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TRLs for Product Development Tools

for Medical Countermeasure Product Development Tools (PDTs)1







Consider availability of animal models and facilities needed for challenge material production and for performance of efficacy challenge models.

If unavailable, planning for attainment of necessary facilities and/or animal models must begin at TRL 1.





Identify threat agent and make link between threat agent or physical exposure and disease or injury processes in humans and animals.

· Review of human clinical disease or injury. Perform natural history studies to determine clinical course of disease or injury in animals and whether the animal species are potentially suitable models to mimic human disease.

· Pathogenesis and pathophysiology studiesdesigned and conducted to evaluate and compare the animal disease or injury process to the human.




· Identify and characterize threat agent: natural variation, characteristics that affect the behavior in vitro and in vivo; physicochemical characteristics, dose rate, and exposure duration of physical agents

· Generate hypotheses for types of animal modelsto be developed for product assessment relevant to human disease or injury and the intended indication.

· Perform exploratory studies to determine mechanisms of action for countermeasure intervention based on potential indications.



· Identify potential assays for measuring product quality and measuring important outcomes in relevant animal models.


· Select type strain candidate(s) or physical/physicochemical forms of challenge material that represent threat agent for further study of production, master banks, identity, purity, potency, stability and assays to measure these characteristics, including performance in animal model(s).

· Lab-scale production.

· Availability of physical agent sources.

· Conduct initial proof-of-concept animal efficacy studies with an identified medical countermeasure.

· Identify in vivo potency and efficacy animal models critical to the likely product development path. The mechanism of action of the product is reasonably well understood.

· Identify critical parameters and outcomes in animal models (change in survival or major morbidity) for Animal Rule.2 [1]



· Develop assaysthat will be used to assess product quality and those that will be used to assess critical outcomes in both animals and humans. Identify critical reagents needed for assays, and assess source (availability, change control and master banks).

· Develop pilot scale production of selected challenge material that preserves critical attributes and develop batch record.

· Develop stability program for challenge material where required.

· Identify facilities for physical agent exposure.

· Animal model(s) development to assess the ability of the product to induce a certain response (potency).

· Animal model(s) tentatively selected that are suitable for continued product development.

· Identify endpoints that satisfy the Animal Rule: enhanced survival or reduction of major morbidity.



· Optimize assaysto assess product quality and ensure that appropriate candidate reference and QC (quality control) reagents for those assays are produced.

· Stability studies of these candidate reference reagents are initiated.

· Optimize assays that will be used to assess critical outcomes in both animals and humans.

· Candidate reference and QC reagents for these assays are produced and stability studies initiated.

· Produce challenge material at pilot scale and establish specifications and acceptance criteria.

· Ensure physical agent exposure facilities are GLP compliant.

· Begin studies to demonstrate efficacy of candidate products using relevant animal model(s).

· Generate database for identification of potential correlates/surrogates of efficacy.




· Validate or qualify appropriate critical assays used to assess physicochemical, in vitro and in vivo animal efficacy, pharmacokinetics/ pharmacodynamics (PK/PD) and/or immunogenic characteristics of the product.

· Candidate reference reagents for these assays are qualified.

· Produce challenge material at pilot scale within established specifications.

· Continue studies to determine dose-response, optimal route of administration and timing/schedule of administration of product in relevant animal efficacy models.

· Define reproducibility of relevant animal model(s) with respect to achieving endpoints.

· Initiate planning for future GLP studies.

Submit protocols for Phase 2 trials to FDA for review.



· Assays used to assess product quality are validated; exception: potency assays may still be under development and not yet validated.

· Assays used to assess critical outcomes in clinical trials and in animal efficacy studies are validated.

· Evaluate human biologic outcomes in Phase 2 clinical studies using validated assays and properly qualified reference and QC reagents.


· Produce consistency lots of challenge material at final scale. (Final scale is determined by requirements of medical countermeasure evaluation.)

· Consistency lots are defined by three consecutive lots where critical threat agent attributes are measured using validated assays where feasible.

· Refine animal models to include appropriate range of product doses, optimal route of administration and timing/schedule using data from Phase 2 clinical studies.

· Conduct animal efficacy studies to demonstrate that product positively impacts endpoints that reflect desired benefit in humans.

· Initiate documentation (SOP's, forms, etc.) and procedures to support future GLP studies.

· Transfer animal models to GLP facility if necessary and conduct studies sufficient to demonstrate successful transfer.

Submit study plans for CMC (chemistry, manufacturing, and controls) validation to FDA for review.

Challenge material production, performance of assays or pivotal challenge efficacy studies may be performed

in more than one facility as determined by specific product development considerations, resource availability, and FDA requirements.

Study plans for large scale Phase 3 clinical trials are submitted to FDA (end of Phase 2 meeting).

Submit plans (and proposed statistical analysis) for pivotal animal efficacy studies to FDA for review.



· Evaluate critical biologic outcomes in Phase III clinical trials or GLP pivotal animal efficacy studies using validated assays and properly qualified reference and QC reagents.

· Validated challenge material as defined by final production specifications and acceptance criteria for pivotal animal efficacy studies/species.

· Authenticate animal models.

· Perform animal efficacy studies with final formulation and dose to produce responses predictive for humans.

· Finalize all GLP procedures.

· Conduct pivotal animal GLP efficacy studies using final product formulationand incorporating prospective statistical plans for BLA/NDA submission



· Transfer and cross-validate assays in additional facilities if necessary.

· Cross-validated challenge material as defined by use of agent in multiple facilities, as appropriate.

· Transfer animal model to additional facilities if necessary.

Submit BLA/NDA to FDA for review. Submit plans for post-marketing studies (if applicable), any restrictions necessary

to ensure safe use, patient information, labeling claims, product label, and promotional packages.


1 This document does not serve as official FDA Guidance nor does it represent the FDA's current thinking on this topic. For the purposes of a regulatory application seeking licensure/approval, additional data my be required by FDA.

2 For additional information on the "Animal Rule", please see

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