pursuing new antibiotic development, especially when there are other therapeutic interests vying for the same resources. Although the FDA attempts to balance the demands of a public health emergency with their needs as a regulatory agency and offers several accelerated routes to licensure, including the proposed animal efficacy rule, there is still a sense that these regulatory processes need to be streamlined even more in order to accelerate drug discovery and development efforts and provide more incentive for the pharmaceutical industry.

Our antiviral amamentarium is even more limited than our antibiotic arsenal. Cidofovir, for example, can only be administered intravenously and is highly nephrotoxic, making it unsuitable for mass casualty use. The clinical utility of ribavirin as an antiviral drug strategy for bioterrorist agents remains unclear.

Antibiotics and antivirals are not the only potential therapeutic defense against bioterrorist agents. Basic research on the anthrax toxin system has led to some exciting prospects for antitoxin targeting. The most promising are the dominant negative inhibitors (DNIs), mutant forms of the protective antigen that block translocation of the virulence factors across the plasma membrane. Currently, DNIs are a very late stage product. If they can be proven efficacious in infected animal models, they could be produced and deployed very rapidly. There are several other approaches in much earlier stages of development.

The use of recombinant monoclonal antibodies is another option which has been implicated for use against several biothreat agents, including anthrax, smallpox, and botulinum neurotoxins. For example, recent research has shown that a small mixture of recombinant monoclonal antibodies provides complete protection in mice against botulinum neurotoxin type A. Antibodies have several advantages as a bioweapons defense tool: they have been shown in multiple studies to be safe; ten have already been approved by the FDA and seventy more are in clinical trials, so their route to licensure is known; the technology and knowledge needed for production are readily available; their overall course through the discovery and approval process is much quicker than those of other types of therapeutics; and the technology platform used to produce and manufacture antibodies could be applicable to multiple agents.

Finally, scaling up research and development of all of these various potential therapeutics will require an evaluation of the availability of and need for additional laboratory capacity. In particular, there are a very limited number of BSL-3 and 4 labs where nonhuman primate studies can be conducted. Hope was expressed that in the future the FDA will accept rodent data in lieu of nonhuman primate data, if it can be demonstrated that the efficacy is the same in rodents as in nonhuman primates. This would allow for more testing in a greater number of facilities, although it would still require at least BSL-3 capability. Aerosol testing requires BSL-4 capabilities, as well as trained, vaccinated personnel.



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