Medical Device Daily Washington Editor

SILVER SPRING, Maryland — The blood products advisory panel that met last Thursday to discuss the re-application for a Phase III trial for Hemopure used to treat trauma/hemorrhagic shock (HS) was peopled with its share of trauma surgeons and ethicists, but the day turned on statistics as argued by a biostatistician. He was outnumbered, but not outflanked.

In the end, the novel nature of the Phase III RESUS trial, combined with a modest set of safety data, kept the majority of the panel from approving a Phase III trial for Hemopure, a blood substitute product developed by BioPure (Cambridge, Massachusetts), despite a phalanx of advocates.

Among the advocates for RESUS was Adil Shamoo, MD, editor and founder of the journal Accountability in Research. Despite his pro-Hemopure position, Shamoo said, “I still think that this is a very troubling type of experiment.“

In the past, he said he had “always come down for 'protection' of subjects“ and that such research “must be very compelling“ in order to be even remotely worthy of consideration. But in this case, he said, the compelling reason is “58% mortality,“ without use of a blood substitute.

“We have to bend over backwards to ensure the appropriate ethical framework,“ he said. He argued that the RESUS protocol “is way better“ than that required by the FDA. And he noted that a data monitoring board would have “absolute power to stop“ the trial.

Ethicists Kenneth Kipnis, a professor of philosophy at the University of Hawaii (Honolulu), said that adverse events “are a feature of many medical treatments, but screening is not always available“ to control for patients who would not benefit. As for the ethics of applying a treatment with uncertain outcomes, he noted that blood transfusions are done though the benefit is less than universal.

Consideration of the adverse event must also address the underlying condition, Kipnis said and the high mortality for those experiencing HS warrants such a trial.

“It makes sense to leap into a crocodile-filled river to escape from a lion,“ he said, adding that the current mortality rates for HS constitute “a pack of lions.“

Kipnis asserted that the number of lives saved by use of Hemopure would substantially outnumber those lost to its widespread use, and that “the RESUS study appears to measure up to scientific and ethical standards.“

Aryeh Shander, professor of anesthesiology at the Mt. Sinai School of Medicine (New York), said that “the current strategies for dealing with hemorrhagic shock are very limited.“

The origin of RESUS was with a group “of committed and concerned physicians,“ he said, by the name of STORMACT (Strategies To Reduce Military And Civilian Transfusion). “As a result of the tumultuous times“ after 9/11, STORMACT was formed to re-evaluate resuscitation in emergency patients.

Shander said that RESUS “is a child of Sept. 11, 2001, born independent of industry,“ and that “the principles of its genesis are still plaguing the medical community both abroad and here at home,“ namely the lack of blood in on-scene trauma.

One of the issues faced by the panel was whether hypertension might affect intracranial bleeding in patients with traumatic brain injury (TBI).

Timothy Buckman, MD, professor of surgery at Washington University School of Medicine (St. Louis, Missouri), said, “I was an anesthesiologist in a level 1 trauma center for 20 years. It seems to me that it's self evident that when you increase a source of bleeding in a closed space, intracranial pressure will increase unless it's treated.“

He noted that such a condition could lead to more massive hemorrhage from the cranium.

Trauma surgeon Carl Hauser, a visiting professor of surgery at Beth Israel Deaconess Hospital (Boston), rebutted that, calling it “absolutely incorrect, and the prospective data demonstrate that it's not the case and that there are a lot of things in medicine that are self evident that are not true.

“I have taken care of a thousand patients a year like that, year in and year out, for the past 25 years, and I can tell you that it's not true.“

Thomas Fleming, PhD, a biostatistician at the University of Washington (Seattle), argued that “anyone involved in a non-inferiority world would be apoplectic“ hearing that the data presented by Biopure constituted evidence of an adequate degree of safety. He said the pre-clinical data “indicate no evidence of increased risk in heart failure or cardiac injury,“ but that data from human trials exhibit a “1.5-fold increase in total death rate, a 3-fold increase in MI [myocardial infarction], a 2.5-fold increase in cardiac arrest, a 2.5-fold increase in heart failure, which were all in fact domains that we were told that the animal data indicated that we shouldn't have an increase.“

“Can we trust those data to indicate that in the RESUS trial context there won't be an increase risk when I presume that in the HEM-115 trial, we would have been somewhat reassured that these data should have indicated that in that context, there would be no increased risk.“

“Nonetheless, there was an increased risk,“ Fleming said, and the risks “carried significant long-term morbidity with them.“

Buckman argued that the panel should “not get hung up on specific adverse events.“ The patients in question are “in deep shock, and … without the most aggressive forms of care, would not survive.“

“When we do have a survivor, it is common that we see pneumonia, it is common that we see significant renal insufficiency requiring dialysis,“ Buckman said, stating further that “the rates at which we see these types of complication all exceed the absolute incidence“ in the elective populations of any age.

He added that when those older than 70 show up in trauma rooms, some will show up with infarction and stroke, not always because of the injury.

“The types of differences that we're talking about in the elective environment are completely washed away in the ordinary frequency of these events in the population that's going to be the target of the RESUS study,“ Buckman insisted.

The panel did not vote on all five of the questions put to it by the agency, but as to whether the data presented was sufficient to detail the incidence of all-cause mortality, the panel seemed less than agreeable.

Hauser maintained that Biopure “put a lot of lipstick on this data, but the reality is that HOBCs will save lives in the absence“ of red blood cells.

Fleming argued: “[W]hat seems logical here is a Phase II trial,“ a stand he took repeatedly despite the roadblock imposed by the requirement of consent under field trauma conditions.

Jay Epstein, MD, medical officer at the FDA Center for Biologics, said that FDA “is willing to consider a Phase III trial,“ but questioned the sort of information such a limited effort might yield. He said that absent a stronger safety profile,“ the benefit of the product to the individual patient is not established, and hence presents ethical dilemmas.

The third question, which was the only of the five to net a full vote of the panel, was whether the available safety data indicate that the benefits outweigh the risks for individual subjects in RESUS. That vote tallied 11 for no, 8 yes, 1 abstention.