RANDOMIZED CONTROL

TRIALS

Dr. Shivashankar. KDepartment of Public Health dentistry

1st Year Post Graduate.

EPIDEMIOLOGYEpidemiological

Studies

Observational Experimental

Descriptive Analytical RCT Field Trials Community Trials

Cross sectional Ecological Case-control Cohort

WHO 1993

Introduction

First published RCT in medicine is credited to Sir A. Bradford

Hill , an epidemiologist for England’s Medical Research Council.

Randomization as a basic principle of experimental design in the

1920s was developed by RA Fisher who presented randomization

as an essential ingredient of his approach to the design and

analysis of experiments, validating significance tests

predominantly in agricultural research

Aim To provide “scientific proof” of aetiological factor and thus permit control of

those diseases.

To provide a method of measuring the effectiveness and efficiency of health

services for prevention, control and treatment of dis and improve health of

community

Randomized trials/ clinical trials STUDY POPULATION: patients

To study new preventive or therapeutic regimen

Subjects allotted in two groups – Treatment Control

Results assessed by comparing outcome in two groups Outcome may vary – outcome of new disease or recovery

from dis.

Advantages: Value of new therapies

Basic steps in randomized controlled trials

Drawing up a protocol

Selecting reference and experimental populations

Randomization

Manipulation and intervention

Follow up

Assessment of outcome

The protocol

Study is conducted under strict protocol

Specifies aims and objectives of study; questions to be answered; criteria for selection of study and control groups; parties involved in trial; stage of evaluation of study

Aims at preventing bias and to reduce sources of error in study

At times preliminary tests ie pilot studies are done – to find feasibility of certain procedures or acceptability of certain policies

Should be agreed by all concerned before trial begins

Selecting reference and experimental populations

Reference/ target population: Population to which findings of trial; if found successful,

are expected to be applicable Can be as broad as a mankind or geographically limited

or limited to persons in specific age, sex, occupational or social group

Experimental population: Derived from reference population - randomly Population that participates in the study They should have same characteristics as reference

group They should be informed, should be qualified and eligible

Randomization Randomization procedure by which participants

are allocated into groups called study and control groups

Attempt to eliminate bias and allow comparability Selection bias

Every individual gets an equal chance of being allocated into any of trial group

Done only after participant has entered the study ie given consent and is qualified

Criteria For Randomization

Unpredictability

Each participant has the same chance of receiving any of the interventions.

Allocation is carried out using a chance mechanism so that neither the participant nor the investigator will

know in advance which will be assigned.

Balance

Treatment groups are of a similar size & constitution, groups are alike in all important aspects and only

differ in the intervention each group receives

Simplicity

Easy for investigator/staff to implement

Methods of Randomization

The common types of randomization include

simple

block

stratified and

unequal randomization

Simple Randomization

Randomization based on a single sequence of random assignments is known as

simple randomization .

The most common and basic method of simple randomization is flipping a coin

Advantage

simple and easy to implement

Disadvantage

At any point in time, there may be an imbalance in the number of subjects on each

treatment

Balance improves as the sample size n increases

Thus desirable to restrict randomization to ensure balance throughout the trial

Stratified randomization The stratified randomization method addresses the need to control and balance the influence

of covariates.

Stratified randomization is achieved by generating a separate block for each combination of

covariates, and subjects are assigned to the appropriate block of covariates.

After all subjects have been identified and assigned into blocks, simple randomization is

performed within each block to assign subjects to one of the groups.

The block size should be relative small to maintain balance in small strata. Increased number

of stratification variables or increased number of levels within strata leads to fewer patients

per stratum.

Subjects should have baseline measurements taken before randomization.

Large clinical trials don’t use stratification.

Block randomization The block randomization method is designed to randomize subjects into groups that

result in equal sample sizes.

This method is used to ensure a balance in sample size across groups over time.

Blocks are small and balanced with predetermined group assignments, which keeps

the numbers of subjects in each group similar at all times.

The block size is determined by the researcher and should be a multiple of the

number of groups (i.e., with two treatment groups, block size of either 4, 6, or 8).

Blocks are best used in smaller increments as researchers can more easily control

balance

Advantage

Balance between the numbers of participants in each group is guaranteed

during course of randomization.

if the trial is terminated before enrolment is completed, balance will exist in

terms of number of participants randomized to each group.

Disadvantage

Analysis of data is more complicated than simple randomization. Also with

fixed blocks, people involved in the trial may be able to predict the group

assignment of participants being randomized at the last in the block.

Block randomization

Unequal Randomization

When two or more treatments under evaluation have a cost difference it may be

more economically efficient to randomize fewer patients to the expensive

treatment and more to the cheaper one.

The substantial cost savings can be achieved by adopting a smaller

randomization ratio such as a ratio of 2:1, with only a modest loss in statistical

power.

When one arm of the treatment saves lives and the other such as

placebo/medical care only does not much to save them in the oncology trials.

The subject survival time depends on which treatment they receive

MANIPULATION:This is to manipulate the studyDone by application or withdrawal or reduction of

suspected causal factorCreates independent variable – whose effect is

then determined by measurement of final outcome ie dependent variable

FOLLOW-UP:Examination of experimental and control groups

at defined intervals of timeAttrition may be seen

ASSESSMENT: of outcome of trials Positive results: benefits of experimental measures Negative results: severity and frequency of side effects and

complications of any

Incidence of negative and positive results is compared in both the groups – and differences if any are tested statistically.

Bias may arise from error of assessment of outcome: Subject variation Observer bias Bias in evaluation

Blinding Single blind trials:

Participant is not aware whether he belongs to study or control group

Double blind trials:Neither the participant nor the doctor is aware of

group allocation or the treatment being received

Triple blind trials:Participant, doctor and investigator all three are

blind

Allocation Concealment Procedure for protecting randomization process so that the

treatment to be allocated is not known before the patient is entered into the study

Protects an assignment sequence before & until allocation Prevents selection bias

Always possible to have allocation concealment

Effective Allocation Concealment

Sequentially numbered opaque sealed envelopes Pharmacy controlled Serially arranged numbered containers (not labelled as A or

B when only two assignments) Central randomization

Types of RCT CLINICAL TRIALS These are essentially experimental

designs used by clinician, epidemiologists to evaluate drugs and clinical or health care procedures

Preventive trials Prevention is synonymous with

primary prevention, and the term “preventive trials” implies trials of primary preventive measures.

Most frequently occurring type of preventive trials are the trials of vaccines and chemo-prophylactic drugs.

Analysis of a preventive trial must result in a clear statement about

The benefit the community will derive from the measure.

The risks involved, and The costs to the health service in terms

of money , men and material resources

DISADVANTAGES- Involve larger no. of subjects Longer time span to obtain results,

Greater number of practical problems in their organization and execution.

Risk factor trials

A type of preventive trial is the trial of risk factors in which the investigator intervenes to interrupt the usual sequence in the development of disease for those individuals who have “risk factors” for developing the disease.

For e.g., the major risk factors of coronary heart diseases are elevated blood cholesterol, smoking, hypertension and sedentary habits.

Cessation experiments Another 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.

The familiar eg is cigarette smoking and lung cancer.

Trial of etiological agents

Aims of experimental epidemiology is

to confirm an etiological hypothesis.

Evaluation of health services

Assess the effectiveness and efficiency of health services.

Most recently, multiphasic screening which has achieved great popularity in some countries was evaluated by a randomized controlled trial in South-East London.

Select suitable population(reference or target population)

Select suitable sample (experimental population)

Make necessary exclusions

Those are eligible

Those who do not wish to give

consent

Randomize

Study group Control group

Manipulation & follow up

Assessment

Design of a RCT

Designs of RCT Concurrent parallel design

Designs of RCTCross-over design

Designs of RCTFactorial design

Designs of RCTCluster design

Designs of RCTSplit Mouth design

Conclusion Epidemiology is the science that studies the

patterns , causes and effects of health and disease in defined populations. Randomized controlled trials are considered as a milestone and provide evidence of golden standard.

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