Randomized Controlled

Trial

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

Randomized controlled trials ””An epidemiological experiment in which An epidemiological experiment in which

subjects in a population are randomly subjects in a population are randomly allocated into groups, usually called study and allocated into groups, usually called study and control groups to receive and not receive an control groups to receive and not receive an experimental preventive or therapetuic experimental preventive or therapetuic procedure, maneuver, or interventition” procedure, maneuver, or interventition”

John M.Last, 2001John 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

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ETHICS

IMPORTANT ISSUE IN CLINICAL TRIALSETHICAL CLEARANCE

* INSTITUTIONAL REVIEW BOARDS

* ETHICAL COMMITTEES

* ICMR GUIDELINES

* FEDERAL/STATE GUIDELINES

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

1. Clinical Trial: Diagnostic, Therapeutic, Prophylactic, Devices, Procedures, Regimens, Protocols

2. Preventive Trial3. Risk Factor Trial4. Cessation experiments5. Trial of etiologic agents6. Evaluation of health system

Types of Randomized Controlled Trials

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

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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

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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

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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

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5. Trials of Etiological Agents:- To confirm or disprove an etiological

hypothesis

6. Evaluation of Health Services:- Domiciliary treatment of PTB was as effective

as more costlier hospital or sanatorium treatment

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MULTICENTER TRIALS

Reasons for Multi-center Trials :

1. To recruit necessary number of subjects within a reasonable time.

2. May assure a more representative sample of the study or target population

3. 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.“

1. The protocol2. Selecting reference and experimental

populations3. Randomization4. Intervention5. Follow up 6. Assessment

Steps in conduct of RCT

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

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2. Selecting Reference and Experimental Populations

a. 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

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Participants must fulfill the following criteria:

- Must give informed consent

- Should be representative of the population

- Should be qualified or eligible for the trial

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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

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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

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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

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6. Assessment- Positive results- Negative results

- Biases: Subject variation, Observer bias, Evaluation bias

- Can be corrected by blinding

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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?

Randomization

Random assignment• Flip a coin– “Heads”—Tx A– “Tails”—Tx B

Randomization

Random assignment• Roll a six-sided dice– Even number—Tx A– Odd number—Tx B

Randomization

Random assignment• Table of random numbers• Computer generated list

‘Almost’ Random assignmentsRandom assignment• Alphabetical– Tx A = patients with last name A–M– Tx B = patients with last name N–Z

• Telephone number/social security number– Tx A = last digit odd– Tx B = last digit even

• Sequential– Tx A = morning patients– Tx B = afternoon patients

• Bed number– Tx A = odd bed number– Tx B = even bed number

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BLINDING

•UNBLINDED, OPEN TRIAL

•SINGLE BLIND

•DOUBLE BLIND

•TRIPLE BLIND

““RANDOMIZED, DOUBLE-BLIND, CONTROLLED RANDOMIZED, DOUBLE-BLIND, CONTROLLED TRIAL” TRIAL” is considered as research design is considered as research design par excellence and “par excellence and “GOLD STANDARDGOLD STANDARD” ” amongst research designs with which amongst research designs with which results of other studies are often results of other studies are often compared. Deviation from this standard compared. Deviation from this standard has potential drawbackshas potential drawbacks

Double-Blinded Single-BlindedDouble-Blinded Single-Blinded