The Impact of Drug-Related QT Prolongation on FDA Regulatory

Decisions

Eunjung Park, Ph.D.

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Drug Indication Year withdrawn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

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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.

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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 200 NDAs reviewed through 2013 •  No drug withdrawn for QT-related proarrhythmia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

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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.

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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.

•  QT prolonger dataset – 46 drugs

•  22% of NDAs in the IRT database •  34 TQT studies •  12 Non-TQT studies

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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%

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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

0

10

20

30

40

50

60

70

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46

drug

QTc

(max

)

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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

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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%)

Mean ()QTc (ms) 17.2

Label

Boxed Warning 3

Warning and Precaution 9

Pharmacology 1

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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 (+)

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Psychiatric Drugs (n=10) Characteristics Number of Drugs

Approval 8 (80 %)

Approval year E14 3

QT Study (%) 5 (50 %)

Mean ()QTc (ms) 15.7

Label

Boxed Warning 0

Contraindication 1

Warning and Precaution 5

Pharmacology 1

Overdosage 1

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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.

•  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.

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Questions?

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References

•  Gobburu et al, Creation of a Knowledge Management System for QT Analyses, Journal of Clinical Pharmacology 51, 1035, 2013

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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

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Oncology Drugs (n=11) Characteristics Number of Drugs

Approval 11 (100%)

Approval year E14 3

QT Study (%) 5 (45%)

Mean ()QTc (ms) 23.3

Label

Boxed Warning 2

Warning and Precaution 8

Pharmacology 1

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