Medical Device Daily Washington Editor

WASHINGTON — Most in industry would testify that getting a product to clinical trials is a trial in itself. And attempting to obtain the FDA's approval for a trial that will not, for practical reasons, permit informed consent is doubly difficult, however well intentioned the sponsor's effort might be.

Thus Biopure (Cambridge, Massachusetts) discovered — on its second attempt that getting the go-ahead to move into phase III trials for its Hemopure blood substitute product — that even a substantial endorsement by a large cross-section of the medical community will not always win the day.

Hemopure is a bovine hemoglobin-based oxygen carrier (HBOC) that also functions to replace blood volume, and Biopure is intent on testing the substance in the RESUS (Restore Effective Survival in Shock) trial, which would examine safety and efficacy in patients who go into hemorrhagic shock as a result of trauma.

The public hearing, which the FDA originally had intended to conduct out of the public eye in July (Medical Device Daily, July 17, 2006), included a presentation by a researcher at the Naval Medical Research Center (Silver Spring, Maryland), three members of the nation's military, a host of doctors and two patients who said they owed their lives to Hemopure.

One of the panelists, a trauma surgeon, made several impassioned pleas to allow the trial to go through, but a biostatistician's arguments about adverse events won the day, and the panel informally recommended that the firm and the agency redesign the trial for a Phase II study with informed consent.

Informed consent is a condition that many supporters and panel members argue is a logical impossibility due to the fact that consent under such conditions is often impossible because the patient is not conscious and that it is, by some accounts, meaningless when the patient's life is in danger.

The trauma surgeon panelist who spoke on behalf of the RESUS proposal, Carl Hauser, MD, a visiting professor of surgery at Beth Israel Deaconess Hospital (Boston), questioned some of the concerns of the FDA.

“What populations and applications should we be looking at? What endpoints?“ he asked. Hauser insisted that some elements of the list of adverse events, serious or otherwise, were “side effects, not adverse effects.“

Hemopure, Hauser said, “will be potentially useful in extreme anemia and long transports.“ The product is “likely to cause coagulopathy, but so do all the others.“ Hauser commented that in his practice as a trauma surgeon, “hypertension is not an adverse effect,“ describing hypotension as a much bigger problem for the patients he sees and that induced hypertension might offset the hypotension that was caused by severe hemorrhage.

“Hypertension is a blessing because I see it as a buffer against my main enemy, which is hypotension.“ Hauser added that a HBOC product that boosted systolic pressure would “avoid the necessity of giving them epinephrine.“

“Waiver of consent must be readily available or acute care research in the U.S. will die,“ Hauser argued.

Toby Silverman, MD, head of clinical review at the Center for Biologics Evaluation and Research at the FDA, reminded the panelists that the RESUS trial would compare Hemopure with lactated Ringer's solution and that the primary endpoint would be a 15% drop in all-cause mortality after 28 days. At present, mortality figures indicate that roughly 58% of the population on whom this would be tested would expire in that time frame, and success in the primary endpoint would drop this mortality rate to 49.4%.

Silverman acknowledged “the important role that oxygen therapeutic agents might play in improving outcomes in traumatic hemorrhagic shock“ and that there is an “unmet military and civilian need for improved outcomes in trauma.“

However, the agency imposed the hold on the RESUS trial over serious adverse events (SAEs), uncertainty over treatment effect, and a wider variability in mortality expectations for individual subjects than clinical trial standards normally tolerate.

The FDA also took the position that the sponsor's “monitoring and therapeutic interventions may not suffice to offset [those] risks,“ Silverman said.

The agency was also concerned about the exclusion of subjects over the age of 70 and the uncertainty of whether RESUS data would be generalizable to routine pre-hospital emergency care, partly because of the training requirements for emergency medical personnel to use Hemopure. However, this last set of concerns did not play a role in the hold the agency applied to the trial.

One of the supporting studies used by Biopure to buttress its arguments for RESUS was the HEM-0115 trial, which used Hemopure in a cohort of patients at hospitals who had checked in for orthopedic surgery. A number of technical considerations dotted the agency's view of HEM-0115, but perhaps the most important of these were that these patients were under no unusual cardiovascular stress and that hospitals are able to readily apply red blood cells, a condition that does not apply in most field emergency conditions.

One of the chief complaints Silverman lodged in her discussion was that “the trial, as designed, is very sensitive to small fluctuations in the assumptions and is not robust“ enough to pick up sufficient benefit/risk information to answer the study questions decisively. The proposed enrollment of RESUS is more than 1,100 subjects.

Speaking in support of the RESUS trial, rear admiral John Mateczun, the deputy surgeon general of the U.S. Navy, told the panel that “hemorrhagic shock continues to be a leading cause of death“ in military operations, 90% of which “occur prior to hospitalization.“

Mateczun pointed out that HBOCs need no refrigeration and are universally compatible, thus making them ideal for a range of applications. He added that this is doubly so in special operations because “evacuation is often impossible,“ sometimes for days.

As for the benefit/risk ratio, Mateczun said that in this population, “many lives would have been saved“ in Iraq “had this product been available“

Editor's note: Part 2 of the Blood Products Advisory Committee will appear in tomorrow's edition of Medical Device Daily.