Attachment I1 - Technology Readiness Level (TRL) for drug and biologics (REFERENCE ONLY).pdf

Integrated Technology Readiness Levels (TRLs) for Medical Countermeasure Products (Drugs and Biologics)

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Integrated Technology Readiness Levels (TRLs) for Medical Countermeasure Products (Drugs and Biologics)[1],[2]

Based on October 2004 DOD Medical TRLs and May 2008 HHS PHEMCE TRLs

NOTE: When using these criteria, a medical countermeasure product should be rated at a particular level only after the sponsor has completed all activities listed at that level (e.g., a product is rated at TRL 4 once it completes all of the activities listed in TRL 4).

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.

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.

TRL 3

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

Begin research, data collection, and analysis 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)).

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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.

Animal Models: Initiate development of appropriate and relevant animal model(s) for the desired indications.

Assays: Initiate development of appropriate and relevant assays and associated reagents for the desired indications.

Manufacturing: Manufacture laboratory-scale (i.e., non-GMP (Good Manufacturing Practice)) quantities of bulk product and proposed formulated product.

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).

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.

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 shelf 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.

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.

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.

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.

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.

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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).

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.

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).

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.

Manufacturing: Complete validation and manufacturing of 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.

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.

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.

[1] This document is designed for evaluating the maturity of medical countermeasure development programs. For a detailed description of development processes for assays and animal models, please consult the Technology Readiness Levels for Product Development Tools (PDTs), developed by the PDT

Working Group of the HHS Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) and available at:

http://www.medicalcountermeasures.gov

[2] This document does not serve as official FDA Guidance nor does it represent FDA's current thinking on this topic. For the purposes of a regulatory application seeking licensure or approval for a specific medical product, additional data may be required by FDA.

[3] Identification of later regulatory stages of clinical development in this document (e.g., Phase 2, Phase 3) may not apply to some products being developed under the "Animal Rule." Other than human safety studies, no additional clinical data may be feasible or ethical to obtain. For additional information on the "Animal Rule", please see: https://www.fda.gov/emergency-preparedness-and-response/mcm-regulatory-science/animal-rule-information

[4] These could include GLP animal efficacy studies required by FDA at this stage in support of an Emergency Use Authorization (EUA). The scientific evidence required for issuance of an EUA will be handled on a case-by-case basis and will depend on, among other things, the nature and extent of the threat at any point during the product development timeline, from the initiation of Phase 1 studies through licensure or approval. GLP animal efficacy study requirements may also vary by product type (e.g., vaccine, therapeutic, prophylactic) and U.S. government agency program office.

[5] For products approved under the "Animal Rule," confirmatory efficacy data are required, if such studies are feasible and ethical, and may be obtained from use during an event.

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