FDA Perspective

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

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

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 Outline • Draft Guidance • Approved cardiac indications • Extrapolation • Pediatric Drug Use Trends • Safety data • Focus of today

4. 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

5. CDER Mission CDER assures that safe and effective drugs are available to the American people

6. Division of Medical Imaging and Radiopharmaceutical Drug Products • Office of New Drugs • Regulates medical imaging drugs • Contrast agents • Radiopharmaceuticals

7. 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

8. 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

9. 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

10. 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

11. Labeled Cardiac Indications by Drug Class

12. 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

13. 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

14. 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

15. 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?

16. Pediatric Use TrendsChild Health Corporation of America’s (CHCA)Pediatric Health Information System (PHIS) Database Inpatient data from 31 free-standing Children’s hospitals with charge level drug utilization data Strengths • First access to pediatric inpatient drug use data • Children’s 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.

17. CHCA PHIS Database* * represents undercount of actual use

18. 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

19. 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

20. ADULTS >16-95 years Timeframe: 1986-2003 N=2997 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 Adverse Events (AERS)Iodinated Contrast Agents (2 drugs)

21. ADULTS >16-95 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 Adverse Events (AERS)Gadolinium* (2 drugs)

22. ADULTS >16-95 years Timeframe: 1988-2004 N= 334 reports Common Event Types Dermatitis Pruritus Urticaria Nausea Cough Headache Dyspnea Deaths: 16 PEDIATRICS 0 - ≤ 16 years Timeframe:1988-2004 N= 0 reports Common Event Types None Deaths: 0 Adverse Events (AERS) Radiopharmaceuticals (2 drugs)

23. ADULTS >16-95 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 Adverse Events (AERS)Microspheres (2 drugs)

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

25. 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?

26. 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?

27. 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?

28. THANK YOU