primary research question and definition of endpoints india 2007
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Primary Research QuestionPrimary Research Questionand Definition of Endpointsand Definition of Endpoints
Mario ChenThe Fundamentals of Biostatistics in
Clinical Research Workshop
India, March 2007
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Research QuestionsResearch Questions
Uncertainty that the investigator wants toresolve.
Interesting, Novel, and Relevant:
Literature
Colleagues
Stakeholders
Feasible: Concrete, researchable issue
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Common error Sinking ship: Avoid overloadingthe study with too many objectives and too muchdata collection
A single primary question around which to focusthe development of the protocol and sample sizeestimates
Secondary research questions: can be related tothe primary question or to other hypotheses
Primary and SecondaryPrimary and SecondaryQuestions/ObjectivesQuestions/Objectives
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Main study variablesMain study variables
Longitudinal Studies (cohort, RCT): Endpoint
Outcome Measure
Response Variable
Case-Control Study:
Exposure Variable
Case Definitions
Other Study Designs:
Main Analysis Variables
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ExampleExample
Primary Objective: To assess theeffectiveness of a new malaria vaccine
Possible endpoints:
Occurrence of a malaria episode
Mortality
Occurrence of malaria related anemia
Secondary objectives and endpoints
Acceptability
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FrameworkFramework
ObjectiveObjective
EndpointEndpoint
Summary measure*Summary measure*
ParameterParameter
PopulationPopulation
IndividualIndividual
SampleSample
PopulationPopulation
* Depends of primary analysis method
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ExampleExample
ObjectiveObjective
EndpointEndpoint
Summary measureSummary measure
ParameterParameter
Vaccine effectivenessVaccine effectiveness
Occurrence of diseaseOccurrence of disease
VE=1-RR (Preventable Risk)VE=1-RR (Preventable Risk)
95% CI for VE95% CI for VE
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Desired (Required)Desired (Required)CharacteristicsCharacteristics
Clinical relevance (clearly reflects researchquestion, mechanism of action, impact on
well-being of individuals).
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Desired (Required)Desired (Required)CharacteristicsCharacteristics
Single primary endpoint: If more than one primary endpoint is used, the
probability of getting a nominally significant
result by chance alone is increased (Type IError).
If the analysis, based on several endpoints,
gives conflicting results, interpretation becomesdifficult.
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Desired (Required)Desired (Required)CharacteristicsCharacteristics
Consistency. Primary endpoint must becapable of being assessed in all subjects
consistently:
Avoid having different endpoints for different
subjects for the same primary objective.
Avoid having different instruments or
techniques applied for the measurement of the
endpoint.
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Desired (Required)Desired (Required)CharacteristicsCharacteristics
Validity of the comparisons. Unbiasedascertainment of endpoints across
comparison groups:
The issue of blinding. Objective endpoints
The Misclassification problem:
Non-differential.
Differential.
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Misclassification (Example)Misclassification (Example)
Scenario: P.falciparum malaria in children
living in holo-endemic area (EIR>100)
~60% infected asymptomatically
MOI ~ 5 strains/child on average
Clinical malaria diagnosis?
Specificity scaleSpecificity scalelow high
FeverFever fever+fever+
parasitaemiaparasitaemia
fever+fever+
highhigh
parasitaemiaparasitaemiaCerebralCerebral
MalariaMalaria
SevereSevere
anaemiaanaemia
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MisclassificationMisclassification(Non Differential)(Non Differential)
Issue: Low specificity (NonIssue: Low specificity (Non--differential) indifferential) in
clinical outcomesclinical outcomes
==
grossgross underestimationunderestimationof true efficacy ofof true efficacy of
interventionintervention
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MisclassificationMisclassification(Differential)(Differential)
Issue:Issue: Low specificity (Differential) inLow specificity (Differential) in
clinical outcomesclinical outcomes==
underestimationunderestimationororoverestimationoverestimation
of true efficacy of interventionof true efficacy of intervention
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MisclassificationMisclassification
RCT: Misclassification can occur both before and
after intervention. Usually non-differential due
to randomization and blinding Cohort:
Misclassification can occur in the classification
of exposure or disease Case-Control:
Misclassification can occur in the classification
of disease or exposure
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Desired (Required)Desired (Required)CharacteristicsCharacteristics
Reliability. The extent to whichmeasurement obtained is reproducible in
repeated administrations. Lack of random
measurement error
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Desired (Required)Desired (Required)CharacteristicsCharacteristics
Completeness. Ascertainment of endpointsshould be as complete as possible:
Consequences of Missing Data:
Sample size Loss of power
Bias Loss of validity
Data collection procedures and instruments
Follow up procedures. Participant retention
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Desired (Required)Desired (Required)CharacteristicsCharacteristics
Statistical Significance. Selected endpointshould be such that it has the potential to
show clinical significance statistically:
Clinical meaningful difference worth detecting
(Effect size)
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ExampleExample
RCT to study the efficacy of prophylacticdoxycycline at IUD insertion1
Primary Endpoint: Pelvic Inflammatory
Disease (PID)
Secondary Endpoint: Unscheduled Visit for
an IUD-related Problem, e.g., bleeding,pain, or discharge
1. Sinei SKA, Schulz KF, Lamptey PR, et al. Preventing IUCD-related pelvic infection:
the efficacy of prophylactic doxycycline at insertion.Br J Obstet Gynaecol 1990;97(5):412-19.
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Estimating the Incidence of PIDEstimating the Incidence of PIDfor Sample Size Calculationsfor Sample Size Calculations
Government officials estimated 40% Ob/GYN from Med School estimated 12%
We conservatively set initially at 6%
Readjusted to 4% based on pilot trial
And after all that, found 1.9% in placebo
group
Effect on power?
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ResultsResults
.004.52-.910.6913.0%8.9%Unsch
Visit
0.17.32-1.50.691.9%1.3%PID
P-value95%CIRRPlaceboDoxyOut-
come
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Alternative EndpointAlternative EndpointDefinitionsDefinitions
Surrogate Endpoints:
Indicator of effect in lieu of the one ofsubstantive interest,
e.g CD4 counts for AIDS mortality
Rationale: Measuring effect sooner and/or forless cost
Highly correlated to the clinical outcome of
interest: Biological plausibility
Trial measuring both true and surrogate endpointand studying their correlation
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Alternative EndpointAlternative EndpointDefinitionsDefinitions
Surrogate Endpoints (Example) Cardiac Arrhythmia Suppression Trial (CAST)
compared encainide and flecainide to placebo
Trial established that the drugs were extremelybeneficial in suppressing arrhythmia
Surprisingly to cardiologists, CAST showed that
the drugs tripled the death rate [Senn S. Statistical
Issues in Drug Development. John Wiley, 1997.]
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Alternative EndpointAlternative EndpointDefinitionsDefinitions
Composite endpoints: Combines multiple measurements into a single
composite endpoint using a pre-specifiedalgorithm
Any one event occurs too infrequently
Sample size
Length of follow-up
Meaningful interpretation
Possibility of conflicting results
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Alternative EndpointAlternative EndpointDefinitionsDefinitions
Composite endpoints (example): Primary endpoint. Occurrence of one or more
of the following critical events associated with
severe disease: Death
Cardiac index less than or equal to 2.2
Ventricular tachycardia or fibrillation Pulseless electrical activity
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Final RemarksFinal Remarks
Choose your study endpoints (especially theprimary endpoint) carefully by considering the
desired characteristics discussed. Involve
colleagues and recent research Define endpoints in the protocol. Rationale and
measurement procedures should be specified a
priori. Redefinition of primary endpoints after unblinding
will almost always be unacceptable, ICH 9