Animal Model Qualification Program

The Animal Model Qualification (AMQ) program is evolving.  The program is voluntary and models qualified through this program will be made public.  The process described below is subject to change as the Qualification Review Teams (QRTs) work with a number of submitters.

The AMQ program is jointly supported by both CDER and CBER, to respond to the need for improved animal models for drug and biological[1] product development under the Animal Rule (21 CFR 314.600 for drugs; 21 CFR 601.90 for biological products). “FDA will rely on the evidence from studies in animals to provide substantial evidence of the effectiveness of these products only when: (1) There is a reasonably well-understood pathophysiological mechanism of the toxicity of the substance[2] and its prevention or substantial reduction by the product; (2) The effect is demonstrated in more than one animal species expected to react with a response predictive for humans, unless the effect is demonstrated in a single animal species that represents a sufficiently well-characterized animal model for predicting the response in humans; (3) The animal study endpoint is clearly related to the desired benefit in humans, generally the enhancement of survival or prevention of major morbidity; and (4) The data or information on the kinetics and pharmacodynamics of the product or other relevant data or information, in animals and humans, allows selection of an effective dose in humans.” (21 CFR 314.610; 21 CFR 601.91)

Product-independent animal models can be evaluated and qualified as part of the qualification program outlined for Drug Development Tools (DDTs)(see 2010 draft Guidance for Industry: Qualification Process for Drug Development Tools). The qualification of animal models will follow the process outlined for other DDTs, closely paralleling that for biomarkers. The initial animal model to be qualified should demonstrate the natural history of the disease/condition caused by the threat agent and will therefore have a narrow context of use. The context of use may be limited to the conclusions that the challenge agent[3] induces a disease/condition in animals that is analogous to the human disease/condition, and that the human disease/condition and animal disease/condition share the same, or very similar, pathogenic mechanisms. 

There are differences in the qualification process that arise because of differences in how animal models are used in drug development as compared to other DDTs.  Some of the more important considerations specific to animal model qualification are listed below.
 

Additional Guidance

In general, animal models for qualification should conform to the principles outlined in the draft Guidance for Industry: Animal Models - Essential Elements to Address Efficacy Under the Animal Rule (PDF - 135KB) (January 2009). 
 

Context of Use

For animal models, the context of use statement may be extensive, it should detail how the model is to be used in drug development, and it should specify details necessary to replicate the model.  Examples of such details include:

• characterization of the animals to be used, including, but not limited to, species, age, gender, screening assays, and exclusion criteria,
• characterization and preparation of the challenge agent,
• procedural information regarding exposure, and
• identification of endpoints and treatment triggers.
   

Qualification Steps for Animal Models

• Natural history studies 

Natural history animal models are conceptually independent of the drugs that may be tested using these models. Submitters should consider qualifying the models used in the natural history studies because they provide the basis for all other studies[4] for that threat agent under the Animal Rule. In this case, qualification implies that a particular species of animal, given a particular threat agent by a particular route, is an adequate representation of the human disease/condition and can be used for development of drugs under the animal rule. Qualification of a natural history model does not imply that the model will be acceptable under tenet two of the Animal Rule which states “a single animal species that represents a sufficiently well-characterized animal model for predicting the response in humans.” Furthermore, the appropriateness of the species of animal used in the natural history studies for development of each drug must still be demonstrated. 

• Progression to efficacy studies 

The purpose of qualifying a model based on natural history studies is to use the model to further drug development toward approval or licensure. For example, when using the model for a treatment indication, triggers of intervention may be identified from the natural history studies, and definition of endpoints may be refined (e.g., development of model-specific euthanasia criteria). Submitting this additional data for review by the QRT may allow modification of the “context of use” for the model to specify the conditions in which the model may be used for treatment indications. Similarly, with appropriate data, the model might also be qualified for use for pre-exposure and/or post-exposure prophylaxis indications. Through further interactions with the QRT and adequate additional data, submitters can tailor or broaden the “context of use” statement(s).    
 

Need for Good Laboratory Practice (GLP) for Nonclinical Studies

Qualification is a regulatory conclusion[5]; thus, the animal studies submitted for qualification are generally expected to be conducted in accordance with GLP regulations (21 CFR part 58).  The FDA recognizes that there may be justifiable limits in conforming to GLP regulations when conducting studies using certain challenge agents, e.g., those requiring Animal Biosafety Level 4 confinement.  In such cases, the deviations should be delineated and explained, and a discussion of the possible impact on study results and conclusions should be submitted for review.