The Impact of Drug-Related QT Prolongation on FDA ...

1 The Impact of Drug-Related QT Prolongation on FDA regulatory Decisions Eunjung Park, DBII / OGD / OPS / CDER / FDA 1 SPS Feb 27 2014 regulatory Background regulatory actions to QT- related cardiac proarrhythmia Withdrawals of high profile drugs from market: Torsades de pointes (TdP) drug Indication Year withdrawn Major Safety Concern Terodiline Urinary Incontinence 1991 QTc Prolongation , TdP Sparfloxacin Antibiotic 1996 QTc Prolongation Terfenadine Antihistamine 1998 QTc Prolongation , TdP Astemizole Antihistamine 1999 QTc Prolongation , TdP Grepafloxacin Antibiotic 1999 QTc Prolongation , Cardiac arrhythmias Cisapride Gastroesophageal reflux 2000 QTc Prolongation , Cardiac arrhythmias Droperidol Schizophrenia 2001 QTc Prolongation , TdP 2 ICH Guidelines E14: Human Thorough QT/QTc (TQT) study Signed in 2005 An examination of a drug s QT/QTc Prolongation liability Expensive and intensive study S7B: Non-clinical cardiac safety pharmacology Signed in 2005 hERG channel Action potential duration (APD) Non-clinical ECG study 3 Scope of ICH E14 New drugs having systemic bioavailability Exemption highly localized distribution/ topically administered/ not absorbed arrhythmias control drug Approved drugs with new dose new route of administration new indication new patient population drug or members of its chemical or pharmacological class have been associated with QT/QTc interval Prolongation , TdP or sudden cardiac death during post-marketing surveillance.

2 4 FDA Efforts IRT-QT review team Interdisciplinary review team for QT evaluation Systematic QT data analysis, archiving and reporting to streamline the review process and allow for a consistent evaluation and process. Reviewing protocols and study reports related to QT assessment across all review divisions. > 200 NDAs reviewed through 2013 No drug withdrawn for QT- related proarrhythmia since implementation of ICH E14 and S7B 5 Sponsor s Concerns Cardiac safety liabilities Delays in drug development Labeling restrictions Negative impacts on physician s prescribing preferences NDA submission of QT prolongers has been reduced. E14 and S7B may bias lead candidate selection and therefore, eliminate potentially useful drugs and reduced patient benefit. 6 Dataset of QT Prolongers E14 guidance Upper bound of the 95% one-sided confidence interval (CI) or 90% two-sided CI for the QTc > 10 msec.

3 QT prolonger dataset 46 drugs 22% of NDAs in the IRT database 34 TQT studies 12 Non-TQT studies 7 Approval Status QT prolongers Number of Drugs (N=46) Approval Status 41 Approved (89%) 4 Complete Response (CR) 1 large dose-dependent QTc increase and sudden cardiac death in the study 3 marginal or questionable efficacy 1 Withdrawn How about non-QT prolongers in the IRT database? 77% 8 QT Effect Size of Approved Drugs (n=46) Category of QTc < 10 ms 10-20 ms > 20 ms Number of drugs 12 22 12 Approval % 83 95 83 0102030405060701234567891011121314151617 1819202122232425262728293031323334353637 383940414243444546drug QTc (max) 9 Labeling No of Drugs Mean QTc (ms) QT- related boxed warning 3 40 Contraindication 5 18 Warnings and Precautions 25 16 Adverse events drug - drug Interaction Overdosage Pharmacology 8 11 10 Drugs in FDA Review Divisions Division Number of QT prolongers (n=46) Anesthesia, Analgesia, and Addiction 2 Anti-infective 5 Antiviral 3 Cardiovascular and Renal 2 Gastroenterology and inborn errors 2 Hematology 3 (1) Medical imaging 1 Neurological 4 Oncology 11 (13 for antitumor) Psychiatry 10 Reproductive and Urologic 2 Transplant and Ophthalmology 1 11 Antitumor Drugs (n=13) Characteristics Number of Drugs Approval 13 (100%) Approval year E14 3 QT Study (%) 5 (45%)

4 Mean ( )QTc (ms) Label Boxed Warning 3 Warning and Precaution 9 Pharmacology 1 12 Examples: Toremifene Indication: treatment of metastatic breast cancer QT Prolongation : 65 ms at 300 mg Boxed warning: QT Prolongation and TdP Toremifene should not be prescribed to patients with congenital/acquired QT Prolongation , uncorrected hypokalemia or hypomagnesemia. High proarrhythmic risk can be outweighed by therapeutic benefit in regulatory decisions Non-clinical study results hERG (+), APD (-), Animal ECG (+) 13 Psychiatric Drugs (n=10) Characteristics Number of Drugs Approval 8 (80 %) Approval year E14 3 QT Study (%) 5 (50 %) Mean ( )QTc (ms) Label Boxed Warning 0 Contraindication 1 Warning and Precaution 5 Pharmacology 1 Overdosage 1 14 Conclusions Eighty-nine % of QT prolongers were approved. Magnitude of QT effects for approved drugs was large. QT prolongers with a mean effect of less than 10 ms were labeled with either no or a minimum safety warning in the FDA labeling.

5 Three drugs with large QT effects and adverse clinical outcomes were approved. FDA approvals are made on the basis of risk-benefit calculations related to the underlying disease. 15 Questions? 16 References Gobburu et al, Creation of a Knowledge Management System for QT Analyses, Journal of Clinical Pharmacology 51, 1035, 2013 17 QT interval, a biomarker of TdP QTc = heart rate corrected QT interval ! QTcF (Fridericia) = QT/RR1/3 ! QTcB (Bazett) = QT/RR1/2 ! QTcI (individually corrected) ! RR= 60/HR Heart s electrical cycle drug Baseline Test day Administer QTc1 QTc2 Placebo Baseline Test day Administer QTc3 QTC4 time TQT Study design QTc = (QTc2- QTc1) - (QTc4- QTc3) QTc = QTc2- QTc4 Baseline and time matched QTc 18 Oncology Drugs (n=11) Characteristics Number of Drugs Approval 11 (100%) Approval year E14 3 QT Study (%) 5 (45%) Mean ( )QTc (ms) Label Boxed Warning 2 Warning and Precaution 8 Pharmacology 1 19