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Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee. Levitra® Tablets (NDA 21-400) (vardenafil HCl) May 29, 2003. Introduction. Mary E. Taylor, MPH Bayer Pharmaceuticals Corporation Vice President, Regulatory Affairs North America. Agenda. Consultants.

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Food and drug administration cardiovascular and renal drugs advisory committee l.jpg

Food and Drug AdministrationCardiovascular and Renal DrugsAdvisory Committee

Levitra® Tablets (NDA 21-400)

(vardenafil HCl)

May 29, 2003


Introduction l.jpg
Introduction

Mary E. Taylor, MPH

Bayer Pharmaceuticals Corporation

Vice President, Regulatory Affairs

North America




Levitra tablets vardenafil hcl l.jpg
Levitra® Tablets(vardenafil HCl)

  • Proposed Indication: Levitra is indicated for the treatment of erectile dysfunction defined as the consistent or recurrent inability to attain and/or maintain a penile erection sufficient for sexual performance.

  • Dosage and Administration: 5, 10, 20 mg (starting dose 10 mg) may be titrated up or down


Regulatory history l.jpg
Regulatory History

  • NDA submitted September 2001

  • Approvable letter received July 23, 2002

  • Application is currently under review

  • Approved in 34 countries including the UK, Germany, and 13 other EU countries; Australia; New Zealand; and several Latin American countries


Timeline l.jpg

3/01 HealthCanada

11/02 FDA Concept Paper

12/97 EUGuidance

QT Interval RegulatoryActivities

2/02 ICH SafetyPharmacology

Vardenafil Development

Phase III

7/02 Approvable Action

5/03 Advisory Committee

9/01 Levitra NDASubmitted

3/03 EuropeanLaunch

Timeline

1998

1999

2000

2001

2002

2003


Cardiovascular renal drugs advisory committee topics l.jpg
Cardiovascular & Renal Drugs Advisory Committee Topics

  • Clinical trial design for the assessment of QT/QTc prolongation

  • Approaches to the correction of the QT interval for drugs that affect heart rate

  • The risk of cardiac arrhythmia associated with different degrees of QT/QTc prolongation


Assessment of the qt qtc effect of vardenafil l.jpg

Assessment of the QT/QTc Effect of Vardenafil

Thomas P. Segerson, MD

Vice President

Medical and Scientific Affairs

Bayer Canada


Agenda10 l.jpg
Agenda

  • Background information on vardenafil

    • Pharmacology and mechanism of action

    • Efficacy and adverse event profile

    • Human pharmacokinetics

  • Vardenafil data relevant to QT/QTc assessment

    • Preclinical effects

    • Clinical pharmacology

    • Phase III clinical studies

  • Study to rigorously evaluate the QT/QTc effect of vardenafil


Vardenafil pharmacology and mechanism of action l.jpg
Vardenafil: Pharmacology and Mechanism of Action

  • Vardenafil is a potent PDE5 (phosphodiesterase type 5) inhibitor (IC50 ~1 nM).

  • Vardenafil is highly specific for the type 5 PDE isoenzyme, inhibition of which leads to cyclic guanosine monophosphate (cGMP) accumulation and corpus cavernosum smooth muscle relaxation.

  • Transient effects of vardenafil on BP and HR are consistent with the distribution of PDEs in vascular tissue.


Vardenafil efficacy data in general and resistant to treatment ed populations l.jpg

*

7.8

*

8

5.9

6

4

1.4

2

0

Placebo

10 mg

20 mg

Vardenafil Efficacy Data in General and ‘Resistant to Treatment’ ED Populations

NA Pivotal Study 100249

Diabetes Study 100250

*

*

8.2

7.4

8

*

5.2

Mean EF Domain† Score Change

6

4

1.8

2

0

Placebo

5 mg

10 mg

20 mg

Treatment Group

†International Index of Erectile Function

*p <0.01 vs placebo


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Frequent Adverse Events* in Placebo-Controlled Phase III Trials

* 2% and more frequent with vardenafil than placebo


Slide14 l.jpg

Pharmacokinetic Profile of Vardenafil after Single 20 mg Oral Dose in Men

  • Elimination:

  • Hepatic 91-95%

  • Renal 2-6%

Concentration at 24h1 - 2% Cmax

mean

Study 10118, n = 24


Human pharmacokinetics of vardenafil and metabolites l.jpg
Human Pharmacokinetics of Oral Dose in MenVardenafil and Metabolites

M1, M4 and M5 are deethylation/ demethylation products of vardenafilmetabolism

Peak concentration of metabolites  50% of vardenafil

vardenafil

M1-glucuronide

M5

M4

M1

14C study (10079), n=4


Pharmacokinetic interaction of vardenafil with ritonavir l.jpg
Pharmacokinetic Interaction of Vardenafil with Ritonavir Oral Dose in Men

Cmax (ng/ml)

*interaction assessed on 10th day of ritonavir 600 mg BID dosing

vardenafil 5mg

vardenafil 5mg & ritonavir*

vardenafil 80mg

Study 100535


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Preclinical QT Data Oral Dose in Men

  • In vitro evaluation showed an IC50 of 30 mM for vardenafil, and 47 mM for sildenafil for inhibition of hERG potassium channel, at least 1000-fold above free concentration after maximum clinical dose*

  • No QTc prolongation found in vivo in Beagle dogs:

    • preclinical model as per guideline

    • pattern of vardenafil metabolites similar to human

    • safety pharmacology studies up to 10 mg/kg in anesthetized and conscious Beagle dogs

    • Tested concentrations 100-fold greater than the human exposure (Cmax) to vardenafil after 20 mg and 10-fold greater than exposure to M1 and M4 metabolites

*Sildenafil 100 mg (NDA #20-885 SBA), Vardenafil 20 mg (Study 100196)


Ecg evaluation in vardenafil nda clinical pharmacology program l.jpg
ECG Evaluation in Vardenafil NDA Clinical Pharmacology Program

  • Paired ECGs were obtained in 6 placebo-controlled studies as part of standard safety assessment of doses up to 80 mg

  • These studies were not designed specifically to detect a QT/QTc effect

  • Equivocal changes on QT/QTc were observed with no obvious dose relationship


Slide19 l.jpg
Incidence of Clinical Adverse Events Which May be a Potential Signal for Ventricular Arrhythmia in Placebo-Controlled Phase III Studies

No events of TdP reported in clinical trials with vardenafil


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All Cause Mortality in Clinical Trials Potential Signal for Ventricular Arrhythmia in Placebo-Controlled Phase III Studies

  • Nine deaths in patients before receiving study treatment

  • Seven deaths in completed phase II/III studies*

    • 1 of 1351 on placebo (0.07%)

    • 1 of 164 on sildenafil (0.61%)

    • 4 of 4814 on vardenafil (0.08%)

    • 1 randomized to vardenafil but did not take drug

  • No deaths on vardenafil were assessed as being related to vardenafil treatment.

  • *As of January 2003


    Study 10929 011 effect of vardenafil on qt qtc interval l.jpg
    Study 10929/011: Potential Signal for Ventricular Arrhythmia in Placebo-Controlled Phase III StudiesEffect of Vardenafil on QT/QTc Interval

    • Goal of study to define effects of vardenafil on QT/QTc interval:

      • At therapeutic doses

      • At supratherapeutic doses

      • At plasma concentrations following maximal potential interaction with CYP 3A4 inhibitors

    • Study design discussed and agreed with FDA

    • Performed by Clinical Pharmacology and Statistics, GSK Pharmaceuticals


    Slide22 l.jpg

    • Treatments Potential Signal for Ventricular Arrhythmia in Placebo-Controlled Phase III Studies:

      • Vardenafil 80 mg

      • Vardenafil 10 mg

      • Moxifloxacin 400 mg

    • Sildenafil 400 mg

    • Sildenafil 50 mg

    • Placebo

    Study 10929/011:

    Objectives and Design

    • Primary Objective: Exclude a greater than 10 msec change from baseline 1-hour post-dose on QTcF interval compared to placebo after vardenafil 80 mg

    • Secondary Objectives:

      • change from baseline of QT/QTc versus placebo at Tmax

      • maximal change from baseline of QT/QTc versus placebo over 4 hr

    • Design: Six-way crossover, single-dose, placebo-controlled study. Doses evaluated, period of evaluation, positive control, statistical analysis all agreed with FDA.


    Study 10929 011 methodology l.jpg
    Study 10929/011 Methodology Potential Signal for Ventricular Arrhythmia in Placebo-Controlled Phase III Studies

    • 59 healthy subjects, age range 45-60 years

    • QT interval determined by a validated central laboratory blinded to treatment; manual digital measurements of 3 beat average in Lead II

    • End of T-wave identified by return to baseline (or, if not possible, tangent method)

    • Subjects were non-ambulatory, supine, fasting


    Study 10929 011 procedures l.jpg
    Study 10929/011 Procedures Potential Signal for Ventricular Arrhythmia in Placebo-Controlled Phase III Studies

    Dose

    Time (h)

    6 ECGs at each timepoint one minute apart

    Baseline

    Study 10929/011



    Placebo subtracted mean change from baseline 90 ci for qtraw hr and qtcf at 1 hour l.jpg
    Placebo-Subtracted Mean Change from Baseline (90% CI) for QTraw, HR and QTcF at 1 Hour

    Study 10929/011; n=58


    Individually corrected qt qtci l.jpg
    Individually Corrected QT: QTci QTraw, HR and QTcF at 1 Hour

    • Alternative to fixed approach to heart rate correction (Fridericia, Bazett)

    • Correction based on each subject’s RR-QT relationship

      • Based on placebo and baseline data (n = 138 per subject)

    • Two approaches

      • Linear relationship, QTci = QT + slope(1-RR)

      • Non-linear relationship, QTciX = QT/(RR)x

    • Same analyses performed as for QTcF

    Study 10929/011


    Slide28 l.jpg
    Placebo-Subtracted Mean Change from Baseline for QTcF and QTci* at 1 hour(Point Estimates of Treatment Effect and 90% CI)

    80 mg

    vardenafil

    10 mg

    400 mg

    sildenafil

    50 mg

    moxifloxacin 400 mg

    QTcF (msec)

    QTci (msec)

    Study 10929/011; n=58

    * linear relationship


    Placebo subtracted mean change from baseline for qtcf and qtci msec at 1 hour post dose l.jpg
    Placebo-Subtracted Mean Change from Baseline for QTcF and QTci* (msec) at 1 Hour Post-Dose

    Study 10929/011; n=58

    *linear relationship


    Placebo subtracted mean change from baseline for qtcf at 1 hour t max and maximum qtcf l.jpg
    Placebo-Subtracted Mean Change from Baseline for QTcF at 1 Hour, Tmax, and Maximum QTcF

    Study 10929/011; n=58


    Qt qtc outlier analysis l.jpg
    QT/QTc Outlier Analysis Hour, T

    • No QTraw value  500 msec

    • No QTcF value  450 msec

    • No change in QTcF  60 msec

    • Only one subject (sildenafil 400 mg) with mean QTcF change  30 msec at any time point (average of 6 ECGs)

    Study 10929/011; n=59



    Summary l.jpg
    Summary Plasma Concentration

    • In clinical trials, vardenafil has been shown to be safe and effective for the treatment of erectile dysfunction in men.

    • Preclinical studies with vardenafil do not predict QT/QTc prolongation or arrhythmia at clinically relevant concentrations.

    • In the clinical development program, there was no evidence of TdP.


    Summary continued l.jpg
    Summary (continued) Plasma Concentration

    • A QT/QTc study of vardenafil 10 and 80 mg conducted in accordance with current regulatory guidance demonstrated a 4-10 msec mean maximum QTc prolongation.

    • Vardenafil shortened uncorrected QT duration compared to placebo, whereas moxifloxacin lengthened it.

    • Vardenafil concentrations achieved cover the range following strong metabolic inhibition.

    • The relationship between corrected QT values and vardenafil doses/concentrations is very shallow (2 msec increment with 8-fold increase in dose).

    • Vardenafil effect on the QT/QTc interval is similar to that of sildenafil, an approved drug in the same class.


    Qt qtc study design heart rate correction risk of cardiac arrhythmia l.jpg

    QT/QTc Study Design, Heart Rate Correction & Risk of Cardiac Arrhythmia

    Joel Morganroth, MD

    Clinical Professor of Medicine

    University of Pennsylvania

    Chief Scientist

    eResearchTechnology


    Slide36 l.jpg

    Agenda Arrhythmia

    • QT/QTc study design issues

    • QT correction factor analysis

    • Clinical relevance of 5 to 10 msec QTc effect


    Fda health canada preliminary concept paper november 2002 l.jpg
    FDA-Health Canada Preliminary Concept Paper: November 2002 Arrhythmia

    The document recommends:

    • Robust and valid determination of cardiac risk (QT/QTc duration) using a validated ECG laboratory with specific design recommendations

    • All bioactive compounds should undergo a “definitive” Phase I QT/QTc assessment


    Slide38 l.jpg

    What are the design issues in a “definitive” Phase I QT/QTc trial that should be considered in light of the marked spontaneous variability in QTc duration?


    Slide39 l.jpg

    Managing Sources of QTc Variability QT/QTc trial that should be considered in light of the marked spontaneous variability in QTc duration?

    • Sample size: usually need >30 per arm to detect small QTc effect with adequate power [used 59]

    • Frequency of baseline and on-therapy ECGs to cover maximum concentration of parent and metabolites; diurnal variation [n=18 at baseline and 30 on each therapy at the same time of day]

    • ECG measurement precision: digital process with manual method in a validated core ECG laboratory [done]

    • Population: male and female volunteers

      [all men due to therapeutic use; age 45-60 yrs]

    • Conditions of the ECG recording (e.g., subjects resting, supine, ECG taken before blood sampling) [done]


    Other aspects of qt qtc trial design l.jpg
    Other Aspects of QT/QTc Trial Design QT/QTc trial that should be considered in light of the marked spontaneous variability in QTc duration?

    • Dose ranging (at least 2 doses, one of which is an appropriate multiple of the recommended dose) - no need to study metabolic inhibitors if supratherapeutic dose meets theoretical maximum exposure

      • [1x and 8x recommended starting clinical dose]

    • Control groups: placebo (interpret spontaneous variability) and positive (assay sensitivity)

      • [both done]

    • Correction of QT (Fridericia, population, individual, Bazett)

      • [Fridericia and individual reported]

    • Statistical plan: placebo-corrected, central tendency and outlier analyses

      • [all done]


    Drug specific factors to consider in the design of a qt qtc study l.jpg

    Drug-Specific Factors to Consider in the Design of a QT/QTc Study

    Pharmacokinetics

    to ensure observation period covers Cmax of parent and metabolites [4-hour sampling appropriate]

    to ensure no carryover effects in a crossover trial [PK of parent and metabolites appropriate for crossover]

    Therapeutic use

    single- vs multiple-dose study [single-dose trial appropriate]

    Heart rate effects of drug

    consider special procedures for heart rate correction when drug increases heart rate [QTci analysis done]


    Slide42 l.jpg

    What Correction Formula Should be Used Study

    to Derive QTc from Heart Rate and QT?

    “The traditionally used Bazett’s formula for correction of

    the measured QT interval for variations in heart rates

    (QTc = QT/RR0.50) has limitations for drugs that significantly increase the heart rate.”

    “Although none of the 30 or so formulae available is entirely satisfactory, the Fridericia correction (QTc =QT/RR0.33), or preferably a study-specific derived formula (QTc =QT/RRx), may be more appropriate.”

    Shah Fundamental & Clinical Pharmacology (2002) 16: 147–156.


    Which correction formula should be used to derive qtc from heart rate and qt l.jpg
    Which Correction Formula Should be Used Studyto Derive QTc from Heart Rate and QT?

    • FDA-Health Canada concept paper, November 2002:

      • “...heart rate corrections using individual patient data have been proposed, applying regression analysis techniques to obtain individual pretherapy QT/RR interval data over a range of heart rates, then looking for a change in regression line with treatment.”

    • Practical limitations of this approach:

      • heart rate range at baseline

      • Need for 50-100 ECGs off therapy [combine baselines and placebo in crossover trials]


    Slide44 l.jpg
    Placebo-Subtracted Mean Change from Baseline for QTcF and QTci* at 1 hour(Point Estimates of Treatment Effect and 90% CI)

    80 mg

    vardenafil

    10 mg

    400 mg

    sildenafil

    50 mg

    moxifloxacin 400 mg

    QTcF (msec)

    QTci (msec)

    Study 10929/011; n=58

    * linear relationship


    Placebo subtracted mean change from baseline for qtc msec at 1 hr post dose l.jpg
    Placebo-Subtracted Mean Change from Baseline for QTc (msec) at 1 hr Post-Dose

    Study 10929/011;n=58


    Population qtc vs hr bazett s and fredericia l.jpg
    Population QTc vs HR: Bazett’s and Fredericia at 1 hr Post-Dose

    Note: data plotted is baseline and placebo data only


    Population qtc vs hr fredericia and individual l.jpg
    Population QTc vs HR: Fredericia and Individual at 1 hr Post-Dose

    Note: data plotted is baseline and placebo data only


    Individual qtc vs hr relationships fridericia and individual l.jpg
    Individual QTc vs HR relationships: Fridericia and Individual

    Note: Data represents fitted linear relationship for baseline and placebo data only


    Individual qtci 2 vs hr relationships l.jpg
    Individual QTci.2 vs HR Relationships Individual

    • Analysis conducted by FDA biostatistician

    • Individual correction (linear) based on baseline data only (n = 108 vs. 138 ECGs)

    • QTci.2/HR relationship: applied to both baseline and placebo data

    • Thus, “The more data used the better the QTci”

    N = 59 Patients


    Qtc statistical reporting issues l.jpg
    QTc Statistical Reporting Issues Individual

    • Central tendency

      • Mean change

      • Mean maximal change

    • Categorical analysis looking for outliers

      • % of patients (not observations) with:

        • a change from baseline of 30-60 msec (sensitive) and  60 msec (specific)

        • new value  500 msec

        • new abnormal T-U waves



    Results of the vardenafil qt qtc study i consider the trial to be valid and the results reliable l.jpg
    Results of the Vardenafil QT/QTc Study Individual I consider the trial to be valid and the results reliable

    • Placebo and the positive control, moxifloxacin, behaved as anticipated in the study

      • placebo = 0 msec; moxifloxacin = 8 msec

    • Vardenafil 10 and 80 mg produced 4 -10 msec change from baseline at 1 hr and at Tmax, using QTcF or QTci

    • Shallow dose response (8x starting dose)


    Results of the vardenafil qt qtc study cont d l.jpg
    Results of the Vardenafil QT/QTc Study Individual (cont’d)

    • QT/QTc effects comparable to sildenafil

    • Vardenafil and sildenafil shortened uncorrected QT duration compared to placebo, whereas moxifloxacin lengthened it

    • Outliers

      • None  60 msec

      • No new > 500 msec

      • No subjects on vardenafil and only 1 subject in sildenafil group with > 30 msec change


    Clinical relevance of a drug induced qt qtc effect risk assessment l.jpg
    Clinical Relevance of a Drug-Induced QT/QTc Effect: Risk Assessment

    • Experience with other compounds

      • terfenadine, cisapride, ziprasadone . . .

      • moxifloxacin

    • Post-marketing surveillance data

      • moxifloxacin PMS data

      • sildenafil PMS data (similar QT/QTc effect and same therapeutic class)

    • Regulatory opinions

      • FDA-Health Canada concept paper

      • Medicines Control Agency (EMEA/CPMP)


    Slide55 l.jpg

    Terfenadine Assessment

    • Mean change in QTc across the 12-hour dosing intervala:

      6 msec

    • Mean change in QTc at Tmax (mean maximum change)a:

      18 msec

    • Mean change in the presence of a metabolic inhibitor (ketoconazole)b:

      up to 82 msec

    a Morganroth, et al., Am J Cardiol 72:26B-32B, 1993

    b Honig, et al., JAMA 269: 1513-1518, 1993


    Moxifloxacin l.jpg
    Moxifloxacin Assessment

    • hERG channel blockade at concentrations approaching clinical concentrations

    • Mean maximum QTc effect = 6-10 msec increase (400 mg PO) and a doubling of the effect with 800 mg PO

    • Minimal effect on heart rate

    • Prolongs both QT and QTc


    Slide57 l.jpg

    Moxifloxacin Cardiac Safety: AssessmentPost-Marketing Surveillance

    Two post-marketing observational studies (n ~ 55,000)

    • No cases of Torsades de Pointes

    • No signal of cardiac arrhythmia or a QT interval prolongation-related cardiac rhythm disorder


    Slide58 l.jpg

    Moxifloxacin Spontaneous Reports of Assessment

    Torsades de Pointes as of May 7, 2003

    • Moxifloxacin (19 million patients; 8-day average prescription; 416,000 patient-years): N=12 TdP

      • Oral: 4 US, 4 Europe

      • IV: 3 US and 1 Europe

    • All 12 cases showed marked confounders except 2 oral (1 with no clinical data)

    • Rate of TdP on oral moxifloxacin in US

      • 4 per 7.7 million patients

      • Comparable to other antibiotics (Brinker FDA)


    Sildenafil fda aers data l.jpg

    Sildenafil FDA AERS Data Assessment

    Torsades de Pointes:

    No cases reporteda from launch to December 15, 2002 (data lock)

    Usage:b

    38.7 million sildenafil prescriptions written worldwide from April 1998 to December 2002

    aSpontaneous reports from FDA Adverse Event Reporting System database

    bUsage data from IMS


    What does a 5 to 10 msec qtc increase mean l.jpg
    What Does a 5 to 10 msec QTc AssessmentIncrease Mean?

    • FDA concept paper notes importance of magnitude of mean maximal QT/QTc effect:

      < 5 msec no TdP

      5 - 10 msecno clear risk

      10 - 20 msec some concern

      > 20 msec substantially increased

      • likelihood of being proarrhythmic

  • QT is a surrogate. There is good evidence (dofetilide, sotalol, terfenadine) that the size of the effect relates to risk of TdP, but there could be other properties that mitigate or enhance risk.

  • - Robert Temple, January 2003, Shady Grove Meeting


    Additional considerations in the assessment of the clinical relevance of vardenafil s qtc effect l.jpg
    Additional Considerations in the AssessmentAssessment of the Clinical Relevance of Vardenafil’s QTc Effect

    • The drug is indicated for use in males (risk of drug-induced TdP lower in males)

    • Single dose, used intermittently

    • Shallow dose response for QTc effects

    • Vardenafil tends to increase heart rate


    Conclusions about vardenafil l.jpg
    Conclusions: About Vardenafil Assessment

    • In a definitive QT/QTc trial, vardenafil and sildenafil showed comparable maximum QTci effects on cardiac repolarization of about 5 msec over an 8x dose range

    • This magnitude is generally considered by regulatory authorities as not associated with TdP

    • No clinically significant outliers with vardenafil

    • Post-marketing surveillance data for sildenafil provides no reports of TdP

    • Thus, the QTc effect of vardenafil should not pose a cardiac safety concern


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