Despite ethical concerns, clinical trial of blood substitute nears completion
By Ted Agres | May 8, 2006
A clinical trial that has been criticized for allegedly violating research ethics and Federal regulations is nearing completion. PolyHeme, an oxygen-carrying resuscitative fluid to treat uncontrolled bleeding, is in the final stages of a Phase III trial at some 30 Level 1 trauma centers in 18 states, and is expected to finish in the coming months.
"We are more than 90% finished. We are past 655 patients out of 720 and are still enrolling patients," said Sophia Twadell, spokeswoman for sponsor Northfield Laboratories of Evanston, Ill. "We expect to done by the end of June."
The trial has drawn criticism from bioethicists because research subjects, who are in hemorrhagic shock at the time of the trial, are not required to give consent.
The FDA approved the PolyHeme study in March 2003 under a 1996 emergency research waiver rule, which lays out a narrow set of circumstances under which Institutional Review Boards (IRBs) can approve research without the informed consent of either incapacitated subjects or their legal representatives. Among other requirements, patients must be in a life-threatening situation when informed consent is not feasible, and available treatments are unproven or unsatisfactory. IRBs must also have previously consulted with community representatives and publicly disclosed that incapacitated individuals can be enrolled without their consent. "Our study meets these criteria," Twadell told The Scientist.
During the study, emergency medical technicians randomly administer either saline solution or PolyHeme to trauma patients in hemorrhagic shock in the field and during ambulance transport. Once in the hospital, those receiving PolyHeme continue to do so unless they or their legal representatives formally withdraw. The control group receives standard blood and saline as required.
The field portion of the trial satisfies the regulations because blood is generally not carried in ambulances, said Nancy M. King, professor of social medicine at the University of North Carolina-Chapel Hill. "But the head-to-head comparison of blood and PolyHeme in the in-hospital portion of the trial is not justifiable according to the regulation," she told The Scientist. "The waiver of consent can only happen when available treatments are unproven or unsatisfactory, and blood is not an unsatisfactory treatment for blood loss."
Twadell, however, contended that recent evidence has cast doubt on early blood transfusions, saying there is a "growing body of evidence that points to the adverse immunomodulatory effects of early blood transfusions in trauma patients."
For the past two years, King and her colleagues have been calling attention to what they consider ethical and regulatory flaws in the PolyHeme trial. Appeals to government regulators and IRBs have been unproductive, "so we decided to do what researchers do: write articles," she said. It appears, however, that the articles have gone largely unheeded.
It's also not clear whether IRBs consulted adequately with community representatives, according to Glenn McGee, director of the Alden March Bioethics Institute in Albany, NY. McGee, editorial board member and columnist for The Scientist, said he and his colleagues surveyed the community surrounding the Albany Medical Center, one of 32 participating facilities nationwide. They found that twice as many people were aware of the trial in Albany than in any other region that had conducted community surveys about the study. "We found a shockingly small number of people knew about the trials" in other communities, McGee told The Scientist. "These studies should be stopped until that discussion has happened."
Still, not all centers are moving forward on the trial. A few, including the Albany Medical Center, have suspended trial enrollment, according to the clinical trial registry. Carl Rosati, the study's principal investigator at Albany, did not respond to requests for comment. Meanwhile, the Senate Finance Committee is seeking to determine whether Northfield and the FDA acted properly, committee spokeswoman Jill Kozeny told The Scientist.
FDA officials did not respond to requests for comment, but sources close to the matter said the agency appears willing to review its guidance on emergency consent waivers in light of the PolyHeme controversy.
email@example.comClarification (posted May 18): When originally posted, the story implied that McGee and his colleagues had found equal rates of informing surrounding communities between Albany and other regions conducting the PolyHeme trial.
Links within this article
Clinical trials listing, Safety and efficacy of PolyHeme in hemorrhagic shock following traumatic injuries beginning in the pre-hospital setting.
K. Kipnis et al, "An open letter to IRBs considering Northfield Laboratories' PolyHeme trial," American Journal of Bioethics, May-June 2006.
Alden March Bioethics Institute
G. McGee, "Salt in the wound," The Scientist, April 1, 2006.
FDA Draft Guidance: Exception from Informed Consent Requirements for Emergency Research (21 CFR 50.24)