The development of blood substitutes, also known as oxygen therapeutics, has been rife with controversy and hurdles over the years. The latest installment in this series of difficulties is outlined in a formal Biopure (Cambridge, Massachusetts) protest of a published meta-analysis of a number of hemoglobin-based oxygen carrier (HBOC) trials that indicated a 30% increase in the risk of death and a nearly threefold chance of having a heart attack; it went so far as to suggest that no further Phase III studies be conducted considering these dangers.

Biopure responded with a letter to the Journal of the American Medical Association (JAMA) asking for a retraction and apology for the article, which was published last month.

"But JAMA has now responded, saying they won't publish our letter because it's already been published in the public domain," A. Gerson Greenburg, MD, Biopure's VP of medical affairs, told Medical Device Daily. The letter was posted on the company's web site and copies distributed to the media.

The original JAMA article coincidentally was published during the same week that FDA and the National Institutes of Health held a workshop on HBOCs, during which the JAMA findings were center stage (MDD, May 5, 2008).

"Until the mechanisms and potential toxicities of HBOC products are better understood, patients cannot be placed at unacceptable risk," wrote lead study author Charles Natanson, MD, of the critical-care medicine department in the NIH Clinical Center.

Biopure's oxygenation therapy product, known as Hemopure, consists of hemoglobin that has been taken out of the red blood cells of cattle and then purified, chemically cross-linked for stability and formulated in a balanced salt solution similar to Ringer's lactate. The resulting hemoglobin solutions do not contain any cells.

"Doing a meta-analysis is an excellent idea when you're looking at an individual drug and a collection of analyses over time," L. Bruce Pearce, PhD, Biopure's director of pharmacology and physiology, told MDD. "It's a very good approach for one drug. What fundamentally bothers us is, this is a collection of different drugs in different settings. The authors want to make sweeping generalizations. For all of these different drugs, you have to know that each one is contributing to the risk. You're not guilty by association. That is something that was completely ignored."

"Disturbingly, so convinced are the [JAMA] authors of their conclusions that they have taken upon themselves the dissemination of the work to regulatory agencies and clinicians around the world demanding that Hemopure be withdrawn from clinical use and all investigations with it stopped in the name of protecting the public," Greenburg wrote to the publication. "At the same time, they have widely disseminated and publicized their actions. This is most irregular and in my opinion unethical."

Pearce said the impact on Biopure has been dramatic. "Considering the timing of the article immediately before the workshop this article says to start all over again and don't do anything in humans. The timing couldn't have been worse."

Biopure has four ongoing Phase II trials of Hemopure for these indications: during percutaneous coronary intervention; for patients undergoing coronary artery bypass graft surgery; for use in lower limb amputation resulting from critical limb ischemia; and in-hospital use in trauma patients.

Hemopure [hemoglobin glutamer 250 (bovine)], or HBOC 201, is approved for sale in South Africa for the treatment of acutely anemic surgical patients.

Biopure also is developing Hemopure, with support from the U.S. Navy, for a potential out-of-hospital trauma indication.

Biopure failed to win approval for a Phase III trial for pre-hospital treatment of hemorrhagic shock resulting from traumatic injury a year and a half ago (MDD, Dec. 17/Dec. 18, 2006).

Despite the original JAMA article, Greenburg said there was a general sense at the FDA meeting that, perhaps, the article was inaccurate and overstated. "At the end of the meeting, it was said to proceed with caution. [And that] when blood is not an option, [substitutes] should be looked at very closely."

Synthetic Blood International's (SBI; Costa Mesa, California) President Dick Kiral agreed with that conclusion. "I just came back from the HBOCs meeting in Bethesda," he told MDD at the time (MDD, May 5, 2008). "There seems to be some safety issues and cardiovascular events reported. The FDA will publish a paper looking at the whole thing overall. But the tone of the meeting was don't treat all HBOCs alike,' in response to the fact that JAMA grouped findings about various products."

Greenburg added that for patients with no other options, oxygenation therapy is the only alternative. "Hemapure can assist in prolonging or saving them from their situation. That's to be weighed against no treatment which could result in organ injury from ischemia. When you look at a therapy that has a slight increased risk of MI [myocardial infarction] or death, weighed against survival ... patients make that decision all the time."

In addition to SBI, other companies in the blood substitute sector include Sangart (San Diego), Northfield Laboratories (Evanston, Illinois), Alliance Pharmaceutical (Evanston, Illinois), HemoBioTech (Dallas) and Hemosol (Toronto), which went bankrupt in its attempt to develop Hemolink (MDD, Nov. 28, 2005).