Development of Biomarkers or Composite Biomarkers for Neurological and Neuromuscular Disorders (R61/R33 - Clinical Trial Optional)
Funding Agency:
- National Institutes of Health
This funding opportunity uses a R61/R33 Phased Innovation Award mechanism. The R61 phase will support biomarker and biomarker signature proof of concept studies to test a hypothesis that a candidate biomarker or biomarker signature is an indicator of a particular concept (a biological process or response to an intervention). Studies must use clinical samples, tissues, and/or data to evaluate the candidate biomarker or biomarker signature (animal studies are not allowed). Studies may also include optimization or additional development of the detection method including preliminary analytical validation needed to measure the biomarker/composite. The purpose of the R33 phase is to conduct preliminary clinical validation of the biomarker or composite biomarker for a specified Context of Use. Context of Use should include defining the category of biomarkers defined in the Biomarkers, EndpointS, and other Tools (Biomarkers, EndpointS, and other Tools (BEST) Resource and how it will be measured and used in clinical trials or clinical practice. Transition from the R61 to the R33 phase is contingent upon the successful completion of Go/No-Go milestones. The milestones should include pre-specified quantitative metrics that demonstrate the construct validity of the biomarker(s) and the concept of interest to demonstrate potential clinical utility, as well as the sensitivity, specificity, and internal validity of the detection method to measure the biomarker or signature. Milestones must be clearly defined, quantifiable, and scientifically justified to allow the investigator and program staff to assess progress in the R61 phase (Please refer to Project Milestones, end of Section I). Completion of a research project resulting from successful application to this NOFO should result in a candidate biomarker or biomarker signature that meets the entry criteria for the companion NOFOs supporting definitive analytical validation of the detection method (PAR-24-095, PAR-24-098)) or definitive clinical validation (PAR-24-097, PAR-24-096).
The definitions of terms within this NOFO:
- Proof of Concept: Establishing that the biomarker acceptably identifies, measures or predicts the concept of interest.
- Internal Validation of the detection method: 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).
- Context of Use (COU): A statement that fully and clearly describes the way the biomarker is expected to be used. The COU should include the biomarker category (susceptibility/risk, diagnostic, monitoring, prognostic, predictive, pharmacodynamic/response, or safety), the modality, method of detection, and clinical population characteristics.
- Concept: In a regulatory context, the concept is the aspect of an individual’s clinical, biological, physical, or functional state, or experience that the assessment is intended to indicate.
- Validation: A process to establish that the performance of a test, tool, or instrument is acceptable for its intended purpose.
- Analytical Validation: A process to establish that the performance characteristics of a test, tool, or instrument are acceptable in terms of its sensitivity, specificity, accuracy, precision, and other relevant performance characteristics using a specified technical protocol (which may include specimen collection, handling and storage procedures). This is validation of the test’s, tool’s, or instrument’s technical performance, but is not validation of the item’s usefulness.
- Clinical Validation: A process to establish that the test, tool, or instrument acceptably identifies, measures or predicts the concept of interest.
- Biomarker categories as defined in the Biomarkers, EndpointS, and Other Tools (BEST) Resources (https://www.ncbi.nlm.nih.gov/books/NBK338448/) include:
- Monitoring biomarkers to track the success of a therapeutic intervention or the disease progression
- Diagnostic biomarkers for detecting clinical manifestation of disease or differentiating between diseases and conditions.
- Prognostic biomarkers used to identify likelihood of a clinical event, disease recurrence or progression in patients who have the disease or medical condition of interest.
- Predictive biomarkers for differentiating individuals based on favorable or unfavorable effect from a therapeutic or other intervention.
- Pharmacodynamic/response biomarkers for demonstrating therapeutic target engagement and response to an intervention.
- Safety biomarkers to indicate the likelihood, presence, or extent of an adverse effect
- Susceptibility/risk biomarkers that indicate the potential for developing a disease or medical condition in an individual who does not currently have a clinically apparent disease.
Application budgets are not limited but need to reflect the actual needs of the proposed project.
February 21, 2025, June 20,2025; October 20, 2025
Carol Taylor-Burds Ph.D
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779
Email: carol.taylor-burds@nih.gov