Medical countermeasures (MCMs) are developed to prepare and protect against both natural and man-made public health threats. TRLs are defined for MCM products, such as a drug or vaccine, and for Product Development Tools (PDTs), such as assays, models, and reagents.

TRL 1

Review of Scientific Knowledge Base

Active monitoring of scientific knowledge base. Scientific findings are reviewed and assessed as a foundation for characterizing new technologies.

Product Development Tools
Challenge Materials

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

Animal Models Using the Animal Efficacy Rule

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 studies designed and conducted to evaluate and compare the animal disease or injury process to the human.

TRL 2

Development of Hypotheses and Experimental Designs

Scientific “paper studies” to generate research ideas, hypotheses, and experimental designs for addressing the related scientific issues. Focus on practical applications based on basic principles observed. Use of computer simulation or other virtual platforms to test hypotheses.

Product Development Tools
Challenge Materials

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.

Animal Models Using the Animal Efficacy Rule

Generate hypotheses for types of animal models to 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.

TRL 3

Target/Candidate Identification and Characterization of Preliminary Candidate(s)

Begin research, data collection, and analysis in order to test hypothesis. Explore alternative concepts, identify and evaluate critical technologies and components, and begin characterization of candidate(s). Preliminary efficacy demonstrated in vivo.

3a. Identify target and/or candidate.

3b. Demonstrate in vitro activity of candidate(s) to counteract the effects of the threat agent.

3c. Generate preliminary in vivo proof-of-concept efficacy data (non-GLP (Good Laboratory Practice)).

Product Development Tools
Assay/Reagents

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

Challenge Materials

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.

Animal Models Using the Animal Efficacy Rule

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.

TRL 4

Candidate Optimization and Non-GLP In Vivo Demonstration of Activity and Efficacy

Integration of critical technologies for candidate development. Initiation of animal model development. Non-GLP in vivo toxicity and efficacy demonstration in accordance with the product’s intended use. Initiation of experiments to identify markers, correlates of protection, assays, and endpoints for further non-clinical and clinical studies.

4a. Demonstrate non-GLP in vivo activity and potential for efficacy consistent with the product’s intended use (i.e., dose, schedule, duration, route of administration, and route of threat agent challenge).

4b. Conduct initial non-GLP toxicity studies and determine pharmacodynamics and pharmacokinetics and/or immune response in appropriate animal models (as applicable).

4c. Initiate experiments to determine assays, parameters, surrogate markers, correlates of protection, and endpoints to be used during non-clinical and clinical studies to further evaluate and characterize candidate(s).

Animal Models
Initiate development of appropriate and relevant animal model(s) for the desired indications.
Assays
Initiate development of appropriate and relevant assays and associate reagents for the desired indications.
Manufacturing
Manufacture laboratory-scale (i.e., non-GMP (Good Manufacturing Practice)) quantities of bulk product and proposed formulated product.
Product Development Tools
Assay/Reagents

Develop assays that 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).

Challenge Materials

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 Models Using the Animal Efficacy Rule

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.

TRL 5

Advanced Characterization of Candidate and Initiation of GMP Process Development

Continue non-GLP in vivo studies, and animal model and assay development. Establish draft Target Product Profiles. Develop a scalable and reproducible manufacturing process amenable to GMP.

5a. Demonstrate acceptable Absorption, Distribution, Metabolism and Elimination characteristics and/or immune responses in non-GLP animal studies as necessary for IND filing.

5b. Continue establishing correlates of protection, endpoints, and/or surrogate markers for efficacy for use in future GLP studies in animal models. Identify minimally effective dose to facilitate determination of “humanized” dose once clinical data are obtained.

Animal Models
Continue development of animal models for efficacy and dose-ranging studies.
Assays
Initiate development of in-process assays and analytical methods for product characterization and release, including assessments of potency, purity, identity, strength, sterility, and quality as appropriate.
Manufacturing
Initiate process development for small-scale manufacturing amenable to GMP.
Target Product Profile
Draft preliminary Target Product Profile. Questions of self life, storage conditions, and packaging should be considered to ensure that anticipated use of the product is consistent with the intended use for which approval will be sought from FDA.
Product Development Tools
Assay/Reagents

Optimize assays to 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.

Challenge Materials

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

Ensure physical agent exposure facilities are GLP compliant.

Animal Models Using the Animal Efficacy Rule

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

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

TRL 6

GMP Pilot Lot Production, IND Submission, and Phase 1 Clinical Trial(s)

Manufacture GMP-compliant pilot lots. Prepare and submit Investigational New Drug (IND) package to FDA and conduct Phase 1 clinical trial(s) to determine the safety and pharmacokinetics of the clinical test article.

6a. Conduct GLP non-clinical studies for toxicology, pharmacology, and immunogenicity as appropriate.

6b. Prepare and submit full IND package to FDA to support initial clinical trial(s).

6c. Complete Phase 1 clinical trial(s) that establish an initial safety, pharmacokinetics and immunogenicity assessment as appropriate.

Animal Models
Continue animal model development via toxicology, pharmacology, and immunogenicity studies.
Assays
Qualify assays for manufacturing quality control and immunogenicity, if applicable.
Manufacturing
Manufacture, release and conduct stability testing of GMP-compliant bulk and formulated product in support of the IND and clinical trial(s).
Target Product Profile
Update Target Product Profile as appropriate.
Product Development Tools
Assay/Reagents

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.

Challenge Materials

Produce challenge material at pilot scale within established specifications.

Animal Models Using the Animal Efficacy Rule

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.

TRL 7

Scale-up, Initiation of GMP Process Validation, and Phase 2 Clinical Trial(s)

Scale-up and initiate validation of GMP manufacturing process. Conduct animal efficacy studies as appropriate. Conduct Phase 2 clinical trial(s).

7a. Conduct GLP animal efficacy studies as appropriate for the product at this stage.

7b. Complete expanded clinical safety trials as appropriate for the product (e.g., Phase 2).

Animal Models
Refine animal model development in preparation for pivotal GLP animal efficacy studies.
Assays
Validate assays for manufacturing quality control and immunogenicity if applicable.
Manufacturing
Scale-up and validate GMP manufacturing process at a scale compatible with USG requirements. Begin stability studies of the GMP product in a formulation, dosage form, and container consistent with Target Product Profile. Initiate manufacturing process validation and consistency lot production.
Target Product Profile
Update Target Product Profile as appropriate.
Product Development Tools
Assay/Reagents

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.

Challenge Materials

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.

Animal Models Using the Animal Efficacy Rule

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 (SOPs, 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.

TRL 8

Completion of GMP Validation and Consistency Lot Manufacturing, Pivotal Animal Efficacy Studies or Clinical Trials, and FDA Approval or Licensure

Finalize GMP manufacturing process. Complete pivotal animal efficacy studies or clinical trials (e.g., Phase 3), and/or expanded clinical safety trials as appropriate. Prepare and submit NDA/BLA.

8a. Complete pivotal GLP animal efficacy studies or pivotal clinical trials (e.g., Phase 3), and any additional expanded clinical safety trials as appropriate for the product.

8b. Prepare and submit New Drug Application (NDA) or Biologics Licensing Application (BLA) to the FDA.

8c. Obtain FDA approval or licensure.

Manufacturing
Complete validation and manufacturing or consistency lots at a scale compatible with USG requirements Complete stability studies in support of label expiry dating.
Target Product Profile
Finalize Target Product Profile in preparation for FDA approval.
Product Development Tools
Assay/Reagents

Evaluate critical biologic outcomes in Phase 3 clinical trials or GLP pivotal animal efficacy studies using validated assays and properly qualified reference and QC reagents.

Challenge Materials

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

Animal Models Using the Animal Efficacy Rule

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 formulation and incorporating prospective statistical plans for BLA/NDA submission.

TRL 9

Post-Licensure and Post-Approval Activities

9a. Commence post-licensure/post-approval and Phase 4 studies (post-marketing commitments), such as safety surveillance, studies to support use in special populations, and clinical trials to confirm safety and efficacy as feasible and appropriate.

9b. Maintain manufacturing capability as appropriate.

Product Development Tools
Assay/Reagents

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

Challenge Materials

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

Animal Models Using the Animal Efficacy Rule

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.

Sources
  1. MedicalCountermeasures.gov. Technology Readiness Levels (TRLs) for Medical Countermeasure Products (Drugs and Biologics) [online]. Available at: https://www.medicalcountermeasures.gov/federal-initiatives/guidance/integrated-trls.aspx.
  2. MedicalCountermeasures.gov. Technology Readiness Levels (TRLs) for Medical Countermeasure Product Development Tools (PDTs) [online]. Available at: https://www.medicalcountermeasures.gov/federal-initiatives/guidance/trls-for-product-development-tools.aspx.