Blood-substitute tests proceed without informed consent.

Patient advocates and medical ethicists are questioning the ethics of an ongoing clinical trial testing a blood-substitute product on hundreds of trauma patients without their consent. The FDA granted Northfield Laboratories, Inc., the maker of PolyHeme, permission to conduct its Phase III clinical trial under an exception to the informed consent rule for emergency research.

The product is made from hemoglobin and is compatible with all blood types. It has a shelf life of more than a year, whereas blood lasts about 42 days. Northfield, based in Evanston, Illinois, says PolyHeme has the potential to save lives, especially in places where blood is not readily available, such as on the battlefield and in ambulances, which typically use saline.

A regulation in effect since 1996 allows research without informed consent if "subjects are in a life-threatening situation, available treatments are unproven or unsatisfactory, and the collection of valid scientific evidence ... is necessary to determine the safety and effectiveness of particular interventions."

In the current trial, which began in 2003, PolyHeme is given to people who are bleeding profusely; usually, they are unconscious, so personnel cannot obtain their consent. At the scene of the injury, half the subjects are given saline, and half are given PolyHeme. Once at the hospital, those given saline are switched to real blood, and those given PolyHeme continue to receive it for up to 12 hours.

Institutional review boards (IRBs) at 32 hospitals approved and signed on to the 720-person trial. By late March of this year, about 655 people had been enrolled.

Some medical ethicists have said that once the patient is in the hospital, withholding blood violates ethical and regulatory standards. In an open letter published in the American Journal of Bioethics, three medical-ethics professors wrote that "the waiver should cease to apply as soon as suitable blood is at hand." The in-hospital phase "mimics a 12-hour period without access to typed and cross-matched blood"--a delay that is "either uncommon or unheard of" in these communities. (Ken Kipnis et al., An Open Letter to IRBs Considering Northfield Laboratories' PolyHeme Trial Am. J. Bioethics, May/June 2006, at 1.)

Northfield said in a press release that although providing blood is the standard of care, "it may not be the optimal treatment for the early care of trauma, and PolyHeme is being evaluated as a potential better alternative."

However, "the thought that there might be something better down the road does not make blood either unproven or unsatisfactory," said Leonard Glantz, associate dean and professor of health law at the Boston University School of Public Health. That idea "is no argument for doing research on people who can't give consent." Glantz is a member of the university's IRB, which reviewed the PolyHeme trial and declined to participate in it.

A few participating IRBs have withdrawn. As of April 24, participation at three hospitals was suspended. "The IRBs that approved it should never have approved it," Glantz said.

In the late 1990s, Northfield tested PolyHeme on consenting subjects in nonemergency situations: patients undergoing surgery on aneurysms in their aortas. The company had trouble enrolling enough patients and shut down the trial in 2000.

Critics say the results of that study were not fully disclosed. The Wall Street Journal reported earlier this year that 10 of the 81 people who received PolyHeme suffered heart attacks, and two died; the trial also suggested links to other serious adverse events. Even doctors who participated in the trial knew only what happened to their own patients, according to the report. (Thomas M. Burton, Amid Alarm Bells, A Blood Substitute Keeps Pumping, Wall St. J., Feb. 22, 2006, at A1.)

In response, Northfield issued a press release saying that it reported all data to the FDA and that the adverse events were probably not due to PolyHeme.

As part of the current trial, participating IRBs must conduct "community consultation." At public meetings, community members are told about the PolyHeme trial and that they may opt out by wearing a blue bracelet from Northfield. But critics say these meetings downplay PolyHeme's risks, and it is highly unlikely that someone chosen for the trial would have heard about it and been able to opt out.

"It's easier to recruit people if they don't know they're being recruited," said Vera Hassner Sharav, president of the Alliance for Human Research Protection. She added that the consent some people have given is invalid because they were not informed of the earlier trial's results.

Several shareholders have filed class actions against North field. Both the Securities and Exchange Commission and Sen. Charles Grassley (R-Iowa), chairman of the Senate Finance Committee, have begun inquiries into the PolyHeme trial. Grassley wrote in a March 13 letter to Department of Health & Human Services Secretary Michael Leavitt that Office for Human Research Protections officials had expressed "urgent concerns" about the PolyHeme trial to the FDA.

The company maintains that an independent data-monitoring committee periodically reviewing the trial's safety data has found "no statistically significant trends or safety issues identified to warrant modification."

According to the professors writing in the bioethics journal, "When deaths occur during the critical 12-hour interval when available blood is medically indicated but being withheld, plaintiffs' attorneys may want to scrutinize the records carefully to ground claims of liability."

Subjects rarely know if they have been injured by an experiment, Sharav noted. "They don't realize that being a research subject is very different from being a patient."

Glantz said this distinction is becoming blurred. "This is not a treatment, even though Northfield and the hospitals that have agreed to it think of it as a treatment," he said.

Informed consent is a "personal, individual human right," Sharav said, "but there are always those who can profit from bypassing it."