FDA delay in acting on heart hazards might have put some in jeopardy, researchers say
MONDAY, April 28 (HealthDay News) -- Experimental hemoglobin-based blood substitutes boost the odds of death and heart attack for recipients, according to an exhaustive review of the data.
These products are not yet approved for use in the United States but have undergone extensive clinical testing.
The study, released early Monday by the Journal of the American Medical Association, has critics charging that the U.S. Food and Drug Administration failed to detect and act on a significant increase in heart attacks and deaths noted in trials of these laboratory-made blood substitutes.
That delay put participants in ongoing trials in jeopardy, they said.
"What I would like to see come out of this is a change in the rules about how the FDA handles data from clinical trials," said study co-author Dr. Charles Natanson, head of the anesthesia section of the U.S. National Institutes of Health's Clinical Center in Bethesda, Md.
"They should not be treated as trade secrets. The results should be made public in a short period of time," he said.
The report looked at data from 16 trials of five experimental artificial blood products, involving 3,711 patients. The researchers found an overall 30 percent increased risk of death and nearly triple the risk of heart attack for persons who got these products compared to those who did not.
Yet five trials of such products are still ongoing in eight countries outside the United States, and the FDA is considering a request for a trial here, the report's authors said.
An artificial blood product -- one with a longer shelf life and without the need for refrigeration required for human blood -- is a long-sought therapeutic goal. All the products described in the report are based on hemoglobin, the oxygen-carrying protein found in red blood.
The problem with such products is that "these hemoglobins do not have the protection of red blood cells," said study co-author Dr. Sidney Wolfe, director of the health research group at Washington, D.C.-based Public Citizen, an advocacy group that is often at odds with government agencies.
"Outside the cell, hemoglobin scavenges nitric oxide," Wolfe explained. "This causes constriction of arteries that is predictive of increased risk of heart attacks and organ damage."
Wolfe and Public Citizen initiated the inquiries that produced the report, starting in 2006. "We learned from the Federal Register that the FDA would hold an advisory committee meeting about a blood product," Wolfe said. "They decided to keep it secret. We sued the FDA, and they canceled the meeting because it was illegal."
Wolfe contacted Natanson, "because I knew he was on advisory committee of the FDA," and they began a search for information on hemoglobin-based blood substitutes. It was not easy to find, because neither the companies testing the products nor the FDA were forthcoming with information, Wolfe charged. Often, the FDA did not report on trial results, because they were regarded as trade secrets, he said.
The only information available in many cases came from press releases. In the case of one product, Polyheme, a report was not published until December, 2006, six years after the trial ended.
"It took a long amount of time, because a meta-analysis like this, if done appropriately, takes an enormous amount of energy and time," Natanson said.
The FDA itself did not do the kind of meta-analysis that produced the journal report, Wolfe said, but the evidence that the products caused harm should have been evident by the year 2000, he said.
"In the eight countries where there are clinical trials, if they had been aware of the cumulative picture, they would not have allowed the trials to go forward," he said.
The FDA "does not concur that a prior meta-analysis would have modified our assessment or resulted in stopping all studies in 2000," said Karen Riley, a spokeswoman for the agency.
"We discussed the safety of these products at several public meetings and workshops," Riley said. "Because of safety concerns, there are no ongoing studies of hemoglobin-based blood products in the United States and no approved products."
The FDA will hold a workshop on the issue on Tuesday and Wednesday. Wolfe said he will attend but will not be allowed to speak because of the meeting format.
A workable artificial blood product is still desirable, Wolfe said, and several products that are not based on hemoglobin are in the early stages of development. Careful animal experiments with those products are needed before human trials can be considered, he said.
"We are not opposed to moving forward, but it needs to be done carefully now that we know what we know," Wolfe said.
The FDA has known for months that the report was being prepared, just as it had information on the possible hazards of the hemoglobin-based products years ago, Wolfe added. "The inevitable conclusion of the paper is that an agency that had more active data before we did should have done something," he said.
Hemoglobin-based blood substitutes are currently approved for use in two countries, South Africa and Russia, noted Dean A. Fergusson, a senior scientist at the Ottawa Health Research Institute in Canada. The new report may well affect those approvals, said Fergusson, who co-authored a journal commentary on the study.
A safe blood substitute would always be useful in emergency treatment, Fergusson said, but the risk-benefit ratio of such a product would have to be established before its general use.
"Blood right now, in America and Europe, is pretty darn safe," he said.
Current alternatives to blood transfusion are described by the American Cancer Society.
SOURCES: Sidney Wolfe, M.D., director, health research group, Public Citizen, Washington, D.C.; Charles Natanson, M.D., head, anesthesia section, National Institutes of Health Clinical Center, Bethesda, Md.; Dean A. Fergusson, Ph.D., senior scientist, Ottawa Health Research Institute, Ontario, Canada; Karen Riley, spokeswoman, U.S. Food and Drug Administration, Rockville, Md.; April, 28, 2006, online Journal of the American Medical Association
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