Chapter 20 - Medical Chemical Defense Acquisition Programs - Pg. 645 - 654

8/3/2019 Chapter 20 - Medical Chemical Defense Acquisition Programs - Pg. 645 - 654

1/10

645

Medical Chemical Defense Acquisition Programs

Chapter 20

MEDICAL CHEMICAL DEFENSEACQUISITION PROGRAMS

KEITH VESELY, DVM, PHD,*ANDJONATHAN NEWMARK, MD

INTRODUCTION

MEDICAL CHEMICAL ACQUISITION ORGANIZATIONS

MEDICAL CHEMICAL ACQUISITION PROCESSES AND CONCERNSConcept DevelopmentTechnology DevelopmentSystem Development and DemonstrationProduction and DevelopmentOperations and Support PhaseAcquisition Manufacturing StrategyAcquisition Test and Evaluation StrategyAcquisition Business and Contracting StrategySpecific Concerns in Medical Chemical Defense

STATUS OF ACQUISITION PROGRAMS OF RECORDLifecycle Management Products

Sustainment ProgramsProducts in Advanced Development

SUMMARY

*Colonel, US Army; Joint Product Manager, Medical Identification and Treatment Systems, Chemical Biological Medical Systems Joint Project Manage-ment Office, 64 Thomas Johnson Drive, Frederick, Maryland 21702

Colonel, US Army; Deputy Joint Program Executive Officer, Medical Systems, Joint Program Executive Office for Chemical/Biological Defense, Skyline#2, Suite 1609, 5203 Leesburg Pike, Falls Church, Virginia 22041; Adjunct Professor, Department of Neurology, F. Edward Hbert School of Medicine,Uniformed Services University of the Health Sciences, Bethesda, Maryland


2/10

646

Medical Aspects of Chemical Warfare

INTRODUCTION

proval (DoD policy stipulates that military personnelwill only receive medical products approved by theFDA. Quad service doctrine, which appears in ArmyRegulation 40-7, states, it is the policy of TSG [The

Army Surgeon General] that drugs used will be thoseapproved by the FDA and procured from suppliers inthe United States.1,2This chapter will briefly describethe US militarys organizations responsible for imple-menting advanced development and will summarizethe status of current programs of record.

The Department of Defense (DoD) requires medicalcountermeasures to treat or mitigate illness resultingfrom exposure to chemical, biological, and radiologi-cal warfare agents. While medical chemical defense

depends on basic and applied science to gain insightinto the pathophysiology, pharmacokinetics, and phar-macodynamics of candidate countermeasures, fieldinga medical countermeasure cannot occur until advanceddevelopment efforts complete full-rate production andobtain US Food and Drug Administration (FDA) ap-

MEDICAL CHEMICAL ACQUISITION ORGANIZATIONS

The acquisition process may be defined as theprocess of developing, acquiring, fielding, maintain-ing, sustaining, and, when necessary, closing out anyweapons or protective system in the US military. A

drug, vaccine, or medical device used to protect theforce against chemical or biological attack is considereda protective system, and medical countermeasuresare developed and obtained using what is knownas the acquisition process. The acquisition processincludes identifying requirements or capability gaps,identifying potential solutions, and developing andacquiring those solutions, whether the acquisitions arefor the development of weapons systems or medicalcountermeasures.

Chemical and biological defense programs withinthe DoD are managed by a triad of equal organizations,each of which handles one aspect of the acquisition

process. The Joint Requirements Office for Chemical,Biological, Radiological, and Nuclear (CBRN) defensegenerates and validates requirements from the field,such as the need for a skin decontaminant or for aspecific chemical detector. The Defense Threat Reduc-tion Agency, through its joint science and technologyoffice for chemical and biological defense, conductsand supports research and development that seeksto meet these requirements and fill capability gaps. Italso maintains a robust science and technology base.This chapter focuses on the third leg of the triad, theorganization responsible for the acquisition of medicalchemical defense items: the Joint Program ExecutiveOffice for Chemical Biological Defense (JPEO-CBD)(Figure 20-1).

In the DoD, all chemical and biological defenseacquisition processes fall under the responsibility ofthe defense acquisition executive (the under secretaryof defense for acquisition, technology, and logistics) atthe DoD level. Within the DoD, the Army is the execu-tive agent for chemical and biological defense and theassistant secretary of the Army (acquisition, logistics,

and technology) is the Army acquisition executiveresponsible for managing these programs.

DoD chemical and biological defense acquisitionprograms are managed by the JPEO-CBD, which is

headed by a two-star general, the joint program ex-ecutive officer. The JPEO-CBD manages $1.5 billionin acquisition programs, of which approximately85% are nonmedical programs (boots, masks, gloves,detectors, collective protection, information systems,

Fig. 20-1.Required capabilities, science and technology, andacquisition responsibilities and interactions.Bio: biologicalChem: chemicalPOM:program objective memorandum

FUT

UREOPERATIONALCAPABILIT

IES

TRANSITION

TECHNOLOGY

Joint Testand

EvaluationExecutive

JointScience andTechnology

OfficeSERVICESSERVICES COMBATANTCOMMANDERS

COMBATANTCOMMANDERS

INPUTFOR

PRIORITIES

INPUTFORPRIORITIES

JointRequirements

Office

Joint

Program Executive

Office for Chem/

Bio Defense

CAPABILITIES DOCUMENTS

BUILD POM

AdvancedC

onceptTechnologyDem

onstrations Adva

ncedConceptT

echnologyD

emonstr

atio

ns


3/10

647


equipment decontamination, etc). The JPEO-CBD isresponsible for developing, acquiring, fielding, andsupporting chemical and biological defense equipmentand medical countermeasures that support the nationalmilitary strategy.

The JPEO-CBD medical programs are managed by a

subordinate organization, the chemical and biologicalmedical systems joint project management office, head-quartered at Frederick, Maryland. This office overseesthree joint product management components: the jointvaccine acquisition program, the newly establishedtransformational medical technologies initiative, andthe medical identification and treatment systems jointproduct management office (MITS JPMO). The jointvaccine acquisition program is responsible for develop-ing and fielding vaccines and associated products toprotect military personnel against biological warfareagents. The transformational medical technologiesinitiative enables the DoD to protect service members

from novel (and potentially genetically engineered)

biological threats through the rapid development ofeffective therapeutic medical countermeasures, mini-mizing risks and saving lives. The advanced develop-ment of therapeutic and diagnostic products, whichincludes chemical defense programs, is managed bythe MITS JPMO. The mission of the MITS program is to

develop and acquire safe, effective, and FDA-approvedproducts for the prophylaxis, treatment, and diagnosisof CBRN warfare agent exposure. The MITS JPMO isalso responsible for the critical reagents program, therepository for reagents (probes and primers) and assaykits used in DoD biological detection/diagnostic sys-tems. All MITS medical countermeasures undergoingadvanced development for use against CBRN agentsare fully integrated into the JPEO-CBD systems of ap-proach to counter threat agents, thereby supporting anintegrated diagnostic, prophylactic, and therapeuticcapability. MITS medical countermeasures supplementand are compatible with all the equipment developed

under JPEO-CBD.

MEDICAL CHEMICAL ACQUISITION PROCESSES AND CONCERNS

The major ground rules for the defense acquisi-tion process are contained in the DoD 5000 seriesdocuments.3,4The federal acquisition regulations andsupplements also pertain to this process.5

Drugs must pass through several phases of clinicaltrials in order to obtain FDA approval (Figure 20-2).All human research trials conducted in support ofthe FDA approval process must follow strict FDAregulations and guidelines (good clinical practices).

In Phase 1 clinical trials, a new drug is first tested ina small group of healthy volunteers (usually 2080)to evaluate its safety, determine a safe dosage range,identify side effects, and determine how the drug isabsorbed, distributed in the body, metabolized, andexcreted. In Phase 2 clinical trials, the study drug isgiven to a larger group of people (usually around sev-eral hundred subjects) to evaluate effectiveness and tofurther evaluate safety. In typical Phase 3 studies, thestudy drug is given to even larger groups of people,up to several thousand, to confirm its efficacy, monitorside effects, compare it to commonly used treatments,and collect drug safety data. However, Phase 3 stud-ies are not used for the approval of medical chemicalcountermeasures because it is unethical to test theeffectiveness of any drug against chemical warfareagents in people. To overcome this obstacle, the MITSJPMO plans to invoke the animal rule (sometimescalled the animal efficacy rule), which allows for thetesting and approval of products when human efficacyclinical trials are not feasible or are unethical,6as DoDaccepts this means to licensure. The Phase 2 clinical

trials are used as expanded safety studies for medicalchemical countermeasure development and may bedivided into multiple arms or studies to address allthe regulatory concerns. Phase 4 (post-marketing)studies are conducted after a drug is already approvedand on the market. Concurrent with the approval, theFDA may require certain post-marketing studies todelineate and document additional information abouta drugs risks, benefits, and optimal use, or it may

collect retrospective data on the safety and efficacyof the product if it is ever used. This is especially truefor drugs approved under the animal rule. All FDA-required Phase 4 studies are the responsibility of thesponsor, whether that is the US Army Office of TheSurgeon General or a system integrator.

Medical CBRN products are developed using a mixof in-house experts and commercial contractors. Withinthe acquisition process, drug development programsmust pass through a series of gates or milestones. Amilestone is a point in which a recommendation ismade and approval is sought regarding starting orcontinuing an acquisition program.

Concept Development (Pre-Milestone A Activities)

Drug development decisions must take place earlierin the acquisition process than the typical DoD weaponsystem development program, requiring earlier userinvolvement. The DoD 5000 series does not requirean analysis of alternatives for drug developmentefforts because they are not typically major defense


4/10

648


acquisition programs. However, an analysis addressesall alternatives (eg, prophylactics, pretreatments, thera-peutics, and nonmedical countermeasures), considersrisk, and performs cost and effectiveness analyses. Ifdevelopment of a drug product is warranted, the tech-nology base assigns personnel, budgets, and facilitiesand begins basic and applied research. Activities dur-ing this phase include assay development and proofof concept animal studies.

The MITS JPMO begins coordinating early withthe technology base to gain technical familiarity withpotential countermeasure candidates and to ensure

that advanced development funding is aligned appro-priately to support a candidate at milestone A. Tech-nology transition agreements are developed with thetechnology base for each product to ensure a smoothtransition to advanced development.

Technology Development

Program management lead shifts from the scienceand technology base to the MITS JPMO at milestoneA. Science and technology and advanced developmentfunds may be used during the technology develop-

ConceptDevelopment

Technology Development48 years

System Development andDemonstration 34 years

Production andDeployment

Operationsand Support

Lab scaleproduction

Assaydevelopment

Proof of conceptanimal studies

Milestone A IND Submission

Process development& pilot lot production

Manufacturingscale up

Clinical & analytical assay development

Dose range & safetyin animals

Phase 1 HumanTrials (safety)

Milestone B

NDA Submission FDA Approval

IOC FOC

Animal Efficacy Trials

Validation& demo lots

Consistencylots

Phase 2 Human Trials(expanded safety)

Definitive animalefficacy studies

Complete toxicologystudies

IOT&E Milestone C (Full Rate Prod.)*

FDAReview

StockpileProduction

Sustain

Post marketingsurveillance

*Under certain conditions a MS C LRIP decision may be inserted prior to FDA approval

Fig. 20-2.Model for integrating pharmaceutical development, FDA regulatory, and the Department of Defense acquisition

processes.*Under certain conditions, an MS C LRIP decision may be inserted prior to FDA approval.FDA: Food and Drug AdministrationFOC: full operational capabilityIND: investigational new drugIOC: initial operational capabilityIOT&E: initial operational test and evaluationMS C LRIP: milestone C low rate initial productionNDA: new drug applicationProd: production


5/10

649


ment stage, allowing MITS to engage with the scienceand technology base early in the process. If multiplecandidates are pursued, down-selection criteria areevaluated during technology development and adown-selection recommendation is typically made atmilestone B.

Between milestones A and B, the MITS JPMO pur-sues process development and pilots lot production ofcandidate drugs under current good manufacturingpractices (cGMPs). Required work includes clinicaland analytical assay development, dose range andsafety studies in animals in accordance with goodlaboratory practices, investigational new drug (IND)submission to the FDA, and Phase 1 human clinicalsafety studies compliant with good clinical practices.Emergency use authorization may be prepared andsubmitted to the FDA for review with, or shortly after,IND submission.

Intellectual property rights are addressed as part of

the product transition package (ie, licensure purchase,the need to trace origin to ascertain if it was govern-ment funded and, if so, claim government purposelicense rights, etc). Intellectual property rights may bea concern for future products, and the MITS JPMO willexamine all available options to ensure that productsare developed and produced in a manner equitable tothe government. Final decision on this approach willbe determined by the MITS JPMO.

System Development and Demonstration

During the system development and demonstra-

tion

phase, the systems integrator, in conjunction withcommercial partners, develops validated processesand produces consistency lots and conducts Phase 2(expanded safety) human studies, definitive animalefficacy studies, and complete toxicology studies.During this phase, the systems integrator files thenew drug application or other necessary regulatorydocumentation and requests FDA submission review.Items carried by service members undergo develop-mental and initial operational tests and evaluationsduring this phase. The system development anddemonstrationphase concludes with FDA approvalof the pharmaceutical.

Production and Deployment

As the production and deployment phase begins,products are stockpiled, and post-marketing surveil-lance is conducted. The MITS JPMO begins investi-gating post-production support plans and shelf lifeextension program efforts while monitoring productstability. Initial operating capability for drug develop-

ment is achieved when the FDA approves the productand the contractor can ensure adequate and efficientmanufacturing capability. The initial operating ca-pability is calculated as 1/x of the troop equivalentdoses required for full operating capability, with xbeing the threshold shelf life. Full operating capabil-

ity is achieved when the required FDA-approvedtroop equivalent doses have been produced for thestockpile.

Operations and Support Phase

The MITS JPMO remains responsible for lifecyclemanagement of the approved pharmaceuticals throughthe operations and support phase of acquisition sus-tainment, maintaining and safeguarding the industrialcapacity to support full production, and addressingregulatory issues such as long-term human safetystudies, shelf life extension, and post-marketing sur-

veillance (ie, Phase 4 clinical trials). MITS transfersprocurement and logistical management to medicallogistics organizations, such as the Defense SupplyCenter Philadelphia or the US Army Medical MaterielAgency, once initial stockpile quantities are in place.Funding for maintaining the stockpile in the opera-tions and support phase is the responsibility of theindividual services.

Acquisition Manufacturing Strategy

The technology base develops a laboratory-scalemanufacturing process that is capable of producing

only small quantities of drug product. This processmust be transferred to a manufacturing facility thatadheres to cGMPs and development efforts initiated toensure technology can be duplicated or new processespursued. One or more small cGMP pilot lots are manu-factured for use in the Phase 1 and 2 clinical trials andanimal toxicity studies. Scaling up the manufacturingprocess, rather than producing additional lots at thesmaller scale, can result in significant cost and schedulesavings. The manufacturing process is validated andconsistency lots are manufactured concurrent withPhase 2 trials. After FDA approval, replenishment lotsare produced to meet requirements, depending on theshelf life approved by the FDA for each product.

Acquisition Test and Evaluation Strategy

The acquisition of medical CBRN defense productsfor the DoD is tailored to comply with the requirementsof both the DoD and the FDA. In a memorandum datedNovember 21, 2003, the deputy under secretary of theArmy required every chemical or biological defense


6/10

650


program, except IND programs, to have a test andevaluation master plan. IND applications accepted bythe FDA must satisfy the test and evaluation masterplan requirement for drug development programs andprovide authority for testing drug products in humanvolunteers in accordance with Army Regulation 73-1,

Test and Evaluation Policy. For soldier-carried items,a modified test and evaluation master plan must beexecuted to ensure compatibility and survivability ofthe item and its packaging.

Acquisition Business and Contracting Strategy

The MITS JPMO is responsible for the advanceddevelopment of medical CBRN drugs. Commercial,off-the-shelf medical products are normally procuredthrough the medical logistics system or through pro-curement contracts issued directly to the vendor bythe servicing government contract office.

If the MITS JPMO pursues product development,it will seek a contractor to serve as the systems inte-grator, generally releasing a request for proposal andmaking it available to full and open competition. If nocommercial entity is identified to serve as the systemsintegrator, MITS will serve as the systems integratorfor products transitioning from the technology baseup to milestone B, at which point a contractor will beselected.

MITS streamlines acquisition by providing aperformance-based statement of objectives (in lieuof a detailed statement of work) in the request forproposal, which might impede competition because

of numerous specific requirements. A performance-integrated product team, consisting of representa-tives from MITS, the Joint Requirements Office, andthe appropriate Joint Science and Technology Officecapability area program office, oversees contractorperformance in accordance with best commercial andgovernment practices. Ad-hoc members are drawnfrom MITS, the US Army Medical Research and Ma-teriel Command, the test and evaluation community,JPEO-CBD, the Office of the Secretary of Defense andother DoD offices, the Department of Health HumanServices and other federal agencies, the technologybase, or the logistics community, as needed. Workingperformance-integrated product teams are formed toaddress issues focused on a specific requirements areapertaining to the product.

The DoD, sponsored by the US Army Office ofThe Surgeon General, currently holds the INDs andapprovals of medical chemical defense products. Thedecision to allow a commercial contractor to hold theIND and drug approval for future products is madeon a case-by-case basis. An approach is recommended

as soon as possible, even as early as milestone A. Therecommendation is based on several factors, includ-ing commercial interest, interagency discussions, andintellectual property rights.

Specific Concerns in Medical Chemical Defense

The biggest challenge in medical acquisition withinthe DoD is that medical development is dictated bythe process of obtaining FDA approval. In this chapter,the phrase FDA approval broadly applies to drugs,biologics, and medical devices. In its strictest sense, theterm approval is usually reserved for drugs, whilelicensure is used for biologics and clearance isused for medical devices. All drugs, vaccines, or medi-cal devices intended for use on or in service membersare regulated by the FDA. In a pharmaceutical, vac-cine, or medical device company, the steps required forobtaining FDA approval drive the drug development

process. Within the DoD, however, medical acquisi-tion is embedded within the acquisition model, whichwas designed around planes, ships, and tanks. Thus,the challenge is to match the DoD acquisition modelwith the process of pharmaceutical development andFDA approval, so decisions that would be made laterin the process in nonmedical military acquisition pro-grams must be made far earlier in the medical realm,allowing INDs to be submitted to the FDA on a timelybasis. The challenge, specifically for the MITS JPMO,is to integrate the FDA regulatory and DoD acquisi-tion processes.

The need for FDA approval of any fielded product

may be self-evident but deserves comment nonethe-less. In civilian medicine, any licensed physician mayprescribe any FDA-licensed product, whether theproduct is for the licensed indication or for some othersymptom. Countless examples exist of off-labelmedications approved for one indication but nowprimarily used for others. In acute nerve agent poison-ing, however, patients must be treated far forward bybuddies or medics and not by licensed physicians. Inthat case, only an FDA-approved product used on-labelcan legally be given by the buddy or medic. Until fullFDA approval for this indication in 2003, the use ofpyridostigmine bromide as a pretreatment against so-man poisoning was an off-label use, notwithstandingthe over 50 years of experience using it for patientswith myasthenia gravis. Until the FDA approved pyri-dostigmine bromide specifically for soman intoxicationpretreatment, the DoD planned to institute a processof informed consent for each service member, meaningeach had the right to decline to use the drug for thatpurpose. Once FDA approval was obtained, however,the DoD acquired the right to order its service members


7/10

651


to take the drug.Peculiarities of medical chemical drug development

create 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 countermea-sure development, and released the animal rule. As aresult, the FDA will consider approving medical chemi-cal, 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-controlled

animal efficacy data, in multiple species, to demon-strate that 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 hydroxocoba-lamin, approved as an antidote for cyanide poisoningin 2007. So far, the animal rule has only been used forproducts specifically intended for medical chemical de-fense, but several products in advanced developmentinclude plans to use the animal rule in their regulatory

development strategies as necessary.Another challenge encountered during medical

chemical drug development concerns the specificindications for which a drug is used in medical chemi-cal defense. Although all of the classical organophos-phorus nerve agents work by inhibiting the enzyme

acetylcholinesterase, under a narrow reading of thestatute, to obtain FDA approval for all potentially en-countered battlefield 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 devel-oper. Stereoisomers (chiral forms of molecules) and

polymorphisms (multiple crystal forms of the samemolecules) must always be considered and the licensedcompounds 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 bioavail-ability in 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 RECORD

The 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).5

Lifecycle Management Products

Several 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 fielded

nerve 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-agentinduced 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 atro-pine and 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 de-contaminated and transferred to a clean environment


8/10

652


where protective suits and masks are not required.MANAA was intended to allow a medic to supervisea group of casualties who were capable of assistingwith their own care. Theoretically, MANAA could freeup medical personnel to treat more severely poisonedor injured casualties in a mass casualty situation. No

other aerosolized treatment for nerve agent poisoninghas been licensed by the FDA. MANAA was approvedby the FDA in 1990.

MANAA is approaching the end of its shelf life.The manufacturer no longer maintains the cGMPmanufacturing line required to produce MANAA.Under the Montreal Protocol, an international treatycreated to phase out ozone-depleting substances,aerosolized products such as MANAA must be dis-continued because they contain chlorofluorocarbons.A congressionally-funded program for a dry powderinhaler atropine (DPIA) seeks to develop a product thatwill replace the MANAA. DPIA is being developed

jointly by a team that includes MicroDose Technolo-gies, Inc, the University of Pittsburgh, and the MITSJPMO. DPIA is anticipated to be FDA approved in 2009,with fielding anticipated the following year.

ATNAA is a product developed to replace andimprove upon the Mark I. It is a dual-chambered au-toinjector that delivers 2.1 mg atropine (as comparedto the 2 mg atropine in the Mark I) and 600 mg 2-PAMCl through a single needle. ATNAA was approved bythe FDA in January 2002 and fielding began in 2003.ATNAA delivers antidotes faster than Mark I becauseit uses a single autoinjector rather than two, cutting thetime needed to administer life-saving treatment to a

nerve agent casualty in half. ATNAA is also smaller,easier to use, and less expensive than the Mark I.

Sustainment Programs

Other products carry FDA approval but requirePhase 4 (post-marketing) studies as mandated by theFDA. For example, the Skin Exposure Reduction PasteAgainst Chemical Warfare Agents (SERPACWA; FisherBioservices, Rockville, Md) is a perfluorohydrocarbon-based barrier cream intended to pretreat vulnerableskin areas (such as the groin, neck, wrists, armpits,waistline, and boot tops) prior to donning protectiveovergarments. SERPACWA provides a passive bar-rier that protects the skin from liquid chemical agentexposure for over 8 hours. While SERPACWA is meantto be used in conjunction with mission-oriented protec-tive posture, some Special Forces units have inquiredabout its use without full mission-oriented protectiveposture protection. The FDA approved SERPACWA inFebruary 2000 and the US Army has purchased initialquantities. SERPACWA also protects against many

natural toxins as well, including poison ivy, suggestinga possible use in civilian medicine. However, SER-PACWA is currently only approved for military use.

Studies are ongoing to determine the compatibilityof SERPACWA with the M291 skin decontaminationkit, a pouch containing six individual decontamina-

tion packets that can provide a total of three completeskin decontaminations. SERPACWA currently has anFDA-approved, 3-year shelf life, and is included in theFDA/DoD shelf life extension program.

Another FDA-approved product awaiting Phase 4trials is soman nerve agent pretreatment pyridostig-mine, which is distributed as 30 mg pyridostigminebromide tablets. In February 2003, this pretreatmentbecame the first drug to be approved by the FDA viathe animal rule.

The FDA has mandated the following post-market-ing studies for this product:

a human serum study to correlate dose re-sponse between pyridostigmine bromideblood levels and red cell acetylcholinesteraseinhibition;

a guinea pig study to correlate blood pyri-dostigmine bromide levels, red cell acetyl-cholinesterase inhibition, tissue acetylcholin-esterase inhibition, and the direct effects uponthe diaphragm;

a nonhuman primate study to look at the samequestions as in the guinea pig; and

an in vitro human intercostal muscle study todetermine if pretreatment can provide partial

protection to soman exposure of the muscle.

The first two studies are complete, the remainingstudies are ongoing.

Products in Advanced Development

The joint service personnel/skin decontaminationsystem (JSPDS) program is tasked with developing animproved skin decontamination capability throughopen competition between commercially availableproducts. The current skin decontamination kit, M291,which has been fielded since 1989, is based on theAmbergard resin (Rohm and Haas, LLC, Philadelphia,Pa) that adsorbs and slowly detoxifies chemical agents.The JSPDS program is under the purview of the JointProject Management Office for Decontamination, withmedical consultation from MITS JPMO. The JointProject Management Office for Decontamination com-petitively chose Reactive Skin Decontamination Lotion(RSDL; E-Z-EM, Inc, Lake Success, NY), developed bythe Canadian Department of National Defence under


9/10

653


a 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 animal

studies 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 pros

and cons of moving to field RSDL as a substitute, con-tinuing to field M291, or using a combination of the two.

The advanced anticonvulsant system is the acquisi-tion program that seeks to develop midazolam in anautoinjector as a replacement for the CANA, whichcontains diazepam, to treat nerve-agentinducedseizures (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 pro-

gram is to obtain FDA approval for midazolam againstnerve-agentinduced seizures. Midazolams 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 obtain-ing FDA 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-to-drug interactions, if any, and

any postmarketing studies the FDA maymandate.

Approval is planned no later than 2011.The improved nerve agent treatment system pro-

gram addresses the shortcomings of 2-PAM Cl asa reactivator of acetylcholinesterase. The programhas two goals. The first is to expand the on-label in-dications for pyridostigmine bromide against more

nerve 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-agentinhibitedacetylcholinesterase.

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 rea-sons are that the number of nerve agents for whichan indication for MMB4 must be determined beforeapproval can be granted, and the design of definitive

animal 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 sub-mission is 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) con-sists of three separate increments. Increment I is theplasma-derived human butyrylcholinesterase, which

carries 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 butyrylcholin-esterase is 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 Bax-ter Healthcare 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 bioscav-enging activity) through Phase 1 clinical trials. Efforts


10/10

654


will be tailored to each technology for evaluatingand maturing that technology (recombinant or smallmolecule) and only one technology will be selectedfor acquisition program initiation at milestone B. Theselected product will solve the problem of short sup-ply and consequent expense that Increment I poses,

but may create challenging safety concerns. An FDA-approved product is anticipated no earlier than 2013.

Increment III is envisioned as a catalytic scavengerof nerve agent, likely to be developed with site-directedmutagenesis. No candidate is yet ready for advanceddevelopment.

Good science is not enough to protect service mem-bers against the threat of chemical warfare agents. Aproduct must be developed and approved for humanuse by the FDA, doctrinally on-label for the envisioneduse. It must also be manufactured, stockpiled, anddelivered, and the user, whether a physician or thecasualtys buddy, must know how to use it, which mayrequire extensive training. Finally, the product mustbe managed throughout its lifecycle and closed out ifdeemed necessary or if a superior product replaces it.

These tasks all fall under the medical chemical acquisi-tion mission. The average licensed product costs $400to $800 million79and the vast majority, 80% to 90%

by some estimates, of products in development failto obtain full licensure. While the clinician or medicalplanner need not know the details of the acquisitionmission or of its constituent parts, it is vital to recog-nize that this process is time- and resource-consuming,yet necessary if military personnel are to have propercountermeasures available should the need arise.

SUMMARY

REFERENCES

1. US Department of Defense. Use of Investigational New Drugs for Force Health Protection. Washington, DC: DoD; 2000.Directive 6200.2.

2. Executive Order 13139, Improving Health Protection of Military Personnel Participating in Particular Military Opera-tions, Federal Register64 (1999): No. 192.

3. US Department of Defense. The Defense Acquisition System. Washington, DC: DoD; 2003. Directive 5000.1.

4. US Department of Defense. Operation of the Defense Acquisition System. Washington, DC: DoD; 2003. Instruction5000.2.

5. General Services Administration, Department of Defense, and National Aeronautics and Space Administration. FederalAcquisition Regulation. Washington, DC: GSA, DoD, NASA; 2005.

6. 21 CFR, Parts 314, 601, Subpart 1.

7. Hollis WW. Test and Evaluation (T&E) Policy for Chemical and Biological Defense Program (CBDP) Systems. US Departmentof the Army, Under Secretary of the Army, Operations Research; 2005. Memorandum, 29 August 2005.

8. DiMasi JA, Hansen RW, Grabowski HG. The price of innovation: new estimates of drug development costs. J HealthEco. 2003:22;151185.

9. Kaitin KI, ed. Postapproval R&D raises total drug development costs to $897 million. Tufts Center for the Study of DrugDevelopment Impact Report. 2003:5:3.

10. US Government Accountability Office. New Drug Development: Science, Business, Regulatory, and Intellectual PropertyIssues Cited as Hampering Drug Development Efforts. Washington, DC: GAO; 2006. Report to Congressional Requesters.2206.

Chapter 20 - Medical Chemical Defense Acquisition Programs - Pg. 645 - 654

Documents

Transcript of Chapter 20 - Medical Chemical Defense Acquisition Programs - Pg. 645 - 654