Randomized controlled trials
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Transcript of Randomized controlled trials
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
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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