BLOOD SUBSTITUTE EFFICACY ENDPOINTS WILL EVOLVE THROUGH CLINICAL EXPERIENCE, FDA HEMATOLOGY HEAD SUGGESTS; RED CELL SUBSTITUTE WORKSHOP FINDS LITTLE CONSENSUS

Blood substitute efficacy endpoints will evolve through clinical experience, FDA Center for Biologics Evaluation & Research Hematology Division Director Joseph Fratantoni, PhD, suggested at an agency cosponsored workshop on criteria for efficacy of red cell substitutes held at the National Institutes of Health Jan. 11.

Acknowledging the minimal consensus among workshop participants on efficacy criteria for blood substitutes, Fratantoni said that "we are going to learn a little bit here and a little bit there" about the efficacy of blood substitutes.

Fratantoni hinted that the scenario for blood substitutes would be to "probably get approval for one sort of indication and get the material out there to be used clinically and start learning about it." He added: "I think we are going to have to build on those experiences."

Pointing to the definitive double-blind and randomized placebo-controlled clinical trials conducted for other hematological products, such as erythropoietin, that made "[everybody] happy at the end," Fratantoni said: "I don't think we are likely to see that in the foreseeable future with blood substitutes. I think we are going to chip away at this."

FDA plans to formulate an addendum to the "points to consider" document on blood substitutes that incorporates suggestions made during the workshop that was cosponsored by FDA, the National Heart, Lung & Blood Institute and the Army. The agency will accept comments on blood substitute efficacy during the next few weeks.

The workshop looked at the use of red cell substitutes in radiotherapy, coronary angioplasty, hemorrhagic shock and resuscitation, hemodilution and perioperative settings. Clinicians, who discussed efficacy endpoints for their respective fields, varied widely in their opinions about whether blood substitutes are ready to enter clinical trials, even though some products are already being used in humans.

Workshop presenter Beverly Teischer, MD, Dana Farber Cancer Center, said she would recommend further clinical trials in the cancer setting "without reservation." Teischer said that data show that Alpha Therapeutic's oxygen carrier Fluosol extended median survival time in brain cancer patients from 54 weeks to 75 weeks and that three of 18 patients have survived out to five years. Fluosol reduced hypoxia in tumors allowing radiation therapy to permeate more of the cancerous area, Teischer explained.

Teischer recommended blood substitute clinical efficacy endpoints in cancer of increased response rate, shorter time to response and longer duration of response. Reduction of hypoxia could be used as a surrogate endpoint, she said.

Kenneth Kent, MD, Washington Hospital Center, District of Columbia, said Fluosol has been shown to improve heart function in angioplasty; however, the availability of an autoperfusion balloon catheter that allows whole blood perfusion largely has supplanted the need for such a product. Kent maintained that the "most promising area" for blood substitutes in coronary care would be post-myocardial infarction to reduce damage to the myocardium.

Fluosol manufacturer Alpha Therapeutic is discontinuing promotion, and eventually marketing, of Fluosol because of limited use. In a Jan. 4 letter to physicians, the company said that "although the product did perform its intended function, the proportion of patients in which this is necessary were smaller than originally expected." The firm said that it will exhaust its inventory of Fluosol, which should take 12 to 18 months.

The use of blood substitutes in hemorrhagic shock was discussed by Colin MacKenzie, MD, University of Maryland, who said that clinical settings would be an excellent place to test red cell substitutes. He maintained, however, that studies in the literature show that substitutes often are no more effective than volume expanders such as albumin for hemorrhagic shock.

MacKenzie's concerns were echoed by Reuven Rabinovici, MD, Thomas Jefferson Medical College, who agreed that based on the scientific literature, he could not recommend clinical trials with red cell substitutes in hemorrhagic shock until more toxicity studies have been conducted. "In order to evaluate the efficacy of any hemoglobin-based factor, it is absolutely necessary to study very thoroughly the physiology of oxygen transport and utilization, and in hemorrhagic shock the exact relationship between oxygen delivery and oxygen consumption and oxygen extraction," he added.

University of California-Davis researcher James Holcroft, MD, asserted that blood substitutes may be appropriate for hemorrhagic shock trauma patients, noting that the agents could be compared to red blood cell transfusion or no transfusion for survival and neurological outcome. Holcroft suggested that blood substitutes might be used without consent in patients with head injuries, since those patients generally have a high rate of mortality.

Commenting on the perioperative setting, Robert Winslow, MD, UC-San Diego, said: "I don't think we are going to come up with very clear criteria of when to use blood substitutes in the elective setting, partly because we can't even do that for red cells." He maintained that there is no standard "transfusion trigger" in surgery.

In addition, Winslow said: "Direct demonstration of efficacy in the elective use of blood -- that is survival, quality of life, symptoms, etc. -- could be impossible as it would be with blood." He suggested, however, that decreased use of allogeneic blood might be considered a "valid goal and efficacy endpoint."

"I kind of agree with the point of view that Steve Gould [Northfield Labs] and others have raised that, if you raise hemoglobin concentration, you have done something good," Winslow said. "I kind of agree with that, but we have to talk about something that is safe without toxicity. To my knowledge, we don't have that product yet," Winslow noted. "We have to understand something about how it transports oxygen. Cell-free hemoglobin does not transport oxygen like red blood cells and neither does fluorocarbon," he maintained.

Despite the uncertainty voiced by some of the clinicians concerning the eligibility of blood substitutes for clinical trials at this time, several companies are forging ahead.

Northfield clinical investigator Steven Gould, MD, said his company plans to begin a Phase II dose-escalation trial with its polymerized hemoglobin-derived (Poly SFH-P) product in resuscitation and hemorrhagic shock the week of Jan. 17. "The goal will be to get to the 24-hour period where all transfusion requirements are given in the form of the poly hemoglobin," Gould said.

Alliance Pharmaceuticals' Peter Keipert, PhD, said his company is planning a clinical trial for its perfluorooctylbromide-based oxygen carrier Oxygent in elective surgery patients to decrease the need for autologous blood transfusions.

Additionally, Somatogen is conducting a Phase I trial with its recombinant human hemoglobin (rHb1.1) in anesthetized surgical patients; Baxter began clinicals of its blood substitute DCLHb in mid-July; Biopure's Hemopure is in Phase I for oxygen deficiency during surgery; and Enzon has said it plans to file an IND for its glycosylated bovine hemoglobin product PEG-hemoglobin in 1994.