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Biopure, Navy Seek Blood-Substitute Study

Posted on: Tuesday, 5 July 2005, 21:01 CDT

Jul. 4--A year after three New England hospitals rejected a controversial test of a blood substitute, the Navy and a Cambridge biotechnology company want to use a similar product on trauma victims.

Like the earlier clinical trial, the proposed new test would equip some ambulance crews with artificial blood for patients bleeding profusely on the way to an emergency room. Some could be given the blood substitute even if they are not alert enough to consent to the treatment.

Military agencies have poured tens of millions of dollars into the research, a potentially huge medical advance that promises to simplify complex blood transfusion procedures in trauma-care settings from emergency rooms to battlefields.

But a year ago, review boards at Boston Medical Center and Massachusetts General Hospital chose not to join the first trial of the blood substitute known as PolyHeme, made by Northfield Laboratories Inc. of Illinois. It is made from modified human hemoglobin, the molecule that carries oxygen from the lungs to other tissue.

Fletcher Allen Health Care, a hospital in Burlington, Vt., also declined to participate.

Twenty other hospitals in cities around the country did sign on and so far have treated 720 patients. Now Biopure Corp. of Cambridge is readying a similar test. In a press release dated June 13, Biopure said Navy medical officials have sought permission from the Food and Drug Administration to test the safety and efficacy of the company's Hemopure, which it calls an "oxygen therapeutic" made from cows' hemoglobin.

Biopure, which faces financial challenges, hopes the study, to be conducted at US hospitals' ambulance services, will help it win FDA approval to market Hemopure.

Alasdair Conn, chief of emergency medicine at Massachusetts General Hospital, which chose not to participate in the first study, said the decision was partly due to an ethical concern: The trial was designed to keep patients on the experimental PolyHeme hours after they could have been switched to blood transfusions. Biopure spokesman Douglas Sayles said the new study is designed so that experimental transfusions could end as soon as patients arrive at the emergency room.

Another consideration, Conn said, was that most of its bleeding patients arrive at the hospital within five to 10 minutes so they can receive standard transfusions. "We've got a small, dense population and good ambulances. Perhaps we're not the right area to test this," he said.

Sayles and a Navy spokesman, Mike Brady, wouldn't say much more about the new trial's protocols or make scientists involved in its design available to answer questions. The subject is too sensitive to talk about yet, said Brady, of the Navy's Bureau of Medicine and Surgery in Washington. An FDA spokeswoman said the agency would not discuss the Navy's proposal or the earlier trial.

Leonard Glantz, professor of health law at Boston University and a member of the Boston Medical Center board that rejected the PolyHeme trial, said he wants more details about the Navy's trial protocols, such as when and why some patients might continue to receive Hemopure after arriving at a hospital.

"There might be a good reason. But if the reason is solely a scientific one, and not related to the welfare of the subject, then I wouldn't be convinced," Glantz said.

All new drugs and medical devices require advanced safety tests before they can be approved for general marketing. However, subjecting patients to medical tests without their consent has led to notorious abuses like the Tuskegee Study, a 40-year experiment in which 399 black syphilis patients in Alabama weren't told they had the disease or offered treatment until the trial was exposed in 1972.

In 1996, the FDA passed rules that allow waivers for research where there is no realistic chance of getting patient approval and the treatment offered major benefits such as in trauma care. The FDA said about 20 trials involving waivers from consent have been approved since that time, though not all of those trials were actually conducted.

One was the PolyHeme trial, begun last year. At a site in the trial, Christiana Care Health System in Wilmington, Del., surgical care director Gerard Fulda said doctors considered the ethical implications of continuing to give patients the artificial blood without their consent for up to 12 hours after the injury, or much later than they could have been switched to regular blood. But studies have shown enough risks with blood transfusions -- a roughly 1 in 250,000 chance of death -- that continuing PolyHeme transfusions might offer a benefit, he said.

Northfield vice president Sophia H. Twaddell said that in a smaller study, Northfield found patients who had got PolyHeme transfusions had lower levels of "immune markers" that seem to indicate risk of organ failure brought on by transfusions.

"We believe there is strong scientific and clinical support for the study design," she said.

The FDA does require companies and hospitals to advertise their trial plans and to investigate alternatives when studies involve waivers of consent. For example, when Detroit's Henry Ford Hospital in 1998 tested LeukArrest -- a drug intended to prevent organ damage during trauma -- on three patients, none were able to sign a waiver. In all three cases, family members were reached within three hours.

In the case of the blood-replacement products, there might not be time to track down family members before it needs to be administered. The average adult has 10 to 12 pints of blood, and the loss of just two pints can send the body into shock. Because wounds can be difficult to close, trauma victims with massive injuries might need transfusions of more than 50 pints. Hospitals nationwide use 32,000 pints a day.

Collecting and distributing blood requires a huge support system and careful screening, making it too complicated to include transfusion supplies in ambulances or medics' backpacks. Most carry only saline, a stopgap measure.

Some new technologies for stanching blood flow have recently come on the market, like the blood-coagulating powder QuikClot, made by Z-Medica of Wallingford, Conn. The company says military doctors credit it with saving 100 lives in Iraq and Afghanistan.

But an artificial blood product would offer more advanced care. Unlike human blood, for instance, Biopure's Hemopure doesn't have to be refrigerated and thus could be easily carried in the field.

The question now is how much detail Biopure and the Navy will have to offer to get their waiver-of-consent trial approved by hospitals, such as the full trial protocol, or specifics about how the study will be conducted. Biopure's Sayles said the company and the Navy haven't decided how much to release, and worry about releasing competitive information.

In the wake of Northfield's experience, ethics specialists including Ken Kipnis of the University of Hawaii say they hope Biopure will disclose its full trial protocols and any reservations that hospitals have about joining in.

In an unpublished paper, Kipnis and others wrote that "When the community will be affected by research, it should be able to review the protocol."

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Source: The Boston Globe

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