In late December, Northfield Laboratories announced the results of Phase III clinical trials of Polyheme, a hemoglobin based oxygen carrier (HBOC), that ended last summer. The Wall Street Journal reported the negative results in "'Preliminary' Findings Of PolyHeme Death Rate Suggest Approval Setback"(12/20/06). We learned that 712 trauma patients with trauma and significant blood loss were enrolled in the study. 46 patients treated with Polyheme died, versus 35 control patients who died from standard treatment. 13.2% of the Polyheme patients died versus 9.6% of the patients of standard treatment. The standard for care is to give saline to the patient during transport only until donor blood is available at the hospital, whereas the trial patients were extended on Polyheme for 12 hours after they reached hospitals.
The response to the negative news was immediate. Quite a few people suddenly distanced themselves from Northfield Labs. West Virginia University hospitals, who enrolled in the Northfield study and is listed on the clinicaltrials.gov site, issued a press release saying that even though ambulances were carrying Polyheme,"The drug, PolyHeme, was never used on any patients in West Virginia, according to Dr. Lawrence Roberts, director of WVU's John Michael Moore Trauma Center". (italics ours) The doctor defended the choice to participate in the study while dismissing the product: ''The data looks like the patients that got Polyheme had worse outcomes. That implies this stuff is no good and you can't use it."
Investors, brokers and some financial reporters, who had once rabidly attacked reporters and sites that brought up patient safety concerns, started echoing "I told you so" headlines back and forth to each other. The stock sunk from $17 to $4. Northfield Labs' CEO, Steven Gould presented to an investor teleconference last month and the WSJ noted his eternal optimism, saying he was
"'encouraged' and 'optimistic' that the company's blood substitute soon will become the first approved by the U.S. Food and Drug Administration to revive hemorrhaging patients." [WSJBurton, Thomas "Blood Substitutes Face Long Odds History, Scientific Concern Hamstring Sector" February 13, 2007].
Cheery as Dr. Gould is, none of this bodes well for patients. The negative results also suggest that past patients also did not receive optimal care for their situation. Doctors, emergency workers and the military as well as future patients would benefit from a new product that delivers oxygen, survives storage and transport, and doesn't require blood matching.
In this clinical trial Polyheme's success is judged according to a simple but slightly unusual criteria. The goal was to show that the product "superior" to, "not inferior" to, or "inferior" to the standard treatment. The future of the product depends on how many people survived the Polyheme group as opposed to the control group. Northfield is now striving to get the FDA to label the Polyheme "not inferior".
The CEO called the shaky results "preliminary". He said that some of the data had errors because of "protocol violators", that is patients were enrolled who for one reason or another should have been excluded. When these patients' data was removed from the analysis, he said, the results of the study looked better would look favorable to the FDA review. The protocol violators died more frequently. Of the 126-patient "protocol violator" group that Northfield seeks to exclude, according to an analysis on Thestreet.com, by Adam Feuerstein, thee death rate of patients getting Polyheme was 17/70 or 23%, versus the controls 7/56 or 12.5%. However, since the trial was originally structured for patients with significant blood loss and trauma. Feurestein points out:
Northfield designed an ambulance trauma trial for Polyheme because it wanted to see how the blood substitute performed in the real world, where all kinds of patients are bleeding to death from all sorts of accidents. After the fact, when the results aren't to its liking, the company can't go back and argue that Polyheme works, but only when conditions are perfect.
Actually, Northfield also chose this particular patient cohort because previous trials of Polyheme (similar to their HBOCs) failed when the products were applied in routine surgery and non-trauma situations. These trials ended badly for patients, so the companies turned their attention to critical care scenarios where donor blood wasn't an option. Since we're at war (perpetually, now), there's a huge potential military market for these products, that may coincide with the uptick in FDA interest. But will the FDA allow Northfield to meet the trial's patient quota with "protocol violators", then in retrospect exclude those patients? Some financial analysts like Feuerstein are doubtful. The FDA's actions will also be followed with interest by those in drug development, and those concerned with patient safety and clinical trials.
Northgate's Phase III trial attracted initial controversy because it necessitated waiving patient consent to test the product in severely injured trauma patients. The trial involved giving a blood substitute in lieu of saline during transport, and for 12 hours after the injury once donor blood was available. Doctors and people involved with patient ethics questioned whether communities were being educated adequately about the trials. People asked why participating doctors and medical centers seemed unknowing about previous failures with the blood substitutes. Fortunately for Northfield, all of this controversy only heated up three years into the trial. Northfield stopped enrolling patients just a few weeks after a story about patient consent aired on 20/20.
However the next trial for an HBOC will be conducted differently. The FDA recently denied the company Biopure, Northfield's neck and neck competitor for over 20 years, latitude to conduct a Phase III trial with its competing product Hemopure. Instead it will conduct a Phase II trial with fewer patients and the use of Hemopure will only be allowed until donor blood is available.
Despite years of work and promises, some people doubt the HBOC's viability, due to decades of failures in clinical trials. The WSJ quoted a former medical director of Biopure Corp. in Cambridge, Massachusetts, a company that makes one of Polyheme's competing products Hemopure, who said that the '"totality of the data' on this class of products is that 'so much harm has been shown, without benefit, that the field should be stopped.'"
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Acronym Required previously wrote about Polyheme and Hemopure in Polyheme© and The Newest Plastic Bracelet. We looked at the history of the products, focusing on on Northfield and Biopure, in Polyheme& Hemopure: Life Savers? Products to Die For?
