Medical Device Daily Associate

In the wake of an article published last week in The Wall Street Journal, and subsequent comments made by Senate Finance Committee chairman Sen. Charles Grassley (R-Iowa) critical of the trial design for the PolyHeme blood substitute being developed by Northfield Laboratories (Evanston, Illinois), the company said it felt “compelled“ to publicly defend its record.

The WSJ article, headlined “Amid Alarm Bells, Blood Substitute Keeps Pumping,“ said about 12% (10) of patients on the product in an abdominal aorta aneurysm trial suffered heart attacks and two out of 81 patients died within seven days of receiving PolyHeme. None of the 71 patients in the trial who received real blood had heart attacks, the paper said, adding that the trial results were intentionally never published.

The article charged that the company “quietly shut down the trial and didn't publicly disclose the results.“

The trial also suggested that PolyHeme was linked to other serious adverse events such as heart rhythm aberrations and pneumonia, the paper said. These events occurred in 54% of the PolyHeme patients vs. 28% in the control group, the article added.

In a statement, the company said the WSJ article contained several errors of fact and misinterprets the Acute Normovolemic Hemodilution (ANH) – described in the article as the abdominal aorta aneurysm – clinical trial protocol and results.

The company said it particularly disagrees with the characterization that Northfield did not disclose the results of the trial or discouraged others from publishing its results. In fact, it said it believes that prompt publication of all the study data would have been favorable to the company.

“We made no effort to discourage the publication of ANH data and in fact, three publications have resulted from the study, with the fourth expected soon,“ said Steven Gould, MD, chairman and CEO of Northfield, in a statement. “We believe that publishing the full data upon closing the study would have shown that PolyHeme could not be isolated as the cause of the observed serious adverse events.“

The company said the ANH trial, described in the article as the abdominal aorta aneurysm trial, was conducted in the late 1990s and was a complex study involving a difficult and unusual procedure in a high-risk population from whom individual consent was obtained.

The protocol resulted in the PolyHeme patients having 60% of their blood volume withdrawn vs. 30% in the control group.

In keeping with the protocol, the company said the PolyHeme group also received substantially more fluids than did the controls, resulting in complex issues with fluid management in those patients.

Northfield said it believes it is unlikely the outcomes in the ANH trial were due to a pharmacologic effect of PolyHeme.

“Because we experienced difficulty in enrolling the number of patients required to complete the study in a timely manner, with FDA approval, we wound down the study over a period of months, not abruptly as the article states. The trial closed in 2000 and the full data were reported to the FDA,“ the statement said.

The company said that it plans to release full study results in April.

Grassley, who has been an outspoken critic of the FDA, which cleared a trial for use of PolyHeme in trauma patients (Medical Device Daily, March 7, 2003) that waives an informed consent requirement – provided the trial is accompanied by a community outreach program – pressed the agency for details on its role in the clinical trial of the blood substitute being tested on patients in 18 states.

Grassley, whose panel has oversight of Medicare and Medicaid programs, has asked the FDA to make a full public disclosure about the PolyHeme clinical trial to his committee no later than March 8 after its safety was called into question in the WSJ article.

“It is outrageous that, for all intents and purposes, the FDA allowed a clinical trial to proceed, which makes every citizen in the United States a potential 'guinea pig' without providing a practical, informative warning to the public,“ the Iowa Republican said in a letter to acting FDA Commissioner Andrew von Eschenbach.

In his letter to the FDA, Grassley expressed concern that patients could be subjected to the experimental blood product unless they were wearing a wristband that says they decline to participate in the study.

Many people probably do not know how to get the wristband, he added. “Why should Americans have to wear a bracelet at all times to protect themselves from a government-sanctioned medical experiment if they happen to get into a car accident?“

In response to Grassley's comments, Northfield said the PolyHeme blood substitute trial for trauma patients met FDA requirements and, after talks with the agency, would continue.

The company said its independent data monitoring committee (IDMC) charged with overseeing this study has on four occasions reviewed the mortality and all serious adverse event data and has four times recommended that the study continue without modification. The IDMC has issued the following statement to Northfield:

“As has been reported to Northfield Laboratories regarding the final assessment of the interim data, including 500 randomized patients, there were no statistically significant trends or safety issues identified to warrant modification or other changes in the current protocol and patient recruitment. The IDMC conclusion is that completion of the trial is appropriate with completion of datasets and final analysis indicated.“

The most recent IDMC okay for the trial, in which about 500 patients have thus far been transfused, took place this past November.

“We believe the markedly different experiences with PolyHeme in the ANH and trauma trials can be attributed to the entirely different protocols, settings, and populations in these studies,“ said Gould. “To suggest the ANH data were withheld to further the trauma trial is patently untrue and damaging to both Northfield Laboratories and PolyHeme.“

Northfield spokeswoman Sophia Twaddell on Friday told Reuters that the FDA, not the company, was the target of Grassley's probe. She did not know if the FDA had contacted the company over the inquiry.

FDA spokeswoman Susan Bro said that continued study of blood substitutes is critical and that the “scientific endeavor at the heart of the Northfield trial and others like it is important.“ She noted that there is a need to find an alternative to human blood, “particularly in emergency and battlefield situations,“ where it “can be critical to survival.“

In recent months, Grassley has been critical of several FDA decisions, most recently taking the agency and Center for Devices and Radiological Health head Daniel Schultz, MD, to task for approving use of Cyberonics' (Houston) Vagus Nerve Stimulation technology for the treatment of depression despite misgivings of other agency staff (MDD, Feb. 21, 2006).

In the wake of massive recalls in Guidant's (Indianapolis) cardiac rhythm management program, he also has asked the FDA to provide his committee with copies of the agency's past five years of annual post-approval reports “for all pacemakers and defibrillators.“ And his request suggested the need for increased dissemination of “performance data“ for these devices.

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