RFA-HL-26-018: Catalyze Product Definition for Small Molecules, Biologics, and Combination Products

RFA-HL-26-018: Catalyze Product Definition for Small Molecules, Biologics, and Combination Products

RFA-HL-26-018 is an NIH R33 Notice of Funding Opportunity (NOFO) for early translational work on small molecules, biologics, and combination products relevant to heart, lung, blood, and sleep (HLBS) diseases and disorders. The official title is broader than the older page title suggested: this is not limited to one narrowly defined “small-molecule biologic combination therapy” category. It supports projects that identify a lead compound series and develop or test a combination-product prototype, including products with a drug, biologic, delivery system, cell or genetic therapy component, or another eligible combination of distinct components.

The notice remains active. Its June 18, 2026 application date has passed, but the NIH key-date table lists October 21, 2026 as the next announced application date. The notice also lists later dates through October 21, 2027 and an expiration date of December 24, 2027. This page therefore describes the next announced round rather than treating the opportunity as closed. The October date is a fixed deadline, not a rolling intake date. Applications are due by 5:00 PM local time of the applicant organization.

Verified details

What the NOFO is meant to support

The program is positioned between an early scientific idea and a product that is ready for more extensive preclinical optimization, safety work, efficacy studies, or independent development support. The proposed work should create decision-quality evidence around a lead series or combination-product prototype. A successful project is expected to be better prepared to enter the NHLBI Catalyze Preclinical program or attract support from another federal or private development partner.

The scientific focus is not simply “drug discovery” in the broadest sense. NIH wants novel targets, mechanisms, or pathways connected to an important HLBS therapeutic gap, supported by a strong biological rationale and preliminary data. The project should explain why the proposed therapeutic agent or combination could improve on existing treatment options and why the planned work is the right next step for the candidate’s development.

For a combination product, the team should identify the distinct components and show that they have been tested in a meaningful way. The official expectations include an identified and validated compound series, testing of the constituent components, and completed in-vitro testing of a combination-product prototype. The application should also characterize current care patterns, unmet needs, and the intended patient population. This context matters because product definition is not only a laboratory exercise; it must connect the candidate to a plausible use and development path.

RFA-HL-26-018 is aimed at projects that have already completed the earlier work supported by the companion RFA-HL-26-017. Projects still centered on target identification, target validation, or testing the individual components of a proposed combination should examine RFA-HL-26-017 instead. The companion distinction is important: an application can be scientifically strong and still be nonresponsive if it is submitted to the wrong stage of the Catalyze sequence.

Expected project readiness

Applicants are expected to bring more than an attractive hypothesis. Before submission, the team should be able to show that it has:

• identified and validated a compound series;
• tested the components of the proposed combination product;
• completed in-vitro testing of the combination-product prototype;
• described the relevant care pattern, unmet need, and patient population;
• developed a detailed intellectual-property strategy;
• prepared preliminary or advanced intellectual-property and regulatory strategies, according to the project’s stage;
• secured a cash match equal to at least 25% of the federal direct costs requested; and
• identified a committed Accelerator Partner to support project development.

The Accelerator Partner is part of the translational plan, not a decorative letter. The application should make clear what the partner will contribute, how that contribution fits the milestones, and how the relationship will help move the project toward the next development decision. The IP and regulatory work should likewise be specific to the candidate, its intended use, and the likely development route.

Funding and award structure

The direct-cost request may not exceed $400,000 per year. The requested period may be up to two years, but the notice says the scope of the project should determine the requested award period. A two-year request should therefore be supported by a realistic work plan and milestones rather than used as a default. Annual budgets should reflect actual anticipated costs.

NHLBI intends to commit total costs of up to $4,466,000 in FY 2026, $4,466,000 in FY 2027, and $4,466,000 in FY 2028. It expects up to 8 new awards in each of those fiscal years, for up to 24 awards across this NOFO and companion RFA-HL-26-017, RFA-HL-26-019, and RFA-HL-26-020. The stated award count remains contingent on appropriations and the number of meritorious applications. It should not be read as a guaranteed number of awards for this single announcement.

The non-federal match is a central budget condition. Recipients are expected to provide at least a 0.25:1 non-federal match of the federal direct costs requested. Applicants should document the source and availability of that match and explain how it supports the project. A budget that requests the full federal ceiling without a credible matching plan is incomplete, even if the science is responsive.

Eligibility

Eligible U.S. applicant categories include public and private institutions of higher education, nonprofits with or without 501(c)(3) status, small businesses and other for-profit organizations, state and local governments, eligible federal agencies, U.S. territories or possessions, tribal governments and organizations, independent school districts, public housing authorities, regional organizations, and other listed public or community organizations. A small company may apply, but the notice does not restrict eligibility to startups. An academic institution, nonprofit, government entity, or other eligible U.S. organization may also apply if it can meet the scientific, administrative, matching, and partner requirements.

Foreign organizations are not eligible to apply. The notice does allow non-domestic components of U.S. organizations and foreign components as defined by NIH policy. That distinction should be resolved with the applicant’s sponsored-research office before submission. A U.S. lead organization cannot assume that every overseas collaborator is treated as a foreign applicant, but it must disclose and manage any foreign component under the applicable NIH rules.

The applicant organization must complete and maintain the registrations required by the NIH How to Apply - Application Guide before the application is submitted. The notice identifies System for Award Management (SAM), the unique entity identifier (UEI), eRA Commons, and Grants.gov. Registration can take six weeks or more, and NIH does not treat unfinished registration as a valid reason for a late submission. Every PD/PI also needs the required eRA Commons credentials in the application profile.

Application preparation and required materials

The application package must be accessed through NIH ASSIST, an institutional system-to-system solution, or Grants.gov Workspace. Applicants should coordinate with their institutional official early because the systems, registrations, and approval chain are part of the submission. After the application is sent through Grants.gov, the organization must track it in eRA Commons and inspect the assembled application before the deadline.

The application must follow the Research (R) Instructions in the NIH How to Apply - Application Guide except where RFA-HL-26-018 gives program-specific instructions. Page limits, form requirements, and the NOFO’s responsive-scope rules are enforced. The allowed application types are New, Renewal, and Resubmission. Clinical trials are not allowed under this R33 opportunity.

One program-specific attachment is especially important: the application must include an IP and Regulatory Strategies attachment named “IP and Regulatory Strategies.pdf”. Applications without that attachment are considered incomplete and will not be peer-reviewed. The strategy should address the project’s development stage. A preliminary plan may be appropriate for an earlier lead-series project, while a more advanced project should provide a detailed path covering ownership, protection, regulatory interactions, and follow-on development.

The research plan should connect each experiment to a product decision. Useful milestones might address compound-series selection, potency and selectivity, physicochemical or biological characterization, combination-product performance, early pharmacokinetics or pharmacodynamics, off-target activity, formulation or delivery questions, and replication of key observations. These examples should be tailored to the proposed candidate; the application should not promise every possible study within a limited R33 budget.

The submission process has several points where a technically strong application can fail administratively. NIH and Grants.gov check the application after submission. Errors must be corrected and a changed or corrected application must be submitted by the due date and time. The applicant is responsible for viewing the application in eRA Commons and confirming that the final version is complete. For the announced October 21, 2026 round, the controlling cutoff is 5:00 PM local time of the applicant organization.

Review and project planning

Applications are evaluated for scientific and technical merit by a special emphasis panel convened by NHLBI under NIH peer-review procedures. Reviewers consider significance, innovation, rigor, the strength of the biological rationale, and whether the proposed work can advance an HLBS-relevant therapeutic. The proposal should explain the unmet need, the candidate’s advantages, the evidence already in hand, and the specific uncertainty the award will resolve.

Reviewers will also look at feasibility. A clear division of work among the applicant, collaborators, CROs, and Accelerator Partner helps establish that the team can execute the plan. The budget should map to milestones and should include the matching contribution. The application should state what evidence would support continuation, what result would cause a pivot, and what useful product information would remain if a key hypothesis fails.

The NOFO includes examples of responsive activities such as synthesis and characterization of a selected library, development or selection of cell lines or vectors for bioactive agents, early physicochemical and computational assessment, solubility and permeability work, initial ADME and pharmacokinetic studies, off-target assessment, characterization of therapeutic agents, prototype assessment, and validation or replication studies. Some downstream work may be relevant only when it arises organically from lead-series characterization. Target identification, basic disease research, diagnostic or prognostic biomarker development, device or tool development, GMP manufacture for clinical use, and stand-alone IND-enabling studies are among the activities that can be nonresponsive or outside the intended scope.

Because this is an R33 rather than a clinical-development award, the project should stop at the product-definition stage described by the notice. The strongest application will leave a clear handoff: what has been learned, what remains to be done in preclinical optimization or safety work, and why the resulting lead series or combination prototype is ready for that next source of support.

Applicant checklist for the October round

Before drafting, confirm that the proposed project is at the RFA-HL-26-018 stage rather than the earlier RFA-HL-26-017 stage. Confirm the HLBS disease relevance, validated compound series, component and prototype data, IP strategy, regulatory strategy, Accelerator Partner, and non-federal match. In parallel, verify SAM, UEI, eRA Commons, and Grants.gov status with the institutional official.

During drafting, build the scientific plan around product decisions and measurable milestones. Keep the scope within the two-year maximum and the $400,000 annual direct-cost limit. Prepare the required “IP and Regulatory Strategies.pdf” attachment, align the budget with the work, and ensure that any foreign component is handled under NIH policy. Then select an approved submission route and allow time to inspect the application in eRA Commons, correct system errors, and submit the final version by 5:00 PM local time on October 21, 2026.

The official NIH notice at grants.nih.gov/grants/guide/rfa-files/rfa-hl-26-018.html controls the application package, eligibility, matching requirement, dates, page limits, and program-specific instructions. The NIH page returned HTTP 403 to the local automated check during this refresh, but its official indexed content verified the current title, next announced date, funding limits, eligibility, and submission requirements. Applicants should consult the official notice again before submitting because NIH notices and application systems can change.