Granted, these sorts of medical advances are difficult to study, ethically as well as scientifically, but something about the decision to give fake blood to unconscious patients in the O.R. without asking the patient just seems wrong. Are natural supplies for blood really that scarce anyway? Or is this a profit-making adventure, with unwitting patients as disposable lab rats.
WSJ.com - Amid Alarm Bells, A Blood Substitute Keeps Pumping:Ten in Trial Have Heart Attacks,but Data Aren't Published; FDA Allows a New StudyDoctors' Pleas Are Ignored
Several years ago a clinical trial of a blood substitute called PolyHeme finished with worrisome results. Ten of 81 patients who received the fake blood suffered a heart attack within seven days, and two of those died. None of the 71 patients in the trial who received real blood were found to have had a heart attack.PolyHeme's maker, Northfield Laboratories Inc., quietly shut down the trial and didn't publicly disclose the results, which are described in internal documents viewed by The Wall Street Journal. It decided the heart attacks might have been due to doctor inexperience in using PolyHeme, not a problem with the product itself.
Now Northfield is in the middle of a new trial. A Food and Drug Administration official, Jay Epstein, calls the earlier data “alarming” but not sufficient to stop Northfield from trying out its product on hundreds of trauma patients.
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 31 medical centers testing the product are required to carry out community-awareness campaigns about the trials. Several hospitals have told community meetings that previous trials showed PolyHeme to be safe, failing to mention the 10 heart attacks in their printed materials.
And speaking of bad PR: this statement is just ridiculous. Now every freaking person who doesn't want to be given fake, experimental blood in the rare case of needing an emergency transfusion has to wear a blue wrist band, at all times?? Talk about your double opt-in policies. Yeesh. If I was at all involved in Wall Street - I'd short this company right now.
Northfield says any American who doesn't wish to participate in the current PolyHeme 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.
... At the time, Northfield was starting what was to be its pivotal trial. Patients were randomly assigned to a group receiving PolyHeme or a control group receiving real blood. This type of study is the gold standard in medicine. The patients in the trial were undergoing surgery to repair aneurysms, or ballooned sections, in their aortas. They gave their consent before participating.After the Baxter product was implicated in deaths in March 1998, the FDA ordered Northfield's study enrollment target expanded to 600 patients from the original 240. Northfield remained upbeat. An August 1999 news release spoke of PolyHeme's “excellent safety profile.” A news release in April 2000 said the study was “producing very important results” but was taking a long time to enroll enough patients. Then in the second half of 2001, Northfield abruptly shut down the study, explaining in a Securities and Exchange Commission filing that it was taking too long to complete.
In August 2001, Northfield tried a long-odds maneuver: It asked the FDA to approve PolyHeme based on earlier research on hospital trauma patients. In that research, PolyHeme wasn't compared with a control group receiving standard therapy. Instead, Northfield compared the results with other hospitals' historical experience with patients who needed blood but didn't get any. These patients were Jehovah's Witnesses who declined blood for religious reasons. In November 2001, the FDA refused to consider the application, citing concern about the validity of the comparison, according to a Northfield SEC filing.
The sudden halt to the big randomized PolyHeme trial left unanswered a critical question: What were the results? Doctors who had taken part were curious. In an arrangement that 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 21 hospitals that had taken part in the study. He says Dr. Gould agreed to the meeting, then canceled 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 results had been published. He says Dr. Gould told him, “Someone's working on it.” Dr. Gan says, “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 the 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 PolyHeme, the trial suggested the product was linked with other serious adverse events such as heart rhythm aberrations and pneumonia. These events occurred in 54% of the PolyHeme patients versus 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 PolyHeme patients died versus 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 for a drug or medical device under study. Still, Northfield persevered.
Dr. Gould says the company doesn't believe PolyHeme caused the heart attacks. Before surgery, patients had their own blood drawn for possible use during the operation. Dr. Gould says several hospitals gave patients both PolyHeme and real blood. Together, he says, the amount of fluid was too much. “It can't be determined,” he says, whether the heart attacks were due to the “capability and experience” of doctors “or to 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 PolyHeme, 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-blood company but left after a dispute with executives there.
The FDA's 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 events.” But, he goes on, “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.
As a result, Northfield was able to embark on a big new trial -- this time in trauma patients such as victims of shootings or car accidents. It started signing up trauma centers in December 2003 and as of early this year about 600 people had taken part. Half get PolyHeme and the other half get saline solution plus real blood. The study measures the death rate at 30 days. Northfield's hope is that PolyHeme will be found equivalent to -- or at least not provably worse than -- the standard therapy. As of late last year, an independent data monitoring board hadn't found any statistical differences between the two groups large enough to warrant halting the study.
Dr. Gould says Northfield typically pays hospitals around $10,000 a patient to participate. Northfield agreed to pay $336,000 to the University of Texas Health Science Center at Houston and $132,468 to the University of Kentucky Medical Center, hospital records show. The hospitals say the money merely covers costs in collecting the data. “This is not a profit-making endeavor -- it is a scientific one,” says University of Kentucky surgeon Andrew C. Bernard. Others participating include the Mayo Clinic, Duke University and Lehigh Valley Hospital in Allentown, Pa.
In the trauma study, patients are in hemorrhagic shock, meaning they are bleeding so profusely that their blood pressure plummets. The typical patient can't offer the informed consent that normally is required for clinical trials. A 1996 FDA rule says it is acceptable to give trauma patients experimental treatments without their knowledge.
Oh, apparently, the risk of being chosen for the study is very small, so you probably don't need to wear a blue wrist band. Still, that's a flippant response if I ever heard one.
Res of the article here (WSJ subscribers only - or email me, and I'll send you a PDF)
7/7/06
update here - The Navy wants it tested too.
update 7-11-06
more here
We've secretly replaced these emergency room patients' blood with Folger's Crystals...
Some random things to think about re trauma care and blood substitutes:
1. Consent is frequently not obtained for trauma care including life-changing things like removing organs and limbs, not to mention administering blood transfusions, which are completed often before the surgeon even knows the patient's name....and those decisions are not reviewed by the FDA or an IRB to determine if that was really the best treatment for that patient. Patients are at the mercy of whichever surgeon happens to be on that night, and what that doctor's individual experience/knowledge tells them is the best course of action, and what competing demands are for his/her time. Maybe there was a better procedure that would have saved that leg or kidney, but the doctor who happened to be on that night wasn't aware of the most up-to-date procedures, or didn't have the expertise to perform it, or had another critical patient that needed their attention so they just didn't have the time. Clinical trial protocols, on the other hand, are set up and reviewed by MANY medical experts before being allowed to proceed; and then the results are reviewed by other experts at intervals to be sure things are not going awry.
2. Are blood supplies that short? Well, at the scene of a trauma there is NONE available, so in that sense, yes they are short. Even once you reach the hospital (5 minutes to hours later), until the patient can be typed (takes 15-20 minutes) only O-negative blood is available to be given, and that IS in critically short supply most of the time. Time to bleed to death: as little as 5 minutes.
3. Receiving six units of donated transfused blood is an independent risk factor for death. i.e. the more transfused blood a patient receives, the more likely they are to die. Risk of death increases with the age of the blood being given (i.e. blood that is reaching the end of its shelf life). And this does NOT include the risk of viral infection from HIV, hepatitis, HTLV III or some virus we don't yet know about and thus are not testing for yet. Receiving blood products in not a risk-free event and hospitals now routinely require a consent form prior to giving ANY blood products to patients. Guess how frequently that doesn't happen with trauma patients.