When the drug known as Recombinant Activated Factor VII arrived on the American market in 1999, it seemed destined for obscurity.
Made by the Danish pharmaceutical company Novo Nordisk and sold under the name NovoSeven, it was approved only for treating "bleeding episodes" in people with rare forms of inherited hemophilia, making it useful to about 3,500 people around the world.
A different fate was set in motion that same year at a medical conference in Israel, when trauma specialists for the American and Israeli militaries decided that the drug might save wounded soldiers on the battlefield.
"We agreed this was something that would benefit our patients," said Dr. Uri Martinowitz, an Israeli hematologist and trauma adviser to the Israeli military. "And we have been fighting to make people understand this ever since."
Factor VII, a powerful blood coagulant that is still approved only for treating hemophiliacs, has been administered to more than 1,000 wounded American troops in Iraq and more than 300 bombing victims in Israel since then, which has caused trauma specialists around the world to rethink conventional strategies for hemorrhage control and blood transfusions. While no large clinical trials have been conducted, anecdotal stories of the drug's life-saving effectiveness can be found throughout the medical literature.
But Factor VII's buzz among some trauma doctors, who see it as a rare breakthrough in their decidedly low-tech specialty, is countered by the concern and even outrage among many hematologists and blood specialists who think that the drug is killing patients by creating blood clots that travel to the heart, brain and lungs. Rather than a breakthrough, they see a desperate and overzealous military and a small group of corporate-backed proponents who have no sound evidence that the drug actually works or is safe.
The financial stakes are high. Novo Nordisk sold more than $800 million worth of Factor VII last year, saying that use for non-hemophiliacs is on the rise. Stock analysts estimate that the product will be a $2 billion-a-year drug if it ever wins approval for use in patients with normal blood.
The American military's chief proponent of Factor VII is Col. John B. Holcomb, a veteran trauma surgeon and commander of the Army's Institute of Surgical Research in San Antonio, Texas.
As a field surgeon in Mogadishu, Somalia, during the "Black Hawk Down" battle in 1993, Holcomb struggled to save the lives of Army Rangers who ultimately bled to death, and he has devoted much of his career to hemorrhage control since then.
Today he is largely responsible for the policies and strategy for treating casualties on the battlefield.
The Israeli link
The main impetus behind the Israeli army's interest in Factor VII was Martinowitz, a retired lieutenant colonel. Soon after he graduated from medical school in 1973, he and his army colleagues were in the Golan Heights surrounded by Syrian tanks and treating waves of casualties from the Yom Kippur war. He became a hematologist soon after and still recalls vividly the young men who bled to death in his care.
"The worst feeling in a physician's life is when you are just standing there, with nothing you can do while your patient dies," Martinowitz said in an interview. "I never wanted to be that helpless again."
From their shared experiences, Holcomb and Martinowitz agreed that combat casualties needed a drug to stop bleeding when transfusions and surgery fail. And they left the meeting in Israel in agreement that Factor VII was a likely candidate.
Within weeks, Martinowitz had injected the drug into a wounded Israeli soldier and reported successful results, the first known use in a non-hemophiliac. Holcomb and Col. John Hess, a U.S. Army hematologist, returned to Israel to conduct tests with Martinowitz on pigs. Soon they were back in the United States doing tests of their own.
All of them say they observed the same thing: When a patient with massive bleeding was injected with Factor VII, often the bleeding stopped. But without approval from the FDA, or at least a clinical trial to justify giving it to non-hemophiliacs, the U.S. Army wasn't ready to embrace it.
Martinowitz, meanwhile, says he got permission from Israeli authorities to place a siren on his motorcycle, and he began racing to hospitals after suicide bombings or other attacks - sometimes even to the blast scene - carting vials of Factor VII to inject into bleeding patients. He discounts the need for large, definitive "Level 1" clinical trials to test the drug, saying that trauma patients can't afford to wait for more testing.
"Yes, the drug has limited Level 1 evidence," said Martinowitz, who has been paid as a consultant for Novo Nordisk. "But do you need Level 1 evidence to use a parachute?"
Even from those earliest days, other doctors worried that Factor VII could cause deadly complications - clots that form in parts of the bloodstream where they are not wanted.
"We've all heard the stories about Uri Martinowitz on his scooter, but that's all he has, are those anecdotes," said Dr. Louis M. Aledort, a professor of hematology at the Mount Sinai School of Medicine in New York. "He's pushing a very dangerous product, without any evidence that it works or that it's safe."
In March of 2001, Holcomb and a group of trauma specialists from around the country gathered in Chicago for a meeting sponsored by Novo Nordisk and began to design a clinical trial to test the drug in trauma patients. They proposed injecting Factor VII into patients who need transfusions of more than eight units of blood, measuring how much blood they needed afterward and comparing it with patients given a placebo.
But the FDA rejected the proposal, citing a lack of evidence that the drug was safe. The same concerns prompted the agency to put a "clinical hold" on the drug, blocking its use for human testing in the U.S.
Novo Nordisk looked outside the United States and sponsored an international trial at a trauma center in South Africa in early 2002 using the same criteria the American doctors had proposed. The findings, based on a study of 277 people, suggested that the drug was no more dangerous than the placebo.
But while presented as a success, the results also concluded that Factor VII was not particularly effective for trauma patients, especially those with penetrating injuries.
Some doctors questioned the significance of the trial, including Drs. Kathryn E. Webert and Morris A. Blajchman of McMaster University in Ontario, who accused the researchers of "information laundering."
"The reader cannot help but wonder whether undue influence from the sponsor was put on the investigators to report the findings in a positive light to better serve the sponsor's marketing objectives," they wrote in a letter published in The Journal of Trauma in January.
But the researchers from South Africa say they simply highlighted the study's most relevant findings. And Holcomb, who got an advance look at the data before it was published in July 2005, was convinced enough of the drug's safety that he introduced Factor VII in Iraq in February 2004, despite the questions about its value for trauma cases.
The FDA lifted its research ban in 2005, based on the results from the South African study.
But questions about deaths linked to the drug, and concerns about the absence of larger, full-scale trials to measure its safety and effectiveness, have created dual hurdles for Factor VII.
In January, the FDA published a paper attributing 43 deaths to clots that developed after injections of Factor VII, mostly in non-hemophiliacs, a finding culled from the agency's database of drug complications. The research could not make a direct link between the drug and the clots that developed, but the FDA was concerned enough to issue a warning about the drug's potential risks.
Doctors at the R Adams Cowley Shock Trauma Center in Baltimore, who had begun injecting trauma patients with Factor VII despite the FDA's concerns - an "off-label" use that is permitted under the law - had become enthusiastic about the potential of the drug, treating almost 300 patients with it since 2001, and they set about reviewing their records to counter the FDA concerns.
Instead, they were alarmed to discover an 8.7 percent rate of major clot-related complications among the patients who had received the drug. A similar survey, published last year by the University of Colorado, found a 9.8 percent complication rate, mostly involving "undesirable clotting."
Shock Trauma doctors say they have been proceeding cautiously since that review, giving the drug to fewer patients and screening out anyone at risk for clotting.
"We have more experience with it than most hospitals, and it has made us more selective about who we give it to," said Dr. Richard Dutton, chief of trauma anesthesiology at Shock Trauma.
Army doctors in Iraq give Factor VII liberally to trauma patients, sometimes before it is clear that they will suffer life-threatening hemorrhage, but doctors at Shock Trauma reserve it for the most critical cases, particularly patients who are bleeding in the brain or taking anti-coagulant medication. They no longer give it to patients with carotid artery injuries because of the risk of stroke, and they are wary of injecting it into any patient who has a damaged artery in the abdomen.
Unlike the Army, the Shock Trauma Center keeps detailed records of the patients who get the drug, tracking their conditions, changes in condition and any complications that arise.
"The Army is a little more cavalier about it than I am," said Dutton, one of the doctors who designed the aborted clinical trial. "I think one reason, to be honest with you, is because no one is looking. The doctors in Iraq have more freedom to do what they think is appropriate. But I also may have a finer appreciation for the complications."
Advocates for Factor VII, while acknowledging a lack of scientific evidence to back up the benefits of the drug, are little fazed by the reports of potential dangers, because they are based on "uncontrolled" data with nothing for comparison.
And some, despite their concerns about the safety, still hold out hope for the drug.
"I don't have proof, but we certainly believe it has saved 40 or 50 lives in our hospital,'` said Hess, who retired from the Army in May of 2001 and took a job at the University of Maryland Medical Center blood bank. "It may have contributed to several deaths. We're trying to sort that out. But a number of us are committed to exploring the use of this drug because of what we've seen."
Lack of research
Despite widespread interest in Factor VII, little scientific research exists to support its use in trauma patients. Most published reports consist of anecdotal accounts or surveys with no placebo patients to put them in perspective.
One reason for the scarcity of scientific research is that doctors have difficulty getting consent forms, which the FDA requires for clinical trials, signed by trauma patients. The FDA has declined to waive its consent requirement for tests of Factor VII, given the drug's potential dangers.
Novo Nordisk is conducting a large clinical trial of the drug in trauma patients but expects it to take several years.
Some scientists and doctors also say that clinical research has been hindered by Factor VII's high cost, which places Novo Nordisk in a position to control testing by deciding which trials to support with free vials of the drug. At a cost of roughly $6,000 a dose, it is one of the most expensive drugs in the world.
"Obviously we're not going to participate in research we're not comfortable with," said Dr. Thomas M. Scalea, chief physician of the Shock Trauma Center. "But yeah, the manufacturer is kind of stacking the deck."
Dr. Jawed Fareed, a scientist at Loyola University in Chicago, said that he wanted to test the drug's safety several years ago but that Novo Nordisk wouldn't cooperate. And his university, as with most others, could not afford to test such an expensive product unless the company cooperated.
Like any scientist who specializes in blood coagulation, Fareed had worked with the drug and knew of its possibilities. And in theory, injecting some into the bloodstream of a bleeding patient would cause clotting only at the site of an injury, where the drug would come in contact with another protein, called Tissue Factor, that is released when blood vessels are damaged. The combination of Factor VII and Tissue Factor is the first step in the complex process that causes platelets to stick together and a clot to form.
But Fareed had also conducted tests on rats and rabbits, seeing disturbing evidence that Factor VII sometimes triggered clotting throughout the vascular system, not just at the site of an injury.
Blood specialists see such systemic coagulation as the worst-case scenario.
So when a representative of Novo Nordisk approached Fareed about putting together a clinical trial, he proposed testing whether Factor VII causes unwanted clots. The representative agreed, and a trial was designed, but the company backed out before it started.
"That kind of research still hasn't been done," said Fareed.
Novo Nordisk officials say they can't work with all the scientists who want to test Factor VII. They have put together their own series of large, multi-hospital clinical trials to keep research focused on the questions that they expect the FDA and other regulators want answered. All of those trials are designed to record not just potential benefits but also related complications.
"When people come to us and they want to conduct studies by themselves, we listen, and we often assist them," said Dr. Michael Shalmi, vice president of biopharmaceuticals for Novo Nordisk. "But we are most interested in studies that are broad enough to reach statistical weight and focused on establishing whether NovoSeven is appropriate for specific [uses]."
Doctors at Massachusetts General Hospital who are putting together a clinical trial to test the safety and effectiveness of Factor VII in surgical patients say they have not invited Novo Nordisk to participate because they want control of the data and how it is interpreted and presented. The cost of such a trial, they said, might approach $1 million.
Few other hospitals or universities are inclined to pursue that kind of study, doctors say, so most Factor VII research is conducted with the manufacturer's participation. Most of the drug's more outspoken proponents are paid consulting or speaking fees by Novo Nordisk.
The Army moves ahead
One exception is the Army, which has devoted a large portion of its medical laboratory in Texas to exploring Factor VII, and whose doctors have injected the drug in more non-hemophiliacs than any civilian medical agency.
Novo Nordisk has a close relationship with the Department of Defense, which is a large buyer of the company's primary product, insulin. Since 2004, the Army has spent roughly $11.2 million on Factor VII, making it one of the drug's largest customers.
Today the Army promotes Factor VII as a new standard in battlefield medicine and is exploring its use not just by battlefield doctors but also by frontline medics and medevac crews. Doctors say they are confident, from firsthand experience and the limited clinical trials available, that the drug is reasonably safe, and they are unwilling to forgo its use to await more tests.
"You can't conduct clinical research in the middle of a war," said Holcomb.
Many civilian doctors say they appreciate the Army's dilemma, given the horrendous injuries Army physicians see in Iraq and the paucity of medical treatments available to control severe bleeding.
But few are willing to embrace widespread use of a drug that has sparked such disagreement and controversy in hospitals in the United States.
Dr. Harvey G. Klein, chief of the department of transfusion medicine at the National Institutes of Health, said he's sympathetic to the situation of military doctors who are responsible for the care of young soldiers bleeding to death before them.
"But there is an obligation, even in a war, to be cautious and to get evaluable data, particularly when the possibility of unexpected downsides is so apparent," he said. "Otherwise, what have you learned? Have you helped them? You don't know, because all you have are the surgeon's anecdotes."