Artificial Blood: The Lifesaving Promise
For decades, Northfield Laboratories has been developing its blood product, Polyheme©. Its latest clinical trial, one of many, has suddenly caught the attention of the nation for its peculiar structure: giving a blood substitute of questionable benefit to trauma patients who cannot give informed consent.
Scientists have been trying to develop artificial blood for centuries and experimenting with almost anything - wine, ale, opium... Artificial blood is one of the holy grails of medicine for obvious reasons, it could potentially eliminate the need for blood type matching, could be reconstituted from dried powder that would be far less perishable than fresh blood, and could be sold to developing countries where blood supplies are scarce and donor is blood deemed "less safe" then in western countries. It would of course also be especially useful in wars, and in this bellicose age perhaps the impetus and funding for blood products has increased. For many reasons, scientists seem eternally motivated to continue their human experiments with blood "products", but of these experiments seem ethically sketchy, even barbaric.
What the Wall Street Journal Said
On Tuesday, February 22nd, the Wall Street Journal published an article by Thomas M. Burton: "Amid Alarm Bells, A Blood Substitute Keeps Pumping", about ongoing clinical trials of the blood sustitute PolyHeme© Northfield's product. The waiver of the the usual patient consents is particularly perturbing because Polyheme© was abandoned in prior trials due to adverse patient consequences. Burton wrote:
"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 [risk of] heart attacks, in their printed materials."
The Food and Drug Administration allows these clinical trials under a special category of research that makes an exception for informed consent requirements. Section CFR. 50.24, waives consent rules for certain trauma patients so that scientists can gather "valid scientific evidence, which may include evidence obtained through randomized placebo-controlled investigations, that is necessary to determine the safety and effectiveness of particular interventions.."
Media Coverage In the Past Three Years
The Wall Street Journal article attracted the attention of Senator Grassley, a Republican representing Iowa, who promptly demanded an inquiry into Northfield Laboratories and the FDA's approval of the trial, actions that Burton follows in the WSJ. However, what's more noteworthy than the sudden attention to these human experiments is the complete lack of public attention for the past three years. Why didn't the study set of "alarm bells" earlier? It's certainly not because of lack of media coverage and questioning, there has been media coverage of the trials since they started in 2003. Here are some articles published in major newspapers that question the ethics of the Polyheme© clinical trials:
- May 20, 2003; "Synthetic-blood testing to begin at Denver Health". The Denver Post.
- December 17,2003; "Artificial blood may get S.A. trial ; Many participants won't have given their consent." San Antonio Express-News.
- February 21, 2004; "Substitute Blood Trial Worries Ethicists", the Boston Globe.
- February 9, 2004; "Blood-substitute test skips consent" in the Chicago Sun-Times.
- February 20, 2004; "Artificial blood tested without patients' consent: Similar tests halted in 1998 when deaths of 20 patients tied to different product". The Ottawa Citizen.
- March 23, 2004 "An Experiment in Saving Lives. Emergency Patients Unwittingly Get Artificial Blood": The Washington Post.
Many newspapers also covered the company's previous trials. But the February 22, 2006 Wall Street Journal article is the only one that generated any sort of national response -- or a Northfield press release.
Is The Blood Substitute Safe?
The company vehemantly disputed the article in a flurry of "news". They specifically deny the Burtons's recounting of past clinical trials, that he described this way:"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..."
The Wall Street Journal goes on to describe how one randomized trial was "abruptly" shut down, and quotes a number of people knowledgeable of the experiments who say that results went unpublished and that trial participants were uninformed. The company denies it all on its website:
"Every investigator and every IRB at every site involved in the current trauma trial was fully informed of the results of all of Northfield's prior trials....Northfield made no effort to dissuade centers from presenting previous trial information in any of their community outreach efforts."
However despite what the company and its president claim, Northfield has not been very frank about the results of its trials. In addition to the Wall Street Journal's extensive account, there are others. The Minneapolis Star Tribune said in its January 30, 2004 article on the Mayo Clinic participation in clinical trials: "The successes of earlier studies showing that some patients who lost all of their blood were kept alive when PolyHeme persuaded the U.S. Food and Drug Administration (FDA) to allow this study to go forward, said officials with Northfield Laboratories". The company's spokespeople have put some spin on the real story, which is that the Food and Drug administration denied the company's request for approval based on the flimsy structure of a previous trial in which Northfield compared their trial results to other, unaffiliated studies. Thus, the FDA requested a new trial. However a Boston Globe article (February 21, 2004), quoted Dr. Steven Gould, president of the company:
"In five clinical trials so far, he said PolyHeme has proven safe even when given rapidly in large volumes. Most recently, the death rate among 171 patients who received rapid PolyHeme infusions was less than half the rate of those who didn't receive blood, according to a study in the Journal of the American College of Surgeons."
One of the most damaging accounts was by The San Diego Reader. The paper published an extensive investigative report by Matt Potter on the Northfield's clinical trials contract with the University of San Diego last July called "Bad Blood". UCSD is one of two medical centers in San Diego that participated in the trials. Press releases on the trial, were highly optimistic - The Reader quotes a doctor from the medical center who says "In a study of PolyHeme from the late 1990s, 75 percent of those treated with it survived, compared with 30 percent treated only with saline solution." But, the paper notes, the trial would only treat individuals south of Route 8 -- the poorer section of town.
Northfield's Restraining Order Against the San Diego Reader
According to the Reader, contrary to the requirements of the trials and Dr. Gould and Northfield's indignant defense, the city of San Diego produced scant information about the trials. What was publicized leaned more towards marketing and recruiting material, as opposed to than the balanced public information that was required in lieu of patient consent. Contrary to the company's claims to transparency, information was tightly controlled - if not censored - by Northfield Laboratories. In a memo sent from Gould to the principal investigator of the UCSD study, published by the Reader, he wrote:
"I urge you to remind your study coordinator and all others associated with the trial that information about patients and the details of the trial at your site are not to be shared with anyone outside the study team." UCSD sent the request on to the City of San Diego, who agreed, "not to disclose to any third party any Confidential information," defined as "all information, data, materials, in whatever form or medium, that [Northfield] treats as confidential and proprietary information."
But this may be just the tip of the ethical allegations iceberg. The Reader's thorough, interesting, and potentially damaging report investigated participant recruitment for the trials, hospital and doctor compensation for the study, as well as adverse events that occurred in the Polyheme© trial. The San Diego Reader found that only a few ambulances servicing only select areas of the city were participating: "...paramedic units in three of the city's poorest communities -- Oak Park, Nestor, and San Ysidro -- had been chosen for the trial because those areas generate the largest number of severe trauma patients..."
The San Diego Reader waited months to get documents they requested from UCSD. The documents they did get were heavily redacted, blank, or refused altogether. Some documents noted trivial communications between the stakeholders, for instance, the City had problems recruiting study participants so in one meeting Northfield suggested offering incentives; "inexpensive give-aways like pens, penlights, mugs with 'Polyheme study' on them...as a thank-you for participation". More troubling, Northfield paid the hospital and principals per patient who "completed" the study, which could financially motivate doctors to continue with Polyheme© even if the patient would have benefited from donor blood. One of the most ethically contentious aspects of the trial is that it requires patients to be treated with Polyheme© for 12 hours, longer than what would be medically necessary in a city hospital where donor blood is available.
The Reader has been unsuccessful in trying to get information about two "adverse events", the details of which were completely blotted out of the documents the paper recieved. One of the "events" was reported to have occurred before the study's official start date.
The San Diego Reader resorted to suing UCSD for the complete records under the "California Public Records Act." In January Northfield filed a restraining order against the San Diego Reader to prevent the company from publishing documents, alleging that they contained "trade secrets". The company was granted the restraining order, but overturnedanother judge overturned it a few weeks later.
Opt Out?
You or I or anyone we know or don't, could meet with some trauma, need blood and end up at a medical centers where the studies are being run, then become a participant in the trial, unbeknownst to any of us. There is an opt out. You can order a light blue plastic bracelet from Northfield Laboratories. The bracelet advises first responders and emergency room staff: "I Decline The Northfield Polyheme Study". They're quite fashionable -- in that plastic, hospital kind of way; snap handily around the wrist or ankle, and moreover could prove to be a lifesaver. They take about two weeks to arrive via U.S. mail and were wrapped in an apology from the post office for running them through some sort of envelope shredder -- the company spared only $.39 to send them letter rate. According to the WSJ article, Northfield says that if you "fail" to get the bracelet and find yourself in a trauma unit, you can then "withdraw from the study, without prejudice, at any time". That is, if you are conscious, which you won't be, have the wherewithal to speak up, and have lived through the initial "clinical trial" vetting.
The trials are winding down, which also means there's actually not much chance that you will be picked to participate. Because of this, the company is probably breathing a sigh of relief, since the article that received national attention was published once the study was mostly completed. True, Northfield Laboratories's stock has dipped, and the current national attention is not positive. Many questions remain. The potential uses for such a product are easy to recognize and highly valued (not only in monetary terms). Will the demand for the product, especially by the U.S. military -- create enough momentum for the product to continue development? Or will Northfield and the FDA be forced to face (and publicize) the results of the trial -- whatever they are? If the trials fail to show a benefit, will the company manage to push Polyheme© along anyway, as they have in the past? And finally, will details of adverse events continue to be redacted, with inevitable explanation that the "event" was "unrelated" to the product?
The Polyheme© story will continue to evolve. Importantly, trials conducted under the FDA waiver of informed consent will also continue. These trials will no doubt be risky (research on competing blood products for instance), and involve research that might be *off-putting* to potential volunteers. Perhaps, like Polyheme©, there will be concerns about litigation and public response so the details of the research will be obscured. Is this something we find acceptable in order to develop this type of product? There are obvious alternatives -- are they more acceptable?
UPDATE July 8th:
The the lastest Wall Street Journal article by Thomas M. Burton discusses possible FDA approval of the Navy's request to expand the trials of Northfield Laboratories Polyheme© product. Also, 20/20 ran a story on on Polyheme yesterday. Here are two short videos that are available on their site today: "Can You Bank on Artificial Blood?" and "Can Artificial Blood Save Lives?" (these links will launch video player from the ABC site). In the wake of this coverage, many people have written to us wanting to know where to get the bracelet. The 20/20 site has a list of 27 cities that are running the clinical trials -- you might want to check that out.
We orderd our bracelets by contacting Northfield Laboratory via their contact information on their website (though the site doesn't promote the bracelet heavily).
--------------------Acronym Required recently wrote another article on Biopure, a company that is also pursuing clearance with the FDA to run Stage III clinical trials in conjunction with the Navy.
Update August 7th: According to the clincal trials site information on Polyheme at www.clinicaltrials.gov, Northfield has completed recruiting patients for this trial.
