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

Medical Chemical Defense Acquisition Programsa license from the Canadian Commercial Corporation,for evaluation against the JSPDS requirements. RSDLneutralizes and removes both vesicants and nerveagents from the skin. Clinical studies completed in 2006show that RSDL can be safely used under ambient andheat-stressed conditions. Results from limited animalstudies suggest that RSDL may be safely used aroundwounds, which is in contrast to M291, which cannotbe used around wounds.With an anticipated shortage of Ambergard resinin 2000, the JSPDS program planned to develop RSDLas a replacement for the M291 system and comparedRSDL with M291 under a DoD foreign comparativetesting program, aiming to obtain FDA approval. TheFDA approved RSDL in 2003. The fielding decision wasexpected in 2007, but as of early December, it had notbeen made. RSDL costs considerably more than M291.Very recently, Rohm and Haas has resumed productionof Ambergard, which will require considering the prosand cons of moving to field RSDL as a substitute, continuingto field M291, or using a combination of the two.The advanced anticonvulsant system is the acquisitionprogram that seeks to develop midazolam in anautoinjector as a replacement for the CANA, whichcontains diazepam, to treat nerve-agent–inducedseizures (see Chapter 5, Nerve Agents). Midazolam ispresently approved for other indications and has beenmarketed for many years as a central nervous systemdepressant, but it does not carry FDA approval as ananticonvulsant, despite being used as such in manyclinical contexts in an off-label fashion. Consequently,the focus of the advanced anticonvulsant system programis to obtain FDA approval for midazolam againstnerve-agent–induced seizures. Midazolam’s action isonset faster and lasts longer than that of diazepam.There may also be less chance of respiratory depressionwith midazolam. If fully developed, midazolam willbe an autoinjector product like CANA.The regulatory developmental strategy for obtainingFDA approval for midazolam as an advancedanticonvulsant system includes using the animalrule. An IND application was submitted to the FDAin April 2006. The Phase 1 clinical study is complete.Developmental concerns with midazolam include thefollowing:• respiratory depression (although probably lessthan with diazepam),• the number of nerve agents for which on-labelindication would be sought,• Phase 2 clinical studies including drug-todruginteractions, if any, and• any postmarketing studies the FDA maymandate.Approval is planned no later than 2011.The improved nerve agent treatment system programaddresses the shortcomings of 2-PAM Cl asa reactivator of acetylcholinesterase. The programhas two goals. The first is to expand the on-label indicationsfor pyridostigmine bromide against morenerve agents than it is presently approved to treat.The second aim is to develop a new oxime, MMB4dimethanesulfonate, to replace 2-PAM Cl. MMB4 wasselected because its spectrum of action is broader thanthat of 2-PAM Cl for reactivating nerve-agent–inhibitedacetylcholinesterase.MMB4 is not FDA approved in the United Statesfor several reasons. For example, one reason is thatmany compound polymorphs are present in MMB4,causing stability and solubility concerns. Other reasonsare that the number of nerve agents for whichan indication for MMB4 must be determined beforeapproval can be granted, and the design of definitiveanimal studies (including determining the number ofagents, animals, and comparisons against 2-PAM Clthat will be needed) must be designed. The regulatorydevelopment strategy for MMB4 includes requestingthe use of the animal rule. An IND application submissionis anticipated in 2008, followed by approvalin 2013. Postmarketing studies may also be requiredby the FDA.The bioscavenger program (see Chapter 7, NerveAgent Bioscavenger: Development of a New Approachto Protect Against Organophosphorus Exposure) consistsof three separate increments. Increment I is theplasma-derived human butyrylcholinesterase, whichcarries few immune potential concerns because it isa human product derived from human serum. Theavailability of this product is limited by the supplyof human serum that is suitable for manufacture ofa licensed product for use in humans. In addition,manufacture of plasma-derived human butyrylcholinesteraseis extremely expensive. Therefore, IncrementI is considered an interim solution to the bioscavengerproblem from the acquisition standpoint. The DoD willdevelop this product through Phase 1 clinical trials,with completion scheduled for 2007. The contractorto the DoD is Dynport Vaccine Company, with BaxterHealthcare Corporation as subcontractor; BaxterHealthcare is the sponsor of the IND application, whichwas submitted to the FDA in May 2006.The Increment II program will develop a productthat is more easily and economically produced thanIncrement I. Increment II will mitigate technical risk bytransitioning two different technologies (a recombinanthuman butyrylcholinesterase raised in a transgenicanimal and a synthetic small molecule with bioscavengingactivity) through Phase 1 clinical trials. Efforts653