Efforts to create an artificial blood substitute to prolong life for wounded soldiers or car crash victims were set back Monday by a study saying the products have led to a 30% increase in the risk of death and a nearly threefold chance of having a heart attack.
The findings in the Journal of the American Medical Association come with sharp criticism of the way the blood products were studied.
Researchers want all such trials halted and blood substitute studies moved back to animal labs. They particularly object to studies in which trauma patients have been given the artificial blood without consent.
Five human studies of blood substitutes are underway in eight foreign countries, the researchers say, and at least one more human trial is being planned for the USA.
The findings are a disappointment to advocates who hope for a way to keep trauma victims alive longer. Because human blood has to be refrigerated and then matched so that the recipient receives the same blood type, emergency medical crews have sought a substitute that could be given to anybody and carried in medics' trauma bags.
"This is the race for the Holy Grail," says Dean Fergusson of the Ottawa Health Research Institute, who co-wrote an editorial on the topic. "Maybe we were a bit too rushed. We have to go back to the drawing board and see exactly where we are."
Specifically, he says, more research is needed to understand why the blood substitutes seem to cause heart attacks. In studies of animals, he says, blood substitutes caused blood vessels to constrict, which could be part of the problem. But some of the risks were hidden and downplayed by blood substitute manufacturers, he says.
"We need to stop and weigh all of the evidence," Fergusson says. "We are dealing with a very immature product. People were enrolled into trials where the risk was not portrayed to them."
The Food and Drug Administration allows blood substitutes to be given to trauma patients across the nation without informed consent under a special rule.
The waiver is allowed only for emergency medical trials that are closely watched by an independent board that monitors patient safety.
Another ethics panel, known as an Institutional Review Board, or IRB, solicits opinions from communities and decides whether the trial should be conducted.
The JAMA researchers, who analyzed 16 clinical trials involving five hemoglobin-based blood substitutes that were tested on 3,711 patients, say manufacturers downplayed risks and withheld scientific results that proved their blood substitutes were dangerous, which made it impossible for each community to make a truly informed decision.
The dangers should have been clear to the FDA in 2000, the researchers say, before trials were approved that would enroll more than 1,000 unsuspecting patients.
"What seems most outrageous is the communities were not told about all the risks," says Charles Natanson, a National Institutes of Health researcher and lead author of the study. "Openness and full disclosure is one of our best defenses for protecting patients."
Even after one blood substitute trial was stopped early because safety monitors saw that patients were being injured by the product, Natanson says, the FDA allowed a similar trial to proceed. In that study of Northfield Laboratories' PolyHeme, 47 of 350 in the treatment group died, compared with 35 of 364 in the control group.
Eleven of the 350 people who received PolyHeme had a heart attack, compared with none of the 364 who did not get the blood substitute, the JAMA analysis says.
In a written statement, Steven Gould, Northfield's chairman and chief executive officer, says he will present data from that trial to a federal panel that convenes today and again Wednesday at the National Institutes of Health in Bethesda, Md., to discuss blood substitute safety.
"Meta-analysis (like the one reported in JAMA) is not designed to provide answers about specific products or to examine fully the risk/ benefit ratio of any particular product," Gould says in the statement.
The JAMA researchers found that while study sponsors "are required by law to report their results to the FDA in a timely fashion after studies are completed ... the data reported by sponsors to the FDA are not made public by the FDA unless the product is approved or an advisory committee is convened to discuss the product."
They want regulatory changes to make the data publicly available.
"We need changes in regulations such that there can't be secret science," Natanson says. "The only way that IRBs can make informed decisions is if they know what the previous risks have been."
Jay Epstein, director of the FDA's office of blood research and review, defends the agency's decisions about human testing of the products despite risks. The agency has found enough differences among the individual products and their intended uses to allow some studies to proceed, he says.
The agency often has more information than it can reveal, Epstein says, but it does not want to keep scientific secrets: "We fully support transparency of decision-making within the limits of the law."