Neuroscience Biomarker Program Mary Ann Pelleymounter, PhD Program Director mary.pelleymounter@nih.gov Victoria Smith, PhD Health Program Specialist victoria.smith@nih.gov

Advancing a Biomarker Candidate from Discovery Through Qualification FDA-NIH Definitions Biomarker: Indicator of a normal or pathological process or of a response to a therapeutic Context of Use: Manner and purpose of use of a biomarker Fit for Purpose: Refers to degree of validation (dependent upon intended use of biomarker) Laboratory Clinical Use Discovery Validation Clinical Utility Qualification Degree of Evidence required Standardized sample source Bioinformatics Identification/POC Begin defining Context of Use Context of Use Analytical validation (establish performance characteristics) Clinical validation (correlation with clinical concept of interest) Large, prospective clinical studies Context of Use Evaluate overall utility for clinical practice and drug development FDA review for qualification Within Context of Use, biomarker provides reliable application and allows specific interpretation

Neuroscience Biomarker Program Goal: Facilitate the development of high quality biomarkers to improve the quality and efficiency of clinical research (Phase II and beyond) Three Pillars: NINDS Funding opportunities that support a rigorous, “fit for purpose” validation process. A Notice of Interest encouraging applications focused on pain biomarkers is in development. Workshop focused on “Best Practices in Neuroscience Biomarker Discovery,” planned for Late 2018/early 2019 Centralized NINDS “one-stop” web page with links to all NINDS biomarker resources and public/private partnership opportunities

Funding Opportunities Supporting a “Fit for Purpose” Validation Process Number Title Mechanism PAR-18-550 Analytical Validation of a Candidate Biomarker for Neurological Disease* U01 PAR-18-549 U44 PAR-18-664 Clinical Validation of a Candidate Biomarker for Neurological Disease (coming soon) PAR-18-548 Clinical Validation of a Candidate Biomarker for Neurological Disease* *Next application due date: March 14, 2018 U01 = Research Project, Cooperative Agreements U44 = Small Business Innovation SBIR Cooperative Clinical Trial Optional

FDA-NIH Standardized Biomarker Definitions Analytical Validation: Establishing that the performance characteristics of a measurement are acceptable in terms of its sensitivity, specificity, accuracy, precision, and other relevant performance characteristics using a specified technical protocol (which may include sample collection and standardization procedures). The level of analytical rigor that is necessary depends upon the characteristics of the biomarker, the detection technology, the type of clinical question or its intended use as a biomarker (diagnostic, predictive, pharmacodynamic, etc). Clinical Validation: Establishing that the biomarker acceptably identifies, measures or predicts the concept of interest. Clinical Utility: The conclusion that a given use of a biomarker will lead to a net improvement in health outcome or provide useful information about diagnosis, treatment, management or prevention of a disease. Use of the BEST (Biomarkers, EndpointS, and Other Tools Resource) standardized biomarker definitions is required https://www.ncbi.nlm.nih.gov/books/NBK338448/

U01 and U44 Cooperative Agreement Mechanisms Year 1 Go/No-Go Milestones Year 2 Extremely Clear, Quantitative and Definitive Milestones are Essential Annual Go/No-Go Point at the end of each year Transition occurs via Administrative Review Go/No-Go Milestones Year 3 Go/No-Go Milestones Year 4 Go/No-Go Milestones Year 5

U01 and U44 Cooperative Agreement Mechanisms Mechanism Name Length Budget U01 Research Project, Cooperative Agreements Up to 5 years Not limited but must reflect the actual needs of the proposed project U44 Small Business Innovation SBIR Cooperative Agreement Phase I: Up to 2 years; Phase II: Up to 3 years Phase I: Up to $700,000 per year; Phase II: Up to $1,500,000 per year. Must be reasonable and appropriate.

PAR-18-550 and PAR-18-549 Analytical Validation of a Candidate Biomarker for Neurological Disease Goals To encourage rigorous analytical validation of candidate biomarker measures or endpoints in a manner that is consistent with FDA guidelines. Evaluation of the assay, its performance characteristics, and the optimal conditions To facilitate the advancement of robust and reliable biomarkers to application in clinical trials and practice (Phase II clinical trials and beyond). Entry Criteria Identified biomarker with a working hypothesis on context of use Developed method of detection, with further potential optimization Plans for management of pre-analytic variables Cogent biological rationale supporting the candidate biomarker Relevance to therapy development or clinical practice

PAR-18-550 and PAR-18-549 Examples of appropriate biomarker validation studies Determination of the Context of Use for the biomarker Analytical validation of a tissue or biofluid, imaging, physiological, or behavioral biomarker assay Analytical validation of biomarkers with clinical intervention such as pharmacodynamic/response biomarkers, predictive biomarkers, safety biomarkers, or monitoring biomarkers Analytical validation of biomarkers without clinical intervention such as diagnostic, prognostic, or susceptibility/risk biomarkers Studies focused on improving standardization or harmonization of assays among laboratories for use in clinical trials The goal for analytical validation should be that the biomarker measurement meets FDA analytical performance criteria https://www.fda.gov/downloads/drugs/guidances/ucm368107.pdf within the scope of the intended Context of Use.

PAR-18-550 and PAR-18-549 Examples of out-of-scope biomarker validation studies Natural history studies aimed at understanding disease pathophysiology, genetic, or epigenetic mechanisms Biomarker identification Initial development of the biomarker detection method (although it is recognized that optimization of that detection method will occur during the validation process) Therapeutic target identification Preclinical animal studies Development of candidate therapeutics Studies focused on clinical validation of a candidate biomarker

PAR-18-550 and PAR-18-549 Analytical Validation can Include the Following Metrics Accuracy Precision Analytical sensitivity Analytical specificity including interfering substances Reportable range of test results for the test system Reference intervals (normal values) with controls and calibrators Harmonization of analytical performance if the assay is to be performed in multiple laboratories Establishment of appropriate quality control and improvement procedures Any other performance characteristic required for test performance with determination of calibration and control procedures. Applicants with assays that have already met the above criteria for analytical validation may apply directly to the companion FOA, "Clinical Validation of a Candidate Biomarker for Neurological Disease”

Clinical Validation of a Candidate Biomarker for Neurological Disease PAR-18-664 and PAR-18-548 Clinical Validation of a Candidate Biomarker for Neurological Disease Goals To encourage rigorous clinical validation of a candidate biomarker using retrospective and/or prospective methods in a manner that is consistent with the purpose of the biomarker To facilitate the advancement of robust and reliable biomarkers to application in clinical trials and practice (Phase II clinical trials and beyond). Entry Criteria Identified biomarker with a working hypothesis on context of use Analytical validation for the candidate biomarker should be completed and consistent with FDA standards Plans for management of pre-analytic variables Preliminary validation data Cogent biological rationale supporting the candidate biomarker Relevance to therapy development or clinical practice

PAR-18-664 and PAR-18-548 Examples of appropriate clinical validation studies Clinical validation studies of the biomarker, with the goal of establishing robust correlations between biomarker and disease or therapeutic response Optimization of analytical validation for the purposes of increasing feasibility in multiple clinical studies and sites Expanded determination of context of use, using FDA guidelines Retrospective, well controlled, multi-site clinical studies using meta-analysis or multiple independent studies Prospective focused and randomized multi-site clinical studies Studies aimed at demonstrating that candidate biomarkers are fit for use in specific contexts relevant to multi-site clinical trials Studies to characterize patient cohorts with biomarkers that will be used to stratify patients or determine inclusion/exclusion criteria in clinical trials Intervention studies where pharmacodynamic, predictive, monitoring, or safety biomarker validation is the focus of the study Non-intervention studies where diagnostic, prognostic and risk/stratification biomarker validation is the focus of the study Studies designed to assess the health impact of a biomarker in clinical practice Studies designed to provide a data package suitable for FDA biomarker qualification

PAR-18-664 and PAR-18-548 Examples of out-of-scope clinical validation studies Natural history studies aimed at exploring disease pathophysiology, genetic or epigenetic mechanisms Applications that propose any animal studies Studies of biomarker identification or technology development Biomarker analytical validation as the sole intent (it is recognized that optimization of the method of detection may continue throughout the clinical validation process) Applications that propose only to create or maintain patient registries Clinical testing of candidate therapeutics Clinical intervention studies other than those necessary to validate biomarkers Applications that request support for infrastructure to establish new clinical trial networks are beyond the scope of this FOA.

PAR-18-664 and PAR-18-548 Clinical Validation can Include the Following Metrics: Demonstration of association of the result of the biomarker assay with a clinical endpoint (e.g., survival, response, disease presence or absence) in samples or data from patients that have been exposed to a uniform intervention or that have or will develop a disease or disorder Definition of the sensitivity and specificity of the assay result within the context of the defined clinical endpoint and clinical population Estimation of the prevalence of the marker within subjects or patients for the intended clinical context Establishment of an appropriate cut-off or threshold for the assay using appropriate statistical analysis

Collaborations Multidisciplinary collaboration must be an integral part of the application: Scientific investigators Assay developers Clinicians Statisticians Consultants Clinical laboratory staff Individuals knowledgeable in the FDA qualification process Individuals familiar with the process of analytical validation, including statistical design and analysis experts.  201705 received 27 applications

Leveraging Existing Research Resources Applicants should leverage existing research resources NINDS Biospecimen, imaging, and data repositories: Parkinson’s Disease Biospecimen Resources: https://pdbp.ninds.nih.gov/biospecimens. This site provides information where specimens may be found and application procedures. NINDS Human Cell and Data Repository: https://nindsgenetics.org/. A resource for providing Stem Cells including iPSCs and Fibroblasts to both academic and industry investigators to advance the study of neurological disorders. NINDS Human Biomarkers Biospecimen and Data Repository (“BioSEND”): https://www.biosend.org. This site provides information about accessing biospecimens and data, with a focus on Parkinson’s Disease, Huntington Disease, and Lewy Body Dementia. NeuroBioBank: https://neurobiobank.nih.gov. This site provides information on obtaining tissue and associated clinical data through the NIH NeuroBioBank. Parkinson’s Disease Biomarkers Program Data Management Resource (DMR): https://pdbp.ninds.nih.gov/researcher. This site provides information on how to access shared Parkinson’s Disease clinical, imaging, molecular, and biological data stored in DMR. Federal Interagency TBI Research (FITBIR): https://fitbir.nih.gov/. This site provides information on how to access shared TBI stored in FITBIR. Resources from private research foundations, other government agencies, and data from ongoing clinical trials 201705 received 27 applications

Qualification of Biomarkers Data obtained after completion of this FOA should be appropriate for use as a component of the package required for FDA qualification of the biomarker:  https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/BiomarkerQualificationProgram/default.htm If biomarker qualification is the intent of the application, applicants are encouraged to collect the clinical data needed to apply to the FDA for qualification.  Researchers are encouraged to initiate the qualification process with the FDA prior to submitting an application to this FOA A plan to obtain advice from the FDA on the development of the biomarker should be included in the application, if applicable.  The FDA Drug Development Tools Biomarker Qualification Program: https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/BiomarkerQualificationProgram/default.htm. 201705 received 27 applications

Questions? Please contact us with any questions or for Pre-Application Consultation: Mary Ann Pelleymounter, PhD Program Director mary.pelleymounter@nih.gov Website: https://www.ninds.nih.gov/Current-Research/Research-Funded-NINDS/Translational-Research/Neuro-Biomarkers Links to Funding Opportunities: Analytical Validation of a Candidate Biomarker for Neurological Disease PAR-18-549:  U44 SBIR PAR-18-550:  U01 Clinical Validation of a Candidate Biomarker for Neurological Disease PAR-18-548:  U44 Coming Soon: U01