Deadly Blood Substitutes
The FDA for a second trial study has OK’d Poly-Heme, a blood substitute, produced by Northfield Laboratories Inc.
Several years ago, ten of eighty-one patients who received the fake blood, suffered a heart attack within seven days. The trial was quietly shut down and Northfield didn’t publicly disclose the results.
The FDA is allowing Northfield to test its blood substitute without the consent of the trauma patients, who often are unconscious. In lieu of patient consent, the thirty-one medical centers testing the product were required to carry out community-awareness campaigns about the trials. Several hospitals have told community meetings that previous trials showed Poly-Heme to be safe, failing to mention the ten heart attacks in their printed materials.
Some veteran doctors are concerned about the push by Northfield, of Evanston, Ill., to test its product without publicly disclosing earlier results. Ronald M. Fairman, chief of vascular surgery at the hospital of the University of Pennsylvania, he repeatedly urged the company to publish the data but got nowhere. “Even now it seems frustrating the multicenter results were not disclosed,” he says.
Northfield’s chief executive, Steven A. Gould, argues doctors pumping too much total fluid-Poly-Heme plus real blood-into patients could well have caused the heart attacks. He says Poly-Heme could help many people, such as those in an ambulance who don’t have access to human blood. “Our experience suggests the risk-benefit balance is in the patients favor,” Dr. Gould says.
In a statement, Northfield denies it “resisted publication” but says: “We did not allocate resources to publication. In retrospect, reporting the full study results earlier would have been better.”
Northfield says any American who doesn’t wish to participate in the current Poly-Heme trial should ask the company for a blue plastic wristband that would alert paramedics. Those who fail to get a wristband and find themselves in a hospital trauma unit “can withdraw from the study, without prejudice, at any time,” the company says.
The trouble with this strategy is how can the average citizen be notified of this danger without a massive news blitz. Furthermore, how is the average person to know to notify Northfield Laboratories Inc?
This is just another case where the FDA is asleep at the wheel.
The making of Poly-Heme begins with outdated donor blood. A protein called hemoglobin in red blood cells delivers oxygen throughout the body. Northfield bursts open red blood cells in giant metal vats, freeing the hemoglobin molecules inside.
Hemoglobin molecules are known to be dangerous if they aren’t held within red blood cells. The molecules tend to seep into the walls of blood vessels and cause inflammation. Most relevant to heart attacks, they can constrict blood vessels and cause clotting. Northfield chemically links one hemoglobin molecule to another in a process called polymerization. Dr. Gould says this removes hemoglobin’s toxicity.
John R. Hess, a University of Maryland research doctor, is skeptical. He once headed the Army’s blood-substitute but shut it down in 1996 after concluding that all the blood substitutes he evaluated were toxic. With hemoglobin, Dr. Hess says, “the lining of the blood-vessel walls become inflamed.
...There’s no reason the modification should change this.”
Northfield has voiced optimism for years. In May 1997, a company news release said, “Poly-Heme is in the stretch with market introduction planned for some time in 1999.” The company’s then-chief executive, Richard DeWoskin, said, “We have advanced to the point that the question of size and scope of the commercial market for our product.”
Critical Question
The sudden halt to the big randomized Poly-Heme trial left unanswered a critical question: What were the results? Doctors who had taken part were curious. In an arrangement that the doctors often reject today, Northfield restricted access to the full data and individual doctors knew only what happened to their own patients.
At the University of Pennsylvania, Dr. Fairman says he and a colleague, Albert Cheung, repeatedly called Northfield’s Dr. Gould. “We said, ‘Let’s sit down and write up the data,’” Dr. Fairman recalls. “He wouldn’t do it.” Dr. Cheung proposed a meeting in Philadelphia of doctors at the twenty-one hospitals that had taken part in the study. He says Dr. Gould agreed to the meeting, and then cancelled it at the last minute.
T.J. Gan, a Duke University anesthesiologist involved in the study, says he called Northfield three years ago to ask if the results had been published. He says Dr. Gould told him, “Someone’s working on it.” Regardless of whatever the problem, you publish it and outline the results.” In its statement, Northfield says company officials don’t recall the specifics of any discussion with Dr. Cheung About a meeting or a conversation with Dr. Gan.
Dr. Gould says he did inform the FDA of the aneurysm trial’s results. The company now says it plans to make public a medical abstract of the study in April.
Besides the heart attacks and deaths in those taking Poly-Heme, the trial suggested the product was linked with other serious adverse events such as heart rhythm, aberrations, and pneumonia. These events occurred on in 54% of Poly-Heme patients vs. 28% in the control group, according to Northfield’s internal documents. The higher rate of heart attacks and serious events was considered statistically significant, meaning there is minimal likelihood they happened by chance. Overall, Eight Poly-Heme patients died verse four on conventional therapy, a difference that wasn’t found to be statistically significant.
Such a stark difference in serious adverse events would often be fatal to drug or medical device under study. Still’ Northfield persevered.
Dr. Gould said the company doesn’t believe Poly-Heme caused heart attacks. Before surgery, patients had their own blood drawn for possible use during the operation. Dr. Gould says several hospitals gave patients both Poly-Heme and real blood. Together he said the amount of fluid was too much. “IT can’t be determined,” he says, whether the heart attacks were due the “capability and experience” of doctors “or the product.”
William D. Hoffman, chief of the cardiac-surgery intensive-care unit at Massachusetts General Hospital in Boston, says blood substitutes made with hemoglobin as a starting point, a class that includes Poly-Heme, are associated with heart attacks and strokes. “It is self-serving and potentially misleading to associate harmful effects with something other than the test drug,” says Dr. Hoffman, who used to work for another artificial drug company but left after a dispute with executives there.
The FDA Dr. Epstein, who is director of the agency’s blood-products office, sides with Dr. Gould, calling Northfield’s theory a plausible one. “Of course it’s alarming there were excess deaths in the treatment group,” he says. “ We are highly mindful of the adverse-event profile in the aneurysm trial, while significant, was not a show-stopper.” The FDA’s review suggested that “volume overload” rather than “any intrinsic toxicity of the product” was responsible for the cardiac events, he says.
Playing Down Risks
In place of individual consent, The FDA has required Northfield and the hospitals participating in the trauma trial to hold public meetings at churches, city halls, and the like in their communities. Materials used at the meetings and filed to the FDA often played down the risks of Poly-Heme.
The Lehigh Valley Hospitals materials for local meetings said, “Past studies have shown that Poly-Heme…has not caused organ damage.” Materials from the Brooke Army Medical Center near San Antonio for meetings last July were even more categorical: “In clinical trials to date, Poly-Heme has demonstrated no clinically relevant adverse effects. Up to now, Poly-Heme has not caused any clinically bad problems.”
Northfield did tell trauma doctors about the heart attacks in the earlier study but did so confidentially and with an explanation that it didn’t believe Poly-Heme was responsible, according to company documents and interviews with doctors. The university of Kentucky’s Dr. Bernard says there is a limit on what the public can be told about the earlier trial results because “everything in the study is confidential.”
Early lat year, Keith Berman, Pasadena, California, medical-products consultant who has studied blood substitutes, urged the FDA to make the earlier trials results public. Last year, the agency required Northfield to mention on its website “serious cardiovascular adverse experiences” with Poly-Heme. Five of the thirty-one hospitals in the trauma study followed suit, but well after many trauma patients had been treated.
Because Northfield needs only about one hundred and twenty more people to complete its study, any individual’s chance of being enrolled is low. However, those who are still worried can get the blue, plastic wristband from the company to signal that they refuse to take part.
While Northfield says Poly-Heme could be useful in rural ambulances, battlefields and other settings where real blood is out of reach for hours, it hasn’t conducted a large-scale test focusing solely on that notion. It says assembling patients for such a trial would be too difficult and time-consuming. “We’ll all recognize that doing [trauma] trial in an urban setting is not ideal, but this was the only way to get the trial done,” says a Northfield spokeswoman.
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