FDA Perspective

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FDA Perspective

• Sally Loewke, M.D.
• Acting Division Director
• Division of Medical Imaging and
  Radiopharmaceutical Drug Products
• CDER/FDA
• February 3 4, 2003

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Use of Imaging Drugs in Conjunction with Cardiac
Imaging Procedures in the Pediatric Population
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Outline

• Draft Guidance
• Approved cardiac indications
• Extrapolation
• Pediatric Drug Use Trends
• Safety data
• Focus of today

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FDA

• Regulatory Agency
• 6 Centers
• CDER Center for DRUGS
• CBER Center for BIOLOGICS
• CDRH Center for DEVICES and Radiologic Health
• CVM Center for VETERINARY MEDICINE
• CFSAN Center for FOODS
• NCTR National Center of Toxicologic Research

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CDER Mission

• CDER assures that safe and effective drugs are
  available to the American people

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Division of Medical Imaging and
Radiopharmaceutical Drug Products

• Office of New Drugs
• Regulates medical imaging drugs
• Contrast agents
• Radiopharmaceuticals

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Contrast Agent

• Medical imaging agent used to improve the
  visualization of tissues, organs and physiologic
  processes by increasing the relative difference
  of imaging signal intensities in adjacent regions
  of the body
• Examples Iodinated agents, Gadolinium,
  Microspheres

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Diagnostic Radiopharmaceutical

• An article that is intended for use in the
  diagnosis or monitoring of a disease or a
  manifestation of a disease in humans and that
  exhibits spontaneous disintegration of unstable
  nuclei with the emission of nuclear particles or
  photons
• Any radioactive reagent kit or nuclide generator
  that is intended to be used in the preparation of
  such an article

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Draft GuidanceDeveloping Medical Imaging Drug
and Biologic Products

• Current Agency thinking
• Indications
• Structure delineation
• Disease or pathology detection or assessment
• Functional, physiological, or biochemical
  assessment
• Diagnostic or therapeutic patient management

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New Drug ApplicationsClinical Assessment

• Components of a Clinical Review for New Drug
  Applications
• Efficacy
• Dose
• Pharmacokinetics
• Clinically relevant endpoints
• Relevant patient population
• Appropriate standard of truth
• Safety
• Identification of major toxicities
• Adverse Event profile
• Risk/Benefit Assessment determines approval

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Labeled Cardiac Indications by Drug Class
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Shift in Perception Regarding Pediatric
Requirements

• Historically Assumption that children were
  little adults
• 1970s Change in thinking
• Today Best Pharmaceuticals for Children Act and
  the Pediatric Research Equity Act

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Extrapolation

• If the course of disease and the effects of the
• drug are similar in adults and pediatric
  patients
• THEN
• FDA may conclude that pediatric efficacy can
• be extrapolated from adequate and well-
• controlled studies in adults, usually
• supplemented with other information obtained
  in
• pediatric patients, such as pharmacokinetic
  and
• safety studies

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Extrapolation When may it not be appropriate?

• Disease is different in etiology, pathophysiology
  and/or manifestations
• Response to therapy is different
• Pathophysiology may be comparable but response to
  therapy not predictably the same in adults and
  children
• Pharmacokinetic parameters are not well-defined
  in adults

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ExtrapolationIs it possible for cardiac disease?

• Differences in the pathophysiology of cardiac
  disease
• Pediatrics congenital heart disease
• Adults atherosclerotic heart disease
• Do differences in etiology and pathophysiology
  affect imaging drug performance?

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Pediatric Use TrendsChild Health Corporation of
Americas (CHCA)Pediatric Health Information
System (PHIS) Database

• Inpatient data from 31 free-standing Childrens
  hospitals with charge level drug utilization data
• Strengths
• First access to pediatric inpatient drug use data
• Childrens hospitals provide information on
  off-label use
• Limitations
• No national projections available
• FDA has drug data beginning in 1999
• No direct link between drug and
  diagnosis/procedure
• Does not capture outpatient use free standing
  imaging centers
• Contrast media or radiopharmaceuticals are
  usually bundled together with the imaging
  procedure and can not be specifically identified.

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CHCA PHIS Database
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Pediatric Safety Data

• Limited knowledge based on few approvals
• Adverse Event Reporting System (AERS)
• Spontaneous and voluntary
• underreporting
• reporting bias
• quality of report
• cannot estimate true incidence rate of events or
  exposure risk

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AERS Search

• Methodology
• Selected specific drugs per drug class
• Combined results
• Most common AEs reported (10 of total or
  greater)
• Deaths
• Search timeframe variable- based on approval dates

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Adverse Events (AERS)Iodinated Contrast Agents
(2 drugs)

• ADULTS
• gt16-95 years
• Timeframe 1986-2003
• N2997 reports
• Common Event Types
• Pruritus
• Dermatitis
• Urticaria
• Deaths 274

• PEDIATRICS
• 0 - 16 years
• Timeframe 1986-2003
• N 68 reports
• Common Event Types
• Urticaria
• Dyspnea
• Facial edema
• Deaths 2

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Adverse Events (AERS)Gadolinium (2 drugs)

• ADULTS
• gt16-95 years
• Timeframe 1988-2003
• N 5,163 reports
• Common Event Types
• Urticaria
• Vomiting
• Nausea
• Dyspnea
• Pruritus
• Deaths 108
• No approved cardiac indication

• PEDIATRICS
• 0 - 16 years
• Timeframe 1988-2003
• N 233 reports
• Common Event Types
• Vomiting
• Nausea
• Urticaria
• Deaths 3
• No approved cardiac indication

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Adverse Events (AERS) Radiopharmaceuticals (2
drugs)

• PEDIATRICS
• 0 - 16 years
• Timeframe1988-2004
• N 0 reports
• Common Event Types None
• Deaths 0

• ADULTS
• gt16-95 years
• Timeframe 1988-2004
• N 334 reports
• Common Event Types
• Dermatitis
• Pruritus
• Urticaria
• Nausea
• Cough
• Headache
• Dyspnea
• Deaths 16

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Adverse Events (AERS)Microspheres (2 drugs)

• ADULTS
• gt16-95 years
• Timeframe 1998-2003
• N 107 reports
• Common Event Types
• Back pain
• Headache
• Deaths 0

• PEDIATRICS
• 0 - 16 years
• Timeframe 1998-2003
• N 0 reports
• Common Event Types None
• Deaths 0

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Conclusions

• Few approvals in the pediatric population
• Limited use data
• Limited safety data
• Differing cardiac disease processes

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Questions for the Panel

• Given the differences in cardiac disease
  processes that occur in adults and children, in
  what cases (if any) can adult data from approved
  imaging drugs be extrapolated to pediatric
  patients in whom cardiac imaging is needed? If
  so, in what cardiac disease states?
• If further studies in pediatric patients are
  needed, please further define the gaps in our
  knowledge regarding imaging agents to be
  evaluated for cardiac imaging applications by
  discussing the following questions
• What imaging agents need further study?
• What populations should be studied?
• What disease states should be studied?
• What endpoints should be used?
• How should a trial be designed?
• How should the standard for comparison be
  defined? Is there a gold-standard?

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Questions for the Panel

• Please discuss the relevance of new developments
  in the field of adult cardiac imaging that may
  have potential application to the pediatric
  population? Can we anticipate the need for
  future drug development for pediatric cardiac
  imaging?

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Focus

• Imaging drugs
• Is there need for additional drug labeling?
• How are these drugs being used in pediatrics?
• For what purpose?
• In what subpopulations?
• How do the imaging results impact management?
• Is extrapolation possible?

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THANK YOU