Federal criminal investigators are exploring the Army's use of a controversial and expensive blood-clotting drug injected into wounded troops in Iraq and Afghanistan.
The drug, called Factor VII, was hailed as a lifesaving breakthrough by military leaders and administered to hundreds of soldiers and Marines earlier in the wars. It has since proved largely ineffective in clinical trials and been the subject of safety warnings by U.S. and European regulators, who say it can cause potentially deadly blood clots.
Within the past several weeks, agents from the Army's Criminal Investigation Command have interviewed scientists and officers at the Army's medical laboratory in San Antonio about Factor VII, according to military sources with knowledge of the investigation. Researchers in San Antonio were among the first to explore Factor VII's role in treating trauma patients and have produced some of the few scientific studies suggesting that the drug saves lives in combat.
The manufacturer, the Danish drug company Novo Nordisk, said it had received a subpoena in January from the Defense Department's inspector general's office. Company officials said they are cooperating with the U.S. attorney's office in Baltimore, which is overseeing the investigation.
Federal investigators and prosecutors, according to agency policy, refused to discuss the investigation or to acknowledge its existence, and a spokeswoman for the Army Medical Command declined to comment.
But statements from Novo Nordisk and interviews with military officials make it clear that the probe is centered on the Army's history with Factor VII, sold under the brand name NovoSeven.
"We do not know the specific reason or scope of this investigation," Novo Nordisk's chief financial officer, Jesper Brandgaard, said in a conference call in February. "The thing we are aware of is that U.S. Army doctors have, at their discretion, been using NovoSeven and the U.S. Army had been purchasing NovoSeven for trauma use within soldiers."
A manufactured version of a natural blood-clotting protein, NovoSeven is approved by the U.S. Food and Drug Administration only for the treatment of rare forms of hemophilia. It is made from cells extracted from the kidneys of baby hamsters and, at more than $6,000 per dose, ranks among the more expensive drugs in the world.
A series of articles in The Baltimore Sun in 2006 chronicled three injured soldiers injected with Factor VII during one 24-hour period at the Army's main trauma hospital in Baghdad. All three survived their combat wounds, but two subsequently suffered blood clots and died. The Army has declined to discuss the cases in detail but told family members that the deaths were not related to the drug.
Army officials with knowledge of the government probe, who asked not to be identified because they are not authorized to speak publicly, said investigators have asked about the Army's research methods and about financial arrangements between the service and Novo Nordisk.
The federal agencies involved conduct criminal probes, rather than civil or advisory investigations, the sources said. One investigator who interviewed employees in San Antonio worked for the Criminal Investigation Command's Major Procurement Fraud Unit.
In a February conference call with investors, during which Novo Nordisk disclosed the subpoena, company officials sought to distance themselves from the Army's less-conventional use of the drug.
"The interesting thing is, we've not been marketing the product to the Department of Defense," said company CEO Lars Rebien Sorensen. "That was a program which was adopted based on a presidential waiver of the label [and] research on NovoSeven in the United States."
It is unclear whether such a waiver was ever sought or granted. Federal law allows the president to waive rules for conducting medical research, including provisions against human research without the subjects' permission, if such a decision is necessary to support military operations and is "in the interests of national security."
But since NovoSeven has been legally available to prescribe since 1999 — even for non-FDA-approved uses, which are allowed at a physician's discretion — no waiver should have been necessary for military trauma use.
Novo Nordisk officials declined to elaborate, but released a statement saying that they are cooperating with the federal investigation and adding: "It is our goal that we conduct our business according to a high ethical standard, living our values and operating our company with integrity, honesty and professionalism."
An FDA spokeswoman said she had no further details.
NovoSeven cannot legally be marketed in the United States for treating trauma, because that is not among its FDA-sanctioned uses. But Novo Nordisk has worked with researchers around the country, including Army researchers, to conduct scientific tests and clinical studies in nonhemophiliacs in hopes of finding evidence it can submit to regulators for approval of new uses for NovoSeven.
Army doctors were involved in crafting the first clinical trial of Factor VII's use in human trauma patients — a study overseen by civilian researchers in South Africa after the FDA refused to allow the trial in the United States. And the Army's earliest Factor VII studies, on pigs, were conducted in cooperation with Novo Nordisk, according to people involved.
Israeli army doctors were the first to use Factor VII to treat combat trauma, injecting it into patients as early as 1999. The U.S. Army's lab in San Antonio conducted extensive tests in the early 2000s, including some in which researchers inflicted wounds on pigs to mimic combat trauma then injected them with the drug.
Based on anecdotal evidence and preliminary data, the Army's treatment guidelines formally recommended the use of Factor VII in combat as early as January 2003 — before substantial clinical trials on human patients had been conducted. Army leaders called it a major discovery and one of the few treatments for major bleeding that could not be controlled with bandages, a tourniquet or surgery.
At the height of the violence in Iraq in 2005 and 2006, some Army trauma physicians were injecting wounded soldiers with Factor VII as soon as patients arrived in the emergency room, often before the nature and extent of their injuries was clear. Guidelines taped to the wall of the combat hospital in Baghdad encouraged prompt and liberal use of the drug.
More conservative use of Factor VII gained widespread acceptance in civilian trauma centers throughout the country, based mostly on anecdotal accounts from doctors who had tried it and on favorable reports from the U.S. military.
In subsequent clinical trials, though, the drug has been shown to be potentially dangerous in such use.
In 2008, Novo Nordisk halted a large-scale trial in trauma patients when it became clear that there was no reduction in the rate of death. This year, the FDA added a "black box" to the label of NovoSeven — the agency's strongest safety warning — saying that the drug can cause unwanted and potentially deadly blood clots in arteries when given to nonhemophiliacs. It cautioned that the drug's value to such patients has not been proven.
Last summer, the European Union's pharmaceutical regulatory body issued revised information about NovoSeven that called unwanted arterial clots "common" and said the drug "should not be used" to treat patients without hemophilia.
America's two 21stt-century wars, with their roadside bombs and military weaponry in the hands of enemies, have posed vexing problems for combat doctors. The U.S. military services have introduced a host of medical treatments since the wars began, including advanced tourniquets and dressings, new transfusion techniques, hypothermia blankets and Factor VII. Yet, for all of the medical innovations, the death rate for wounded American troops has climbed.
The death rate for combat casualties in Iraq and Afghanistan who suffer severe injuries, which the military defines as anyone unable to return to duty within three days, is 20.7 percent, compared with just over 22 percent during the Vietnam War and World War II.
Advancements in body armor and emergency care from medics, corpsmen and "combat lifesavers" have led to improvements in the percentage of battlefield casualties who survive long enough to reach a hospital. The "killed in action" rate for American troops in the past decade is 16 percent, compared with 18 percent to 20 percent in Vietnam.
But that also means that modern combat hospitals receive more patients with mortal wounds than in earlier wars. The "died of wounds" rate in Iraq and Afghanistan, or the percentage of casualties who die after reaching a military hospital, is nearly 6 percent, almost double the rate in Vietnam.