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Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee

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

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  1. Food and Drug AdministrationCardiovascular and Renal DrugsAdvisory Committee Levitra® Tablets (NDA 21-400) (vardenafil HCl) May 29, 2003

  2. Introduction Mary E. Taylor, MPH Bayer Pharmaceuticals Corporation Vice President, Regulatory Affairs North America

  3. Agenda

  4. Consultants

  5. 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

  6. 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

  7. 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

  8. 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

  9. Assessment of the QT/QTc Effect of Vardenafil Thomas P. Segerson, MD Vice President Medical and Scientific Affairs Bayer Canada

  10. 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

  11. 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.

  12. * 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

  13. Frequent Adverse Events* in Placebo-Controlled Phase III Trials * 2% and more frequent with vardenafil than placebo

  14. 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

  15. Human Pharmacokinetics of Vardenafil 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

  16. 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

  17. 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)

  18. 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

  19. 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

  20. 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

  21. 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

  22. Treatments: • 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.

  23. 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

  24. Study 10929/011 Procedures Dose Time (h) 6 ECGs at each timepoint one minute apart Baseline Study 10929/011

  25. QTraw , HR, and QTcF Mean Change from Baseline (SE) 1 hour after Placebo Study 10929/011; n=58

  26. Placebo-Subtracted Mean Change from Baseline (90% CI) for QTraw, HR and QTcF at 1 Hour Study 10929/011; n=58

  27. 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

  28. 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

  29. Placebo-Subtracted Mean Change from Baseline for QTcF and QTci* (msec) at 1 Hour Post-Dose Study 10929/011; n=58 *linear relationship

  30. Placebo-Subtracted Mean Change from Baseline for QTcF at 1 Hour, Tmax, and Maximum QTcF Study 10929/011; n=58

  31. 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

  32. Observed & Population Predicted QTcF versus Vardenafil Plasma Concentration

  33. Summary • 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.

  34. 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.

  35. QT/QTc Study Design, Heart Rate Correction & Risk of Cardiac Arrhythmia Joel Morganroth, MD Clinical Professor of Medicine University of Pennsylvania Chief Scientist eResearchTechnology

  36. Agenda • QT/QTc study design issues • QT correction factor analysis • Clinical relevance of 5 to 10 msec QTc effect

  37. 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

  38. 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?

  39. 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]

  40. 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]

  41. 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]

  42. 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.

  43. 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]

  44. 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

  45. Placebo-Subtracted Mean Change from Baseline for QTc (msec) at 1 hr Post-Dose Study 10929/011;n=58

  46. Population QTc vs HR: Bazett’s and Fredericia Note: data plotted is baseline and placebo data only

  47. Population QTc vs HR: Fredericia and Individual Note: data plotted is baseline and placebo data only

  48. Individual QTc vs HR relationships: Fridericia and Individual Note: Data represents fitted linear relationship for baseline and placebo data only

  49. 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

  50. 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

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