A few months ago, Acronym Required wrote an article called "Polyheme© and the Newest Plastic Bracelet", about Northfield Laboratory's clinical trials of Polyheme©, a reconstituted hemoglobin product for trauma patients. The Phase III trials, which randomly assign patients with severe blood loss in life-threatening trauma either Polyheme© or typical saline solution, are being conducted throughout the U.S. and are predicted to continue through the 4th quarter of this year.
The trials concern many ethicists and doctors because the participants, all victims of severe trauma, are not in a condition to be able to consent to the trial. Consent is a cornerstone of medical research. Most troublesome is that trial conditions demand that the patient continue being administered Polyheme© for an hour after they reach the medical center where the key life saver, human donor blood, is available. (Maybe designed to more realistically test conditions where the substance might be used, like on battlefields).
While no-consent trials might have their place in product development for trauma applications, many critics assert that the company and participating research centers are not providing required and critical information to potential participants. Most citizens in participating cities have no idea about the existence of the trial or its risks. As well, it seems like unfavorable patient survival data from previous trials on Polyheme© is being suppressed even as patients have been being enrolled for several years in Phase III trials across the country. For
instance the government of Norfolk, Connecticut, (PDF) notified citizens of the trials in a newsletter, "Civic Connection" (May 24,2004):
"Norfolk Fire Rescue (NFR) has a history of being a leader in the field of emergency medical services (EMS). ...Norfolk was selected, along with EMS systems and trauma centers across the country for the final phase of the [Polyheme] study. Phases I and II of the study showed that PolyHeme increased the survival of critical patients that were bleeding and no patient had any sort of adverse reaction to PolyHeme."[emphasis added]
Another center in Georgia recently signed up for clinical trials and Dr. Dennis Ashley, director of trauma services at the Medical Center, was quoted by The Macon Telegraph (Georgia), July 12, 2006 : "'Having this resource on hand is a great benefit for us and the country as a whole'". The newspaper noted "Polyheme is considered by Ashley to be better than a traditional blood transfusion because it is universally compatible with every blood type and reduces the chance of virus transmission.". We're not so naive to think that the press always represents situations accurately, but this is what the citizens are led to believe, while the true history of Polyheme© is NOT being told to prospective patients and is quite different. As the Wall Street Journal reported on February 22nd, in a previous study of cardiac surgery patients:
"...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."
Northfield Laboratories is a persistent company that has a lot of experience in the area of hemoglobin replacement products, which is potentially good for science and patients. But does their single minded determination to bring a product to market threaten to trump what's ethical for trauma patients and good for research (and "the country")?
What's Afoot for Northfield Now
Since our last article 4 months ago, Northfield has progressed with clinical trials.
The Securities and Exchange Commission (SEC), and the Finance Committee of the United States Senate are currently looking into allegations about the results of Polyheme© in previous trials.
The company bought a manufacturing plant in Illinois, and its stock price has increased.
It has been named in several investor class action lawsuits.
The clinical trials have attracted more attention from several TV "exposés", including 20/20.
The 20/20 piece focused on the lack of patient knowledge about the trials as well as the [ preposterous ] proposal that citizens who want to opt out of the study order and wear a light blue plastic bracelet 24 hours a day if they choose not to participate in the trial. Here are two short videos available from ABC's site: "Can You Bank on
Artificial Blood?" and "Can Artificial Blood Save Lives?" (these links launch videos hosted at the ABC site).**
The company continues to deny the veracity of negative reports and lawsuits, and provides upbeat news for investors. They are also mulish about providing any information for the results of their current trials, especially where deaths occurred. In addition to the
suit against the San Diego Reader in an attempt to prevent the paper from releasing information about patients who died during the study, several investigators associated with the trials in question were stymied trying to get promised information from the company. A John Hopkins doctor took issue with several points in a Northfield Laboratory press release that falsely suggested that he was endorsing Polyheme©:
"Contrary to a statement made as part of a press release by Northfield Laboratories of Evanston, Ill, on Feb. 22, 2006, a Johns Hopkins Medicine faculty member, Edward Norris, M.D., is not presenting information about a clinical trial of the company's blood substitute PolyHeme at the annual meeting of the Network for the Advancement of Transfusion Alternatives (NATA) in April 2006; was not given access to full study results from Northfield; and does not and cannot substantiate Northfield's claim that PolyHeme was unlikely to have been the cause of 10 heart attacks and 2 deaths in patients receiving the blood substitute as part of a clinical trial that ended in 2000."
Northfield has been pursuing the goal of getting a product to market for over two decades and has perhaps learned that bad results are better left unpublished, thus avoiding the risks of negative press and dampened investor enthusiasm.
Meanwhile, Northgate's competitor Biopure will be meeting with the FDA tommorrow, July 14, 2006, to review its proposal (with the Navy) to conduct its own no-consent clinical trials of its cow hemoglobin based oxygen-carrying solution (HBOCs) in civilian trauma patients across the U.S. The FDA has repeatedly
denied Biopure's requests to continue product trials. Now, apparently with the help of the Navy, Biopure has persuaded the FDA to reconsider its proposals. This announcement, made by the company in mid-April and recently publicized, is surprising for several reasons. Is this the same company whose officers, including the former President and CTO, general counsel, and CEO, were just months ago named in suits by SEC for misrepresenting the results of earlier trials? The same company, who's most recent clinical trials were highly criticized by the FDA?
Like Northfield Laboratories, from 1996-2002 Biopure seemed to be making headway with Hemopure©. It was the head of a field of competitors and headlines were ripe with expectant enthusiasm. An article in the New York Times titled, "Scalpel! Clamp! . . . Hemopure?; A New Urgency in the Race for Blood Substitutes", published March 4, 2001, detailed the company's progress with Phase III trials of the product. A Silicon Valley reporter wrote an article titled: "Biopure on Verge of Biotech Holy Grail". "Biopure, however, is the only company developing a human blood substitute based on a manipulation of low-cost, always-available cow blood." The companies stock skyrocketed with all the good news.
BioPure and Northfield Laboratories: How To Succeed in the Cutthroat HBOC Market?
As an aside, these products are only marginally "fake blood", or "artificial blood", as news reports so often proclaim, they're hemoglobin carriers. So while they're more useful than Ketchup, they don't replace the physiological functionality of real blood except to carry oxygen--undeniably, no small feat. They were mostly intended to replace Ringer's solution, especially on the battlefield. The goal, a solution which could be stored for longer periods then donor blood, would not require matching, and that could be carried more easily in battle, is a product of tremendous value. That said, any substance that is going to be infused into the body, bathing organs and cells that are dependent on a plethora of physiological functions of blood (many still unknown), is extremely vexing to develop. Blood has myriad vital functions that these solutions can't perform, but nevertheless the solutions are used to replace blood. The research is difficult and laden with pitfalls. Clearly, tenacity and persistence are key to Biopure's and Northfield Laboratory's success; and they have been enormously successful, all things considered, since most players in this market have disappeared, while decades later Biopure and Northfield Laboratories are still pursuing commercially viable applications.
Stephen Gould, the president of Northfield Laboratories, founded the company to pursue his academic HBOC research in 1985. Carl W. Rausch ex-president and chief scientist of Biopure (now resigned), founded that company in 1984 to develop a product from his academic research.
Initial results were not positive. In 1978 a small amount of an early hemoglobin product was given to six health volunteers." According to Gould, the substance was severely toxic to volunteers, which "scared the daylights" out of the scientists. For Biopure's former head Carl Rausch, it was a "mission" to make the substance work.
The companies were neck and neck throughout the 1990's, progressing through Phase I and II trials before launching Phase III trials with much fanfare and promise.
Both companies' first trials were for elective surgery. Biopure first tested its product for orthopedic surgery patients, Northfield Laboratories first tested its product for cardiac surgery patients. Both companies expected to begin selling products in the U.S. in 1999, then they predicted their respective products would be on the market in 2000.
Both companies scaled up manufacturing facilities in 2001.Northfield Laboratories, leased additional facilities. Biopure built one plant and announced plans for others overseas.
Their tenacity extends not only to difficult research, but to having tough enough guts to ride out unfavorable, sometimes fatal results with their products.They also seem to possess preternatural optimism, sometimes blatant denial, about the futures of their products. Could these companies success also be due to their business approach -- a highly confidential sometimes misleading representation of research results?
Both companies were secretive with trial results. In 2001 the investor site The Street, wrote a critical article about Biopure, saying that the company was claiming their product was safe but was being "extraordinarily secretive", while doctors reported problems like cases of kidney failure and elevated blood pressure. Northfield Laboratories did not release trial results in 2001, "making it impossible for outsiders to judge Polyheme's safety..", reported the Boston Globe. Northfield, which previously refused to publish now controversial results from previous trials, has also recently withheld data about deaths during clinical trials, although it reports that auditors have no complaints with current trials. Biopure is still promising to publish previous Phase III trials.
Northfield Laboratories finished phase III trials in 2001 and applied for approval from the FDA. The agency denied Northfield Laboratories application for undisclosed "scientific and regulatory issues." Biopure finished phase III trials in 2001 and delayed filing with the FDA. In 2003 the FDA found 220 questions and inconsistencies with Biopure's application including questions about why most subjects had been taken off Hemopure "due to investigator concerns about safety . . . and subjects experiencing adverse events."
Both companies may have conducted clinical trials for elective surgery patients where the results were apparently negative, but went unpublicized. The Street, writing about Hemopure's apparent safety issues in 2001,mentioned " A little-known study of Hemopure conducted by German doctors in the mid-1990s gave the product a failing grade and foreshadowed some of its current problems." The Wall Street Journal publicized the results of an unpublished 2002 study of Polyheme where the experimental patients had more heart attacks with then the control group.
Both companies have denied past negative results to proceed with clinical trials. In a September, 2001 web cast, when asked whether there were any serious adverse events documented that were considered directly related to Polyheme©, Gould said, "The answer to that is a strong -- no." A Boston Globe headline from August 2001 reported "Biopure Shares Soar 23% on Trial Results Firm Says Tests Show Blood Substitute's Safe."
In 2003 Biopure's luck started to turn. The company started laying off its workforce and key management left, but mysteriously, the company continued to release positive news about a pending FDA approval. The security and exchange commission started looking into the CEO's stock holdings (and sell-offs). Familiarly, class action law suits were filed. The stock sunk to $.35 per share. In September of 2005 the Securities and Exchange commission filed a complaints against several company executives including the co-founder, CEO and general counsel, alleging that even when the FDA repeatedly denied the companies requests to proceed with clinical trials based on its judgment of "an unreasonable and significant risk of illness or injury" to human subjects but for 8 months key officers made misleading claims about the company's progress. Later in the month, after 21 years with the company, cofounder Carl W. Rausch resigned in light of more SEC complaints. In April of this year he settled complaint the SEC had filed against him for $40,000 dollars. The other former officers were also scheduled to go to trial this spring, and we don't know the outcome of those SEC complaints. In the 8 months that Biopure purportedly misled the public the company raised $35 million dollars in stock offerings.
Considering the history of Biopure, the July 14th meeting with the FDA seems curious. But once you realize the value of a hemoglobin replacement and the investment that the taxpayers have in the development of such a solution, it makes more sense. The company reports that "to date, Congress has appropriated $18.5 million to the Army and Navy for the development of Hemopure" for trauma applications.".
Furthermore, Thomas Burton reported last week in the Wall Street Journal, some changes in the FDA review board that have contributed to the FDA's change in position:
"In an unusual step, the Navy, the sponsor of the proposed research, was able to recommend some doctors to be on the panel. Additionally, two well-known skeptics of substitutes who initially had been named as advisory consultants to the panel -- Charles Natanson, a critical-care specialist with the National Institutes of Health and John Hess, director of the University of Maryland's blood bank -- have in recent weeks been disinvited."
In another article yesterday, also in the Wall Street Journal (subscription), Mr. Burton reported that the FDA was holding a closed meeting, inaccessible to the public. According to the WSJ article, the FDA reports that there are "trade secret and/or confidential information", necessitating the closed meeting. But the company reports that they have "no objection" to a public meeting. The article quotes Sidney M. Wolfe, director of Public Citizen Health Research Group, who said: "Now that we know the company isn't objecting, but only the military, I am 10 times more worried than I was before".
UPDATE: July 14th: Following a Public Citizen lawsuit against the FDA, the agency has apparently canceled the meeting, and will reschedule a public meeting.
Are we Monkeys? The Role of Congress, the Navy and the FDA and the Proposed RESUS* Trials
Both companies are in the midst of pursuing clinical trials, although many companies that were listed as competitors throughout the 1980's and 1990's have long since dropped their products. Both Biopure and Northfield, in addition to their other positive and questionable attributes, also have the patience to wait for favorable political events.
Both companies changed their application focus from elective surgery, to trauma. Both companies took advantage of a the 1996 FDA ruling on no-consent trials.
Both companies are funded by military grants, and this may increasingly be an advantage. In a recent development, the no-consent allowance for civilian clinical trials which was passed in 1996 was extended to the military in 2002. This provides the beleaguered companies critical funding, and apparently political clout with the FDA.
It seems like the Polyheme© clinical trials are the beginning of a pattern, rather then an unfortunate aberrance from how no-consent clinical trials will be conducted. Clearly a viable product is coveted and these companies need to stay alive by sly market moves, tenacity, and persistence. Who is responsible for enforcing that elusive but catchy concept of "corporate responsibility"? What is it? We are naive to continue to wait for Northfield Laboratories or Biopure to divulge publicly how patients fared in the last clinical trials, to address ethical concerns that abound from many fronts, or for Northfield to put easily accessible information on its website about the baby blue plastic opt-out bracelet.
The military is now empowered with congressional funding to pursue these "RESUS" (Restore Effective Survival in Shock) trials with Biopure. This a new level of co-mingling between congressional funding, private profit, and public medical welfare. The FDA is the government agency responsible for protecting the public from potentially harmful food and drugs. Commenting on the lack of information available for the Polyheme© product in light of the no-consent trials, William Hoffman, chief of cardiac-surgery intensive care at Massachusetts General Hospital and former medical director of Biopure once commented that the FDA "'should have monitored what went on in the communities in terms of informing people' about deaths and heart attacks."' (Burton, Thomas, Wall Street Journal March 10, 2006: "PolyHeme: Blood-Substitute Study Is Criticized by U.S. Agency").
While we wait for any sort of transparent vetting of these issues, by the companies, Congress, or the FDA, anyone who didn't participate in the Polyheme© trial may soon have another opportunity to participate in Biopure's trial with its product, Hemopure©. Perhaps, if the public doesn't have a say or a view into the decision making process used to determine whether the trials proceed, than we can suggest a bracelet color for the Hemopure opt-out clause (after we mull over our choice for American Idol of course).
*RESUS: Restore Effective Survival in Shock. Even in the world of clever acronyms, this does seem to be a slightly cynical choice--
** Acronym Required has received countless requests about where to get the bracelet for the Polyheme© trials. It is difficult to track down, but is available via the company's investor relation contact info, as well as at the medical centers conducting the trials.
Update August 7th: According to the clincal trials site information on Polyheme at www.clinicaltrials.gov, Northfield
has completed recruiting patients for this trial.