Medical Device Daily

The blood substitute landscape isn’t particularly smooth, outfitted as it is with high regulatory hurdles and landmines hardly designed to build shareholder confidence.

On the heels of the failure byBiopure (Cambridge, Massachusetts) to win approval for a Phase III trial (Medical Device Daily, Dec. 17/Dec. 18, 2006) of its faux blood product, NorthfieldLaboratories (Evanston, Illinois) disclosed less-than-adequate results of a pivotal Phase III trial, for its blood substitute PolyHeme. The news sent the value of the company’s shares plummeting in after-hours trading.

Northfield said that because of discrepancies in the initial data, the database would be unlocked and corrected before statistical analyses are completed and finalized. The company said it hopes to have final data in four to six weeks.

Even before the preliminary data were released, the company’s shares dropped $2.90, or 20.25%, in regular trading Tuesday to $11.42. In after-hours trading, after trial results were released, shares fell as much as $5.86, more than 50%, to $5.56.

Though the trial results made investors skittish Tuesday, the company’s confidence in PolyHeme would appear to be unshaken — at least in terms of its conference-call rhetoric.

Steven Gould, MD, CEO and chairman of Northfield, said the company continues to believe that there is an unmet medical need for a hemoglobin-based oxygen-carrying red blood cell substitute and that PolyHeme is that product.

“This was a tough study with many variables, and that resulted in a high incidence of violations,” Gould said during the late Tuesday afternoon call. “It is possible that the final results will differ from the preliminary results released [Tuesday].”

PolyHeme — Northfield’s sole product — is an oxygen-carrying red blood cell substitute intended for the treatment of life-threatening blood loss, when blood is needed but not immediately available. It is a solution of chemically modified human hemoglobin that requires no cross matching and is compatible with all blood types, according to the company. It also is supposed to have a shelf life of more than 12 months, a feature importantly targeting both civilian trauma and battlefield uses.

Of the 712 patients who were randomized and received some study treatment — 349 who took PolyHeme, and 363 who received a standard treatment of salt-water solution and blood — 46 patients treated with PolyHeme died while 35 patients in the control group died. The results represent a confidence level of 7.3%, 0.3% higher than the level needed to meet the study’s primary goal.

After removing patients with protocol violations, including errors in eligibility and treatment regimen, the confidence interval level came in at 5.8%, well below the 7% upper limit set as a noninferiority goal of the study, the company said.

“We believe these results in the per-protocol population represent the clearest evidence to assess the potential benefit of PolyHeme in this setting,” Gould said.

He said the company received the initial draft top-line data from its contract research organization (CRO) Dec. 14. During its review and interpretation of these results, two discrepancies in the dates of death for patients in the study, in which mortality is the primary endpoint, were identified.

The CRO was notified and agreed that the two data points were inaccurate. To ensure absolute accuracy before the database is relocked, Northfield said it has requested verification by the CRO of all critical variables and has also initiated an independent verification.

The FDA has been notified but the study results will not be submitted until final, the company said. Because of the interest in the study, however, Gould said the company decided to report the preliminary results now.

During the question-answer session of Tuesday’s conference call, Gould declined to answer specific questions about the two patients whose death dates were inaccurate.

“At this point I’m not going to discuss those because it would be premature,” Gould said. “I’m going to refrain from talking about things that are unofficial, and stick with what we have.”

Gould said Northfield plans to move forward with the submission of a Biologics License Application for the product and will review the data and submit it to the FDA once the final results are in.

The randomized, controlled open-label, multi-center pivotal Phase III study was designed to evaluate the safety and efficacy of PolyHeme when used to treat patients in hemorrhagic shock following traumatic injuries beginning in the pre-hospital setting. Treatment began at the scene of injury, continued in the ambulance during transport, and for up to 12 hours post-injury or a total of 6 units. Patients then received donated blood if they continued to bleed.

“Our goal is really to understand the outcome of the study,” Gould said.

The company said it was the first study in the U.S. to evaluate the use of an oxygen-carrying fluid starting at the scene. Blood is not commonly used in the pre-hospital setting or during ambulance transport to the hospital, Northfield said.

The current approach to resuscitation of the trauma victim begins with the rapid infusion of a solution that does not carry oxygen, such as salt water.

The second stage of resuscitation involves infusion of blood or red blood cells.

At the hospital, patients requiring urgent blood transfusion have immediate access to Type O blood, but it takes roughly 45 minutes to one hour to obtain fully cross-matched compatible blood.

PolyHeme provides volume replacement in lieu of salt water, and also provides oxygen-carrying capacity, Northfield says.

The fact that the trial enrolled patients during life-threatening situations added to its complexity, Gould emphasized.

The trial involved more than 3,500 emergency medical personnel and 300 ambulances and was conducted in 18 states throughout the U.S., at 32 Level I trauma centers, and included more than 150 physicians and thousands of laboratory and other hospital staff.

Survival was assessed with respect to seven covariates: age, gender, injury severity score, mechanism of injury (blunt vs. penetrating), systolic blood pressure at randomization, Glasgow Coma Score, and volume of crystalloid received prior to randomization. The noninferiority boundary was based on the potential to provide a benefit in situations where transfusion of blood was indicated but not available.

The shortfall of the trial’s preliminary data is just another hurdle in what has been an uphill battle for Northfield to create a safe and effective artificial blood substitute. The company has been the target of stories by the Wall Street Journal because regulators allowed Northfield to test PolyHeme on trauma victims without their consent.

Northfield responded by citing its adherence to FDA regulations allowing a waiver of informed consent “when patients are in a life-threatening situation” and “when current therapy is unproven or unsatisfactory,” (Medical Device Daily, July 17, 2006).

Obtaining consent from patients in trauma situations has been a key issue that has dogged companies in this sector, frequently raised by ethicists who question the validity of protocols in this situation, even though cleared by the FDA.

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