PolyHeme is a solution of human hemoglobin extracted from red blood cells that has been modified using a multi-step polymerization process. The purified hemoglobin is associated into tetramers and is incorporated into an electrolyte solution. The polymerization of the hemoglobin represents the critical advance in the development of artificial blood. Previous attempts using non-polymerized hemoglobin caused vasoconstriction. Also, filtration of free globin chains by the kidney causes renal failure. The company currently uses expired human blood from which the hemoglobin is extracted and purified. The hemoglobin molecule is then pyridoxylated to raise the P50. Subsequently, this hemoglobin is polymerized with glutaraldehyde.
Because PolyHeme is a hemoglobin solution and does not contain intact red blood cells which express ABO antigens, cross-matching of the product or typing of the patient is not necessary. This is required with units of red blood cells. PolyHeme is manufactured from human red blood cells that have been tested similar to red blood cell units. In addition, during the manufacturing process steps are performed that would reduce the risk of viral infection. It has a shelf life of over twelve months. PolyHeme can be stored at room temperature, versus red blood cell units which require refrigeration. The storage conditions and lack of need for compatibility testing would make PolyHeme advantageous in emergency situations as well as in treating combat casualties. Another advantage is its acceptance by some patients seeking bloodless medical care. Of note, not all patients who object to blood transfusions will accept PolyHeme as the hemoglobin is derived from human blood. PolyHeme only provides oxygen carrying capacity and does not provide coagulation/clotting factors or platelets.
PolyHeme, like all hemoglobin solutions, has an intravascular dwell time significantly shorter than the 120 day dwell time of transfused red blood cells. The result is that the effects of infusion are temporary and it may be necessary to transfuse red blood cells after PolyHeme is excreted. PolyHeme, like all hemoglobin solutions, interfers with many laboratory tests, especially those measured spectrophotometrically. Finally, similar to other hemoglobin solutions, it has been associated with an increased risk of myocardial infarction (heart attack) in patients receiving it during the Phase III trial.
Development and production
On May 23, 2006, Northfield Labs selected Jacobs Engineering Group Inc. to provide engineering services for a new biological manufacturing facility. The facility will consist of commercial manufacturing space in a facility adjacent to Northfield Laboratories' existing pilot plant operations in Mt. Prospect, IL and will include production modules, laboratories, warehousing, utility support, and offices.
Additionally, on June 16, 2006, Northfield Labs announced it signed an agreement to purchase a Template:Convert/sqft property it had been leasing to be used as the first planned commercial facility to manufacture PolyHeme. The Mt. Prospect, IL facility was purchased for $6.7 million and is expected to be capable of producing at least 100,000 units of PolyHeme annually.
Clinical trials and consent controversy
Polyheme finished a Phase III trauma trial in June 2006.
The testing was completed at more than 25 Level I trauma centers in the United States under a Food and Drug Administration special category (21CFR 50.24) in 1996 that allows its use without patient consent in special circumstances. PolyHeme was the 15th such experiment allowed by the FDA. Although Northfield Laboratories came under scrutiny for this trial, enrollment of the 720 patient trial was completed on July 31, 2006.
The controversy arose from the fact that the participants in this study were incapable of giving their consent due to the nature of their injuries. The only way to opt out from the study was by wearing a special bracelet prior to needing emergency care (the bracelet can be requested by calling 717-531-5829). Even though this practice is sanctioned by the FDA as necessary emergency research, patients’ rights groups protested the study.
Petition for fast track
In a financial analysts and investors meeting on August 8, 2006 in New York, Northfield Labs revealed that it had just sent in an application to the FDA for Fast Track designation of PolyHeme and that by law, the FDA was supposed to provide a response within two months. If a Fast Track designation is approved, Northfield planned to request for Priority Review when it submit its Biologic License Application (BLA) sometime in the first half of the year 2007. Fast Track is a feature of the FDA Modernization Act of 1997 and is intended to facilitate the development and expedite the review of products intended for the treatment of serious or life-threatening conditions and which demonstrate the potential to address an unmet medical need for such a condition. It was also re-stated that the company expected to report top-line results of PolyHeme's Phase III study in the fall of 2006.
In a press release on October 10, 2006, it was released that Northfield Labs and the FDA had both agreed to defer the Fast Track designation until the availability of the top-line result in the fall. Fast Track designation was deferred because the FDA needs to know not just the product, but also the indication for which the product will be used. The indication was yet to be determined because the PolyHeme Phase III trial had two primary endpoints of superiority and non-inferiority. And until the release of the top-line result, whether either, both or none of the endpoints were met is unknown.
The Phase III trial was designed as an "active-control dual superiority-noninferiority trial comparing the survival of PolyHeme patients to those who received standard treatment (salt water plus blood)". On December 19, 2006, Northfield Labs released preliminary results of the trial, and the mortality data was disappointing: 13.2 percent of patients receiving PolyHeme died versus 9.6 percent among the control group. This news led to Northfield shares plummeting more than 50%. However, the company remains optimistic, noting that of the 712 randomized treatment patients, 20% of the PolyHeme group and 15% of the control group were protocol violations, leaving a valid total of 586 patients. Northfield is currently re-evaluating the study database to determine if any additional statistical errors are present. They expect to announce any release of the final results only after error corrections are complete. Additional safety data is also expected from the CRO in four to six weeks from the December 19 announcement.
Further Clinical Trial Controversy
Results of the Phase III trial were published in the Journal of the American College of Surgeons January 2009 (electronic publication November 2008). There were claimed to be no significant difference in outcomes between the conventionally-resuscitated group and the Polyheme-treated group. Concern about coronary ischaemia was addressed, and the uncomfortable fact that 3% of the polyheme group were reported to suffer myocardial infarction compared to only 1% in the control group was softened by a claim that a blinded committee of experts were unable to discern a difference between the groups. Investigators concluded that 'although there were more adverse events in the Polyheme group, the benefit-to-risk ratio of Polyheme is favorable when blood is needed but not available'<ref> J Am Coll Surg 2009 Jan:208(1):1-13 </ref>.
- Blood substitutes
- Blood transfusion
- Blood type
- Golden hour (medicine)
- Level I trauma center
- Northfield Laboratories
- Official website of the maker of PolyHeme, Northfield Laboratories.
- Participating Trauma Centers.
- Federal Regulation 21CFR 50.24 allowing Exemption of Informed Consent.
- PolyHeme's patent.
- U.S. FDA's Community Disclosure of Institutional Review Boards.
- U.S. Senator Dick Durbin's $3.5 million Defense Appropriation for PolyHeme Development.
- A participating Trauma Center's discussion on the above so-called "controversy".
- Northfield Laboratories Releases Summary Observations from Its Elective Surgery Trial ie. "the ANH trial".
- Northfield Laboratories Strongly Disputes Wall Street Journal Story Conclusions.
- Northfield Laboratories Statement Regarding Its Pivotal Phase III Trial, in response to critics about its waiver of informed consent status.
- Northfield Labs' response to ABC 20/20 segment regarding patient safety and waiver of informed consent status.
- Fake Blood, Real Controversy
- PolyHeme - and the Newest Plastic Bracelet
- PolyHeme Lawsuits
- Northfield Labs PolyHeme description
- Northfield -- Jacobs Engineering contract.
- Northfield's Mt. Prospect, IL facility purchase.
- Phase III PolyHeme Trial Completion
- Application for Fast-Track status sent to FDA.
- Preliminary Top-Line Results of Phase III study.
- Study publication 2009