Experimental blood substitutes raised the risk of heart attack and death, yet U.S. regulators allowed human testing to continue despite warning signs, says a scathing new report.
The U.S. Food and Drug Administration fell short, the report contends, even as red flags popped up during studies by five biotech companies. Rules barred the agency from releasing company trade secrets, and that kept some information hidden and may have led to unnecessary heart attacks and deaths, wrote the authors, who are government scientists and consumer advocates.
"There shouldn't be secret science," said the lead author of the report, Dr. Charles Natanson, of the National Institutes of Health Clinical Center. Safety data need "to be made public expeditiously so science can build on the mistakes" of previous research, he said.
The report, being published online Monday by the Journal of the American Medical Association, is the latest analysis of the risks of blood substitutes, which have been in testing for more than a decade.
It was written by scientists with the NIH Clinical Center and advocates with the watchdog group Public Citizen. The clinical center in Bethesda, Md., seeks to ensure the safe and ethical conduct of clinical research.
A safe replacement for blood would be a breakthrough for medicine and a big money-maker for companies that produce it. It could save lives on battlefields. Unlike ordinary blood, it could, theoretically, be stored for years without refrigeration. It also would work with any blood type and would not carry infections like hepatitis or the AIDS virus.
By the end of 2000, a dozen studies of blood substitutes had been completed. By then, FDA officials would have known enough about cumulative risks to put a halt on further experiments, the JAMA report contends.
But the FDA looked at each product and each use separately -- in surgery, in trauma, in stroke patients -- rather than pooling the results to get a fuller picture of the risk, Natanson said.
In 2006, after a lawsuit by Public Citizen protesting a closed-door hearing, the FDA halted a test by the Navy, which planned to use a blood substitute on civilian trauma victims. Such tests raised ethical concerns about giving trauma patients an experimental product without their consent.
Dr. Jay Epstein, director of FDA's office of blood research and review, defended 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, Epstein said Friday in a conference call with reporters.
Currently, there are no approved blood substitutes or clinical studies of them in the United States. However, American companies are testing them on people in South Africa and seven European countries. South Africa has approved one of the products, Hemopure, made by Biopure Corp., based in Cambridge, Mass., for use in anemic surgery patients.
"It is highly unlikely, I'd say impossible, that any of these countries are aware of the risk," said study co-author Dr. Sidney Wolfe of Public Citizen.
In the new report, researchers analyzed 16 randomized controlled studies of five different blood substitutes. More than 3,700 patients were involved. The studies included elective surgery, trauma and stroke patients.
Researchers found a 30 percent higher risk of death overall for patients who received transfusions using the blood substitutes; 164 of those patients died. Among those who received ordinary blood products or saline transfusions, 123 died.
The risk of heart attack was nearly tripled in the groups receiving blood substitutes. There were 59 heart attacks in that group compared with 16 heart attacks in the group that didn't get the new products.
Experts speculate that hemoglobin in the blood substitutes scavenges nitric oxide from the blood, causing blood vessels to constrict and sticky platelets to build up. That increases the risk of heart attacks.
The report comes as the besieged FDA reacts to numerous other troubles.
Contaminated blood thinner from China recently highlighted the agency's shortage of inspectors abroad. In September, an inspector general's report found the FDA does little to oversee human safety in clinical trials by drug companies.
Last year, new legislation was adopted to give the FDA more power to act when problems emerge with drugs already on the market -- action prompted by the furor over the withdrawal of the risky painkiller Vioxx in 2004.
Even with the new law, the FDA needs more financial support, Natanson said.
"They're hardworking people. They're trying their best," he said. "If we really want them to be an agency that is going to protect us, we need to support them."
But companies may be withholding key information from the FDA, said one former biotech employee.
Dr. William Hoffman, former chief medical officer at Biopure, left the company in 2000 after management prevented him from telling the FDA that he believed one of the company's studies should be stopped. Hoffman said Biopure management has changed since then.
"The FDA knows more than anyone at any of the individual companies, but they may not know the whole story," Hoffman said. "There may be information withheld from the FDA."
Most developers of blood substitutes are one-product companies, and their existence depends on the fate of the product, said Hoffman, now director of cardiac-surgery critical care at Massachusetts General Hospital in Boston.
"Drug development is expensive. In order to get a drug to market you have to keep good news coming out so the value of the company remains high," Hoffman said.
Two companies whose products were included in the new report called the analysis flawed.
"There are vast differences among these products that make any pooling of data flawed, especially across different clinical experiences," Biopure vice president Dr. A.G. Greenburg wrote in an e-mail.
Dr. Steven Gould, CEO of Evanston, Ill.-based Northfield Laboratories Inc., said in a statement that pooled analysis can be "a useful tool to raise questions" involving a class of drugs, but is "not designed to provide answers about specific products or to examine fully the risk-benefit ratio of any particular product."
Gould said Northfield would present a summary of research on its product, PolyHeme, at an FDA discussion of the safety issues this week.
In disclosures required by JAMA, Natanson reported that he is an unpaid consultant to the FDA on Hemopure and was once paid $10,000 to review a blood substitute study by Hemosol Corp. of Canada.