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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

Food and Drug AdministrationCardiovascular and Renal DrugsAdvisory Committee

Levitra® Tablets (NDA 21-400)

(vardenafil HCl)

May 29, 2003


Mary E. Taylor, MPH

Bayer Pharmaceuticals Corporation

Vice President, Regulatory Affairs

North America

levitra tablets vardenafil hcl
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
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

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








cardiovascular renal drugs advisory committee topics
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

Assessment of the QT/QTc Effect of Vardenafil

Thomas P. Segerson, MD

Vice President

Medical and Scientific Affairs

Bayer Canada

  • 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
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












10 mg

20 mg

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

NA Pivotal Study 100249

Diabetes Study 100250








Mean EF Domain† Score Change







5 mg

10 mg

20 mg

Treatment Group

†International Index of Erectile Function

*p <0.01 vs placebo

frequent adverse events in placebo controlled phase iii trials
Frequent Adverse Events* in Placebo-Controlled Phase III Trials

* 2% and more frequent with vardenafil than placebo


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

  • Elimination:
  • Hepatic 91-95%
  • Renal 2-6%

Concentration at 24h1 - 2% Cmax


Study 10118, n = 24

human pharmacokinetics of vardenafil and metabolites
Human Pharmacokinetics of Vardenafil and Metabolites

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

Peak concentration of metabolites  50% of vardenafil






14C study (10079), n=4

pharmacokinetic interaction of vardenafil with ritonavir
Pharmacokinetic Interaction of Vardenafil with Ritonavir

Cmax (ng/ml)

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

vardenafil 5mg

vardenafil 5mg & ritonavir*

vardenafil 80mg

Study 100535


Preclinical QT Data

  • 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
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
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

all cause mortality in clinical trials
All Cause Mortality in Clinical Trials
  • 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
Study 10929/011: Effect 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


    • 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
Study 10929/011 Methodology
  • 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
Study 10929/011 Procedures


Time (h)

6 ECGs at each timepoint one minute apart


Study 10929/011

placebo subtracted mean change from baseline 90 ci for qtraw hr and qtcf at 1 hour
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
Individually Corrected QT: QTci
  • 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

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

80 mg


10 mg

400 mg


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
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
Placebo-Subtracted Mean Change from Baseline for QTcF at 1 Hour, Tmax, and Maximum QTcF

Study 10929/011; n=58

qt qtc outlier analysis
QT/QTc Outlier Analysis
  • 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

  • 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
Summary (continued)
  • 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

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

Joel Morganroth, MD

Clinical Professor of Medicine

University of Pennsylvania

Chief Scientist




  • 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
FDA-Health Canada Preliminary Concept Paper: November 2002

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

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?


Managing Sources of QTc Variability

  • 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
Other Aspects of QT/QTc Trial Design
  • 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

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


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]


What Correction Formula Should be Used

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
Which Correction Formula Should be Used to 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]
Placebo-Subtracted Mean Change from Baseline for QTcF and QTci* at 1 hour(Point Estimates of Treatment Effect and 90% CI)

80 mg


10 mg

400 mg


50 mg

moxifloxacin 400 mg

QTcF (msec)

QTci (msec)

Study 10929/011; n=58

* linear relationship

population qtc vs hr bazett s and fredericia
Population QTc vs HR: Bazett’s and Fredericia

Note: data plotted is baseline and placebo data only

population qtc vs hr fredericia and individual
Population QTc vs HR: Fredericia and Individual

Note: data plotted is baseline and placebo data only

individual qtc vs hr relationships fridericia and individual
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
Individual QTci.2 vs HR Relationships
  • 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
QTc Statistical Reporting Issues
  • 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
Results of the Vardenafil QT/QTc StudyI 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
Results of the Vardenafil QT/QTc Study(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
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)


  • 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

  • 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

Moxifloxacin Cardiac Safety: Post-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

Moxifloxacin Spontaneous Reports of

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

Sildenafil FDA AERS Data

Torsades de Pointes:

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


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
What Does a 5 to 10 msec QTc Increase 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
Additional Considerations in the Assessment 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
Conclusions: About Vardenafil
  • 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