Two days before last Christmas, the Food and Drug Administration (FDA) quietly issued the US Army an approval for a “manufacturing change or addition” to a drug known as pyridostigmine bromide, or “PB” for short. The Army keeps a stockpile of the drug as a preventative measure against deadly soman nerve gas, but the FDA’s announcement hardly made a ripple in the headlines before the holidays began and politics in Washington screeched to a halt.
At the time, reports that ISIS was working to develop nerve agents and other chemical weapons were surfacing in the media, but there was no way to know whether ISIS had anything to do with the FDA’s regulatory move. A reporter at Forbes, who was perhaps the only member of the media to cover the announcement, noted that the FDA had approved a new “oral dosage form” of the drug, but documents that would normally accompany such an approval were not available on the FDA’s website. The FDA has yet to release the documents despite requests from Truthout, including a request under the Freedom of Information Act (FOIA).
Two months later, PB was once again on trial in Congress, but the discussion had nothing to do with ISIS. The House Committee on Veterans Affairs was observing the 25th anniversary of the Persian Gulf War, and depending on whom you talk to, PB may be one likely cause of Gulf War Illness, a mysterious cluster of chronic symptoms that includes insomnia, fatigue, headaches, indigestion, dizziness, respiratory disorders and memory problems. The illness affects as many as 250,000 veterans of the United States’ first war with Iraq.
Meanwhile, a former FDA reviewer named Ron Kavanagh filed a whistleblower complaint with the Department of Defense alleging that his former employer gave the Army the green light to use PB as a nerve gas prophylactic in the second war in Iraq despite data showing that it would do little to protect soldiers. By his calculations, the drug could make nerve gas even more deadly. FDA officials knew this, he claimed, but the agency granted the Army approval anyway for reasons unknown.
Kavanagh says he was fired from the FDA in 2008 after threatening to blow the whistle on the agency’s 2003 approval of PB as well as approvals for antipsychotic drugs that he claims were based on false information provided by pharmaceutical companies. He says the Obama administration has failed to hold the FDA accountable and protect him as a whistleblower.
In the months after Kavanagh filed the complaint, the FDA changed PB’s marketing status to “discontinued” on its website. An FDA spokeswoman said that a drug’s sponsor — in this case, the Army — determines a drug’s marketing status. However, a spokeswoman for the Army’s medical command told Truthout that it has never “discontinued” PB for its intended use against soman and reserves the right to administer it in the field.
ISIS has reportedly recovered aging stockpiles of chemical weapons and launched crude weapons containing mustard gas in its effort to defend against US-supported Iraqi and Kurdish forces advancing on its stronghold in the Iraqi city of Mosul. Soman has not been reported in Iraq or Syria, but if the nerve agent were to appear there, then PB could once again be prescribed to US troops on the ground.
A Massive Human Experiment
PB’s main use has nothing to do with nerve gas: The drug is traditionally given to patients suffering from a severe muscle disorder. However, its claim to fame rests in being one of the most controversial drugs in recent military history. In hopes that the drug could protect soldiers from Iraq’s stockpiles of chemical weapons, the FDA issued a special waiver in 1991 allowing the Department of Defense to enlist thousands of soldiers in what congressional investigators and other critics would later call a massive human experiment.
At the time, the FDA had not approved PB to protect against nerve gas and had only a few animal studies on hand to suggest that it might work. Human testing was impossible because it would require exposing subjects to deadly soman, but what if Saddam Hussein administered the nerve agent instead? With the FDA waiver in hand, the military ordered hundreds of thousands of US troops to take PB pills during the Persian Gulf War. Despite orders from the FDA, soldiers were often provided little or no information about the drug.
Complaints from soldiers and a congressional probe into the matter gave both the FDA and the Pentagon black eyes after the war, especially after media reports began linking PB to severe but seemingly unexplainable health problems reported by veterans. The Army claimed that it distributed the drug to protect soldiers, not to conduct research. A federal appeals court agreed, but critics charged that the military had brazenly ignored basic medical ethics by ordering human subjects to take an investigational drug without their informed consent.
PB is supposed to be taken as a preventative measure against soman in particular, and the drug is only thought to work when used in concert with antidotes administered after exposure. Congressional investigators found that US soldiers were often unaware of this information, despite studies suggesting that the drug could make antidotes less effective in treating exposure to other nerve agents.
As it turned out, Iraqi forces never used soman during the conflict, but soldiers were exposed to a different nerve gas — sarin — after US airstrikes blew up Iraq’s chemical weapons depots and sent the poison blowing through the atmosphere, a blunder that US officials unsuccessfully tried to cover up. However, US officials did have reason to believe that soman could be a threat. The Reagan and Bush administrations allowed exports of materials used to make various chemical and biological weapons to the Iraqi regime during the Iran-Iraq war of the 1980s, when nerve agents were used against Iranian forces with devastating results.
Since the end of the Persian Gulf War, independent researchers appointed by Congress and supported by veterans groups have been sparring with government-sponsored researchers and the Department of Veterans Affairs (VA) over whether PB can be listed besides oil well fires, pesticides and sarin gas as likely causes of Gulf War Illness.
The drama played out once again before the House committee in February after the Institute of Medicine issued a report advising Congress to defund research on PB and other environmental hazards, echoing instead the position of the VA, which has long argued that the illness is more likely the result of mental stress. Former members of a Congressional research committee shot back with their own report causally linking Gulf War Illness to PB, pesticides and other toxic exposures. Along with veterans groups, they warned Congress against letting the VA off the hook for medical benefits.
In 2013, a former VA epidemiologist turned whistleblower told Congress that the VA routinely hides and obscures data in large studies of veterans, particularly data related to environmental hazards soldiers face in Afghanistan and Iraq, in order to avoid paying costly benefits.
“Pesticides, PB, nerve gas released by destroying Iraqi facilities — all are cases of friendly fire,” said James Binns, the former chair of the Research Advisory Committee on Gulf War Veterans’ Illnesses, in a January statement. “That may explain why government and military leaders have been so reluctant to acknowledge what happened, just as they tried to cover up Agent Orange after Vietnam.”
A Whistleblower Speaks Out
As PB made its way back into the headlines, Dr. Ron Kavanagh sprang into action. The former FDA reviewer had noticed the agency’s approval of the manufacturing change back in December, and he assumed the military was preparing to give the drug to soldiers involved in the campaign against ISIS in Iraq.
In his latest whistleblower complaint and a petition to the White House, Kavanagh explains that giving soldiers PB before a soman attack could cause more fatalities, not less. FDA officials knew this, he claims, but gave the Army approval to use the drug in 2003 for reasons that remain unexplained.
In the early 2000s, the rhetoric of “terrorism” and “weapons of mass destruction” dominated the debate over the impending war in Iraq. The FDA had already rejected two applications from the Army to approve PB, but the military was persistent in seeking an approval. A law passed in 1999 gave the president authority to waive informed consent requirements for giving investigational drugs to soldiers, but George W. Bush, perhaps wary of the blowback over PB that followed his father’s incursion in Iraq, did not take advantage of it.
Federal law requires human trials for most drugs that come before the FDA, but in 2002 the agency acted on orders from Congress and approved the so-called “Animal Rule,” which exempts the agency from those legal requirements “when human efficacy studies are not ethical or feasible.” The rule was specifically tailored for drugs like PB that are thought to protect against lethal substances like chemical weapons, making human trials incredibly dangerous.
As the name implies, approvals made under the Animal Rule are based solely on animal trials. PB’s ability to protect against soman has been tested on monkeys, guinea pigs, rats and other animals, but never on humans. Kavanagh was one of the reviewers who examined these studies as the FDA considered whether to approve PB in the early years of the Bush administration. He says the studies do not reflect battlefield conditions — animals in some studies received soman injections instead of inhaling the nerve agent, for instance — and the data doesn’t add up.
Kavanagh says he told Russell “Rusty” Katz, the former head of the FDA’s neurology division, that the data on PB did not meet the Animal Rule’s criteria. In October 2002, Katz wrote an email informing top FDA scientists that the animal studies were not sufficient to approve PB for soldiers and recommend a proper dose, but reviewers were working with the Defense Department to find better surrogate data in the absence of human trials.
In January 2003, as US forces were preparing for the invasion of Iraq, the Army resubmitted its application for PB, and within weeks Katz issued a recommendation for PB’s approval, along with other top officials. Katz made his recommendation despite “inconsistencies” in the animal data and called on the Army to conduct future research. Kavanagh says it appeared that Katz was under pressure, and the agency’s final approval documents note that there were ongoing disagreements about PB among reviewers. Truthout’s attempts to reach Katz have so far been unsuccessful.
“Rusty was a great guy,” Kavanagh said. “Whatever his staff said, he backed them up. This was only time I ever saw him [fail to] do that.”
PB and soman both act on an enzyme that controls an important neurotransmitter responsible for crucial muscle activity, such as respiration. PB temporarily blocks this enzyme, but soman blocks it irreversibly, causing death. With other nerve agents, this type of chemical change may take hours, but with soman, it can occur within minutes, making it difficult to administer antidotes in time, especially in a war zone. Researchers theorize that, by taking PB before exposure, some of the enzyme would be blocked by PB and protected from soman, and then returned to the body after the PB wears off, giving soldiers treated with antidotes a better chance of survival.
However, Kavanagh says there’s one glaring problem with this theory. PB has a half-life of about three hours. Soman kills within minutes. Taking PB before soman exposure would only increase the amount of enzyme compromised in the body, and the victim would likely die before the PB wears off and releases life-saving enzymes protected from soman.
“Soldiers who previously would have received a sub-lethal dose and would have survived with evacuation and treatment would now die immediately due to the additive toxicity, and soldiers who would have not needed to be evacuated would now need to be evacuated in order to receive treatment,” Kavanagh explained. “The increased numbers of wounded soldiers might thereby overwhelm the ability to evacuate and the ability to treat them, resulting in even more deaths.”
In his recommendation for approval, Katz wrote that, in order for PB to be effective, the timing “must be appropriate.” The drug’s label also warns against taking PB immediately before or after soman exposure. However, Kavanagh says timing is not an issue, and PB simply would not prevent soman poisoning in humans.
Dr. Beatrice Golomb, a former member of Congress’s independent Gulf War Illness research committee, has studied PB in connection to Gulf War Illness for years. Her research suggests that, like pesticides with similar modes of action, PB can cause lasting health problems by interfering with neurotransmitters. This conclusion has put her at odds with the VA on more than one occasion. The Army says giving PB to soldiers is safe because it has been prescribed to patients suffering from myasthenia gravis, a severe muscle condition, for decades, but Golomb says that argument is full of holes.
“People don’t study side effects [of PB] with myasthenia gravis [patients] much because, without treatment, they die,” Golomb said. “But the limited literature suggests that they do [experience] the same long-term effects.”
Echoing Kavanagh’s concerns, Golomb says there are a lot of questions concerning the “net risk benefit balance” of using PB to protect against soman, because in this case, PB is used to protect neurotransmitter sites with something that is “still harmful but not as bad.”
“Even for soman, the risk/benefit balance is complicated because clearly, when you are given both agents, there is a time period where [enzyme inhibition] will be worse no matter what,” said Golomb, who is currently surveying veterans suffering from Gulf War Illness about their continued struggles to receive appropriate treatment.
Golomb and Kavanagh both point out that, despite fears that Saddam Hussein developed soman weapons with the help of US exports in the 1980s, only nerve agents like sarin, VX and tabun have actually shown up in the Iraqi theater. PB has been shown to make antidotes less effective in treating both sarin and VX in rodents. Kavanagh says his attempts to convince directors of the FDA’s clinical pharmacology office that approving PB for the Army would put the lives of troops at risk went nowhere.
“In the meetings … I had to repeatedly explain the science and why it wouldn’t work and would kill soldiers,” Kavanagh told Truthout. “They would listen and ask me to repeat it and then at the end of the meeting say something to the effect of ‘so you’re going to recommend approval, right?'”
“I went through the proper channels where you’re supposedly protected, but I’m proof that isn’t the case,” says Kavanagh, who is calling on the Obama administration to protect whistleblowers instead of throwing them in jail.
A Culture of Corruption?
Kavanagh says the PB approval is indicative of the culture at the FDA, which has generated plenty of whistleblowers over the years. He can rattle off instances in which he was told to gloss over industry data that didn’t add up, or to reword reviews to streamline drug approvals. Reviewers who played along received promotions, while reviewers who did not were saddled with heavy workloads and had trouble getting ahead.
“They don’t come out and order you to do anything, but the message is clear,” Kavanagh says.
The FDA, which regulates about $1 trillion in products, often finds itself in the middle of opposing political forces, especially in its drug review department. Congress oversees the agency and, at the behest of the powerful pharmaceutical lobby, has passed legislation incentivizing the streamlining of drug approvals. Consumer groups argue that the FDA is under constant pressure to brush aside safety concerns to bring new drugs on the market, while advocates for patients of diseases requiring novel treatments often push the agency to approve new drugs faster.
In this highly charged atmosphere, scientific disagreements at the agency are not uncommon. Last month, Dr. Janet Woodcock, the head of the FDA’s drug evaluation department, overruled her own staff and won the approval of a controversial drug to treat muscular dystrophy. Patients and the industry pushed hard for the approval, but FDA reviewers fought against it, arguing that the drug was no better than a placebo. After a top reviewer opposed to the approval left the agency in the midst of the power struggle, the company sponsoring the drug watched its stock value skyrocket.
“In business management they say you manage what you measure,” Kavanagh says. “At the FDA, the measurements are number of approvals and time it takes to approve a drug. There is no measurement of how many safety issues are caught. Consequently, the only impetus is to increase approvals and decrease time to approvals. There is no impetus for safety, as it’s not measured.”
In addition to the issues he has raised with the PB approval, Kavanagh is concerned about a class of controversial antipsychotic drugs often prescribed to people with severe mood disorders and schizophrenia. These drugs can have severe side effects, and some critics say they should not be used at all. Others argue that, for some patients and their caregivers, the potential benefits do outweigh the risks.
Kavanagh says drug companies provided misleading and false information about antipsychotics trials to the FDA in an attempt to hasten approvals, keep safety warnings off drug labels and expand the number of patients eligible to receive a prescription. He has provided some of the evidence to Truthout, particularly in regards to the drug Saphris, an antipsychotic that Kavanagh claims doesn’t work very well for certain conditions and could kill patients and nursing infants. In 2012, Kavanagh filed a federal lawsuit on behalf of the government against several large drug companies under the False Claims Act, but the Justice Department declined to intervene, and the case was dismissed.
The Army is not a massive drug company looking for its next blockbuster product, so why did its medical command spend years pushing the FDA to approve PB? Perhaps the Army and Kavanagh simply have a scientific disagreement, and the Army wants every available tool in case troops encounter soman, whether in battle against desperate extremists or lying around old chemical weapons facilities in Iraq. A PB approval on the books may also shield the military and the VA from angry veterans of the Persian Gulf War.
One thing is for certain. In the 30 years since the US sided with Saddam Hussein and secretly aided the dictator’s efforts to gas Iranian troops into submission, soman has proven to be an elusive threat. Nations have since signed sweeping treaties banning chemical warfare. Rogue groups like Al-Qaeda and ISIS have pounced on deteriorating chemical weapons stockpiles, but have so far been unable to deploy them on a mass scale.
Still, the US remains heavily involved in the Middle Eastern conflicts today as Iraqi forces battle for control of Mosul, where one US serviceman has already lost his life to a roadside bomb. Like the chemicals that kill, the legacy of war is one of persistent violence and evolving threats, a deadly stone kicked further down the road.