind. “RANDOMIZED, DOUBLE-BLIND, CONTROLLED TRIAL” is considered as research design par excellence and “GOLD STANDARD” amongst research designs with which results of other studies are often compared. Deviation from this standard has potential drawbacks

A clinical trial must employ one or more intervention techniques. These may be : Prophylactic Diagnostic Therapeutic agents Devices Regimens Procedure

STEPS IN CONDUCT OF RCT: The protocol Selecting reference and experimental populations Randomization Intervention Follow up Assessment

CLINICAL TRIAL Improved Not Improved -- ALLOCATION Improved INTERVENTION GROUP Not Improved Population - - - - Of patients - - - - With the - - - - Condition - - - - SAMPLE -- ALLOCATION Improved CONTROL GROUP Not Improved

1. The Protocol Aims and objectives, Research questions, Selection criteria, Sample size, procedures up to the evaluation of outcome Prevents bias and reduces the sources of errors Preliminary test runs – feasibility or operational efficiency

2. Selecting Reference and Experimental Populations Reference or target population - population to which the findings of the trial, if found successful, are expected to be applicable (eg. drugs, vaccines, etc.) b. Experimental or study population - actual population that participates in the experimental study

Participants must fulfill the following criteria: Must give informed consent Should be representative of the population Should be qualified or eligible for the trial

SAMPLE SIZE Clinical trials should have sufficient statistical power to detect differences between groups considered to be of clinical interest. Therefore, calculation of sample size with provision for adequate levels of significance and power is essential part of planning.

3. Randomization Heart of the control trial Procedure: Participants are allocated into study and control groups Eliminates bias and allows comparability

Both groups should be alike with regards to certain variables that might affect the outcome of the experiment - Best done by using table of random numbers

RANDOMIZATION Randomization tends to produce study groups comparable with respect to known as well as unknown risk factors, removes investigator bias in the allocation of subjects and guarantees that statistical tests will have valid significance levels.

4. Manipulation / Intervention Deliberate application or withdrawal or reduction of a suspected causal factor It creates an independent variable

5. Follow Up Implies examination of the experimental and control group subjects at defined intervals of time, in a standard manner, with equal intensity, under the same given circumstances Attrition: Inevitable losses to follow up

6. Assessment Positive results Negative results Biases: Subject variation, Observer bias, Evaluation bias Can be corrected by blinding

BLINDING UNBLINDED, OPEN TRIAL SINGLE BLIND DOUBLE BLIND TRIPLE BLIND

Some Study Designs: Concurrent Parallel Study Designs 2. Cross Over Type of Study Designs

CROSS OVER DESIGN INTERVENTION SUBJECTS RANDOM ALLOCATION CONTROL PERIOD 1 PERIOD 2 INTERVENTION SUBJECTS RANDOM ALLOCATION CONTROL CROSS OVER DESIGN

ETHICS IMPORTANT ISSUE IN CLINICAL TRIALS ETHICAL CLEARANCE * INSTITUTIONAL REVIEW BOARDS * ETHICAL COMMITTEES * ICMR GUIDELINES * FEDERAL/STATE GUIDELINES “INFORMED CONSENT”

Types of Randomized Controlled Trials: 1. Clinical Trial Concerned with evaluating therapeutic agent, mainly drugs eg. Evaluation of beta-blockers in reducing cardiovascular mortality Not all clinical trials are susceptible to being blinded

2. Preventive Trials: Trial of primary preventive measures eg. Vaccines - Analysis of preventive trials must result in clear statement about benefits to community, risk involved and cost to health

3. Risk Factor Trials: Investigator intervenes to interrupt the usual sequence in the development of disease for those individuals who have risk factor for developing the disease Primary prevention of CHD using clofibrate to lower serum cholesterol

4. Cessation Experiment: An attempt is made to evaluate the termination of a habit which is considered to be causally related to disease Cigarette smoking and lung cancer

5. Trials of Etiological Agents: To confirm or refute an etiological hypothesis 6. Evaluation of Health Services: Domiciliary treatment of PTB was as effective as more costlier hospital or sanatorium treatment

MULTICENTER TRIALS Reasons for Multi-center Trials : 1. To recruit necessary number of subjects within a reasonable time. May assure a more representative sample of the study or target population Enables investigators with similar interest and skills to work together on a common problem

PHASES OF TRIALS Phase I Trials: Initial studies to determine the metabolism and pharmacologic actions of drugs in humans, the side effects associated with increasing doses, and to gain early evidence of effectiveness; may include healthy participants and / or patients

PHASES OF TRIALS Phase II Trials: Controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with disease or condition under study and to determine the common short-term side effects and risks

PHASES OF TRIALS Phase III Trials: Expanded controlled and uncontrolled trials after preliminary evidence suggesting effectiveness of the drug has been obtained, and are intended to gather additional information to evaluate the overall benefit-risk relationship of the drug

PHASES OF TRIALS Phase IV Trials: Post-marketing studies to delineate additional information including the drug’s risks, benefits, and optimal use