1. Public Comments “Favorable Risk-Benefit Ratio of CEUS” Paul A. Grayburn, MD Food and Drug Administration Silver Spring, MD May 2, 2011

2. PAUL A. GRAYBURN MD ICUS Board Member Associate Editor, American Journal of Cardiology Editorial Board, Circulation, JACC, Heart NIH funded clinical investigator NIH study section reviewer for K23-25 grants Qualified to judge clinical contrast echo studies presented today

3. WHAT IS ICUS ? Multidisciplinary Medical Society Cardiology Radiology Vascular medicine GI Hepatology Etc. International membership - 55+ countries Exclusively focused on the use of ultrasound contrast to improve care of our patients worldwide

4. OVERVIEW Post-2007 studies: CEUS agents are safe CEUS agents improve accuracy of diagnosis and change patient management Positive overall risk-benefit ratio Boxed warnings chill use and negatively impact care of our patients

5. ACC/AHA/ASE 2003 GUIDELINES FOR CLINICAL ECHOCARDIOGRAPHY “Echocardiographic contrast agents may improve diagnosis in free wall rupture and in identifying intracardiac thrombus.”

6. CEUS: MURAL THROMBUS Coli S et al. Not so mural thrombus. Circulation 2006;113:e38

7. CEUS: LV Pseudoaneurysm There is a risk to not using ultrasound contrast agents!

8. LV PSEUDOANEURYSM 500,000 STEMI per year in US* 1-6% have LV rupture* Immediate death Pseudoaneurysm formation (high death risk) Treatment is immediate surgery Echo 26% sensitive to detect PSA** Contrast is diagnostic If only 1% have PSA (5000 pts per year) contrast could be mandatory and potentially life-saving in 3750 * ACC/AHA Guidelines; ** Frances et al, JACC 1998

9. ICAEL ECHO LAB ACCREDITATION STANDARDS Intersocietal Commission for Accreditation of Echocardiography Laboratories (ICAEL) New standards issued July 2010, effective December 2010 Conclusion: Ultrasound contrast agents play important role in improving accuracy Recommends and/or mandates use of ultrasound contrast agents in specified circumstances First time CEUS is part of minimal standard of care

10. PROSPECTIVE ANALYSIS: IMPACT OF CONTRAST ECHOCARDIOGRAPHY ON EVALUATION OF VENTRICULAR FUNCTION AND CLINICAL MANAGEMENT IN A LARGE PROSPECTIVE COHORT MUSTAFA KURT, MD, ET AL. DEPARTMENT OF CARDIOLOGY, THE METHODIST HOSPITAL J Am Coll Cardiol, 2009; 53:802-810 (Published online 11 February 2009). © 2009 by the American College of Cardiology Foundation © 2009 by the American College of Cardiology Foundation EXPEDITED PUBLICATION

11. IMPACT OF CEUS ON PATIENT CARE Kurt M, et al. J Am Coll Cardiol 2009;53:802-810

12. CEUS IMPROVED CLINICAL CARE/MANAGEMENT CEUS decreased uninterpretable studies - 11.7% to 0.3% CEUS decreased technically difficult studies - 86.7% to 9.8% CEUS changed therapeutic decisions - 10.4% Additional procedures (usually TEE or nuclear imaging) were avoided, or therapy changed - 35.6% of patients Overall cost savings

13. Khawaja et al. Am J Cardiol 2010;106:742-747 POOLED OR FOR ALL-CAUSE MORTALITY WITH OR WITHOUT ECHOCARDIOGRAPHY CONTRAST AGENTS

14. INCIDENCE OF ALLERGIC/ANAPHYLACTIC REACTIONS WITH ECHOCARDIOGRAPHY CONTRAST AGENTS Studies Patients ReceivingAllergicAnaphylactic Contrast Agent (n) Reactions (n)Reactions (n) Abdelmoneim et al1010,79221 Gabriel et al134,78600 Dolan et al1242,408NANA Shaikh et al152,91410 Main et al1658,254NANA Wei et al1778,38364 Kusnetzky et al1412,47500 Anantharam et al111,15020 Total110,500 11 (0.009%)5 (0.004%) Khawaja et al. Am J Cardiol 2010;106:742-747

15. American Society of Echocardiography Multicenter Registry Retrospective 13-site registry (January 1, 2001-September 30, 2007) 66,164 doses of Definity and 12,219 doses of Optison (5% of transthoracic/28% stress) Severe adverse reactions in 8 patients (0.01%) Anaphylactoid reactions in 4 patients (0.006%) No deaths No SAE in hospitalized patients Conclusions: The incidence of severe adverse reactions to ultrasound contrast agents is lower than, or similar to, that reported for contrast agents commonly used in other cardiac imaging tests. Wei K. et al. J Am Soc Echocardiogr 2008;11:1202-1206.

16. Acute Reactions Acute Hypersensitivity Reactions IgE mediated type I Reaction after repeated exposure Reaction stronger upon repeated exposure Reaction does not cease without treatment Low reaction rate CARPA Reaction possible without prior exposure Reaction milder or absent upon repeated exposure Spontaneous resolution Higher reaction rate Szebeni J. Toxicology 2005:216:106-121

17. REACTIONS TO MMR VACCINE Mild Problems - Fever (up to 1 person out of 6) - Mild rash (about 1 person out of 20) - Swelling of glands in the cheeks or neck (rare) Moderate Problems - Seizure (jerking or staring) caused by fever (about 1 out of 3,000 doses) - Temporary pain and stiffness in the joints (up to 1 out of 4) - Temporary low platelet count, which can cause a bleeding disorder (about 1 out of 30,000 doses) Severe Problems (Very Rare) - Serious allergic reaction (less than 1 out of a million doses) - Several other severe problems have been known to occur after a child gets MMR vaccine. But this happens so rarely, experts cannot be sure whether they are caused by the vaccine or not. These include: - Deafness - Long-term seizures, coma, or lowered consciousness - Permanent brain damage http://www.cdc.gov/vaccines/vac-gen/side-effects.htm#mmr

18. CONTRAST ECHOCARDIOGRAPHY PERCENTAGE OF TOTAL ECHOCARDIOGRAPHY Arlington Medical Resources FDA Black Box Warning

19. Additional CEUS clinical applications Myocardial perfusion imaging Vascular imaging (carotid artery) Liver perfusion imaging Prostate imaging Ovarian, breast, testicular, sentinel lymph node imaging Therapeutic ultrasound: Ultrasound-directed, site-specific drug/gene delivery systems

20. SUMMARY These agents are safe and the boxed warning is not justified by data or by clinical experience These agents benefit patients by improving accuracy of diagnosis Failure to use CEUS in appropriate patients increases the risk/expense of misdiagnosis and alternative testing FDA black box warning decreased use of CEUS, despite guidelines and accreditation standards supporting that this is standard of care FDA should remove the black box warning in the interest of public health