The Impact of Drug-Related QT Prolongation on FDA Regulatory Decisions

Transcription

1 The Impact of Drug-Related QT Prolongation on FDA Regulatory Decisions Eunjung Park, Ph.D. DBII / OGD / OPS / CDER / FDA SPS Feb

2 Regulatory Background Regulatory actions to QT-related cardiac proarrhythmia Withdrawals of high profile drugs from market: Torsades de Drug pointes Indication Year Major Safety Concern (TdP) withdrawn Terodiline Urinary Incontinence 99 QTc prolongation, TdP Sparfloxacin Antibiotic 996 QTc prolongation Terfenadine Antihistamine 998 QTc prolongation, TdP Astemizole Antihistamine 999 QTc prolongation, TdP Grepafloxacin Antibiotic 999 QTc prolongation, Cardiac arrhythmias Cisapride Gastroesophageal reflux 2000 QTc prolongation, Cardiac arrhythmias Droperidol Schizophrenia 200 QTc prolongation, TdP 2

3 ICH Guidelines E4: 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) 3

4 Scope of ICH E4 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. 4

5 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 200 NDAs reviewed through 203 No drug withdrawn for QT-related proarrhythmia since implementation of ICH E4 and S7B 5

6 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. E4 and S7B may bias lead candidate selection and therefore, eliminate potentially useful drugs 6 and reduced patient benefit.

7 Dataset of QT Prolongers E4 guidance Upper bound of the 95% one-sided confidence interval (CI) or 90% two-sided CI for the!!qtc > 0 msec. QT prolonger dataset 46 drugs 22% of NDAs in the IRT database 34 TQT studies 2 Non-TQT studies 7

8 Approval Status QT prolongers Number of Drugs (N=46) Approval Status 4 Approved (89%) 4 Complete Response (CR) large dose-dependent QTc increase and sudden cardiac death in the study 3 marginal or questionable efficacy Withdrawn How about non-qt prolongers in the IRT database? 77% 8

9 QT Effect Size of Approved Drugs (n=46) 70!!QTc (max) drug Category of!!qtc < 0 ms 0-20 ms > 20 ms Number of drugs Approval %

10 Labeling No of Drugs Mean!!QTc (ms) QT-related boxed warning 3 40 Contraindication 5 8 Warnings and Precautions 25 6 Adverse events Drug-Drug Interaction Overdosage Pharmacology 8 0

11 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 () Medical imaging Neurological 4 Oncology (3 for antitumor) Psychiatry 0 Reproductive and Urologic 2 Transplant and Ophthalmology

12 Antitumor Drugs (n=3) Characteristics Approval Approval year! E4 QT Study (%) Mean!(!)QTc (ms) Number of Drugs 3 (00%) 3 5 (45%) 7.2 Label Boxed Warning 3 Warning and Precaution 9 Pharmacology 2

13 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 (+) 3

14 Psychiatric Drugs (n=0) Characteristics Approval Approval year! E4 QT Study (%) Mean!(!)QTc (ms) Number of Drugs 8 (80 %) 3 5 (50 %) 5.7 Label Boxed Warning 0 Contraindication Warning and Precaution 5 Pharmacology Overdosage 4

15 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 0 ms were labeled with either no or a minimum safety warning in the FDA labeling. 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. 5

16 Questions? 6

17 References Gobburu et al, Creation of a Knowledge Management System for QT Analyses, Journal of Clinical Pharmacology 5, 035, 203 7

18 QT interval, a biomarker of TdP Heart s electrical cycle TQT Study design Baseline Test day Drug QTc Administer Baseline QTc2 Test day Placebo QTc3 Administer time QTc = heart rate corrected QT interval! QTcF (Fridericia) = QT/RR/3! QTcB (Bazett) = QT/RR/2! QTcI (individually corrected)! RR= 60/HR QTC4 Baseline and time matched QTc!!QTc = (QTc2- QTc) - (QTc4- QTc3)!QTc = QTc2- QTc4 8

19 Oncology Drugs (n=) Characteristics Approval Approval year! E4 QT Study (%) Mean!(!)QTc (ms) Number of Drugs (00%) 3 5 (45%) 23.3 Label Boxed Warning 2 Warning and Precaution 8 Pharmacology 9