National Institute of Neurological Disorders and Stroke (NINDS)
The NIH announces its intention to publish a Funding Opportunity Announcement (FOA) to solicit applications on Discovery of Biomarkers and Biomarker Signatures to Facilitate Clinical Trials for Pain Therapeutics. The purpose of this intended Funding Opportunity Announcement (FOA) is to promote the discovery of strong candidate biomarkers or biomarker signatures for pain that can be used to facilitate the testing of non-opioid pain therapeutics in Phase II clinical trials. The biomarkers or biomarker signature will be developed through clinical research specifically focused on the identification of pain biomarkers or biosignatures that predict and/or monitor response to pain therapeutics. The resulting biomarkers or biomarker signatures may be focused on a single pain condition or on several pain conditions with common underlying pathophysiology. Applications to identify biomarkers or biomarker signatures that predict or monitor a therapeutic response across several related pain conditions should feature Multiple Principal Investigator (MPI)-led teams that represent each of the related pain conditions and associated clinical networks. The MPI-led teams are expected to decide upon a single set of measures or biomarker modalities including, but not limited to a combination of omics, Quantitative sensory testing (QST), actigraphy, Electroencephalography (EEG), digital measures, etc., as components of the biosignature for all pain conditions represented in the application. Applications should feature centralized resource groups that will coordinate clinical trials and standardize all sample or data collection methods, technology development, statistical analysis, and algorithm development across the pain conditions under investigation. Applications seeking to develop biomarkers or biomarker signatures that will be used to predict and/or monitor a therapeutic response for a single pain condition may also feature MPI-led teams that represent the cross functional expertise necessary for biomarker and/or signature development, along with the same types of centralized resource groups that coordinate clinical trials and standardize sample or data collection methods, technology development and statistical analysis. Studies to be supported by this FOA may include those necessary for the identification and initial biological, analytical, and clinical validation of pain biomarkers or biomarker signatures, and must include human samples and data as the source for candidate biomarkers or signatures identification and development if possible. If not, biomarkers or signatures resulting from identification in animal models must be verified in human samples at the end of the UG3 phase or during the UH3 phase. This initiative aims to deliver therapeutic response prediction and/or monitoring candidate pain biomarkers or biomarker signatures that are ready for definitive analytical and clinical validation appropriate for use in clinical trial design or decision-making in clinical practice.
The FOA is expected to be published in February of 2022 with an expected application due date in March 2022.
Applications to this intended FOA must propose a research plan designed to develop biomarkers or a biomarker signature that will facilitate Phase II clinical trials for pain therapeutics by serving as a tool to monitor or predict response to a therapeutic. The biomarker should reflect specific pain pathophysiology substrates that are modulated by a therapeutic intervention, reflecting target engagement or overall response to a therapeutic intervention. The biomarker or biosignature may also predict response or lack of response to a therapeutic intervention. The therapeutic itself can either be novel (validated by showing evidence of efficacy in an appropriate animal model that is relevant to human pain condition) or could be well validated in humans, but must have strong, robust evidence of efficacy as demonstrated by statistical significance in repeated studies with clinically meaningful effect size. The desired candidate biomarker or biosignature resulting from completion of this research should be sufficiently robust to withstand definitive analytical and clinical validation.
Phased Award Mechanism and Transition to UH3
This funding opportunity uses a UG3/UH3 (Exploratory/Developmental Phased Award Cooperative Agreement) Phased Innovation Award mechanism. The UG3 phase will support preparatory studies including activities such as study planning and finalization of team organization, along with initial sample collection, initial identification of the biomarker or biomarker signature, detection method development, preliminary analytical validation of the detection method and correlational studies to define the association between the biomarker or biomarker signature with disease pathology, target engagement or response to an intervention. The UH3 phase will support continued method development, algorithm development and further analytical, biological, and clinical validation as the signature or algorithm is developed. Activities in the UH3 phase must include the use of human samples or measures from human subjects as data sources. If the initial biomarker discovery activities were focused on samples or data from animal models because the therapeutic used to develop the biomarker is novel, it is required that evidence of translation to humans (i.e., ability to reliably detect in humans, other adjunct evidence) is provided in the UH3 phase.
Milestones and Transition from the UG3 to the UH3 Phase
Transition from the UG3 to the UH3 phase is contingent upon the successful completion of Go/No Go milestones proposed for the UG3 phase. These milestones are required as a part of the application but may be further refined by the PD/PI and NIH program staff at the start of each project and updated as needed. The NIH Program Official will contact the applicant to discuss the proposed milestones prior to the award. The Program Official and Project Scientist will discuss with the Program Director(s)/Principal Investigator(s) any recommended changes to the research plan or suggestions from peer reviewers, and the plan will be revised as appropriate prior to the award.
The milestones must be clearly defined, quantifiable, and scientifically justified to allow the investigator and program staff to assess progress in the UG3 phase and the potential for development of a candidate biomarker or signature in the UH3 phase. Milestones could address, for example, 1) Evidence that study planning and team coordination is in place, 2) Evidence that metrics for clinical enrollment have been met, 3) Evidence that quality assurance parameters for sample collection or detection method performance have been met, 4) The desired magnitude and reliability of the association between the biomarker and target engagement or responses to an intervention in preliminary studies, 5) Desired precision, accuracy and dynamic range of the biomarker detection method, and 6) Initial prediction accuracy of the biomarker signature for response to the therapeutic.
Because successful biomarker and biomarker signature development are inherently high-risk proposals, it is expected that there will be significant attrition as projects progress. At the end of the UG3 phase, NIH program staff and leadership will determine if the project will advance to the UH3 phase. NIH program staff and leadership will also conduct an annual administrative review throughout the grant period. If needed, additional meetings to administratively review progress may take place. If justified, future year milestones may be revised based on data and information obtained during the previous project period. The administrative reviews will be based on:
• Successful achievement of annual and UG3 transition milestones
• The overall feasibility of project advancement, considering data that may not have been captured in milestones
• HEAL Programmatic priorities
• Availability of funds
Applications are not being solicited at this time.
Please direct all inquiries to:
Ram Arudchandran, PhD
National Institute of Neurological Disorders and Stroke (NINDS)