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Executive Summary

HEMOGLOBIN-BASED OXYGEN CARRIERS: REPERFUSION INJURY ANIMAL MODEL "should be considered" by companies that are developing red blood cell-derived blood substitutes, FDA's Division of Blood and Blood Products said in an Aug. 21 draft document on the safety evaluation of hemoglobin-based oxygen carriers. "A model designed to produce reperfusion injury (thought to be mediated by a free radical mechanism) should be considered," the document suggests. "Such a model would be a relevant test of clinical situations that involve ischemia." The draft "points to consider" document builds on conclusions reached by FDA's Blood Products Advisory Committee in March and outlined in a draft "consensus statement." The consensus statement, based on the results of closed session meetings with a handful of companies involved in developing blood substitutes, recommended a number of specific preclinical and clinical studies to address incidences of liver and kidney toxicities seen in previous, limited trials of blood substitutes ("The Pink Sheet" March 19, T&G-13). FDA's "points to consider" will be published for comment in an upcoming Federal Register notice. The draft will also appear as a call for comments in a future issue of the journal Transfusion. The suggestions in the document are not intended to be all-inclusive, but are meant to help companies working on hemoglobin-based blood substitutes develop their IND safety and efficacy testing programs and provide FDA with up-to-the-moment data on the state of blood substitute development. Noting that the "mechanism(s) of toxicity has not been elucidated," the draft document points out that "for many of the observed effects, the underlying cause is not known." Concluding, therefore, that HBOC products should require thorough evaluation, the draft introduction states: "The recommended testing scheme that follows is based upon a hypothesis that the primary cause of toxicity is related to a fundamental mechanism (e.g., involving oxygen radical or iron) and that the effects seen are the results of activating any number of triggered enzyme or cellular systems." "While meaningful information can be obtained from [toxicity] studies in normal animals," the draft notes that "special animal models will be needed to obtain a complete safety profile." These special animal models should be "fully instrumented to measure cardiac and pulmonary function, should be stressed so as to resemble the clinical use of the HBOC [hemoglobin-based oxygen carrier] (e.g., volume depleted for resuscitative indication); ischemic model for PTCA [percutaneous transluminal coronary angioplasty]; repetitive administration for sickle cell disease, etc.," the document specifies. Additionally, "concomitant medications and other agents should be included, e.g., contrast agents with HBOC for PTCA indication. Controls should include use of approved oxygen carriers [e.g., red blood cells] and plasma expanders." Going into far greater detail on animal testing than the March consensus statement, the "points to consider" recommends that studies be performed on several animal species. The FDA draft also suggests that renal function is appropriately evaluated by a battery of tests. Once safety of a product is established and studies progress to humans, the draft notes that the interactions, if any, of HBOCs and the disease process "are poorly understood," and should be taken into account when dealing with patients and not healthy volunteers. The draft suggests that manufacturers should consider a third general category of safety testing: product characterization. The document lists a number of physicochemical tests that might be considered, but notes that not all would necessarily be required. Efficacy of blood substitutes is addressed only briefly in the draft, but the document does note that "manufacturers should consider their approach to demonstrating efficacy at an early stage of development." Efficacy, like safety, should be demonstrated for conditions that will mirror actual clinical presentations. Of "particular importance" in demonstrating efficacy, the draft says, are the function of the substitute "in the presence of red cells"; "measurement of tissue and organ function"; and a comparison of the substitute and red blood cells.



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