primary research question and definition of endpoints india 2007

8/3/2019 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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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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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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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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Reliability. The extent to whichmeasurement obtained is reproducible in

repeated administrations. Lack of random

measurement error


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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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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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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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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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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

primary research question and definition of endpoints india 2007

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