FDA said to have ignored blood-substitute dangers
Signs of heart attack, MI risks were there in 2000
By ignoring red flags of dangers posed to patients subjected to tests of hemoglobin-based blood substitutes (HBBS), the U.S. Food and Drug Administration (FDA) allowed trials to continue when stopping them eight years ago would have saved lives, a blistering report released in April asserts.
HBBS have generated controversy since initial trials in the mid-1990s, and during trials by five manufacturers, evidence emerged that the products are associated with an increased risk of death and heart attack — but the trials continued. The authors of an analysis of studies linking HBBS to the risk of heart attack and death in surgical, trauma, and stroke patients conclude the FDA should send the products back to the animal testing stage. The findings were released online by the Journal of the American Medical Association (JAMA).1
The development of a blood substitute that has a long shelf-life, does not need refrigeration, and doesn't cause infection is a much desired lifesaving option for surgical and trauma patients with shock, particularly in rural areas and military hospitals.
"To date, a large proportion of blood substitutes in development have been hemoglobin-based products. Yet randomized, controlled trials completed as early as 1996 have raised questions about the safety of these products and have failed to demonstrate clinical benefit," writes Charles Natanson, MD, of the National Institutes of Health. "Nonetheless, at least one of these products is approved for use outside the United States and new clinical trials are being conducted or planned worldwide."
Natanson led an analysis of studies linking HBBS to the risk of heart attack and death in surgical, trauma, and stroke patients.
According to the researchers, in 16 trials involving five different blood substitutes and 3,711 patients, there were a total of 164 deaths among HBBS-treated patients and 123 deaths among patients in the control groups. The products, at least one of which is no longer in production, are Hemopure (Biopure Corp., Cambridge, MA); PolyHeme (Northfield Laboratories Inc., Evanston, IL); Optro (Baxter Healthcare Corp., Deerfield, IL); Hemolink (Hemosol BioPharma Inc., Mississauga, Ontario, Canada); and Hemospan (Sangart Inc., San Diego). Overall, the authors report:
- the HBBS products were associated with a 30% increased risk of death;
- there were a total of 59 heart attacks among HBBS-treated patients and 16 heart attacks among patients in the control groups;
- combined, there was a 2.7 times increased risk of heart attack among patients receiving HBBSs.
The authors report the increased risk was not restricted to a particular HBBS or clinical indication. All should be withdrawn from human trials and return to trial in animals for further research, the authors conclude.
"The pattern of increased risk demonstrated by a variety of HBBSs across an array of clinical settings argues for a policy whereby any new or existing HBBSs should be subjected to pre-clinical studies in animal models that replicate the known toxicities of HBBSs demonstrated in humans before further clinical trials of this class of product are allowed to proceed," according to Natanson's group.
No human trials under way in United States
Natanson et al say a lack of timely reporting may have endangered more trial subjects than necessary by allowing repeated trials with the blood agents despite emerging safety concerns.
"Sponsors [of trials] are required by law to report their results to the Food and Drug Administration (FDA) in a timely fashion after studies are completed, even if they do not publish their findings. However, the data reported by sponsors to the FDA are not made public by the FDA unless the product is approved or an advisory committee is convened to discuss the product," the authors explain.
"The cumulative mortality analysis indicates that prompt meta-analyses of the HBBS trials by the FDA most likely would have demonstrated significant risks by 2000. Had the agency placed a moratorium on trials at that point, product-related deaths and [heart attacks] in subsequent trials most likely would have been prevented. However, such data were not available to scientists, the public, institutional review boards, or competing HBBS manufacturers."
Five trials of HBBSs reportedly are ongoing in eight different countries outside the United States and at least one trial is being planned for the United States, according to the JAMA report. The FDA allowed one product, PolyHeme, to be given to 720 trauma patients without informed consent under emergency medical trials monitored by patient safety boards, a move that drew considerable fire during the trial period (which ended in 2006).
Reference
Natanson C, Kern SJ, Lurie P, et al. Cell-free hemoglobin-based blood substitutes and risk of myocardial infarction and death: A meta-analysis. JAMA. 2008;299[19]: doi:10.1001/jama.299.19.jrv80007. Available online at http://www.jamamedia.org).
By ignoring red flags of dangers posed to patients subjected to tests of hemoglobin-based blood substitutes (HBBS), the U.S. Food and Drug Administration (FDA) allowed trials to continue when stopping them eight years ago would have saved lives, a blistering report released in April asserts.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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