LECTURE 20 2011 - Trial Objectives Superiority...

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Trial Objectives Superiority, Non-inferiority, and Equivalence
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Questions of Interest Is the new treatment better than the control treatment that I am using now? (superiority trial) If it is not better , is the new treatment as good (not unacceptably non-inferior) as the control treatment that I am using now? (non-inferiority trial) Can I use the new treatment and the control treatment interchangeably? (equivalence trial) Non-inferiority and equivalence trials are usually considered when there is an active control.
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Definitions (ICH Guidelines – E9) Superiority trial – a trial with the primary objective of showing that the response to the investigational product is superior to a comparative agent (active or placebo control). Equivalence trial – a trial with primary objective of showing that the response to two or more treatments differs by an amount which is clinically unimportant (active control). Non-inferiority trial – a trial with the primary objective of showing that the response to the investigational product is not clinically inferior (or not unacceptably inferior) to a comparative agent (active or placebo control but usually active) – very common in the regulatory setting either for a new treatment or for a new label indication.
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Reasons for Active Controls An active treatment (comparator) with established efficacy exists. If superiority can be established, the standard of care is improved. If the outcome is morbidity/mortality a short- term trial with use of a placebo is not practical (recall papers by Temple and Ellenberg).
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The Number and Type of Active Comparator Studies Vary by Sponsor (Commercial versus Non-Commercial) Among published reports of trials between June 2008 and September 2009 in major medical journals, 97/212 (46%) used an active comparator. 36/108 (33%) with commercial sponsors and 61/104 (59%) with non-commercial sponsors. 18/36 (50%) of active controlled commercial trials were non-inferiority versus 5/61 (8%) of non-commercial trials. JAMA 2010; 303:951-958
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Examples – Non-Inferiority - 1 Is a new left ventricular assist device that provides a “bridge” to heart transplant as effective in keeping patients alive until a heart becomes available as one of the FDA-approved devices? Is a new vaccine for pertussis (whooping cough) that has an improved safety profile as effective in preventing whooping cough as the currently licensed vaccine? Is a single dose of a drug (low dose) equivalent to a twice a day dose (high dose)?
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Examples – Non-Inferiority - 2 Is a short course of treatment for latent TB infection (3 months of INH plus rifapentine) as effective as 9 months of INH in preventing active TB?
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Example - HIV Trial: Abacavir-Lamivudine-Zidovdine vs Indinavir-Lamivudine-Zidovudine JAMA 2001;285:1155-1163.
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