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Red cell substitutes

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Table 1 Products and Status, 2006 Generation “First” “Second”

“Third”

“Fourth”

Technology Red cell lysis Polymerized Hb

Product SFH PolyHeme

Company

Effects

Academic Warner Lambert Renal failure GI symptoms Discontinued Northfield ? Phase III trauma Hemosol Cardiac events Discontinued Biopure Vasoconstriction ? Indication US Army Vasoconstriction Discontinued Baxter Death (stroke, trauma) Discontinued Somatogen Vasoconstriction Discontinued Ajinomoto/Apex Generally safe Sepsis trials Enzon Generally safe Discontinued

HemoLink HemoPure Intramolecular crosslink ␣␣-Hb HemAssist rHb1.1 PEG conjugation PHP PEG conjugation PEGhemoglobin PEG conjugation Hemospan Sangart

Generally safe

Zero-link

?

ZL-HbBv

Status

Oxyvita

Phase III elective surgery Preclinical

Abbreviations: SFH, stroma-free hemoglobin; PHP, pyridoxal phosphate hemoglobin polyethyleneglycol; ZL-HbBv, bovine hemoglobin polymerized with Zero-Link technology (see text); Hb, hemoglobin; PEG, polyethylene glycol; GI, gastrointestinal.

unexpected cardiac toxicity in its clinical trials, and the clinical indications for HemoPure have not been announced by the company. Northfield Laboratories pioneered modern clinical trials of oxygen carriers. The company initially reported a series of surgical patients that received relatively large amounts of PolyHeme, showing the product could be used instead of red cells for transfusion.23 A Biological License Application (BLA) was submitted to the US Food and Drug Administration (FDA) in August 2001 based on the results of a trauma trial in 171 patients, but the FDA issued a refusal to file letter, citing difficulties in the design of the clinical protocol. The results of the trial, eventually published in the scientific literature, showed that patients with severe traumatic blood loss were treated in hospital with up to 20 units of PolyHeme (⬃ 50 g of hemoglobin per unit). Nine of 12 patients (75%) with red cell hemoglobin levels less than 1 g/dL survived the traumatic injury compared to a group of historical controls in which only 16% of patients survived with the same hemoglobin level.24 To address the difficulties with the use of historical controls, Northfield Laboratories designed a 720-patient phase III trauma trial, in which patients are randomized at the point of injury to receive either PolyHeme or standard of care (infusion of crystalloid solutions). Upon reaching the hospital, the standard of care arm receives blood as indicated, while the PolyHeme arm receives additional PolyHeme up to 12 hours, and thereafter receives blood if indicated. Northfield Laboratories has a Special Protocol Assessment (SPA) with the FDA that includes the dual primary end points of both superiority and noninferiority compared with blood. The company has not disclosed its power analysis for the study but is planning for a total enrollment of 720 patients. A Data Safety Monitoring Board (DSMB) will review the safety data, and the company’s press releases to date have announced that analysis after enrollment of 60, 120, 250, and 500 patients has not resulted in either adjustment of the power of the

study or breaking the blind to evaluate any imbalance in safety. A controversial aspect of the Northfield Laboratories’ phase III study is its conduct under a waiver of consent, approved by the FDA, for circumstances in which a therapy may be life-saving but the patient may not be conscious or otherwise able to give fully informed consent. The applicability of this waiver has been challenged by ethicists on the basis that since PolyHeme is not FDA-approved, there is insufficient evidence to support the assumption that it is lifesaving. Northfield Laboratories anticipates that the results of the study should be available sometime in the first half of 2007. Assuming PolyHeme is able to achieve at least the noninferiority end point, the company would then submit its BLA to the FDA. Whether the license is issued would depend not only on the results of this phase III study but on approval of Northfield Laboratories’ manufacturing methods and their compliance with Good Manufacturing Practices (GMP) guidelines. Northfield Laboratories has not published data in the peerreviewed literature since 2002, and the scientific development of the product or any follow-on products is unknown. One recent independent publication from a US Army laboratory indicates poor performance of PolyHeme in an animal model of traumatic blood loss.25

Intramolecularly Cross-linked Hemoglobin: The Third Generation The US Army reorganized its Blood Research Division at the Letterman Army Institute of Research (LAIR) in San Francisco in 1985, based on its views, first, that human immunodeficiency virus (HIV) transmission by stored blood was a

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