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THE LANCET Neurology Vol 2 May 2003 http://neurology.thelancet.com268

On Feb 5, 2003, the US Food and Drug Administration (FDA) approvedpyridostigmine bromide (PB) for useby American servicemen in combatsituations as a prophylactic against thenerve gas soman. This is the first timethe FDA has approved a drug on thebasis of its effectiveness in animalstudies alone. An amendment to FDAregulations passed on July 1, 2002,now allows such approval when, forethical reasons, the efficacy of aproduct cannot be tested in humanbeings.

PB was first approved in 1955 forthe treatment of myasthenia gravis.“It is important to note that PB has a long-established medical use inhumans for the clinical treatment ofmyasthenia gravis, at dosages muchhigher than that prescribed to troops to protect against the deadlynerve agent soman”, says WilliamFitzPatrick (Virginia PolytechnicInstitute and State University,Blacksburg, VA, USA). “So it has beentried in humans—just for differentpurposes.” However, many veteransof the 1991 Gulf War claim that PB,which was given to about 250 000servicemen, caused some cases of GulfWar syndrome. There is also evidencefrom animal studies to suggest thatPB can cause brain and muscledamage.

The FDA amendment applies onlyto “new drugs and biological productsused to reduce or prevent the toxicity ofchemical, biological, radiological, ornuclear substances” (Federal Register2002; 67: 37988–98). Products mustshow effectiveness in (normally) morethan one animal species and have likelybenefit to human beings. In addition,doses for use in human beings must becalculable and users must be informedof the approval status. The patho-physiological mechanism of toxicityand its reduction by the product mustbe reasonably well understood, andafter-sales follow-up is obligatory,whenever possible. And, of course, theproduct still has to be safe, asdetermined by small-scale human-safety studies. But although theamendment was passed to save lives ina post-September 11 world, is it really

reasonable to expose people to aproduct that might have side-effectswhen its efficacy is unproven?

“No individual can be asked toundergo, as an experimental subject, apotentially lethal or irreversiblydisabling intervention”, says RichardAshcroft (Imperial College, London,UK). “The FDA proposal, does, in

effect, shift the risk from a smallnumber of experimental subjects to a(potentially) large number of peopleaffected by chemical or biologicalassault. These are forced to use whatmight be an unsafe or ineffectiveprophylactic in the absence ofanything better, and where thealternative may be death. But I thinkmost people would choose to run that risk. In ethical and public policy terms, the amendment seemsreasonable.”

Such sentiment is common. “Thefirst human exposure would beethically justified when the potentialfor benefit outweighs the uncertainrisk”, explains William Carpenter Jr(Maryland Psychiatric ResearchCenter, Baltimore, MD, USA). JerryMenikoff (University of Kansas,Kansas City, KS, USA) agrees:“Assuming there is no other drug yetproven to be effective in reversing theeffects of one of these [weapons], I’dbe happy to have this kind of stuff inmy backpack if I were in a war where Imight be exposed.”

In fact, the new ruling may not beso radical. “We already accept this in other areas”, explains Menikoff. “For example, the FDA can allowcompanies to sell devices that have asmall market without proof of efficacywhen the costs of testing would render production uneconomical.‘Humanitarian approval’ is permittedas long as these devices are safe. Thekey point here—and with the newruling—is that each case must beresolved individually.”

Policy makers were criticised inthe 1991 Gulf War when PB, whichwas still an investigational drug at thetime, was issued to troops (the USPresident can waive normal approvalfor military use in such situations).The question now is, althoughapproved by the “animal” route, is itethical to demand that PB—or anyother such product—be used byservicemen? And what aboutcivilians? According to FitzPatrick,“good arguments exist for coerciveintervention in a military context withordinary drugs and vaccines. I don’tthink the new rule really changesanything. If PB is the best availableprotection for troops facing possiblesoman exposure, it can be legitimatelyadministered by command to protecttroops who all depend on each other’sbattle readiness. In a civilian context,there could be a similar issue if, say,there were a bad smallpox epidemic,but things would have to get prettybad before there was talk ofmandatory civilian vaccination.”

Alejandro Reyes (AlcaláUniversity, Spain) fears, however, thatthese developments could pushclinical-trial ethics down a slipperyslope. “In trials, informed consent isfundamental. In the military context,however, consent may not be‘informed’ but ‘deformed’ by fear ormilitary discipline. Whether this newmethod of approval is right or wrongis secondary to remembering thatclinical trial legislation exists as itdoes because it was unanimouslybelieved that people have universalrights simply because they arepeople.”Adrian Burton

Take your pyridostigmine: that’s an (ethical?) order!

Newsdesk

Warfare in the 21st century

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