3. 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
4. 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
5. 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
6. Basic steps in randomized controlled trials
Drawing up a protocol
Selecting reference and experimental populations
Randomization
Manipulation and intervention
Follow up
Assessment of outcome
7. 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
8. 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
9. 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
10. 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
11. Methods of Randomization
The common types of randomization include
simple
block
stratified and
unequal randomization
12. 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
13. 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.
14. 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
15. 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
16. 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
17. MANIPULATION:
This is to manipulate the study
Done by application or withdrawal or reduction of
suspected causal factor
Creates 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 time
Attrition may be seen
18. 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
19. 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
20. 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
21. Types of RCT
CLINICAL TRIALS
These are essentially experimental designs
used by clinician, epidemiologists to
evaluate drugs and clinical or health care
procedures
22. 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.
23. 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
24. DISADVANTAGES-
Involve larger no. of subjects
Longer time span to obtain results,
Greater number of practical problems in
their organization and execution.
25. 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.
26. 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.
27. Trial of etiological agents
Aims of experimental epidemiology is to
confirm an etiological hypothesis.
28. 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.
29. 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
35. 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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