FDA To Weigh Using Fake Blood In Trauma Trial

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IF THE U.S. NAVY gets its way, hundreds of civilian trauma patients could -- without their consent -- be given a blood substitute that has been linked in other large clinical studies to increases in hypertension, heart attacks and other serious cardiac problems.

The Food and Drug Administration has blocked the new Navy trial three times in the past year, but now is reconsidering after months of jockeying among the Navy, the agency and Biopure Corp., the Cambridge, Mass., maker of the blood substitute.

The agency has scheduled a closed-door hearing for next week on whether the Navy-designed trial can proceed. More than 900 badly hemorrhaging civilian accident victims around the country would be involved, with paramedics giving some the blood substitute, called Hemopure, and others saline solution en route to hospitals.

Such non-consent studies are rare but legal where federal regulators determine there's no practical way to obtain consent, such as when patients are in shock or unconscious. There also must be a reasonable likelihood that individual patients would benefit from the treatment under scrutiny.
Scientists have been hunting for a safe, workable blood substitute for decades. Artificial blood, with oxygen-carrying ability, could eliminate the need to match blood types of donor and recipient in some settings, and enjoy a far longer shelf life than donor blood. It could also reduce the risk of hepatitis or HIV infection, although donor blood has become very safe over the past two decades.

The Navy, which provides all medical care for injured U.S. marines and sailors, has been particularly eager for a workable blood substitute. Donor blood lasts only about 42 days before its oxygen-carrying capacity is diminished, while artificial blood could be stored aboard ships for an estimated three years.

But efforts to develop blood substitutes have encountered safety problems over the years. Some companies have gone out of business or exited blood-substitute research when past efforts failed.

Northfield Laboratories of Evanston, Ill., is nearing completion of a civilian non-consent study involving its own blood substitute, PolyHeme, and 720 trauma patients around the country. In a previous trial of surgery patients, 10 of 81 people who received PolyHeme suffered heart attacks, versus zero of 71 receiving donor blood. Northfield says it doesn't believe its product caused the heart attacks, but the Securities and Exchange Commission and Sen. Charles Grassley, chairman of the Senate Finance Committee, are investigating whether the company properly disclosed those results in federal filings and community meetings. Northfield says it is cooperating with the investigations but declined to comment further. Nine of the original 31 medical centers that agreed to participate in the trial are no longer testing patients with PolyHeme.
Past studies have raised questions about Biopure's Hemopure as well. In 1998, the company began a clinical study comparing its substitute with donor blood in consenting orthopedic-surgery patients. William G. Hoffman, then Biopure's medical director and now director of cardiac-surgery critical care at Massachusetts General Hospital, says he concluded during the study that the blood substitute wasn't working well and was "harmful," and urged Biopure to stop the trial. Edward Jacobs, a Biopure founder and then senior vice president, says the company consulted outside cardiologists and "their opinion was to go ahead."

Evidence from that study, along with a separate study in general surgery patients, linked Hemopure to more complications such as strokes and mini-strokes than donor blood, FDA documents show. Biopure disputes some of the FDA numbers. But in a draft response to the agency, Biopure acknowledges that there were more cases of cardiac arrest, more fluid in the lungs and more hypertension among patients who got Hemopure than those who received donor blood.
Navy officials declined to comment on why they want to conduct a trial with a product that has shown such negative side effects. But in documents submitted to the FDA, the Navy has maintained that a study of trauma patients would be significantly different from the trial with surgery patients. The Navy also argues that the oxygen-carrying capacity of Biopure's product could lower the death rate in trauma patients by 25% versus patients getting saline. "If we could replace saline with the thing that we need most, oxygen-carrying capacity, that would be the best," says the Navy's Surgeon General Vice Admiral Donald Arthur. "Our interest is in field conditions where there is no blood."

Biopure's vice president for medical affairs, A. Gerson Greenburg, says the company's product "has an acceptable safety profile" and that a blood substitute can serve "a societal good whereby you're saving [donor] blood for other people." He says many adverse events in past studies weren't necessarily linked to Hemopure.

The Navy proposed the new study of civilian trauma patients in 2004, saying that conducting such a study in combat wouldn't be practical. Documents show the FDA concluded, based on its review of existing Biopure research on surgery patients, that there were "highly significant differences" showing more "serious adverse events" with Hemopure than with blood. On July 8, 2005, the FDA told the Navy its study couldn't proceed "because subjects would be exposed to an unreasonable and significant risk of injury."

Daniel Freilich, who heads Navy blood-substitute research, responded with a series of letters criticizing the FDA, writing in one that the agency's stance "is not scientifically and clinically rigorous." The Navy also argued that the FDA had permitted Biopure's competitor, Northfield, to pursue its own study with a similar product.

On Oct. 13, Biopure CEO Zafiris G. Zafirelis wrote to Jesse Goodman, director of the FDA's Center for Biologics Evaluation and Research, suggesting that an FDA reviewer wasn't objective and had a possible conflict of interest. In March, the FDA's Dr. Goodman wrote to Mr. Zafirelis that he had assigned three other high-ranking officials to preside over Biopure decisions, according to the people familiar with the matter.
Earlier this year, the FDA scheduled the advisory panel meeting for next week. In an unusual step, the Navy, the sponsor of the proposed research, was able to recommend some doctors to be on the panel. Additionally, two well-known skeptics of substitutes who initially had been named as advisory consultants to the panel -- Charles Natanson, a critical-care specialist with the National Institutes of Health and John Hess, director of the University of Maryland's blood bank -- have in recent weeks been disinvited.