title: Utility of positive controls in assessing assay sensitivity in ICH S7B and ICH E14 guidance for evaluation of QT/QTc interval prolongation.
abstract: Positive controls have often been used in nonclinical and clinical cardiovascular safety studies to evaluate the study's assay sensitivity with respect to drug-induced prolongation of the QT interval of the electrocardiogram (ECG). If the study is able to detect such QT prolongation by the control, then a finding of negative QT effect of comparable size for the test drug will constitute evidence that the test drug does not in fact prolong the QT interval by the amount of regulatory concern. Current regulatory guidance regarding QT interval prolongation includes ICH S7B (nonclinical) and ICH E14 (clinical). 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 show that positive controls, when powered at 80%, can be beneficial in 58% of nonclinical QT studies with Prob(S)=0.8; when powered at 90%, positive controls can be beneficial 73% of clinical QT studies with Prob(S)=0.9, where Prob(S) represents the probability of success with no QT risk at the stage of development.
authors.affiliation: Global Statistical Sciences and Toxicology, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, IN 46285, USA. chiangay@lilly.com
authors.forename: Alan Y
authors.initials: AY
authors.lastname: Chiang
authors.forename: Craig H
authors.initials: CH
authors.lastname: Mallinckrodt
authors.forename: Alex A
authors.initials: AA
authors.lastname: Dmitrienko
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Leishman
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D004353:Drug Evaluation, Preclinical; D015507:Drugs, Investigational / Q000633:toxicity*; D004562:Electrocardiography / Q000187:drug effects*; D017408:Guidelines as Topic; D006801:Humans; D012680:Sensitivity and Specificity
chemical_list: D015507:Drugs, Investigational