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