Randomized Controlled Trial Subodh S Gupta Dr. SushilaNayarSchool of Public Health MGIMS, Sewagram
Progression of Study Design: Clinical Research • Isolated Case Reports • Case Series • Cross-Sectional study • Case-Control Study • Cohort Study • Randomized Clinical Trial • Meta-Analysis EXAMPLE: • The role of oxygen in retrolental fibroplasia RLF among premature infants.
Progression of Study Design: Clinical Research • First Case - Feb. 14, 1941, Dr. Clifford, Boston • Case Series - 1941 (Silverman 1980) • Ca-Co Study (53 RLF Children, 298 Normal Children) • Association was observed. Still, it was postulated that poor health of infants necessitated longer hours of oxygen. Poor health and not oxygen use caused RLF.
Progression of Study Design: Clinical Research • Cohort Studies: Contradictory Results • I RCT: Gallinger Muncipal Hospital, Washington, DC • II Collaborative Multi-centre Trial • Confirmed the role of oxygen in the etiology of Retrolental Fibroplasia
Progression of Study Design: Community Research • Ecological Study • Cross-Sectional Study • Case-Control Study • Cohort Study • Randomized Community Trial • Meta-Analysis EXAMPLE: Lipid - Atherosclerosis Association
Progression of Study Design: Community Research • Analysis of Death Rates from CAD according to per capita fat consumption in 20 countries Hypothesis of L-A association. • CS Studies: Framingham and Evans County Heart Studies (Dawber et al 1971, Cassel 1971) • Case-Control Studies confirmed Association. • Cohort Studies (Truett et al 1967, Tyroler et al 1971) • Community Based Controlled Trials of Lipid Reduction (Lipid Research Clinics Program)
Observational study NO Example: Comparing the history of needle sharing among IV drug abusers who have HIV antibodies with those who do not Decision # 1 Alter the events under study? Example:Impact of health education on needle sharing habits Yes The investigator applies an intervention, & observes the effect on the outcome Experimental study Deciding which one to use The investigator observes the events without altering them
Cross-sectional study Each subject is examined on only one occasion NO Example: Study of needle sharing habits and HIV antibodies measured at the same time Example:Cohort study that assesses current needle sharing habits of group of IV drug abusers and observes who subsequently develop HIV antibodies Yes Each subject is followed over A period of time Longitudinal study Deciding which one to use For observational studies Decision # 2 Make measurements on more than one occasion?
Deciding which one to use • Can you alter the events under the study? • How strong is the hypothesis? • How common is the disease or health event which is to be studied? • How common is the exposure/ determinants of the health event? • Do you want to study the different factors/ determinants of a health event or disease? Or; Do you want to see the multiple effect of an exposure? • How much resources do you have?
Randomized controlled trials ”An epidemiological experiment in which subjects in a population are randomly allocated into groups, usually called study and control groups to receive and not receive an experimental preventive or therapetuic procedure, maneuver, or interventition” John M.Last, 2001
Randomized Controlled Trial • A true experiment • 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.
Why RCT? • ”Gold standard” in epidemiological research • Makes study groups comparable • Controls for confounding (known and unknown) • Prevents selection bias
“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
Advantages • Most efficient for investigating causality • Ensure ‘ONLY ONE’ factor is different: confounding factors do not confuse the results • Ensure that treatments are compared efficiently • Look for effects of combinations of treatments, interaction between treatments and personal characteristics • Only study design which can help us evaluate a new treatment (medicine, other procedures etc.)
Disadvantages • Share many of the disadvantages of cohort study • Ethical concerns • It may not be possible for all kinds of questions that we have • Intervention studies screen out ‘problem’ subjects, such as the very young, the elderly and pregnant and lactating women
Ethical Considerations • Major issue for ‘Randomized Controlled Trial’ • Proper information to all the study subjects • Informed consent • The trial is conducted ethically • Avoid bias in results • Sample size is adequate to give the results • What if, before the study is completed, there is evidence that one treatment is better than the other one
ETHICS IMPORTANT ISSUE IN CLINICAL TRIALS ETHICAL CLEARANCE * INSTITUTIONAL REVIEW BOARDS * ETHICAL COMMITTEES * ICMR GUIDELINES * FEDERAL/STATE GUIDELINES
Types of Randomized Controlled Trials • Clinical Trial: Diagnostic, Therapeutic, Prophylactic, Devices, Procedures, Regimens, Protocols • Preventive Trial • Risk Factor Trial • Cessation experiments • Trial of etiologic agents • Evaluation of health system
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
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.“
WHAT IS CLINICAL TRIAL • A clinical trial is defined as a prospective study comparing the effect and value of interventions against a control in human beings • Study participants must be followed forward in time. They need not all be followed from an identical calendar date.
Must contain a control group against which the intervention group is compared. • At baseline, the control group must be sufficiently similar in relevant respects to the intervention group so that differences in outcome may reasonably be attributed to the action of the intervention. • Most often a new intervention is compared with best current standard therapy.
Stages of experimentation • Phase I: dose-finding • Phase II: preliminary evidence of efficacy • Phase III: comparisons to standard therapy • Phase IV: post-marketing surveillance
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; usually conducted on healthy volunteers
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
Steps in conduct of RCT • The protocol • Selecting reference and experimental populations • Randomization • Intervention • Follow up • Assessment
1. The Protocol • Rationale • Aims and objectives, Research questions • Design of the study: selection of patients, drugs and doses, assessment, withdrawals, data analysis, data discharge • Ethics: patient consent, adverse events • Documentation • Procedure
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
Avoidance of bias • Use of a control group • Blindness • Randomization • Consent before randomization
Control group • Placebo • Most widely accepted treatment • Most accepted prevention intervention • Usual care • Accepted means of detection
Randomization: Definition • Not a random sampling • Random allocation • Known chance receiving a treatment • Cannot predict the treatment to be given • Eliminates selection bias • Similar treatment groups
Only one factor is different • Randomization tries to ensure that ONLY ONE factor is different between two or more groups • Observe the consequences • Attribute Causality
Randomization • We want to assign a group of subjects to one of two groups—Treatment A or Treatment B • How can we do this in a random manner?