PolyHeme:
Blood-Substitute Study Is 
Criticized by U.S. Agency

THOMAS M. BURTON / Wall Street Journal 10mar2006

A little-known federal agency charged with protecting patients in medical research has expressed ethical concerns about a study of a Northfield Laboratories Inc. blood substitute being given to hundreds of trauma patients without their consent.

Criticism of the 720-patient trial has been mounting from doctors and medical-ethics officials as a key senator is investigating the Northfield trial. Two hospitals participating in the study have suspended enrolling patients in it since a Wall Street Journal story about the study was published Feb. 22.

The federal Office for Human Research Protections [OHRP] has expressed "urgent ethical concerns" to the Food and Drug Administration about the conduct of the trauma study, says Sen. Charles Grassley, the Iowa Republican who is chairman of the Senate Finance Committee. Sen. Grassley declined to elaborate, but committee investigators are planning to meet with OHRP officials today to be briefed on the agency's concerns.

OHRP is the part of the Department of Health and Human Services that monitors research practices in government trials. While the FDA has overseen Northfield's research — and granted the company permission to do the current study without gaining patients' consent — the OHRP has offered criticism of Northfield's latest study.

At issue is a study of the experimental blood substitute PolyHeme, made by Northfield, Evanston, Ill. The artificial blood is being infused into 360 badly injured and hemorrhaging trauma patients, while 360 others get saline solution in the ambulance, then donor blood at the hospital. Few patients will know whether they get PolyHeme or blood and many won't know they are participating.

Northfield previously tested PolyHeme in a study of aneurysm-surgery patients. In that trial, 10 of 81 patients given the blood substitute suffered heart attacks, including two who died. None of the 71 patients on standard therapy, including donor blood, had heart attacks. Northfield halted the trial in late 2001 without completing it.

The company has said the heart attacks and other adverse events — such as heart-rhythm aberrations and pneumonia — could have been caused by an excess of total fluids given to PolyHeme patients. The deaths and heart attacks weren't publicly disclosed by Northfield or most of the hospitals to patients and their communities while publicizing the new study over the past two years. Northfield didn't comment about the OHRP actions.

The FDA allowed Northfield to conduct the new study without getting patients' consent because the agency feels that new therapies that hold promise for improved trauma treatment, such as blood substitutes, can't practically be tested if doctors must wait to ask oft-unconscious patients for permission. The agency also said "regulations provide medical, legal and ethical safeguards for this kind of research endeavor" and that it "will continue to explore how best to guide these kinds of studies."

Sen. Grassley is investigating whether patients in the new study are aware of the previous study's deaths and heart attacks, and whether it's appropriate to conduct the new study without patients' consent.

William Hoffman, chief of cardiac-surgery intensive care at Massachusetts General Hospital and former medical director of Biopure Corp., a blood-substitute company in Cambridge, Mass., says the FDA "should have monitored what went on in the communities in terms of informing people" about deaths and heart attacks.

The new Northfield study is also drawing questions about whether it's ethical to withhold donor blood from study patients when the benefits of PolyHeme are as yet uncertain. In the current issue of the journal Ethics & Human Research, Nancy M.P. King, a social-medicine professor at the University of North Carolina School of Medicine, writes that denying half of the patients blood in the hospital doesn't meet a key FDA criterion for allowing a non-consent trial, which is that standard therapy be "unproven or unsatisfactory."

"In the hospital setting, [donor] blood is neither," she writes along with colleagues from the University of Pennsylvania School of Medicine and the University of Hawaii.

An October 2004 FDA draft document entitled Guidance to Industry also raises questions about whether blood should be withheld from patients. "In the hospital setting," it said, "the use of [a blood substitute] would not be expected to result in a survival advantage over the use of red blood cells."

Northfield said that donor blood "may not be the optimal treatment for the early care of trauma patients, and PolyHeme is being evaluated as a potential better alternative." A spokeswoman said Northfield is "on strong scientific, legal and ethical ground."

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[Related Article]

Army To Partner in 
Trauma Blood Substitute Study

NELIA SCHRUM / Brooke Army Medical Center / Transformation 19jul2005

FORT SAM HOUSTON, Texas – A blood substitute that might save lives on the battlefield will be tested in San Antonio through a research protocol already underway in 22 communities across the nation.

Brooke Army Medical Center and University Hospital are participating in a groundbreaking national clinical trial to evaluate the safety and usefulness of PolyHeme, an oxygen-carrying blood substitute, in increasing survival of critically injured and bleeding patients.

Under the study protocol, treatment would begin before arrival at the hospital, either at the scene of the injury or in the air ambulance, and continue during a 12-hour post injury period in the hospital.

Since blood is not presently carried in ambulances, the use of PolyHeme in these settings has the potential to address a critical unmet medical need for an oxygen-carrying solution where blood is currently not available.

The study will compare the survival rate of patients receiving PolyHeme to that of patients who receive the current standard of care, which is saline solution.

“We are excited to be included in this groundbreaking clinical trial,” said Col. Toney Baskin, an Army trauma surgeon and the principal investigator on the study.

Trauma-related injuries are a leading cause of death among Americans under 45 according to the Centers for Disease Control and Prevention National Center for Injury Prevention and Control, Baskin said.

“Almost one in five trauma patients die from their injuries,” Baskin said. “If we can begin to treat these patients very early with an oxygen-carrying solution and keep their hemoglobin levels up, we might well see more survivors.”

Because the patients eligible for this study are unlikely to be able to provide informed consent due to the extent and nature of their injuries, the study will be conducted under

federal regulations allowing for clinical research in emergency settings using an exception from the requirement for informed consent.

Use of this provision in a study protocol is granted by the Institutional Review Board responsible for approval of the research study if the board finds that patients are in a life-threatening situation requiring emergency medical intervention, currently available treatments are unsatisfactory, potential risks are reasonable, and participation in the study could provide a direct benefit to the patients enrolled.

Baskin said that San Antonio Airlife personnel would use the blood substitute. San Antonio Airlife has a paramedic and a nurse aboard each of their flights bringing trauma patients to facilities like Brooke Army Medical Center.

PolyHeme looks like blood, but only stays in a patient’s system for about 24 hours.

“It can buy you time in a trauma situation,” Baskin said. “But it will not eliminate the need for blood banks.”

He said that current research indicates the product is very safe and that there are no serious adverse events attributable to the use of PolyHeme.

PolyHeme, is a universally compatible, immediately available, oxygen-carrying resuscitative fluid designed for use in urgent blood loss when blood is not immediately available.

PolyHeme has previously been studied in the hospital setting in trauma patients demonstrating an improved survival, according to the Journal of the American College of Surgeons, October 2002.

PolyHeme is manufactured by Northfield Laboratories Inc., of Evanston, Ill. It requires no cross matching, making it immediately available and compatible with all blood types, and has an extended shelf-life of more than 12 months.

source: http://www.defenselink.mil/transformation/articles/2005-07/ta071905a.html 10mar2006