Data from a trial of a whole blood substitute that was suspended one year ago, has revealed a higher mortality among patients receiving the substitute than those receiving saline. The substitute, HemAssist, made by Baxter Healthcare was administered to subjects admitted to emergency rooms and experiencing severe blood loss, under a controversial 1996 Food and Drug Administration (FDA) protocol that allows testing without the direct consent of patients. Of four studies operated under this rule, two—including the HemAssist trial—have recently been terminated, renewing concern that individuals are being exposed to risk without informed consent. The dropped trials have also caused anxiety among researchers that corporate sponsors will avoid such studies in the future.
The rule was intended to facilitate research in emergency medicine, in which patients arrive unconscious at hospital and decisions must be made rapidly. Under the system, products can be tested without patients' consent, but only if stringent requirements are met to inform the community about a trial taking place at their local hospital before, during and after it is done. Such a trial is said to be run under a 'no-consent' protocol.
In drafting the rule, regulators hoped to allow companies to develop products specifically for emergency medicine, a field that often relies on off-label use of an established product. "If a drug or biologic or device becomes FDA approved and has been tested in a controlled setting, that doesn't necessarily mean that you can transfer that information to a trauma setting or the battlefield," explains Susan Fish, research director of Emergency Medicine at Boston City Hospital. The no-consent rule provides a testing ground for emergency room products.
And bioethicists contend that the no-consent rule is ethically inappropriate, regardless of its apparent utility. George Annas, Professor of Health Law at Boston University's School of Public Health, argues that when the rule change was debated, "there was no good rationale for doing [emergency medicine] research without consent. In emergency rooms people use this lunatic thing called implied consent, but you don't imply anything by having a heart attack."
Last month, researchers at Mid-Carolina Cardiology, North Carolina, described difficulties encountered in another no-consent trial—testing a CPR vest developed by Cardiologic Systems (Ann. Emerg. Med.33, 224−229; 1999). The cost and difficulty of complying with the tough regulations resulted in the trial's termination despite apparently promising early results. Although Baxter overcame these problems, the negative results meant that the company abandoned development of HemAssist and is now focusing on pre-clinical research of a new blood substitute, the market for which is estimated at $2-4 billion annually.
"I think because of Baxter's experience and the extreme amount of money required to do this type of study ... drug companies are going to shy away from [such] research," says Max Koeningsberg, medical director for the Chicago North EMS system and a leading investigator on the HemAssist trial.
FDA senior policy analyst, Bonnie Lee, says that the agency has an ongoing review of the regulations, but substantial alteration to this rule in the near future is unlikely: "I have heard that the rule is too burdensome. We certainly didn't mean for it to be easy—its purpose is to protect subjects." Different regulations must be applied to emergency situations, explains Lee. "If my child has been in a car accident and is bleeding profusely, you need to intervene as quickly as possible whether I'm there to sign a form or not," she says.
