HEAL Initiative: Discovery of Biomarkers and Biomarker Signatures to Facilitate Clinical Trials for Pain Therapeutics (UG3/UH3 Clinical Trial Optional) | RFA NS 24 018

Opportunity Information: Apply for RFA NS 24 018

The HEAL Initiative funding opportunity titled "Discovery of Biomarkers and Biomarker Signatures to Facilitate Clinical Trials for Pain Therapeutics (UG3/UH3 Clinical Trial Optional)" (RFA-NS-24-018) is a National Institutes of Health (NIH) cooperative agreement designed to speed up the development of reliable, clinically useful pain biomarkers. The central aim is to identify and validate strong candidate biomarkers or multi-measure biomarker signatures (biosignatures) that can make Phase II testing of non-opioid pain treatments more efficient and informative. In practical terms, NIH is looking for clinical research programs that can produce objective measures that either predict who will respond to a given pain therapy and/or track whether a therapy is working over time, so that mid-stage trials can be run with better participant selection, clearer endpoints, and stronger interpretability.

The FOA is focused on biomarker discovery and biosignature development tied directly to therapeutic response, not just general pain characterization. Projects are expected to be structured around clinical research that links candidate measures to treatment effects, meaning applications should be built to evaluate whether a biomarker or signature can predict response (treatment selection or stratification) and/or monitor response (pharmacodynamic or longitudinal tracking) in the context of pain therapeutics. The end product NIH wants is a set of measures that can realistically be deployed in Phase II clinical trials of non-opioid pain therapeutics to improve decision-making about whether a therapy is working and for whom.

A key design feature is flexibility around pain conditions, paired with an expectation of rigor and standardization. Applicants may focus on a single pain condition or multiple pain conditions that share a common underlying biology or pathophysiology. For multi-condition proposals, the FOA strongly emphasizes Multiple Principal Investigator (MPI)-led teams that include leaders representing each pain condition and the relevant clinical networks. These teams are expected to agree on one harmonized set of measures or biomarker modalities to serve as the biosignature across all included conditions. The idea is to avoid siloed approaches where each condition uses different tools; instead, NIH is pushing for coordinated, comparable data and a unified signature that can generalize across related pain states.

The announcement explicitly encourages biosignatures built from one or more measurement modalities, reflecting how pain biology and treatment response may not be captured by a single test. Examples of modalities named in the FOA include omics-based measures (such as genomics, proteomics, metabolomics), quantitative sensory testing (QST), actigraphy, EEG, and digital measures, among others. The expectation is that applicants will justify why their selected modalities are appropriate for predicting or monitoring treatment response and how combining them (if proposing a multi-modal signature) improves performance, robustness, or clinical usability compared with any single measure alone.

To make results credible and reusable across sites and conditions, the FOA expects applications to include centralized resource groups. These centralized components are intended to coordinate clinical trial-related activities and enforce consistency across the program, including standardized sample and data collection methods, technology development, statistical analysis plans, and algorithm development. In multi-condition projects, these centralized resources are especially important because they ensure that data generated across different condition cohorts can be pooled or compared without being undermined by inconsistent procedures, instrumentation differences, or variable analytic pipelines. For single-condition projects, the same centralized approach is still expected, serving to professionalize and unify the operational, technical, and analytic work so the biomarker or biosignature is built on reproducible foundations.

Even when the project is limited to one pain condition, NIH is still looking for MPI-led teams, but the rationale shifts slightly: the MPI structure should reflect cross-functional expertise needed for biomarker or biosignature development. That typically means combining clinical pain expertise with complementary strengths such as biostatistics, computational modeling and machine learning for signature development, assay development or bioinformatics for omics, neurophysiology for EEG-based measures, digital health analytics for wearable or smartphone-derived metrics, and clinical trial operations for implementation. The overarching message is that biomarker development is multidisciplinary by necessity, and NIH wants teams organized to handle that complexity from the start rather than bolting on key expertise later.

From an administrative standpoint, the opportunity is offered as a cooperative agreement under the UG3/UH3 mechanism, and it is labeled "Clinical Trial Optional." Cooperative agreements generally imply substantial NIH programmatic involvement compared with standard grants, often including active coordination, milestone oversight, and collaborative expectations. The UG3/UH3 structure commonly supports a phased project, where an initial stage supports planning, set-up, and early feasibility work, with progression to the later stage tied to meeting predefined milestones. While specific milestone language is not included in the provided excerpt, applicants should expect that the program will be managed with go/no-go decision points consistent with a phased cooperative agreement model.

Eligibility is broad and includes many kinds of organizations that can support clinical research, technology development, and multi-site coordination. Eligible applicants listed in the source include state, county, and municipal governments; special district governments; independent school districts; public and private institutions of higher education; federally recognized tribal governments and other tribal organizations; public housing authorities; nonprofits with or without 501(c)(3) status; for-profit organizations (other than small businesses) as well as small businesses; and other entities. The FOA also highlights additional eligible categories such as Alaska Native and Native Hawaiian Serving Institutions, Asian American Native American Pacific Islander Serving Institutions (AANAPISIs), Hispanic-serving Institutions, Historically Black Colleges and Universities (HBCUs), Tribally Controlled Colleges and Universities (TCCUs), faith-based or community-based organizations, eligible federal agencies, regional organizations, non-U.S. (foreign) entities, and U.S. territories or possessions. This breadth is consistent with the HEAL Initiative's emphasis on building capable, diverse consortia and ensuring that expertise and participant populations can be drawn from many settings.

In summary, this HEAL Initiative FOA is aimed at producing actionable pain biomarkers or biomarker signatures that directly support Phase II trials of non-opioid pain therapeutics. Successful applications are expected to be clinically grounded, multi-disciplinary, and operationally centralized, with harmonized measures and standardized methods that can stand up across sites and, when relevant, across multiple related pain conditions. The program is less about exploratory measurement for its own sake and more about delivering validated predictors and monitoring tools that make pain therapeutic trials faster, cleaner, and more likely to yield clear answers.

• The National Institutes of Health in the education, health, income security and social services sector is offering a public funding opportunity titled "HEAL Initiative: Discovery of Biomarkers and Biomarker Signatures to Facilitate Clinical Trials for Pain Therapeutics (UG3/UH3 Clinical Trial Optional)" and is now available to receive applicants.
• Interested and eligible applicants and submit their applications by referencing the CFDA number(s): 93.121, 93.213, 93.233, 93.273, 93.394, 93.395, 93.396, 93.837, 93.838, 93.839, 93.840, 93.853, 93.865, 93.866, 93.867.
• This funding opportunity was created on 2023-02-15.
• Applicants must submit their applications by 2023-10-23. (Agency may still review applications by suitable applicants for the remaining/unused allocated funding in 2026.)
• Eligible applicants include: State governments, County governments, City or township governments, Special district governments, Independent school districts, Public and State controlled institutions of higher education, Native American tribal governments (Federally recognized), Public housing authorities/Indian housing authorities, Native American tribal organizations (other than Federally recognized tribal governments), Nonprofits having a 501 (c) (3) status with the IRS, other than institutions of higher education, Nonprofits that do not have a 501 (c) (3) status with the IRS, other than institutions of higher education, Private institutions of higher education, For-profit organizations other than small businesses, Small businesses, Others.

Apply for RFA NS 24 018

[Watch] Creating a grant proposal using the step-by-step wizard inside the applicant portal: