In light of the gadolinium controversy: The impact of recent verdict by major regulators
Mak Wen Yao , 17 days ago
MRI contrasts agents are crucial for clearer imaging – but are now under scrutiny in view of the recent issues pertaining its safety and efficacy.
After a year-long review, the European Medicines Agency (EMA) finally suspended three contrast agents used in MRI scans on 21 July 2017. This was due to concerns that a potentially toxic metal in the agents, gadolinium can deposit in the brain tissue. The regulator did not find evidence of harm, but acted to “prevent any risks.”
The contrast agents, collectively known as gadolinium chelates, have been long used as a contrast medium for magnetic resonance imaging (MRI) scans. These chemical agents function as a "dye" that enhances the MRI images for better quality scans and more accurate diagnosis of the underlying condition.
The EMA’s decision means several intravenous linear products – gadodiamide, gadopentetic acid and gadoversetamide – would be suspended within the EU. The review was conducted by the Pharmacovigilance Risk Assessment Committee (PRAC), responsible to appraise post-marketing safety evidence of medicines for human use.
Gadolinium retention in the body
The gadolinium-based contrast agents (GBCA), were thought to be safe and well-tolerated by patients when used according to recommendations. However, in recent years, there is a growing body of evidence that refuted the established safety of GBCA.
More than a decade ago, the contrast agents were also the focus of regulatory reviews and lawsuits filed by patients, as due to existing kidney impairment, they have been placed at risk of developing potentially fatal kidney disease – their kidneys could not excrete gadolinium.
When patients underwent MRI scans and were exposed to GBCA, substantial evidence indicated gadolinium would accumulate in various tissues including the brain, bone and kidneys. The retention of GBCA in these tissues was also cumulative in nature – further increasing the exposure led to increased concentrations in the body.
Free forms of the gadolinium ion are known toxic heavy metals. However, when it is chelated to a carrier molecule, the resultant complex reveals to exhibit little toxicity while retaining the gadolinium contrast properties.
Conventional understanding of GBCA states that the bond between the gadolinium ion and the chelating agent was sufficiently strong – to allow the contrast agents to be removed from the human body as a whole. However, the PRAC review discovered that "linear agents have a structure more likely to release gadolinium, which can build up in the body tissues."
EMA decision stirred controversy
EMA’s decision has received backlash from the vendors of these agents – with many requesting the agency to re-evaluate the evidence. GE Healthcare, which markets Gadodiamide (Omniscan) in Malaysia and Singapore, issued a statement that conveyed the company's disappointment with EMA's recommendation. Another linear contrast agent, Magnevist – marketed by Bayer (also available in Malaysia and Singapore) – further echoed GE’s concerns; but assured that they would delve into “whether there are any clinical implications.”
Singapore’s Health Services Authority (HSA) has also warned against the use of Omniscan or Magnevist in patients with severe renal failure. All other GBCAs were also advised to be used “only when absolutely necessary”.
Given the potential impact of gadolinium retention in the body, the US Food and Drug Administration (FDA) has also launched its investigation into the safety of GBCA. On 22 May 2017, the agency announced that it will maintain the existing recommendation on all GBCAs, including those that are associated with higher rate of retention in the brain.
FDA did not take a parallel course of action with EMA, as no adverse health effect was identified. Although gadolinium was shown to retain within the brain tissue, bone and skin – this evidence was not sufficient to establish a causal relationship with any adverse clinical outcome.
The agency assured to continue monitoring the use of these agents and urged both patients and healthcare professionals to report any side effects associated with the use of GBCA.
Reactions towards the decisions
The EMA’s decision to suspend the marketing authorisation for linear contrast agents has prompted patients and physicians to seek alternative imaging solutions.
As the medical community becomes more aware of the potential for gadolinium bio-retention in the body, the safety of these agents will be put under intense scrutiny. In addition, regional pharmaceutical regulatory bodies are expected to clarify their respective position on this issue in near future – to provide guidance to local healthcare professionals to approach this issue.
However, establishing a direct causal relationship between GBCA and adverse health outcome is also not an easy feat. High-quality data may only become available after several years of investigations. Currently, the risk-adverse medical community is expected to lean towards what the EMA is recommending – and refrain from unnecessary, albeit insufficiently proven, risks to their patients. MIMS
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Sources:
https://www.statnews.com/pharmalot/2017/08/02/ema-fda-mri-scans-dyes/
http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2017/07/WC500231829.pdf
https://www.ncbi.nlm.nih.gov/pubmed/27053146
http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2017/03/news_detail_002708.jsp&mid=WC0b01ac058004d5c1
https://www.fda.gov/Drugs/DrugSafety/ucm559007.htm
http://www.auntminnie.com/index.aspx?sec=ser&sub=def&pag=dis&ItemID=116837
http://www.hsa.gov.sg/content/hsa/en/Health_Products_Regulation/Safety_Information_and_Product_Recalls/Dear_Healthcare_Professional_Letters/2007/Important_safety_warnings_for_gadoliniumbased_contrast_agents_Omniscan_and_Magnevist.html
http://pubs.rsna.org/doi/pdf/10.1148/radiol.2015150805
https://www.linkedin.com/pulse/what-verdict-gadolinium-mri-contrast-agent-mri-scan-group
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