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Baltimore Sun
November 21, 2006
The Army pushed to use Factor VII for treating trauma cases, but concern has built that research into its safety was inadequate
By Robert Little, Sun Reporter
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.
November 21, 2006
The Army pushed to use Factor VII for treating trauma cases, but concern has built that research into its safety was inadequate
By Robert Little, Sun Reporter
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.