LECTURE 08 2011

- Endpoints(also Outcomes Major Response Variables Follow from objectives of the study Outline General endpoint considerations Surrogate endpoints

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Endpoints (also Outcomes, Major Response Variables) Follow from objectives of the study.
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Outline General endpoint considerations Surrogate endpoints Composite endpoints Safety outcomes (adverse events)
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Major Problems that Limit Interpretation of Randomized Trials Inappropriate controls Endpoints which are not clinically relevant Inadequately powered studies Poor follow-up Improper interim analyses
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Primary Endpoint Key variable in design and analysis Basis for sample size, therefore stated a priori Response variable given major attention in report Usually, but not always, e.g., Cox-2 trials on GI bleeding, relates to efficacy. In some studies the primary endpoint encompasses efficacy and safety, e.g., mortality in CHF study, lipid study, HIV treatment study “A clinical endpoint that provides evidence sufficient to fully characterize the effect of a treatment in a manner that would support a regulatory claim for treatment” (O’Neill RT, Cont Clinical Trials , 1997;18:550-556)
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Secondary Endpoints There are usually several efficacy endpoints and these are commonly referred to as secondary endpoints or secondary efficacy endpoints. Safety endpoints must also be specified and are usually consider secondary Discontinuation of study treatment Side effects/adverse events Serious adverse events and safety reports (FDA regulations) O’Neill (FDA) defines a secondary endpoint as one that “provides additional characterization of treatment effect but that is not sufficient to characterize fully the benefit or to support a claim for a treatment effect”.
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Characteristics Desired for Endpoint Relevant; easy to interpret Easy to diagnose Can be ascertained and classified in an unbiased manner Sensitive to treatment differences Measurable within a reasonable period of time
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General Considerations - 1 More commonly occurring endpoints (high incidence) will result in smaller sample sizes than less frequent events (low incidence) as long as expected relative difference between treatment groups is similar CHD + non-fatal MI vs. CHD death Continuous response variables usually result in smaller sample sizes than binary or time to event BP change vs. % with normal BP HIV RNA change vs. % < 50 copies/mL HIV RNA change vs. progression to AIDS
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General Considerations - 2 More serious events should be considered along with less serious ones Count CHD deaths along with non-fatal MIs Related to this, some events may have to be included to avoid misinterpretation due to informative censoring (this could result in a loss of power) Non-arrhythmic deaths along with arrhythmic deaths (DEFINITE, NEJM 2004) Death and missing data along with change in exercise duration (PICO, Heart 1996) Progression to AIDS or death from any cause (SMART, NEJM 2006)
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MRFIT Primary: CHD Death Secondary: CHD Death or non-fatal MI All deaths NuCombo Study
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This note was uploaded on 11/21/2011 for the course PUBH 7420 taught by Professor Ph7420 during the Spring '07 term at Minnesota.

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- Endpoints(also Outcomes Major Response Variables Follow from objectives of the study Outline General endpoint considerations Surrogate endpoints

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