FDA to Weigh Using Fake Blood in Trauma Trial

July 11, Wall Street Journal

By THOMAS M. BURTONIf the U.S. Navy gets its way, hundreds of civilian trauma patients could --without their consent -- be given a blood substitute that has been linked inother large clinical studies to increases in hypertension, heart attacks andother serious cardiac problems.The Food and Drug Administration has blocked the new Navy trial three timesin the past year, but now is reconsidering after months of jockeying amongthe Navy, the agency and Biopure Corp., the Cambridge, Mass., maker of theblood substitute.The agency has scheduled a closed-door hearing for next week on whether theNavy-designed trial can proceed. More than 900 badly hemorrhaging civilianaccident victims around the country would be involved, with paramedicsgiving some the blood substitute, called Hemopure, and others salinesolution en route to hospitals.Such non-consent studies are rare but legal where federal regulatorsdetermine there's no practical way to obtain consent, such as when patientsare in shock or unconscious. There also must be a reasonable likelihood thatindividual patients would benefit from the treatment under scrutiny.Scientists have been hunting for a safe, workable blood substitute fordecades. Artificial blood, with oxygen-carrying ability, could eliminate theneed to match blood types of donor and recipient in some settings, and enjoya far longer shelf life than donor blood. It could also reduce the risk ofhepatitis or HIV infection, although donor blood has become very safe overthe past two decades.The Navy, which provides all medical care for injured U.S. marines andsailors, has been particularly eager for a workable blood substitute. Donorblood lasts only about 42 days before its oxygen-carrying capacity isdiminished, while artificial blood could be stored aboard ships for anestimated three years.But efforts to develop blood substitutes have encountered safety problemsover the years. Some companies have gone out of business or exitedblood-substitute research when past efforts failed.Northfield Laboratories of Evanston, Ill., is nearing completion of acivilian non-consent study involving its own blood substitute, PolyHeme, and720 trauma patients around the country. In a previous trial of surgerypatients, 10 of 81 people who received PolyHeme suffered heart attacks,versus zero of 71 receiving donor blood. Northfield says it doesn't believeits product caused the heart attacks, but the Securities and ExchangeCommission and Sen. Charles Grassley, chairman of the Senate FinanceCommittee, are investigating whether the company properly disclosed thoseresults in federal filings and community meetings. Northfield says it iscooperating with the investigations but declined to comment further. Nine ofthe original 31 medical centers that agreed to participate in the trial areno longer testing patients with PolyHeme.Past studies have raised questions about Biopure's Hemopure as well. In1998, the company began a clinical study comparing its substitute with donorblood in consenting orthopedic-surgery patients. William G. Hoffman, thenBiopure's medical director and now director of cardiac-surgery critical careat Massachusetts General Hospital, says he concluded during the study thatthe blood substitute wasn't working well and was "harmful," and urgedBiopure to stop the trial. Edward Jacobs, a Biopure founder and then seniorvice president, says the company consulted outside cardiologists and "theiropinion was to go ahead."Evidence from that study, along with a separate study in general surgerypatients, linked Hemopure to more complications such as strokes andmini-strokes than donor blood, FDA documents show. Biopure disputes some ofthe FDA numbers. But in a draft response to the agency, Biopure acknowledgesthat there were more cases of cardiac arrest, more fluid in the lungs andmore hypertension among patients who got Hemopure than those who receiveddonor blood.Navy officials declined to comment on why they want to conduct a trial witha product that has shown such negative side effects. But in documentssubmitted to the FDA, the Navy has maintained that a study of traumapatients would be significantly different from the trial with surgerypatients. The Navy also argues that the oxygen-carrying capacity ofBiopure's product could lower the death rate in trauma patients by 25%versus patients getting saline. "If we could replace saline with the thingthat we need most, oxygen-carrying capacity, that would be the best," saysthe Navy's Surgeon General Vice Admiral Donald Arthur. "Our interest is infield conditions where there is no blood."Biopure's vice president for medical affairs, A. Gerson Greenburg, says thecompany's product "has an acceptable safety profile" and that a bloodsubstitute can serve "a societal good whereby you're saving [donor] bloodfor other people." He says many adverse events in past studies weren'tnecessarily linked to Hemopure.The Navy proposed the new study of civilian trauma patients in 2004, sayingthat conducting such a study in combat wouldn't be practical. Documents showthe FDA concluded, based on its review of existing Biopure research onsurgery patients, that there were "highly significant differences" showingmore "serious adverse events" with Hemopure than with blood. On July 8,2005, the FDA told the Navy its study couldn't proceed "because subjectswould be exposed to an unreasonable and significant risk of injury."Daniel Freilich, who heads Navy blood-substitute research, responded with aseries of letters criticizing the FDA, writing in one that the agency'sstance "is not scientifically and clinically rigorous." The Navy also arguedthat the FDA had permitted Biopure's competitor, Northfield, to pursue itsown study with a similar product.On Oct. 13, Biopure CEO Zafiris G. Zafirelis wrote to Jesse Goodman,director of the FDA's Center for Biologics Evaluation and Research,suggesting that an FDA reviewer wasn't objective and had a possible conflictof interest. In March, the FDA's Dr. Goodman wrote to Mr. Zafirelis that hehad assigned three other high-ranking officials to preside over Biopuredecisions, according to the people familiar with the matter.Earlier this year, the FDA scheduled the advisory panel meeting for nextweek. In an unusual step, the Navy, the sponsor of the proposed research,was able to recommend some doctors to be on the panel. Additionally, twowell-known skeptics of substitutes who initially had been named as advisoryconsultants to the panel -- Charles Natanson, a critical-care specialistwith the National Institutes of Health and John Hess, director of theUniversity of Maryland's blood bank -- have in recent weeks been disinvited.Neither FDA officials, Dr. Natanson, Dr. Hess nor Dr. Goodman would commentfor this article.