FDA has requested a boxed warning with additional warnings about the risk of nephrogenic systemic fibrosis (NSF) resulting from exposure to gadolinium-based contrast agents (Magnevist, MultiHance, Omniscan, OptiMARK, ProHance) in individuals with acute or chronic severe renal insufficiency. Severe renal insufficiency is defined as a glomerular filtration rate <30mL/min/1.73m2. Investigators who will be using gadolinium as part of MRI studies should ensure that they are appropriately screening participants for potential kidney problems. A properly obtained medical history is generally an adequate screening, but in elderly subjects or those who are cognitively impaired, where a history may be difficult to obtain, it may be necessary to include lab work to test kidney function.
The FDA issued a safety announcement on July 27, 2015 stating that they are investigating the risk of brain deposits of gadolinium following repeated use of gadolinium-based contrast agents (GBCAs) for MRIs, and whether these gadolinium deposits are harmful or can lead to adverse health effects (see: http://www.fda.gov/Drugs/DrugSafety/ucm455386.htm). The announcement states the concern relates to patients who have undergone 4 or more scans. Though it is only under investigation at this time, the Full Board felt that participants in protocols using gadolinium should be informed. To address this issue, the Full Board requests the following:
A) Since the advisory relates the potential risk to individuals who have had 4 or more gadolinium MRI scans, protocols should contain the following exclusion criterion so that likelihood of the total number of lifetime gadolinium MRI scans will remain below 4. For a protocol involving:
1. One gadolinium scan, a history of more than 2 scans with gadolinium should be excluded.
2. Two gadolinium scans, a history of more than 1 scan with gadolinium should be excluded.
3. Three gadolinium scans, a history of any scan with gadolinium should be excluded.
4. Four or more gadolinium scans, the PI would need to justify the risk in light of the evidence prompting the FDA investigation and adjust the eligibility criteria accordingly. However, by implication the Board may not be able to approve it.
B) The Board agreed that the advisory was “significant new information” which may relate to the subject’s willingness to continue participation and therefore must be provided to the subject according to 45CFR46:
Requirements for Informed Consent. Therefore, the IRB is requiring that investigators provide currently enrolled participants with additional information (orally or in writing) regarding the FDA announcement and document this in the participant’s chart.
C) The CF should explain the issue, with language such as “The Food and Drug Administration (FDA) has issued an announcement stating they are investigating a possible risk of adverse health effects from repeated use of gadolinium for MRI. Though the FDA has not reached a conclusion at this time, you should not participate in this study if you have previously had more than (insert # consistent with item (a) above) MRI scan with gadolinium.”
D) A discussion template should be prepared conveying similar information to be the basis for discussion with currently enrolled participants.
E) In order to ensure that individuals are systematically queried about previous gadolinium scans, please operationalize questions to determine whether an individual has had a previous gadolinium scan and add this information to the PSF. For example, individuals should be asked whether they had an MRI with an i.v. injection (i.e., “Did they give you an injection?”) in case people do not know the term “gadolinium.”
F) The Board also considered known risks of gadolinium, namely vomiting and allergic reactions, and determined updated guidelines for the conduct of gadolinium MRI in the NYSPI MRI suite. Allergic reactions are rare, but can be severe. Vomiting is less rare and occurs in about 1% of cases, and provision should be made to promptly remove participants from the scanner to avoid risks of aspiration.
1. The PSF should clearly state who is responsible for safety procedures during the MRI scans, either the MRI unit staff or the study staff. The MRI Center has safety procedures, including management of nausea/vomiting, and management of allergic reactions including assessment of the participant, administration of epinephrine if indicated, and calling emergency response teams if indicated. If the study staff are responsible for overseeing the MRI scan and MRI-related safety procedures, the PSF must indicate that they will be trained by the Medical Director of the MRI Center and his designees and confirm that the study team will abide by the MRI Center Safety Protocol.
2. The MRI CF should state that if a participant feels nauseous during the MRI, he/she should alert the staff immediately. Because vomiting does occasionally occur as an adverse event of gadolinium contrast agents, it is important for a participant to alert staff so that he/she can be promptly removed from the scanner.
3. The MRI CF should also inform participants of the type of symptoms to be aware of if they were to have an allergic reaction to gadolinium. The Hatch MRI center in its guidelines provides such a list to subjects/patients.