1. CONTRAST AGENTS AND RADIOPHARMACEUTICALS IN CHILDREN WITH CARDIAC DISEASE: SHOULD THEIR USE BE STUDIED? John C. Ring, MD, FAAP, FACC Associate Professor of Pediatrics (Cardiology and Critical Care Medicine) University of Tennessee Health Science Center College of Medicine Member: American Academy of Pediatrics Committee on Drugs United States Food and Drug Administration Center for Drug Evaluation and Research Pediatric Advisory Subcommittee Meeting February 3 & 4, 2004 Rockville, Maryland

2. WHAT WE KNOW ABOUT THIS QUESTION Congenital and acquired heart disease is common in children and of considerable clinical importance. Accurate diagnosis is central to effect a good outcome. The diagnostic use of intravascular contrast agents and radiopharmaceuticals is likely to increase in this patient population. Current use is guided by good intentions rather than data.

3. WHAT DOES THE LITERATURE SAY? Key words utilized –intravascular contrast agents and radiopharmaceuticals –children –cardiac disease –complications Pertinent databases were exhaustively searched –PubMed Medline1950-Present –BIOSIS Preview1969-Present –EMBASE Drugs and Pharmacology1980-Present –CINAHL1982-Present Minimal information was found

4. WHAT DOES THE AAP SAY? “Knowledge is good!” and “Children are not little adults.”

5. CARDIAC DISEASE IMPACTS CHILDREN OF BOTH SEXES AND EVERY ETHNICITY REGARDLESS OF AGE Reported frequency of CHD = 2.03-8.56/1000 (median = 5.93) live births Confirmed cases = 2.03-4.30/1000 (median = 3.99) ACHD: 8,500 children with operated CHD reach adulthood annually (Am.J.Cardiol. 1982; 50: 560-568.) Inflammatory cardiac disease Kawasaki syndrome: 3-3.5 x 103 new cases/year in the U.S. acute rheumatic fever: incidence (U.S.) = 0.5-3.1/100,000 population myocarditis: histopathology in 16-21% of children dying suddenly (JAMA. 1985; 254: 13211325.)

6. THE ULTIMATE COST IS THE CHILD’S POTENTIAL LOST The AAP is “committed to the attainment of optimal physical, mental, and social health and well-being for all infants, children, adolescents, and young adults”. Mission Statement: American Academy of Pediatrics Congenital anomalies are the 5th ranked cause of years of premature mortality in the U.S. (MMWR 1988; 37: 47-48.) structural CHD account for 6/15 most lethal congenital malformations

7. OPTIMAL INTERVENTIONS DEPEND ON GOOD IMAGING Applies to both surgical and catheter- directed procedures Higher risk interventions reduce the “acceptable margin of diagnostic error” Different imaging modalities are complimentary rather than competitive

8. USE OF THESE AGENTS IS LIKELY TO INCREASE The volume of interventional cardiac procedures performed in children is increasing rapidly. 35-60% of catheterizations include an intervention interventional procedures require more/different angiography The number of adult patients with congenital heart disease is burgeoning; thus, the assessment of myocardial function and blood- flow becomes more important. Interventional radiology is increasingly applied to non-cardiac areas of pediatric practice, e.g. embolization of AVM in the CNS and catheter- directed thrombolysis.

9. WHAT PEDIATRIC CARDIOLOGISTS WANT TO KNOW Are non-ionic contrast agents really that safe (or have I just been lucky…or good)? Is there a maximum volume of contrast I can inject safely? Does that change with… –age –lesion/co-morbidities –program of injections? Is there an agent that will give me adequate opacification at lower volumes in large patients? (How can I earn as much as the internists do?)

10. WHY WOULDN’T YOU STUDY THESE AGENTS? Philosophical considerations Practical considerations “Fruits of FDAMA”

11. Pediatric Exclusivity Statistics As of December 31, 2003

12. RECOMMENDATIONS The FDA should exercise its authority to require that studies be performed regarding the use of intravascular contrast agents and radiopharmaceuticals in children with cardiac disease. Contrast studies should focus on dosing considerations, balancing safety concerns with imaging effectiveness. A different regulatory posture may need to be considered in order to study these agents.

13. TO LEARN MORE CONTACT INFORMATION John C. Ring, MD, FAAP, FACC Physician Office Building, Suite P-215 777 Washington Ave. Memphis, TN 38105 901.572.3292 (voice) 901.572.5107 (FAX) jring@utmem.edu