Animal Models for Assessing Countermeasures to Bioterrorism Agents (2011) / Chapter Skim
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Appendix C: Developing Animal Models for Use in Animal Rule Licensure: The NIAID Approach
Appendix C: Developing Animal Models for Use in Animal Rule Licensure: The NIAID Approach
Pages 109-122
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From page 109... ...
The reason for the intense focus on animal models for biological threats is twofold: first, no model has yet passed the ultimate test of supporting product licensure, and second, product developers generally don't have the in-house capability to conduct animal model development in biocontainment, and researchers who do have the capability aren't directly responsible for, and sometimes only peripherally involved in, product development. NIAID's approach to animal model development is product-neutral, whereas manufacturing and clinical development are inherently product-specific activities.
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From page 110... ...
Further product specific refinements may be required, but are left to the sponsors or advanced development contracts in the context of pivotal, product-specific studies. NIAID's independent investment in the development of product-neutral animal models has been quite successful and this white paper will share examples of the most important product-neutral lessons learned and guiding principles to apply to other animal models moving forward.
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From page 111... ...
2. DESCRIPTION OF NIAID'S ANIMAL MODEL DEVELOPMENT PROGRAM NIAID began to address the challenge of developing biodefense medical countermeasures by first convening Blue Ribbon Panels, which developed a Strategic Plan for Biodefense Research and Research Agendas for CDC Category A Agents and Category B and C Priority Pathogens, in 2002-2003.
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From page 112... ...
3.2 Pathogen Issues One of the next challenges encountered in developing animal models is the challenge material itself. Selecting a strain or isolate that is representative of the pathogen is a critical decision, as it is highly desirable to use one strain/isolate throughout a product or model development program.
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From page 113... ...
Having established procedures to make the challenge material, it is now time to select a challenge route and dose for testing countermeasure efficacy. There are a number of challenge routes of interest, and a number of relationships between animal model and human disease.
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From page 114... ...
This section will describe the NIAID's most valuable lessons learned, organized by pathogen, concluding with some pathogenindependent observations on study-specific issues encountered. The examples presented here are germane to the development of animal models and do not represent all of the work performed for NIAID; product specific information such as correlates of protection, while applicable to any vaccine, do not necessarily inform animal model development.
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From page 115... ...
In retrospect, the obstacles encountered led to a better understanding of some of the critical parameters around this animal model. In contrast to the robust rabbit post-exposure vaccination model, development of a similar model in non-human primates has met many difficulties.
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From page 116... ...
Given the dynamic nature of animal models of infectious disease, there were multiple variables to consider. Initial efforts focused on the challenge spores and the aerosol delivery.
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From page 117... ...
Now that these models are nearly as far as they can go in a product-neutral fashion, the next step planned is replicating these models at additional sites, one of the final tests of a good model. 4.2 Smallpox NIAID had very clear guidance from FDA that animal models to support licensure of a next generation smallpox vaccine would require a respiratory challenge route, not the intravenous challenge model that was the most advanced model at that time.
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From page 118... ...
As two smallpox countermeasures have been handed off from NIAID to BARDA for further development, it is unlikely that NIAID will contribute much more data to our understanding of these models. The disadvantage of further model development occurring in the context of specific product development pathways is that such data may not become publicly available for future countermeasures.
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From page 119... ...
These are not unique to biodefense animal models, however they deserve mention regardless. NIAID aspires to develop animal models in accordance with the three R's (replace, reduce, refine)
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From page 120... ...
One of the working groups chartered under this committee structure was the Product Development Tools Working Group (PDT WG) , which I was asked to co-chair, charged with ensuring the availability of biocontainment facilities, animal stocks, animal model development," validated" experimental protocols and "validated" assays.
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From page 121... ...
One can think of the PDT TRLs as capturing three successive phases of animal model development: product independent, product dependent and product specific. Product independent studies are the early studies of the disease itself, such as pathogenesis and natural history studies and do not require a product to be available.
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From page 122... ...
NIAID's models are assessed as models in their own right, without a concomitant assessment of a product. NIAID's objective approach to animal model development, along with a high level of investment, has been very successful and should be viewed as the standard when approaching Animal Rule efficacy to support medical countermeasures for biological threats.
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