Utility of Positive Controls in Assessing QT Interval Sensitivity

• Activity Number: 468
• Type: Contributed
• Date/Time: Wednesday, August 4, 2010 : 8:30 AM to 10:20 AM
• Sponsor: Biopharmaceutical Section
• Author(s): Alan Y. Chiang*+
• Companies: Eli Lilly and Company
• Keywords: Assay Sensitivity ; E14 ; QT Interval ; Positivie Control ; S7B

Abstract

Positive controls have been often used in nonclinical and clinical cardiovascular safety studies to evaluate the study's assay sensitivity. If the study is able to detect such QT prolongation by the control, then a finding of negative QT effect of that size for the test drug will constitute evidence that the test drug not in fact prolong the QT interval by the amount of regulatory concern. Current regulatory guidance regarding QT interval prolongation includes ICH S7B and ICH E14. However, the underlying null hypothesis settings of the two documents are quite different. This paper quantitatively evaluates the utility of positive controls in nonclinical and clinical studies in which a test drug and a positive control are simultaneously assessed in a study. The results are summarized via joint probabilities of outcomes, and the actual benefits of including a positive control are discussed.