Transcript experimental studies

EXPERIMENTAL STUDIES
Presented by: Samarpita Dutta
FRAMEWORK:

Introduction
 Types of experimental studies
 Randomized control trial
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Types of randomized controlled trial (RCT)
Phases of clinical trial
Design and conduct of an RCT
General plan and protocol of an RCT
Study population
Randomization
Blinding
Sample size
Trial designs
Expressing results of a randomized control trial
Problems in conduct of an RCT
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Reporting and interpretation
Field trials
 Community trials
 Quasi-experimental studies
INTRODUCTION
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The idea of epidemiology has its origins almost 2000 years
back- Hippocrates – environmental factors can influence the
occurrence of disease
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Formal beginnings of epidemiology- until 19th century- John
Snow- risk of cholera in London was associated with source of
drinking water supply
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“The study of distribution and determinants of health-related
states or events in specified populations, and the application of
this study to the control of health problems.” (John Last, 1995)
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Epidemiologic studies -observational or experimental
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Observational studies allow nature to take its course: the
investigator measures but does not intervene
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Experimental studies: investigator intervenes.
EPIDEMIOLOGIC STUDY DESIGNS
TYPE OF STUDY
ALTERNATE
NAME
UNIT OF
STUDY
OBSERVATIONAL Descriptive
Analytical
EXPERIMENTAL
Ecological
Cross-sectional
Case control
Cohort
•Co relational
•Prevalence
•Case reference
•Follow-up
•Population
•Individuals
•Individuals
• Individuals
Randomized
controlled studies
Intervention studies
Clinical trials
Patients
Field trials
Community trials
Healthy people
Community
intervention studies
Communities
WHY THE NEED FOR EXPERIMENTAL STUDIES?
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Because of variability
We wouldn’t need a science of experimental design if
– If all units (patients; communities) were identical
– If all units responded identically to treatments
We need experimental design to control variability so that treatment
effects can be identified
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The idea of controlling variability through design has a long
history
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In 1747 Sir James Lind’s studies of scurvy
“Their cases were as similar as I could have them. They all in general had
putrid gums, spots and lassitude, with weakness of their knees. They lay
together on one place … and had one diet common to all….
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Lind then assigned six different treatments to groups of patients
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In 1904, Karl Pearson suggested matching and alternation in
typhoid trials
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Randomization for experimental studies was established by R.A.
Fisher in 1923
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In 1937, Sir Bradford Hill advocated alternation of patients in
trials rather than randomization
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The first modern randomized clinical trial in medicine is usually
considered to be the trial of streptomycin for treating
tuberculosis
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It was conducted by the British Medical Research Council in
1946 and reported in 1948
RANDOMIZED CONTROLLED TRIAL
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A randomized controlled trial is an epidemiological experiment
to study a new preventive or therapeutic regimen.
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Subjects in a population are randomly allocated to groups,
usually called treatment and control groups
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Results are assessed by comparing the outcome in the two or
more groups.
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The outcome of interest will vary but may be the development of
new disease or recovery from the established disease.
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For example, a trial conducted in Bangladesh (Molla et al, 1985) compared the
use of rice-based and glucose based oral rehydration solution in 342 patients
with acute watery diarrhoea during an epidemic of cholera in Bangladesh.
The study showed that the glucose component of the solution could be replaced
by rice powder with improved results, as indicated by decrease in mean stool
output and intake of solution
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TYPES OF RANDOMIZED CLINICAL TRIAL

THERAPEUTIC TRIAL: In this type therapeutic agent or
procedure is given an attempt to cure the disease, relieve the
symptom or prolong the survival of those with the disease.
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INTERVENTION TRIAL: In this type investigator intervenes
before a disease has developed in individuals with
characteristics that increase their risk of developing the
disease.
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PREVENTIVE TRIAL: In this type, an attempt is made to
determine the efficacy of a preventive agent or procedure
among those without the disease. These trials are also
referred to as prophylactic trials.
SR.
NO.
1.
TYPE
THERAPEUTIC
EXAMPLES
AZT treatment for AIDS
Simple mastectomy for breast cancer
Early photocoagulation for persons who have developed
Diabetic Retinopathy
(Early Treatment Diabetic Retinopathy Study Research
Group,1991)
Beta Blocker Heart Attack Trial, 1982
2.
INTERVENTION
AZT treatment of HIV positive patients without AIDS
Mammography to detect asymptomatic breast cancer
Cholesterol lowering drugs to reduce risk of MI
e.g. Coronary Primary Prevention Trial, Oslo Heart
Study.
3.
PREVENTIVE
Hepatitis B vaccination to prevent hepatitis and HCC
Education on use of condoms to reduce risk of HIV
transmission
PHASES OF A CLINICAL TRIAL
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PHASE I
– The researchers test an experimental drug or treatment in a
small group of people (20-80)
– It is tested for the first time in humans to evaluate its safety
– Determine a safe dosage range (Maximally Tolerated dose),
and
– Identify any toxic or side effects
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PHASE II
– The experimental study drug or treatment is given to a larger
group of people (100 300) with the target disease
– To look for the pharmacokinetic and pharmacodynamic
effects of the drug on these patients
– To see if it is effective and to further evaluate its safety.
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PHASE III:
– The experimental study drug or treatment is given to large
groups of people (1,000 3,000)
– To confirm its effectiveness
– Monitor side effects
– Compare it to commonly used treatments, and
– Collect information that will allow the experimental drug or
treatment to be used safely.
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PHASE IV:
– Also called as the “Post Marketing Surveillance”,
– Post marketing studies delineate additional information
including the drug's risks, benefits, and optimal use.
STEPS IN CONDUCT OF A RANDOMIZED
CONTROLLED TRIAL
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The protocol
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Selecting reference and experimental populations
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Randomization
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Intervention
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Follow up
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Assessment
GENERAL PLAN AND PROTOCOL OF A CLINICAL TRIAL
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The plan of a clinical trial is formally stated in a “protocol”
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It contains the objectives and the specific procedures to be used
in the trial.
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It should be written before the start of the trial
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Contain information as the methods for selecting and then
allocating the study groups, details on performance of any
laboratory tests or administration of drugs
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Once the protocol has been written, the epidemiologist compiles
the “manual of operations”.
GENERAL OUTLINE OF A PROTOCOL FOR CLINICAL TRIAL
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Rationale and background of the study
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Specific objectives for the study
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Concise statement of the study design (masking, randomization
schemes, types and duration of treatments, number of patients)
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Criteria for including or excluding patients
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Outline of treatment procedures
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Definition of all clinical, laboratory and other methods
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Methods of assuring integrity of the data
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Major and minor outcomes
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Provisions for observing and recording side-effects
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Procedures for handling problem cases
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Procedures for obtaining informed consent forms from the
concerned subjects
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Procedures for periodic review of the trial
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Procedures for termination of the trial
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Procedures for analysing results
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Procedures for communicating results of trial to study subjects
and other interested persons
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Appendices: Forms
STUDY POPULATION AND RECRUITMENT OF
PARTICIPANTS
POPULATION AT LARGE
Population
without
condition
Definition
of condition
POPULATION WITH CONDITION
Entry criteria
With condition
but ineligible
STUDY POPULATION
Enrolment
Eligible but
not enrolled
STUDY SAMPLE
RANDOMIZATION
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Randomization is of central importance in clinical trials
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Critical element of randomization- unpredictability of next
assignment.
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It prevents selection bias and ensures against accidental bias.
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It produces comparable groups, and eliminates the source of
bias in treatment assignments
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Can be achieved through random number tables or computer
generated.
DESIGN AND CONDUCT OF A RANDOMIZED
CONTROLLED TRIAL
BLINDING
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To remove the sources of bias in the observation 3 procedures
have been developed- single masking, double masking or triple
masking- also called as blinding.
TYPES OF BLINDING
SINGLE
DOUBLE
TRIPLE
SUBJECT
X
X
X
OBSERVER
-
X
X
DATA ANALYST
-
-
X
SAMPLE SIZE
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Clinical trials need to be designed with adequate power to
answer the question being posed.
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If N denotes the required sample size in each arm, then it is
given by the formula:
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2N= 2[ Zα√{2p(1-p)} + Zβ√{pc(1-pc)+ pi(1-pi)}]2
(pc-pi)2
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Where, pc= prevalence or anticipated event rate in control arm,
pi= prevalence or anticipated event rate in intervention arm, and
p= (pc + pi)/2
TRIAL DESIGNS
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PARALLEL DESIGN:
– Participants are allocated to the intervention and control
groups and stay in that group until the end of the study
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CROSS-OVER DESIGN:
– Each participant serves as his or her own control.
– In the simplest case, half of the participants would receive
intervention followed by control, and the other half the
reverse.
– Advantage -smaller sample size may be required.
– Disadvantage Outcome in this design needs to be reversible
 Secondly there is assumption of no carry-over effect from
one period to the next.
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Planned cross-over
Unplanned cross-over
FIGURE: DESIGN OF A PLANNED CROSS-OVER TRIAL
UNPLANNED CROSS-OVER
FIGURE: UNPLANNED CROSS-OVER
FACTORIAL DESIGN
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If there is an interest in studying more than one intervention at a
time, a factorial design may be more effective than a parallel
design
EXAMPLE OF FACTORIAL DESIGN (PHYSICIANS’ HEALTH STUDY)
Randomized
22,071
Aspirin
11,037
Beta carotene
5,517
Placebo,
11,034
Placebo
5,520
Beta carotene
5,520
Placebo
5,514
BETACAROTENE
+
ASPIRIN
-
+
Betacarotene
+Aspirin
Aspirin only
-
Betacarotene only
Neither Aspirin,
nor betacarotene
EXPRESSING RESULTS IN AN RCT
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Relative risk (RR):
– ID(exposed)/ID(unexposed)
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Relative risk ratio(RRR):
– (1-RR)
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Absolute risk reduction(ARR):
– ID(unexposed)-ID(exposed)
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Efficacy= (Rate in those who receive placebo)- (Rate in those who receive vaccine)
Rate in those who received the placebo
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NUMBER NEEDED TO TREAT (NNT): The number of patients
who would need to be treated (NNT) to prevent one adverse
outcome such as death. This can be calculated by:
NNT= __________________1__________________
(Rate in untreated group) - (Rate in treated group)
or,
1/ Absolute risk reduction(ARR)
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NUMBER NEEDED TO HARM (NNH) - Risk of side-effects by
calculating the number needed to harm to cause one additional
person to be harmed.
INTENT TO TREAT ANALYSIS:
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Also called as Randomized or Method Effectiveness Analysis.
It compares the outcome according to the randomized group
(Gold Standard) and adherence to intervention is not necessary
Advantages:
Randomization is maintained:
Treatment assignment is based on chance alone.
Randomization provides Theoretical foundation for Statistical
test of significance.
Disadvantages:
Does not take into account - protocol violation.
Groups do not remain comparable at the end
Analysis may underestimate the adverse effect.
PER PROTOCOL ANALYSIS:
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In this type analysis is done for only those who fully complied to
the protocol
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It does not include cross-over in final analysis
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Provides a fair idea of efficacy for treatment
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However, it may be biased, as randomization is compromised
AS TREATED ANALYSIS
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Subject analyzed according to treatment taken or not.
(no relation with randomization).
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Non compliant from treatment and vice versa analyzed
accordingly.
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AT is shown if ITT shows no effect ( why trial done).
REPORTING AND INTERPRETATION OF RCT
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Background and rationale
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Specification of the primary question and response variables
used to assess it.
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Pre-specified secondary questions
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Nature of the study population including eligibility criteria and
informed consent.
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Sample size calculations and assumptions used for that
calculation.
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Basic study design and allocation procedures
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Data collection procedures including efforts to minimize biases.
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Presentation of key baseline characteristics, by group.
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Process measures such as adherence, concomitant therapy
use, participants lost to follow.
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Results for the primary outcome, secondary outcomes and
adverse events.
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Adverse effects
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Special analyses, such as subgroups, covariate adjustment, and
data derived hypothesis.
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Interpretation, implications and conclusion in context of the
study and information external to the trial
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A structured abstract that accurately reflects the body of the
paper.
CONSORT STATEMENT
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The CONSORT (Consolidated Standards for Reporting Trials)
statement is used worldwide to improve the reporting of
randomized controlled trials.
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The CONSORT 2010 Statement is this paper including the 25
item checklist in the table and the flow diagram.
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It provides guidance for reporting all randomised controlled
trials, but focuses on the most common design type—
individually randomised, two group, parallel trials.
Flow diagram of the progress through the phases of a parallel randomised trial of two
groups (that is, enrolment, intervention allocation, follow-up, and data analysis)
PROBLEMS ENCOUNTERED WHILE CONDUCT OF AN RCT
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Volunteers and non participants
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Non-compliance and refusal to continue in the trial
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Lost to follow up
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Co-Interventions
FIELD TRIALS
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Involve people who are disease free but presumed to be at risk;
Data collection takes place in the field, usually among noninstitutionalized people in the general population.
Field trials are often huge undertakings involving major logistic
and financial consideration.
COMMUNITY TRIALS
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Experiments -involve communities
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Unit of study – groups in community
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For higher prevalence of risk factors for a certain disease in a
population
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In a community trial the epidemiologist selects two communities
that are similar in many respects as possible.
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Community assent for participation in the trial is obtained from
various political and other community leaders following which
the trial is started.
CONDUCT OF A COMMUNITY TRIAL
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Community trials have six stages. Each stage depends upon
successful completion of the previous stage:
 Development of a protocol
 Community selection and recruitment
 Establishment of a baseline and community surveillance
 Intervention selection and assignment
 Oversight and data monitoring
 Evaluation
GENERIC DESIGN OF COMMUNITY TRIAL
QUASI-EXPERIMENTAL STUDY
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Ideally, an experimental design should have three essential
elements of “randomization”; “controls” and “blinding”.
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Sometimes one may not be able to randomly allocate subjects
into two groups or at times the placebo part of the comparison
group may not be possible.
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Such circumstances, when an intervention has been given to
one group of subjects and not given to another group but the
procedure of random allocation or placebo control has not been
enforced for various reasons of impracticability or ethics, are
called as “Quasi-experimental” studies.
ETHICAL CONSIDERATIONS IN A RANDOMIZED CLINICAL
TRIAL (Hill,1977)
REGISTRATION OF CLINICAL TRIALS IN INDIA
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The Clinical Trials Registry–India is an online, primary register
of the WHO’s International Clinical Trials Registry Platform.
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It was launched on 20 July at the National Institute of Medical
Statistics, New Delhi.
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Registration is voluntary and free
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The register is searchable free of charge.
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Public disclosure of all 20 items in the WHO Trial Registration
Data Set is mandatory for a valid registration number to be
allocated.
REFERENCES:
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Detels R, Beaglehole R, Lansang MA, Gulliford M. Oxford textbook of public
health. Volume 2 . Methods of public health. 5th edition, Oxford University Press,
2009.
Beaglehole R, Bonita R, Kjellstorm T. Basic epidemiology. WHO, Geneva, 2002.
Gordis L. Epidemiology. Third edition, Elsevier Saunders. 2004
Lillienfield DE, Stolley PD. Foundations of epidemiology. Third edition. Oxford
University Press, 1994.
MacMohan B, Pugh TF. Epidemiology Principles and methods. Fifth edition,
Little, Brown and Company, Boston, 1970.
Fletcher RH, Fletcher SW. Clinical epidemiology The essentials. 4th edition,
Lippincot Williams and Wilkins, 2005.
Textbook of public health. AFMC, Pune in collaboration with WHO India Country
Office.
Kenneth F Schulz, Douglas G Altman, David Moher, for the CONSORT Group.
CONSORT 2010 Statement: updated guidelines for reporting parallel group
randomised trials; BMJ; 2010; 340:698-702.
Donner Allan. Approaches to sample size estimation in the design of clinical
trials-a review. Statistics in medicine, 1984; 3; 199-214.