Randomized controlled trials

Dr. Shivashankar. K
Department of Public Health dentistry
1st Year Post Graduate.

EPIDEMIOLOGY
Epidemiological
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 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

 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 RCT
Cross-over design

Designs of RCT
Factorial design

Designs of RCT
Split 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.

References
 Last John M. ed. (1983). A Dictionary of epidemiology, A handbook
sponsored by the IEA, Oxford Univ. press.
 Lowe,C.R. and J. Kostrzewski, (1973) Epidemiology, A guide to
teaching methods, Churchill Livingstone.
 Centers for Disease Control and Prevention. Principles of Epidemiology
an Introduction to Applied Epidemiology & Biostatistics. 2nd Ed.16-30.
 Bhalwar R. Textbook of Public Health and Community Medicine.1st
ed.2009.131-
 Park K. Park’s textbook of preventive and social medicine. 22nd edition,
2013. Banarsidas Bhanot publishers, Jabalpur, India. 56-
 Beaglehole R, Bonita R, Kjellstrom T. Basic Epidemiology.2nd edition.
World Health Organization.2006. 4, 6-11, 26.
 Dr. Rathai rajagopalan1, dr. Priyadarshini m.Deodurg2, 2013dr.
Srikanth;
 Overview of randomized controlled trials ;asian journal of clinical
research;6;3

 William G Rosthstein;1995,Readings in American Health care;wiscosian
press.
 Morabia A. Epidemiologic methods and concepts in the ninteenth century
and their influences on the 20th century. In : Holland WW (editor). The
history of Epidemiology. Oxford University Press 2007: 17-30.
 Lenin ,2007;measure of effect of relative risk and odds ratio;ABC of
epidemiology.
 Health Research Methodology: A Guide for training in Research
Methods;WHO Regional Publications.
 Thomas.C.Timmreck;An Introduction to Epidemiology 2nd Edition,
 Porta M. A dictionary of epidemiology. 5th edition. Oxford, New York:
Oxford University Press, 2008.
 Rothman J, Greenland S. Modern epidemiology. Second edition.
Lippincott - Raven Publishers, 1998.
 Bhopal R. Study design. University of Edinburgh.
 NLM. An introduction to Clinical trials. U.S. National Library of Medicine,
2004
 Songer T. Study designs in epidemiological research. In: South Asian
Cardiovascular Research Methodology Workshop. Aga-Khan and
Pittsburgh universities.

Randomized controlled trials

More Related Content

What's hot (20)

Viewers also liked (20)

Similar to Randomized controlled trials (20)

More from ●๋•ѕнιναshankar●๋• kengadaran★彡 (9)

Recently uploaded (20)

Randomized controlled trials