Technology Readiness Levels

1 Review of Scientific Knowledge Base

Scientific findings are reviewed and assessed as a foundation for characterizing new technologies.

2 Development of Product Hypothesis

Activities: Scientific studies to identify and validate disease target. Screen potential compounds (High-Throughput Screening, antibody, etc.) to develop preliminary hits. Develop assays to test activities of candidate compounds in vitro. Initial intellectual property search for patentability. Characterize disease epidemiology.

Milestones: Identify compound series.

3 Identification and Characterization of Product Candidate

Activities: Decision on which compounds to advance in development. Synthesize novel series of compounds; test efficacy and toxicities in vitro. Test pharmacokinetics/toxicity of selected compounds in relevant in vivo models on a non-GLP level. Survey relevant patent literature to identify white space and assess patentability of compound series. Survey clinical literature to characterize current care patterns and unmet need(s). File a provisional patent on the pharmacophore. Synthesize and assess several potential lead compounds.

Milestones: Demonstrate in vitro efficacy. Preliminary efficacy demonstrated in vivo in appropriate small animal model. Identify lead series. File patent.

4 Optimization and Initial Demonstration of Safety and Efficacy

Activities: Initiate experiments to identify markers, assays, and endpoints for further non-clinical and clinical studies. Assess endpoints for relevant impact in clinical practice. Conduct in vivo distribution and elimination studies as well as non-GLP in vivo toxicity, efficacy, and pharmacokinetics studies of the lead compound.

Milestones: Finalize formulation appropriate for route of administration. First draft of Target Product Profile. Determine regulatory strategy. Characterize current reimbursement mechanisms, economic burden of illness and treatment costs. Identify preclinical candidate compound and animal models for GLP toxicology studies.

5 Advanced Characterization of Product and Initiation of Manufacturing

Activities: Develop a scalable and reproducible manufacturing process amenable to GMP. Develop assays/analytical methods for product characterization and release (potency, purity, ID, sterility, etc). Perform IND-enabling toxicology studies. Identify Key Opinion Leaders (KOLs) that can help design a clinical trial strategy/sequence, including collection of health economic and longer-term patient outcomes measures. Identify clinical sites and begin contract negotiations. Begin stability testing on drug substance (i.e., API).

Milestones: Identify candidate. Demonstrate acceptable ADME characteristics and/or immune responses in GLP animal studies as necessary for regulatory filing. Identify manufacturing partners. Pre-IND meeting with FDA.

6 Regulated Production, Regulatory Submission, and Clinical Data

Activities: Prepare and submit IND. Initiate Phase I study.

Milestones: Manufacture GMP-compliant pilot lots. Prepare and submit regulatory package to FDA and conduct Phase 0 and/or 1 clinical trial(s) to determine the safety and pharmacokinetics of the clinical test article.

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

Activities: Post Phase 2 meeting with FDA. Determine dosing and treatment population for Phase 3 study.

Milestones: Scale-up and validate GMP manufacturing process at a scale compatible with USG requirements. Complete stability studies of the GMP drug product in a formulation, dosage form, and container consistent with Target Product Profile. Complete Phase 2 clinical trials.

8 Completion of GMP Validation and Consistency Lot Manufacturing, Clinical Trials Phase 3, and FDA Approval or Licensure

Milestones: Finalize GMP manufacturing process. Complete clinical efficacy trials (e.g., Phase 3), and/or expanded clinical safety trials as appropriate. Prepare and submit New Drug Application (NDA) or Biologics Licensing Application (BLA).

1 Review of Scientific Knowledge Base

Scientific findings are reviewed and assessed as a foundation for characterizing new technologies.

2 Development of Product Hypothesis

Activities: Scientific "paper studies" to generate research ideas, hypotheses, and experimental designs for addressing the related scientific issues. Characterize disease epidemiology. Use of computer simulation or other virtual platforms to test hypotheses where possible. Initial intellectual property search for patentability and to refine prototype configuration options.

3 Identification and Characterization of Product Candidate

Activities: Explore prototypes, identify and evaluate critical technologies, critical design features needed, and components. Survey clinical literature to characterize current care patterns and unmet need(s). Initiate user feedback on prototypes.

Milestones: Demonstrate in vitro efficacy. Preliminary efficacy and safety demonstrated ex vivo or in vivo. Identification of reimbursement and regulatory classification (pathway identification). File a provisional patent.

4 Optimization and Initial Demonstration of Safety and Efficacy

Activities: Collection of user feedback on prototypes utilized to refine design inputs and identify new ones as needed. Iteration and elimination of prototype designs based user feedback, bench testing, ex vivo and non-GLP in vivo testing. Integration of critical technologies. Initiation of animal model development for desired indication (if necessary). Initiation of experiments to identify endpoints for further non-clinical and clinical studies.

Milestones: Initiate design control activities, establish design and development plan, capture design inputs. Determine Instructions for Use (IFU), and regulatory and clinical strategy. Characterize current reimbursement mechanisms, economic burden of illness and treatment costs. Preliminary FDA meeting. Non-GLP in vivo efficacy demonstration in accordance with the product's intended use.

5 Advanced Characterization of Product and Initiation of Manufacturing

Activities: Develop test methods for device characterization, performance testing, and product release (if relevant). Explore potential manufacturing options as well as manufacturability and sustainability of device design, including third-party partners. Develop a scalable and reproducible manufacturing process amenable to GMP.

Milestones: Demonstrate intended device design to address go criteria. Design inputs to support regulatory filing (design freeze). Preliminary FDA meeting (depending on device type and classification). First draft of a Target Product Profile/product label and reimbursement strategy.

6 Regulated Production, Regulatory Submission, and Clinical Data

Activities: Initiate manufacturing using scalable and reproducible process. Integrate quality. Complete testing, bench, in vitro and in vivo GLP study, if necessary, intended to verify and validate the product design (per design controls) to support regulatory submission at design freeze. Initiate shelf life/product stability studies. Finalize packaging of the device and sterilization validation.

Milestones: Manufacture GMP-compliant devices. Complete design verification and validation testing. Prepare and submit regulatory package to FDA (510k, IDE, as needed).

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

Activities: Validate manufacturing processes at scale intended to support production. Implement Corrective and Preventive Action (CAPA) and other quality requirements. Support activities needed to complete clinical trials (for De Novo or Premarket Approval [PMA] pathway, if needed).

Milestones: Design transfer activities such as scale-up and validate GMP manufacturing process. Complete clinical trials (as needed for Investigational Device Exemption [IDE] or Early Feasibility Study [EFS]). Regulatory submission of results.

8 Completion of GMP Validation and Consistency Lot Manufacturing, Clinical Trials Phase 3, and FDA Approval or Licensure

Milestones: Complete Design Transfer into finalized GMP manufacturing process. Prepare and submit for market approval: Premarket Approval (PMA), Premarket Notification or 510(k), Humanitarian Use Device (HUD) or Humanitarian Device Exemption (HDE). Prepare postmarket clinical strategy/surveillance plan.

1 Review of Scientific Knowledge Base

Active monitoring of scientific knowledge base. Identify links between disease in humans and animals

2 Development of Product Hypothesis

Activities: Scientific "paper studies" to generate research ideas, hypotheses, and experimental designs for addressing the related scientific issues. Characterize disease epidemiology. Initial intellectual property search for patentability.

3 Identification and Characterization of Product Candidate

Activities: Explore assay components via prototypes and screening; identify and evaluate critical technologies and components, and begin characterization of lead design. Survey clinical literature to characterize current care patterns and unmet need(s). Initiate user feedback.

Milestones: Demonstrate preliminary assay with simplified sample/artificial matrices. Demonstrate sensitivity and specificity with spike/recovery studies in the appropriate matrices.

4 Optimization and Initial Demonstration of Safety and Efficacy

Activities: Integration of critical technologies and components (including hardware and software). Select appropriate candidate reference and quality control (QC) reagents.

Milestones: Assay/test method validation in accordance with the product's intended use (sample type, volume, assay components). Establish draft Target Product Profile. Characterize current reimbursement mechanisms, economic burden of illness and treatment costs. Formulate initial regulatory and reimbursement strategies.

5 Advanced Characterization of Product and Initiation of Manufacturing

Activities: Design freeze. Develop a scalable and reproducible manufacturing process aligned with regulatory guidelines (as needed). Finalize quality control (QC) criteria.

Milestones: Identify supply chain and/or manufacturing partners. Demonstrate acceptable performance as necessary for regulatory filing and for impact on clinical care. Preliminary FDA meeting.

6 Regulated Production, Regulatory Submission, and Clinical Data

Milestones: Manufacture product compliant with quality protocols. Submit regulatory package based on regulatory classification (e.g., Clinical Laboratory Improvement Amendments [CLIA] vs. In Vitro Diagnostics [IVD]).

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

Milestones: Assays used to assess product quality are validated. Validate assays used to assess product quality and critical outcomes in clinical trials and animal efficacy studies.

8 Completion of GMP Validation and Consistency Lot Manufacturing, Clinical Trials Phase 3, and FDA Approval or Licensure

N/A