March 2006 Archives

Polyheme© and The Newest Plastic Bracelet

| Comments

Artificial Blood: The Lifesaving Promise

Idecline Northfield Laboratories has been developing its blood product Polyheme© for decades. 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 and do not give informed consent.

Scientists have been trying to develop artificial blood for centuries and apparently have experimented with an array of substitutes including "wine, ale and 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 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"; and some of these experiments are seen as 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 clinical trials are done via a Food and Drug Administration *special* category of research that makes an exception for informed consent requirements under section CFR. 50.24, waiving consent rules for certain trauma patients so that scientists can gather, in their words: "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, since there has been 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 one randomized trial was "abruptly" shut down, and quotes a number of people knowledgeable of the experiments who say that results that 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. 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." (In many articles, the doctors running the trials, not company officials, gave misleading safety information to journalists).

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 blackened out, 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", and was granted the restraining order. That order was overturned by another judge 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, 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 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.

CMAJ: The Last of The Hawkeyed Editors

In the past few decades there has been increasing pressure on medical journals to appease major advertisers, primarily pharmaceutical companies, as the journals expand to large, very profitable entities. There are trade-offs to this business decision since independent medical journalism can be a great advocate for patient health, but does not always support the quickest route to the industry profits - media and pharmaceutical in this case. Politics tends to take sides; public health, or industry. With fair regularity there are clashes between editors and publishers about journalistic independence and integrity as the often competing interests overlap and vie for the doctors' attention on journal pages.

The latest of these rows happened last month, as Dr. John Hoey and Anne Marie Todkill, the editor and senior deputy editor of the Canadian Medical Association Journal (CMAJ) (or JAMC (Français)) were fired from their posts on February 20. The publisher, Graham Morris for the Canadian Medical Association (CMA), indicated that the journal needed a "fresh start". His action provoked protests from doctors and editors across North America who view Morris' reason for the dismissal as specious, merely an excuse to rid the association of an editor who wasn't ideologically aligned with their interests. Three other editors have quit in the aftermath.

The firing was by some accounts instigated by a CMAJ poll, where women who ordered Plan-B medication at drugstores via prescriptions were asked to report back about their experiences. The journal found that the pharmacists were "collecting and recording personal information, including sexual history", as well as names and addresses in pharmaceutical company databases. (Montreal Gazette, February 23, 2006). The practice is apparently illegal. However when the journal editors went to publish their findings they were pressured by the publisher to alter the results because the Canadian Pharmaceutical Association complained about the report. They complied with the publishers demands, but the next week Hoey wrote about the compromise in an editorial, prompting one of the final rows between editor and publisher.

Dr. Hoey was the editor of the journal for ten years. During his tenure he was a strong advocate for better patient healthcare and en route, he eloquently and unabashedly challenged policies and practices that compromised care. In 2001, following the death of a 15 year old girl taking the Cisapride, a drug for heartburn that was taken off the market in the U.S. in 2000 after multiple deaths, the editor criticized Canada's drug oversight board for lagging behind the FDA. He noted that Cisapride was not the first drug Health Canada (the country's FDA equivalent) had failed to flag, "but it is the last time that we [CMAJ] will merely observe". The journal then posted all FDA warnings on its website and mailed the warnings to doctors.

The editor clashed with the publishers again in 2002 after writing an editorial on a legislative issue that would have required doctors to rotate through emergency rooms. The legislation was drafted following chronically understaffed emergency rooms and the death of a cardiovascular patient who was turned away from a regional hospital when its emergency room closed, then died on the way to a second hospital. In his letter, Hoey criticized the doctors for betraying patient trust and implicitly supported the bill: "the physician-patient relationship is based on trust, the physician-government relationship on necessity." The Canadian Medical Association of course opposed the bill and the publishers labeled his discordant view "repugnant". Hoey later reported that "they may have considered the option of firing me at the time". (Ottawa Citizen, November 26, 2002)

In an editorial following the incident, October 29, 2002 in CMAJ titled: "An Editorial on Editorials", Hoey explained the necessity of independent journalism:

"...the arm's-length relationship CMAJ has enjoyed with the CMA, a policy of editorial independence formally endorsed by the International Committee of Medical Journal Editors, of which CMAJ is a founding member...assures the autonomy of the journal and safeguards its credibility."

Dr. Hoey held the view that the journal's responsibilities extended beyond rote publication of medical research, to the doctor-patient relationships, to legislation, and to "health determinants", including politics:

"Some readers have expressed the view that any comment on international politics is inappropriate in our journal: the medical profession, or medical journal editors at the very least, they argue, should stay out of political debate. For our part, we fail to see how health can be viewed as apolitical, or how medicine can be practised in an ideologic vacuum. Even though medicine strives toward humanitarian ideals that it perceives as universal, all human action occurs in social and political contexts."

In the past couple of years the journal had increased the pressure on pharmaceutical companies. Hoey pressed for policies requiring authors to list their drug company affiliations when submitting research. In February of 2004 an editorial lambasted the pharmaceutical companies for not releasing negative clinical trial results and for "deceiv[ing] physicians, their patients and, perhaps, shareholders...a flagrant abuse of the trust." (The Montreal Gazette, February 17, 2004). The editorial noted that Health Canada was complicit to the practice. The editor took both the FDA and Health Canada to task over 'suppressed' Vioxx risk data. Most recently he came out against calls by physicians for a more privatization in healthcare, a position that was articulated on the online site in direct conflict of the views of the CMA, but than quickly revised, according to Lancet.

Hoey certainly had his share of publicly contentious, media worthy moments, but his leadership also successfully increased the stature of the journal; its impact factor more than tripled during his tenure and CMAJ received public service awards for its journalism. He was acutely aware of the risks of forthrightness but refused to stand down. After the dismissals of the editors New England Journal of Medicine and the Journal of the American Medical Association in 1999, he wrote in "When Journals are Branded, Editors Get Burnt, The Ousting of Jerome Kassirer from The New England Journal of Medicine"; "The international medical community was reminded of the perils of - and necessity for - editorial independence with the firing of Dr. George Lundberg as editor of JAMA in January of this year that followed his fast-tracking of a politically sensitive article". (CMAJ September 7, 1999)

Kaissirer, the NEJM editor was "sacked" in a dispute over a decision for the publishers to sell the NEJM brand for non-related products. Hoey supported the ideals Kassirer had failed to solidify at NEJM and was a staunch proponent for the lofty goal of medical journal "stewardship":

"...This is the notion of intellectual custodianship. In a prescient editorial written a month before he [Kassirer] was sacked, and echoing, perhaps, our own thoughts, Kassirer wrote: 'When a membership society's journal gains international respect. . . the journal in some sense transcends its local ownership and becomes the property of the worldwide professional community and the public. In such instances, the journal's owners have a formidable public responsibility as stewards....'

That stewardship includes the responsibility to ensure, on the one hand, that a journal's reputation for reliability and scientific rigour is not diluted by specious association[s]...The reputation of the NEJM was built on the intellectual contributions and just plain hard work not only of its editors but also, and more importantly, of the authors who report research that is, directly or indirectly, funded by the public and of the reviewers, correspondents and many others who contribute to the journal without financial compensation."

Yesterday a former chief justice of the Supreme Court (Canadian) was appointed to help sort out the CMAJ upheaval; an appropriately authoritative figure, we suppose. The editorial board is reportedly holding out for a commitment to independence from the CMA that doesn't seem to be forthcoming. Although people are calling for the firing of the publisher and the reinstatement of the editor, we see these as unlikely future events. The world is decidely moving steadfastly towards more and more privatization, and privatization is a force to be reckoned with. But "fresh starts" don't always turn up daisies. The move may smooth the way for the CMA, but will it improve care? What is medicine about? Perhaps Canada should look across the border and see beyond the profits of the U.S. medical system, the muddy confluence of business, patient, physician, and for-profit insurance interests that collide in the messy landslide of patient care.

Medical journalism subsumed by business interests, follows the way of journalism subsumed by the same. Hoey wrote in "An Editorial on Editorials":

We don't believe that it behooves journalists in any guise to say things merely for the sake of being provoking. At the same time, if our commentaries caused no discomfort to anyone (including ourselves) we would worry even more than we usually do about how well we are doing our job.

Dr. Hoey's keen, well-written commentary and active role in the Canadian healthcare system via CAMJ will no doubt be missed.

--------------------------

Last May, Acronym Required wrote about the increasingly interdependent relationship between pharmaceutical companies and medical journals in "Just The Facts....mmm....No! Not THOSE Facts: Science Reporting in Medical Journals".

Oysters on the Hudson

The New York Times author William Grimes reviews "The Big Oyster", by Mark Kurlansky, in "Before There Were Bagels, New York Had the Oyster". In an interesting sounding book, Kurlansky, the author of "Cod" and "Salt", details the history of the perished Hudson oyster. In Grimes' review, he contemplates "The Big Oyster" author's vision that the Hudson will be rejuvenated someday (in the nature sense here -- apart from the business sense).

"...[T]eeming mass of sturgeon, striped bass and shad swimming through the Narrows...up the Hudson...acres of fecund oyster beds...cleanse the waters of New York.

"This is no fantasy", Grimes says. Then, at the end of the book review, after contemplating the reality of the NY metropolis, its effluent, and its unlikely coexistance with oysterbeds, he asks "Is paradise lost forever?"

He points to groups like the Baykeepers, an environmental group devoted to the estuaries (who coincidentally, discuss the "commons" on their home page). The group projects hopefully that the estuaries and their oysters can be restored and served on NY restaurant tables. Oyster lovers we are, but realists also we tend to side with Grimes, who says: "You first."

Octavia Butler

Octavia Butler died this week. Butler wrote captivating science fiction, short stories such as the award-winning Bloodchild, as well as fiction such as the Patternist series and was known for her humane, if to this reader sometimes alarming stories. Butler was an African American woman who dominated a genre not known for African American women. If she had challenges though, she was as matter of fact about her efforts to publish, as she was of her habit of writing a different sort of family history into science fiction:

"When I began writing science fiction, when I began reading, heck, I wasn't in any of this stuff I read," Ms. Butler told The New York Times in 2000. "The only black people you found were occasional characters or characters who were so feeble-witted that they couldn't manage anything, anyway. I wrote myself in, since I'm me and I'm here and I'm writing."

Octavia Butler achieved acclaim as the recipient of a MacArthur fellowship, two Hugo Awards and Nebula awards. Here is a tribute to her via YouTube

follow us on twitter!

Archives