The FDA has just accepted Bayer Schering Pharma's New Drug Application for Gadovist, a gadolinium-based contrast agent currently sold in Europe and other parts of the world, but not in the United States.  A New Drug Application is the procedure a drug company uses to formally request the FDA to allow it to sell a drug in the United States.

Although Bayer's application for Gadovist is new, Gadovist itself is not.  Gadovist has been approved for sale in the European Union since 1998.  However, until recently, Bayer has not sought approval for selling it in the United States.  This decision  --  whatever its basis  --  has put Americans at risk.

Gadovist has a macrocyclic molecular structure, which means the gadolinium ion is surrounded by an organic chelate.  In contrast, Magnevist, the Bayer contrast agent sold in the United States, has a linear ionic molecular structure.  Magnevist's molecular structure is less stable than Gadovist's macrocyclic structure.  As a result, European regulatory agencies recognize than Magnevist is less safe than Gadovist.  The EU equivalent of the FDA requires the Magnevist label to state that it is contraindicated (not recommended) for use on people with severe renal impairment.  Gadovist does not have this restriction.

In May 2007, the FDA ordered all manufacturers of gadolinium-based contrast agents to warn of the risk of Nephrogenic Systemic Fibrosis (NSF) for people with kidney disease.  However, the FDA considered specifically targeting General Electric product Omniscan and recommending that it never be used on people with kidney failure.

The current warning required for gadolinium-based contrast agents applies to all brands of gadolinium-based contrast agents.  The warning does not state that gadolinium-based contrast agents should never be used for patients with renal failure, just that they only should be used if the diagnostic benefits outweigh the risk of developing NSF.

However, one FDA staff member recommended more.  In a recently released FDA document, FDA staff member Dr. Louis Marzella stated that “a contraindication for Omniscan is warranted in patients with severe renal insufficiency.”  The term “contraindication” means a recommendation against using a specific medical treatment under certain circumstances.

In the United States, GE’s product Omniscan has an approximately 30% market share of gadolinium-based contrast agents.  Bayer HealthCare’s product, Magnevist, is the market leader, with a 50% market share.  But despite Omniscan’s smaller market share, in the data reviewed by the FDA in 2007, there were nearly twice as many incidents of NSF among people treated with Omniscan as there were for people treated with Magnevist.

The optimistic sounding conclusion of a recent study on the safety of gadolinium-based contrast agents is misleading to the extent it fails to address the risk of Nephrogenic Systemic Fibrosis (NSF), also known as Nephrogenic Fibrosing Dermopathy (NFD).  The study, published by members of the Department of Radiology at the Mayo Clinic, concludes that “gadolinium contrast agents are associated with a very low rate of adverse effects.”  Hunt, et al., Frequency and Severity of Adverse Effects of Iodinated and Gadolinium Contrast Materials: Retrospective Review of 456,930 Doses, AJR: 193, October 2009.

This conclusion masks the fact that occurrences of NSF were not counted as part of the study.  Incidents of NSF were not counted because the study defined “adverse effects” to only include side effects that occurred during or immediately after administration of the gadolinium-based contrast agent.

The study reports that of 158,439 doses of gadolinium contrast agents between 2002 and 2006, there were only 64 “cases of adverse effects” for gadolinium.  But the devil is in the details, in this case the study’s definition of “adverse effect”:  “Adverse effect was defined as a reaction occurring in the radiology suite during contrast administration or within 30 minutes of administration.” (Emphasis added)

This definition means that cases of NFS were not even considered in the study.  Why?  Because the symptoms of NSF appear later than 30 minutes after the administration of the gadolinium-based contrast agent.  Generally, NSF symptoms appear between several days and several months after injection of a gadolinium-based contrast agent.  Indeed, symptoms have been documented as appearing as long as 18 months later.

Even the cause of NSF does not occur within 30 minutes after administration of the gadolinium-based contrast agent.  This is because for a person with normal functioning kidneys, the contrast agent flushes out in approximately 90 minutes.  On the other hand, the people who contract NSF are those who still have the contrast agent in their system several hours later, when the gadolinium-based contrast agent begins breaking down.  It is only at this point, well after the 30 minute post-administration period considered in the study, that the toxic gadolinium is dispersed throughout the body.