Medical Aspects of Chemical Warfare (2008) - The Black Vault

Medical Chemical Defense Acquisition Programsto take the drug.Peculiarities of medical chemical drug developmentcreate even greater challenges. For example, unlike anaturally occurring microbial illness, the disorderscaused by chemical warfare agents are not expectedto occur in the general population on a regular basis.Thus, the standard model for testing drugs in clinicaltrials is insufficient because exposing volunteers tochemical warfare agents is unethical. Consequently, theusual route for testing and demonstrating both safetyand efficacy of medical countermeasures in humans isnot feasible. In 2002 the FDA recognized this problem,unique to chemical and biological warfare countermeasuredevelopment, and released the animal rule. As aresult, the FDA will consider approving medical chemical,biological, and radiological countermeasures whenhuman safety data and sufficient animal efficacy dataare presented without definitive human efficacy data.This rule allows for the submission of well-controlledanimal efficacy data, in multiple species, to demonstratethat the product is likely to have clinical benefitsin humans, in lieu of definitive human efficacy studies.So far, only two products have been fully licensed bythe FDA under this rule, pyridostigmine bromide forpretreatment against soman poisoning, approved in2003 (see Chapter 5, Nerve Agents), and hydroxocobalamin,approved as an antidote for cyanide poisoningin 2007. So far, the animal rule has only been used forproducts specifically intended for medical chemical defense,but several products in advanced developmentinclude plans to use the animal rule in their regulatorydevelopment strategies as necessary.Another challenge encountered during medicalchemical drug development concerns the specificindications for which a drug is used in medical chemicaldefense. Although all of the classical organophosphorusnerve agents work by inhibiting the enzymeacetylcholinesterase, under a narrow reading of thestatute, to obtain FDA approval for all potentially encounteredbattlefield nerve agents, DoD would haveto obtain FDA approval against each individual nerveagent. Instead, DoD plans to seek FDA approval fora whole class of acetylcholinesterase inhibitors. Asmentioned earlier, pyridostigmine bromide carriespretreatment licensed indication only against soman.This issue is a matter of present discussion with theFDA, but remains unresolved.Specific manufacturing challenges exist and arealso of concern to the FDA and the advanced developer.Stereoisomers (chiral forms of molecules) andpolymorphisms (multiple crystal forms of the samemolecules) must always be considered and the licensedcompound’s purity must be ensured. Impurities mustbe removed or minimized and characterized. A specificmedical chemical defense challenge is that drugs mustoften be formulated for compatibility and bioavailabilityin an autoinjector delivery system, which israrely used in other drug development programs. Thischallenge was met by the antidote treatment nerveagent autoinjector (ATNAA) program, in which theactual dose of atropine in the autoinjector had to bemodified.STATUS OF ACQUISITION PROGRAMS OF RECORDThe programs of record in medical chemical defensewithin the DoD may be divided into three categories:lifecycle management products (fielded), sustainmentprograms (FDA-approved products; post-marketing orPhase 4 trials required), and advanced developmentprograms (products not yet fielded). 5Lifecycle Management ProductsSeveral products have gained full FDA approvalfor an intended indication and are presently fielded.The Mark I (Meridian Medical Technologies Inc,Bristol, Tenn) nerve agent antidote kit descends fromthe AtroPen (Meridian Medical Technologies Inc), anatropine autoinjector, first developed in the 1950s fornerve agent and insecticide poisoning (see Chapter 5,Nerve Agents). The Mark I kit consists of an atropineautoinjector and a second autoinjector containing2-pralidoxime chloride (2-PAM Cl). It achieved FDAapproval in the 1980s and is the mainstay of fieldednerve agent antidotes. As such, it has a large hold onthe civilian and military markets. The Mark I is beingphased out and replaced with the ATNAA.The convulsant antidote nerve agent (CANA) is anautoinjector for intramuscular administration of 10 mgof diazepam. The CANA is used as an anticonvulsantfor nerve agent poisoning and was FDA approvedin December 1990. It is the only approved treatmentspecifically for nerve-agent–induced seizures. Theautoinjector has a unique shape that allows a medicor buddy to distinguish it from Mark I, ATNAA,atropine-only, and other autoinjectors in a situationof light discipline.The medical aerosolized nerve agent antidote(MANAA) is an aerosol inhaler that contains atropineand was developed as a follow-on treatment fornerve agent casualties under medical supervision.It is intended for use after administration of eitherMark I or ATNAA and after the casualty has been decontaminatedand transferred to a clean environment651