title: Do Studies Evaluating QT/QTc Interval Prolongation with Dietary Supplements Meet FDA Standards: A Systematic Review.
abstract: OBJECTIVE
  Dietary supplement use is continuously increasing, but the safety evaluation of these products remains partial. While dietary supplements have no mandate for assessing cardiovascular safety, all new drug entities (NDE) are required to undergo a thorough QT/corrected QT (QTc) assessment to determine their propensity to impact cardiac repolarization. Independent investigators and manufacturers of dietary supplements voluntarily initiate safety studies; however, the quality of these studies is controversial. We sought to compare studies evaluating the QT/QTc effects of dietary supplements based on the International Conference of Harmonization (ICH)-E14 recommendations for NDE.
  
  
  METHODS
  Twenty-six published dietary supplement studies assessed QT/QTc interval prolongation. Sample sizes ranged from nine subjects to 206 among the 15 crossover studies, six parallel design studies, and five observational studies. A plan to account for electrocardiogram (ECG) morphological abnormalities was included in 10 studies, and two studies reported cardiovascular adverse events. Eight studies found a significant change in QT/QTc intervals.
  
  
  CONCLUSIONS
  The majority of studies included in this review contained many of the critical elements recommended by the ICH E14, which includes the U.S. Food and Drug Administration guidance document for QT/QTc interval assessment. Compared with the thorough QT (TQT) standards, studies are typically well performed but can be bolstered by some study design changes. More than 30% of the included studies showed some degree of ECG changes, suggesting the need for continued cardiovascular safety assessment of dietary supplements.
authors.affiliation: a Doctor of Pharmacy Program, Thomas J. Long School of Pharmacy and Health Sciences, University of the Pacific , Stockton , CA , USA.
authors.forename: Tinh An
authors.initials: TA
authors.lastname: Nguyen
authors.affiliation: a Doctor of Pharmacy Program, Thomas J. Long School of Pharmacy and Health Sciences, University of the Pacific , Stockton , CA , USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Kurian
authors.affiliation: a Doctor of Pharmacy Program, Thomas J. Long School of Pharmacy and Health Sciences, University of the Pacific , Stockton , CA , USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Leong
authors.affiliation: b Thomas J. Long School of Pharmacy and Health Sciences, University of the Pacific , Stockton , CA , USA.
authors.forename: Umang M
authors.initials: UM
authors.lastname: Patel
authors.affiliation: c Department of Pharmacy Practice , Thomas J. Long School of Pharmacy and Health Sciences, University of the Pacific , Stockton , CA , USA.
authors.forename: Sachin A
authors.initials: SA
authors.lastname: Shah
mesh_terms: D019587:Dietary Supplements / Q000592:standards*; D017277:Drug Approval; D004341:Drug Evaluation / Q000592:standards*; D004562:Electrocardiography / Q000187:drug effects; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced*; D014481:United States; D014486:United States Food and Drug Administration / Q000592:standards*
keywords: ECG; QT/QTc prolongation; TQT study; dietary supplement