The impact of drug-related QT prolongation on FDA regulatory decisions.

Since 2005, most new drugs are evaluated for QT prolongation in a thorough clinical QT assay (TQT), per International Conference of Harmonization guideline (ICH E14) [1]. To date, the TQT/QT studies of over 200 new drug applications (NDAs) have been reviewed for QT effects by the U.S. Food and Drug Administration (FDA). It has been recognized that QT prolongation has influenced regulatory decisions, but a systematic review of this subject has not been reported. The purpose of the present exercise was to evaluate the regulatory outcome of drugs that tested “positive” in the TQT study. Drugs that prolongedQTwere identified from a database of TQT study reviews [2] performed by the FDA within the period from May, 2006 to March, 2013. Thedefinition ofQT prolongation in thedatabase follows the ICH E14 guideline, i.e., the upper bound of the 95% one-sided confidence interval for the largest time-matched difference from placebo corrected control exceeds 10 ms. The following information was collected for those drugs: status of application, approved drug labeling, magnitude of QT interval prolongation, therapeutic area, and submission year. QT data were collected from FDA QT reviews and individual TQT study reports submitted in support of sponsors' applications. Drug labels were accessed at the public website, drugs@FDA [3]. A total 205 TQT/QT studies of newdrugs submitted to the FDA thru March, 2013 were evaluated for QT prolongation. Forty-six drugs (22%, 46 out of 205)were identified as prolonging theQT interval. Fortyone of those 46 drugs were approved (89%). Interestingly, the approval rate for QT “negative” drugswas 77%. Five drugswere not approved; one applicationwaswithdrawnby the sponsor, and four received a Complete Response letter. The major reason for the Complete Response Letter was lack of efficacy; a QT-related safety concern led to a major deficiency for one drug (2%, 1 out of 46). To understand the labeling implications related to QT prolongation of approved drugs, the FDA drug labeling was investigated. Of the 41 approved drugs, 3, 5 and 25 have QT-related BoxedWarnings, Contraindications, and Warnings and Precautions, respectively. The QT effects of 8 drugs were described in the adverse reactions, drug interactions, overdosage and clinical pharmacology sections. InTQT/QTstudies, thevalues of baselineand timeadjustedmaximum QT change, ΔΔQTc, were collected. The mean, minimum and maximum effect sizes of the 46 drugs that prolonged QTwere 17.1, 7.3 and 64.6 ms, respectively. We categorized drugs by magnitude of mean QT prolongation: mild, QTc b 10 ms, moderate, 10–20 ms and severe prolongation, N20 ms. The percentages of drugs in each category were 26% (n = 12), 49% (n = 22) and 26% (n = 12), respectively (Fig. 1). Half of the QT prolongers were in the moderate category. There is no apparent relationship between magnitude of QT prolongation and drug approval; approval rates of mild, moderate and severe QT prolongers were 83%, 95%, and 83%, respectively. In contrast, the severity of safety warnings was related to magnitude of QT prolongation in TQT studies. Mean effect size of QT prolongation of drugs with no safety warning, warning and precaution, contraindication and boxed warning are 10.3, 15.6, 18.1 and 40 ms, respectively. The therapeutic areas of QT prolongers were diverse, with 12 different areas represented. Oncology and psychiatric indications were the most common indications (21 of 46) for drugs testing positive for QT prolongation. Interestingly, 45% (5 out of 11) of oncology drugs showed severe QT prolongation, but all anticancer QT prolongers (n= 11) in the database were approved. Three oncology drugs were labeled with boxed warnings related toQTprolongation.Nilotinib (maximumQTprolongation, 18 ms), vandetanib (39.3 ms) and toremifene (64.6 ms) fall in this category. Nilotinib is indicted for the treatment of Philadelphia chromosome positive chronicmyeloid leukemia and has awarning for QT prolongation and sudden deaths. Vandetanib is indicated for the treatment of thyroid cancer and has a boxwarning of QT prolongation, Torsade de Pointes and sudden death and is available only through a restricted distribution program. Toremifene is indicated for the treatment of metastatic breast cancer and has a boxed warning of QT prolongation. FDA recommends not using these drugs in patients with hypokalemia, hypomagnesemia and congenital long QT syndrome andwith drugs known to prolong the QT interval. These cases illustrate that even high proarrhythmic risk associated with QT prolongation can be outweighed by therapeutic benefit in regulatory decisions of oncology drugs. To understand the trend of sponsors' submissions of QT prolonging drugs, the percentages of TQT studies testing positive by submission year is shown in Table 1. The analysis was limited to drugs submitted during and after 2005, since TQT studies were only performed routinely in that time frame. Overall, the trend showed that the percentages of QT prolonging drugs submitted to the FDA decreased during this time period – from 60% in 2005 to 10% in 2012 (Table 1). In conclusion, 89% of drugs testing positive for QT prolongation in the TQT/QT studies were approved, with labeling to address safety