Cardiac Safety in Oncology Therapeutic Drug Development: Science of Oncology Symposia

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Cardiac Safety in Oncology Therapeutic Drug
DevelopmentScience of Oncology Symposia

• Christopher H. Cabell MD MHS
• Duke Clinical Research Institute
• January 3rd, 2006

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Outline

• Cardiac Safety and the FDA
• Cardiac Safety in Oncology Trials
• Evaluation of Non-Cardiac Drugs
• ICH E14 and Oncology Drugs
• Integrated Cardiac Safety Assessment

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Outline

• Cardiac Safety and the FDA
• Cardiac Safety in Oncology Trials
• Evaluation of Non-Cardiac Drugs
• ICH E14 and Oncology Drugs
• Integrated Cardiac Safety Assessment

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Cardiac Safety of Non-Cardiac Drugs
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FDA Focus on Safety
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Post-Marketing Safety Commitments

• 80 NDAs require a post-market study
• Post-marketing study commitments
• 1330 to date
• 65 have not been started

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Safety and the FDA
Dr. David Graham, FDA
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Slide Courtesy of Janet Woodcock, MD Acting
Deputing Commissioner of Operations - FDA
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FDADrug Approval
Okie S, NEJM.20053521063-6.
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PDUFA strengths

• 77 increase in the number of review staff
• Dramatic shortening of review time
• Priority 14.9 6.7 months
• Normal 27.2 23.1 months
• Better science and more reviewers in the
  pre-market review process
• Safety not originally part of PDUFA
• Until 2002 ? money could not be spent on safety
  issues

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PDUFA Critics

• Impartiality impaired
• Pharma is customer
• Scientific debate discouraged
• GAO report
• Shifting of funding away from other activities
• Post-marketing safety surveillance
• Increased workload
• High turnover rates
• Reduced training

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HHS Inspector GeneralFDA Survey 2002

• Push to approve
• 18 of staff felt pressure to approve
• Concerns on safety, efficacy, or quality
• Priority reviews
• 58 said not enough time to conduct an in-depth,
  science-based review

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Safety and EfficacyDiametrical Opposition

• Efficacy
• Faster studies
• Surrogate markers of outcome
• Lower budgets
• Safety
• Long term studies in target populations
• Very large to detect small signals
• Expensive

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The EnvironmentCardiac safety

• Drugs pulled from the market
• Rofecoxib Oct 2004
• Cisapride Jul 2000
• Grepafloxacin Nov 1999
• Astemizole Jun 1999
• Sertindole Dec 1998
• Terfenadine Feb 1998
• Increased regulatory demands
• S7A, S7B, E14

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Guidance Documents

• S7A
• Safety and Pharmacology Studies for Human
  Pharmaceuticals
• S7B
• Safety Pharmacology Studies for Assessing the
  Potential for Delayed Ventricular Repolarization
  by Human Pharmaceuticals
• E14
• Clinical Evaluation of QT/QTc Interval
  Prolongation and Proarrhythmic Potential for
  Non-Antiarrhythmic Drugs

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Outline

• Cardiac Safety and the FDA
• Cardiac Safety in Oncology Trials
• Evaluation of Non-Cardiac Drugs
• ICH E14 and Oncology Drugs
• Integrated Cardiac Safety Assessment

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Cardiac Safety in Oncology Trials

• Risk of death due to malignancy ?100
• small risk of torsade even if not precisely
  defined
• New agents designed to replace older drugs
• having other frequent significant toxicities
• Eligibility concomitant med restrictions
• not acceptable in oncology trials
• Expectation for disease control even in Phase 1
• extended placebo dosing, crossover, washout not
  acceptable

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Emerging Requirements for Cardiac Safety Testing

• Advantages for most therapeutic areasDefinitive
  QTc effect established early in healthy
  volunteers
• Uniform methods enable cross-product comparisons
• Monitoring requirements defined for later
• Dilemmas for oncology
• Impact of QTc prolongation not well established
  for oncology
• Therapies not suitable for testing in healthy
  volunteers
• Placebo / positive control trials difficult
• Patients want active therapy
• Co-morbidities, con meds, etc. confound results

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Assessing Cardiac SafetyKey Questions for
Oncology

• When Comprehensive Testing is Necessary?
• What is the Optimal Strategy?
• What is the Best Design?

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Outline

• Cardiac Safety and the FDA
• Cardiac Safety in Oncology Trials
• Evaluation of Non-Cardiac Drugs
• ICH E14 and Oncology Drugs
• Integrated Cardiac Safety Assessment

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Clinical TrialsOverall Approach

• Drugs are expected to receive a clinical
  electrocardiographic evaluation, beginning early
  in clinical development, typically including a
  single trial dedicated to evaluating their effect
  on cardiac repolarization (Thorough QT Study)

ICH E14
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Utility of a TQT Clinical Development Lifecycle

• Comprehensive Cardiac Risk Assessment
• Not about approvability
• Negative TQT
• Collection of on-therapy ECGs in accordance with
  the current practices
• Positive TQT
• Expanded ECG safety evaluation during later
  stages of drug development

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ICH E14 GuidanceTiming in the Clinical
Development Lifecycle
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TQT in the Clinical Development Lifecycle

• Is a thorough QT study always required?
• Yes, almost always
• New drugs with systemic bioavailablity
• Approved drugs
• New dose, new route ? ? Cmax
• New indication, new population
• No, rarely
• Inability to study healthy volunteers / patients
• Still need cardiac safety data

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What is the optimal timing?

• Early in clinical development
• Usually not the first study
• Timing depends on
• How early need to know QT effects
• Data needed to design QT study
• Pre-clinical signal
• Other expected developmental issues
• PK, PD, efficacy, safety
• Presence of backups / competitors
• Prior to Phase III initiation

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What does a TQT Look Like?

• Healthy volunteer
• Phase I type
• Specifically powered for ECG endpoints
• ??QTc of 5-10 msec
• One-sided a to exclude gt 10 msec ?
• At least 4 arms (parallel or x-over)
• Drug at target dose
• Drug at supratherapeutic dose
• Placebo
• Positive control

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TQT 4 ArmsTarget / Supra-therapeutic

• Target dose
• Based on Phase IIa / POC
• Assess concentrations beyond the expected
  therapeutic range
• A dose that is substantial multiples of the
  anticipated maximum therapeutic exposure
• Supratherapeutic dose
• Use metabolic inhibition
• 5-10 x (maximally tolerated / safe)

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TQT 4 ArmsPlacebo / Positive Control

• Placebo
• Needed for placebo correction (??QTc)
• Minimize bias
• Positive control
• Moxifloxacin, ibutilide, sotalol, other
• Assay sensitivity

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Definition of a Negative Study

• Clinical Definition
• The largest time-matched difference from placebo
  is around 5 msec or less
• Statistical Definition Rejection of HO
• HO ?max 10 msec
• HA ?max lt 10 msec
• ?max largest time-matched mean difference from
  placebo

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Outline

• Cardiac Safety and the FDA
• Cardiac Safety in Oncology Trials
• Evaluation of Non-Cardiac Drugs
• ICH E14 and Oncology Drugs
• Integrated Cardiac Safety Assessment

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ICH E14 and Oncology Survey of growing impact on
oncology drug development programs
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Design Tree for Cardiac Safety Testing in Oncology
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Baseline QTc Eligibility RequirementsEmerging
inconsistencies for protocols and patient care

• 500 ms Grade 3 per CTCAE v3.0 used in NCI
  Depsipeptide phase 1 program
• 490 ms Used by some sponsors
• 470 ms - Grade 2 per CTCAE v3.0
• 460 ms Used by some sponsors Criteria to
  resume treatment in arsenic trioxide (Trisenox
  label)
• 450 ms Females in non-oncology studies cutoff
  across genders in some oncology studies
• 430 ms Males in non-oncology trials

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Distribution of Individual QTc Values in Healthy
Volunteers and Patients with Advanced Cancer
Sarapa et al, Risk management and eligibility
criteria for QTc assessment in patients with
advanced cancer, Proc. ASCO, 2005
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Implications of Conservative QTc Rules applied
to oncology studies patient care

• If 450 msec - defines QTc level of concern
• 10-15 (or more) cancer patients excluded from
  access to new anticancer agents
• Oncology treatments are reduced
  or stopped

Varterasian et al, Baseline QTc and eligibility
for clinical trials in oncology. J. Clin. Oncol.
213378-3379, 2003Sarapa et al, Risk management
and eligibility criteria for QTc assessment in
patients with advanced cancer, Proc. ASCO, 2005
(abstract 3047)
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QTc AssessmentAdministration of Cancer
Treatments

• ZD6474 (Astra Zeneca) - an investigational
  anticancer agent with promising antitumor
  properties
• 300mg achieves target efficacious exposure
• Protocol dose reductions based on QTc
  changesConservative rules similar to ICH E14
  precedents
• QTc prolongation seen in 4 patients (7) dosed
  up to 300 mg ? so dose reduced by 50 in 2 pts
  (to subtherapeutic?)
• Patients tolerate reduced dose w/out QTc
  prolongation- Unintended consequences
  Both given subtherapeutic exposure?

Reference Holden SN et al, Annals of Oncology,
May 19, 2005
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NCI Common Terminology Criteria for Adverse
Events (CTCAE v3.0)
Grade 5 Fatal outcome

• QTc of major concern (Grade 3)
• Higher than ICH E14
• Not defined by change 60 msec

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Proposed Eligibility and Dose Reduction Criteria
for Oncology
When appropriate, patients with prolonged QTc can
still receive treatment at same dose - with
additional monitoring
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Schema of Dedicated QTc Study in Oncology

• Goal to characterize QTc after high exposures
  that are expected peri- or post-approval.
  gtValue when PK-PD not characterized in early
  development, e.g. granisetron
• Similar to TQT moxifloxacin quality ECG PK
  conditions
• Different from TQT Broader eligibility 1-day
  placebo uniform granisetron re-dosing
  extended treatment analysis employs mean change
  and categorical/outliers by CTCAEv3.0

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E14 ComplianceQTc Data Collection
Patient Access Risk-Benefit Considerations

• QTc assessments in oncology are challenging
• Risk management considerations needed -
  in addition to costs

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Cardiac Safety in Oncology TrialsBeyond QT
Assessment

• Antimetabolites
• CHF, ischemia, arrhythmias
• Biologic response modifiers
• Arrhythmias, CHF
• Differentiation agents
• Ischemia, prolonged QT
• Antibodies
• CHF, arrhythmias
• Hormones
• vasospasm

• Anthracyclines
• Cadiomyopathy, pericarditis, SVT, ectopy
• Topoisomerase inhibitors
• Vasospasm, ischemia
• Alkylating agents
• CHF, heart block
• Microtubule-targeting drugs
• Ischemia, CHF, AV block

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Outline

• Cardiac Safety and the FDA
• Cardiac Safety in Oncology Trials
• Evaluation of Non-Cardiac Drugs
• ICH E14 and Oncology Drugs
• Integrated Cardiac Safety Assessment

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Integrated Cardiac Safety Assessment

• Compound evaluation
• Protocol designs
• ECG testing
• Imaging (Echo, Cardiac MRI)
• Execution
• Clinical data integration
• Data management
• Statistics
• Event adjudication (CEC)
• Safety surveillance
• Regulatory submission

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Cardiac Safety Critical Path InitiativePublic
Private Partnership
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Cardiac Safety At Duke
Duke University
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Therapeutic Areas

• Cardiology
• ACS
• MI
• Heart failure
• Devices
• Drug Device
• Infectious disease
• Oncology
• Pediatrics
• Psychiatry
• Respiratory
• Substance abuse

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Experience in Global Support

• Installed base of an international service
  support network
• Actual trial experience in more than 46 countries
  around the world

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Experience Clinical Expertise

• 11 Duke Faculty Cardiologists
• US Board Certification
• Clinical trials experience
• gt 100 years
• Therapeutic expertise
• Arrhythmias / electrophysiology
• Genetic predisposition
• Heart failure
• Ischemia
• Safety surveillance
• Pediatrics

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Technology Multiple Platforms

• Paper ECGs
• Digital calipers
• Digitized paper
• Static ECGs
• Mortara Eli 250
• Continuous 12-lead
• NEMON DR 180
• Mortara H12
• Future
• Phase I Telemetry
• 1Q 2006

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Conclusion

• Cardiac Safety Assessment is Critical Part of
  Drug Development
• New Guidance Documents Exist
• ICH E14
• Oncology Programs have Special Considerations
• Integrated Cardiac Risk Assessment is Necessary

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Cardiac Safety in Oncology Therapeutic Drug
DevelopmentScience of Oncology Symposia

• Christopher H. Cabell MD MHS
• Duke Clinical Research Institute
• January 3rd, 2006