Cardiovascular and Renal Drugs Advisory Committee

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Cardiovascular and Renal Drugs Advisory Committee

• Safety Considerations in the Development of
  Ultrasound Contrast Agents
• June 24, 2008
• Dwaine Rieves, MD

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Cardiovascular and Renal Drugs Advisory Committee

• Introduction to Products
• AC Background
• AC Goals

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Introduction to Ultrasound Contrast Agents (UCA)

• Core gas within molecular shell
• Generally lt size of RBC
• Administered IV
• Larger bubbles embolize to lungs
• Other bubbles enter L heart
• Echogenic contrast

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Ultrasound Contrast Agents (UCA)

• Approved use
• LV chamber/endocardial border
• Potential approval goals
• peripheral vessels
• vascularity in organs
• myocardial perfusion
• other?

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Marketed Ultrasound Contrast Agents

• Optison (US)
• albumin perflutren
• Definity (US)
• lipid perflutren
• SonoVue (non-US)
• lipid sulfur hexafluoride

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AC Background 9/2007 US UCA

• 190 reports of patients with serious
  non-fatal events
• hypotension
• dyspnea
• loss of consciousness/seizure
• arrhythmia/cardiac arrest
• otherurticaria, back pain
• 4 deaths within 30 minutes
• General pattern
• underlying chronic conditions
• stress test
• acute unstable conditions

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Other Background Considerations

• Optison (1997)
• off market since 11/2005
• premarket safety database 300
• postmarket exposure (Premier) gt 200 K
• Definity (2001)
• premarket safety database 1700
• unstable patients excluded
• postmarket exposure (Premier) gt 260 K
• PMC to perform a surveillance study of Definity
  as it is used in clinical practice

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• SonoVue (2001, non-US)
• Approved for echo, macrovascular and
  microvascular doppler
• Three fatal AE prompted echo contraindications
• acute MI or certain patients with angina
• acute or class 3/4 cardiac failure
• severe cardiac rhythm disorders
• severe pulmonary hypertension
• ARDS
• Arterial hypotension PA hypertension in pigs
  pattern suggestive of clinical correlate

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Animal Data Species Considerations
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Label Revisions 9/2007

• Boxed warning
• serious cardiopulmonary reactions
• Contraindications
• unstable/high risk patients
• Monitor all patients
• during for 30 minutes post-test
• EKG/oxygen saturation

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Following 9/2007 Label Revisions

• Physician concern re
• contraindications
• monitoring plans
• Published data
• no PA alterations in humans
• limited details
• Developed risk assessment management plan
  (RMP)
• Update labels

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2008 Label Changes RMP

• Altered boxed warning
• Prior contraindications
• Monitoring focused on
• high risk patients
• RMP
• HCP education re risks/usage
• New studies required under FDAAA
• Pulmonary hemodynamics
• Observational study of critically ill

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AC Goals

• Visibility/shared experience
• Sponsor summary of experience
• Identify lessons learned
• Stimulate discussion/education
• Identify essential considerations for future
  preclinical clinical development
• Anticipate future discussion of imaging
  products
• Unique efficacy for diagnostics
• Unique study designs

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AC Concepts

• We are not focusing upon
• any specific contrast agent
• any recommendations for specific regulatory
  action
• We are focusing upon shared
• experiences from companies
• perspectives from AC members

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Agenda

• Dr. Sanjiv Kaul Clinical
• Dr. Robert Hamlin Preclinical
• Bracco Imaging SonoVue
• Break
• GE Healthcare Optison
• Lantheus Medical Imaging Definity
• OPH
• FDA introduction to questions
• Discussion