The medical questions about the Army's use of Factor VII, its one-time wonder drug, have largely been resolved by the scientific evidence: Yes, it is potentially dangerous. No, it doesn't seem to work.
But to critics of the drug's use, some practical questions remained. Such as: Why was an obscure and extremely expensive hemophilia drug embraced by Army leaders as a treatment for combat injuries? And why was it injected into thousands of wounded troops and civilians in Iraq and Afghanistan despite a near-complete lack of evidence that it was safe or saved lives?
A federal whistle-blower lawsuit unsealed in Baltimore on Friday offers the first hints of an answer.
In a deal with the U.S. Department of Justice, the drug's Danish manufacturer, Novo Nordisk, agreed to pay $25 million to resolve allegations that it illegally promoted the drug to the Army as a treatment for traumatic bleeding.
The company did not admit wrongdoing. But neither did the government back down from its charge that the company engaged in unlawful marketing that helped persuade the Army to treat combat casualties with a largely experimental drug that was not approved for such use by the Food and Drug Administration.
Beginning in 2000, according to the government's claims, Novo Nordisk promoted the drug, also known as NovoSeven, to military doctors and entered into research agreements with Army hospitals. It provided funding for trials in which military officersl participated, and gave "donations and other gifts" to nonprofit foundations on behalf of military physicians. Those practices "caused the military to use NovoSeven in its trauma patients," the agreement states.
"Federal law prohibits pharmaceutical manufacturers from marketing drugs for unapproved uses, and restricts them from creating a financial incentive for doctors that may conflict with the interests of their patients," said Maryland U.S. Attorney Rod J. Rosenstein, whose office announced the settlement Friday. "Drugs should be marketed only for purposes for which they have been deemed safe and effective, and prescribed only because they are expected to benefit the patient."
A Novo Nordisk spokesman said the company would not comment beyond what was included in its signed agreement with the government.
"It's only an allegation," said Novo Nordisk spokesman Ken Inchausti. "We've cooperated with the Justice Department fully, and at the end of the day have reached a settlement that they consider appropriate."
A message left for representatives at the Army Medical Command was not returned.
Approved by the FDA only for treating rare forms of hemophilia, Factor VII was introduced as a treatment for combat trauma in Iraq in 2003 — before clinical testing of such a use on humans had begun.
By 2006, Army protocol in Baghdad called for injecting it into virtually every casualty with signs of serious bleeding. Some Special Forces units in Afghanistan supplied combat medics with the drug, to inject in the field. And based on anecdotal reports of success by military doctors, it was widely adopted as a treatment for traumatic injuries by trauma centers throughout the world.
Numerous clinical studies have since shown, however, that Factor VII is ineffective at controlling traumatic bleeding and can potentially cause blood clots that lead to heart attacks and strokes. A series of articles in The Baltimore Sun in 2006 detailed the Army's enthusiasm for Factor VII and profiled three soldiers injected with it in Baghdad. Two subsequently died of clot-related complications. The FDA added a safety warning to the drug's label last year.
Physicians who study the development of drugs said the history of Factor VII reveals the potential perils of overeager manufacturers with untested treatments.
"The idea that 'we do it because we think it's a good idea' just doesn't wash in medicine, even if you happen to be wearing a uniform when you say it," said Dr. Jerry Avorn, a Harvard University medical professor who has written several journal articles about the influence pharmaceutical manufacturers can have on clinical research. "You need evidence."
"In the case of [Factor VII], it looks like the widespread use of the drug was not likely to have come from well-done medical research, because there was very little of that done."
Most of the $25 million fine paid by Novo Nordisk was based on the military health care system's cost of buying Factor VII for unapproved uses. A dose of the drug can cost from $6,000 to $10,000, depending on its size.
Last year Novo Nordisk reported annual sales of NovoSeven of almost $1.6 billion — mainly for treatment of hemophilia. Company officials say roughly 15 percent of its sales are for unapproved uses, or as much as $250 million last year.
The genesis of Friday's settlement was a federal whistle-blower lawsuit filed in 2008 by two men: a Novo Nordisk employee, and a military doctor who deployed to Iraq in 2006 and 2007 and served as the head of anesthesia at the Army's trauma research center in San Antonio. Under a federal law governing whistle-blower lawsuits, the two will share more than $3.5 million of the fine collected from Novo Nordisk.
Dr. Ian Black, the Army physician named as a plaintiff, said he filed the lawsuit after seeing patients suffer complications that he thought were related to the drug, and after years of futile efforts to change the Army's practices from the inside.
"I wasn't trying to assign blame or to make money, I just wanted it to stop," he said. "This was not a one-man crusade. There were lots of people who had concerns. And I know there were other physicians who had personally seen patients with adverse side effects that they thought were related to Factor VII."
Military leaders have justified the drug's use by pointing to a survival rate on the modern battlefield that they call the highest in history. Among troops wounded in combat in Iraq, for instance, 89 percent survived, compared to roughly 84 percent in the Vietnam War.
But historically, the military measures the effectiveness of medical care by focusing only on casualties who can't return to duty three days after injury. Among those more seriously wounded casualties, the death rate in military combat hospitals crept upward throughout most of the war in Iraq and was nearly double the rate of Vietnam's by the end of 2009.
When asked for data on the current death rate for serious casualties in Iraq and Afghanistan, a Department of Defense spokesman said the Pentagon no longer tabulates the information necessary to calculate it.