UPDATED CITIZEN PETITION:
Removal of “black box” from ultrasound contrast agent (“UCA”) warnings

I. Introduction

The International Contrast Ultrasound Society (“ICUS”) is a not-for-profit grassroots medical society that is dedicated to advancing the safe and appropriate use of contrast enhanced ultrasound (“CEUS”) imaging to improve patient care and save lives. ICUS members include physicians, nurses, sonographers, scientists, other medical and ultrasound professionals, and members of the general public. Physician members represent a broad range of medical specialties including cardiology (echocardiography), radiology (body imaging including liver and kidney), pediatrics, vascular imaging, internal medicine, gastro-intestinal medicine, emergency medicine, intensive care, obstetrics and gynecology, and others.

CEUS is an enhanced form of diagnostic ultrasound imaging that utilizes UCAs (sometimes also known as “ultrasound enhancement agents” or “UEAs”) to improve the functionality, clarity and reliability of ultrasound scans, thereby helping physicians more accurately diagnose and treat medical conditions and monitor therapy. UCAs are safely and routinely used by physicians throughout the world.

The FDA first mandated boxed warnings on UCA labels in 2007. A boxed warning (or “black box”) is the strongest warning required by the FDA and signifies a significant risk of a serious or even life- threatening reaction that would be out of proportion with the potential benefits of the product. The UCA boxed warnings followed spontaneous reports of a small number of serious adverse events (“SAEs”) that occurred after UCA administration. However, the reported SAEs were not contemporaneously adjudicated and some were later attributed to underlying medical conditions and/or other medication. Since 2007, peer-reviewed publications have consistently shown that UCAs are exceedingly safe, efficacious and save lives. (1)

In response to the growing body of compelling safety and efficacy data, the FDA has narrowed UCA boxed warnings and contraindications, approved a new UCA, and approved the use of CEUS for new indications and new patient populations including children. At present, the boxed warning on all three FDA-approved UCAs is limited to the stated risk of “serious cardiopulmonary reactions, including fatalities.” (2-4)

Since the FDA’s most recent and appropriate actions on UCA product labels, the body of relevant scientific literature has continued to mature and now convincingly shows that UCAs are among the safest diagnostic imaging products available. (1,5-23) In light of these overwhelming safety data, what remains of the warning inside the “black box” cannot be considered evidence-based. Indeed, the continued existence of the “black box” may actually harm patients by deterring judicious UCA use in those most likely to derive a benefit — including critically ill hospitalized patients. (1)

Accordingly, in September 2018, the undersigned, on behalf of ICUS, submitted a Citizen Petition under §§ 502 and 505 of the Federal Food, Drug & Cosmetic Act (21 U.S.C. §§ 352 and 355; “FDCA”). The Petition respectfully requested that the Commissioner of Food and Drugs (the “Commissioner”) remove the boxed warnings from UCA product labels. The Petition also supported continued inclusion of appropriate warnings in the Warnings and Precautions section of UCA labels, without a “black box.” A decision is pending.

The purpose of this Updated Citizen Petition is to provide additional references promulgated since the 2018 ICUS submission so that the Commissioner will have the benefit of the latest available information. This Updated Citizen Petition also calls attention to expanded clinical experience with UCAs globally — including beneficial uses of UCAs for imaging patients suffering from the novel coronavirus. (24) ICUS respectfully requests that the Commissioner consider this Updated Citizen Petition in place of the document submitted in 2018.

We appreciate and share the FDA’s commitment to the best interests of patients. We also recognize that removal of a “black box” requires clinical evidence that risks are less severe than previously thought. This Petition will provide that evidence.

We also note that, following the initial ICUS submission in 2018, virtually every major ultrasound organization, along with numerous individual CEUS experts, filed their own statements with the agency in support of the ICUS Petition and removal of the “black box” from UCA product labels. To our knowledge, not a single statement was submitted in opposition to the ICUS Petition or in favor of retention of the “black box.”

For the full Citizen Petition, please click here

For reference documents to the Citizen Petition, please click on the individual links below:

 Reference_1_Safety With Echocardiographic Contr…

 Reference_2_Prescribing Information for Optison…

 Reference_3_Prescribing Information for Definit…

 Reference_4_Prescribing Information for Lumason…

 Reference_5_Thinking outside the box the ultras…

 Reference_6_Safety of myocardial flash-contrast…

 Reference_7_Safety of Contrast Ultrasound Agent…

 Reference_8_Incidence of adverse events associa…

 Reference_9_Acute mortality in hospitalized pat…

 Reference_10_Acute mortality in hospitalized pa…

 Reference_11_Safety of contrast adminstration f…

 Reference_12_The safety of Definity and Optison…

 Reference_13_Safety of Contrast Agent Use Durin…

 Reference_14_Safety of Contrast in Stress Echoc…

 Reference_15_Safety and efficacy of commerciall…

 Reference_16_Safety of contrast agent use durin…

 Reference_17_A retrospective comparison of mort…

 Reference_18_Administration of Perflutren Contr…

 Reference_19_CaRES (Contrast Echocardiography R…

 Reference_20_Safety of echocardiographic contra…

 Reference_21_The safety profile of perflutren m…

 Reference_22_Acute Mortality in Critically Ill …

 Reference_23_An observational study of the occu…

 Reference_24_Benefits, Open questions and Chall…

 Reference_25_World Federation For Ultrasound in…

 Reference_26_American Institute of Ultrasound i…

 Reference_27_Society for Pediatric Radiology (S…

 Reference_28_Society of Radiologists in Ultraso…

 Reference_29_Society of Diagnostic Medical Sono…

 Reference_30_American Society of Echocardiograp…

 Reference_31_Safety of Contrast-enhanced Ultras…

 Reference_32_Safety of Ultrasound Contrast Agen…

 Reference_33_Retrospective Analysis of Contrast…

 Reference_34_Implementation of echocardiographi…

 Reference_35_Impact of Contrast Echocardiograph…

 Reference_36_Improved efficiency and diagnostic…

 Reference_37_American Society of Echocardiograp…

 Reference_38_American Society of Echocardiograp…

 Reference_39_IAC Adult Echocardiography Standar…

 Reference_40_Appropriate Use Criteria for Echoc…

 Reference_41_Transcript for the May 2nd 2011 Jo…

 Reference_42_Retrospective analysis of the safe…

 Reference_43_Safety of Sulfur Hexafluoride Micr…

 Reference_44_Meta-analysis of adverse cardiovas…

 Reference_45_Safety and feasibility of contrast…

 Reference_46_The FDA and New Safety Warnings.pdf

 Reference_47_Complement activation related pseu…

 Reference_48_Implementing a liver contrast prog…

 Reference_49_Apical Pseudoaneurysm Following Co…

 Reference_50_Paediatric Contrast-enhanced ultra…

 Reference_51_FDA warns that gadolinium based co…

 Reference_52_Improving Diagnosis in Health Care…

 Reference_53_Highlights of a Report From the Na…

 Reference_54_Use of CEUS LI-RADS for the Accura…

 Reference_55_Contrast-enhanced ultrasound imagi…

 Reference_56_Resolution of indeterminate MRI wi…

 Reference_57_Contrast-enhanced US in Local Abla…

 Reference_58_Contrast-Enhanced Ultrasound for t…

 Reference_59_Carotid Intraplaque neovasculariza…

 Reference_60_Recommendations for the Assessment…

 Reference_61_Incidence of PFO in 1000 consecuti…

 Reference_62_Authors’ Reply to Letter. Role of …

 Reference_63_Role of Contrast-Enhanced Ultrasou…

 Reference_64_Federal RegistryJuly 6 2020.pdf

 Reference_65_A Practical Approach to Contrast E…

 Reference_66_FDA requires removal of some presc…

 Reference_67_Implications of Removing Rosiglita…

 Reference_68_FDA removes Boxed Warning about ri…

 Reference_69_Guidelines and Good Clinical Pract…

 Reference_70_The EFSUMB Guidelines.pdf

 Reference_71_Healthy Innovation Safer Families …