NIH RFA-DA-25-060: High Priority HIV and Substance Use Research (RM1 Clinical Trial Optional)

NIH RFA-DA-25-060: High Priority HIV and Substance Use Research (RM1 Clinical Trial Optional)

Quick summary

This is an active NIH/NIDA funding opportunity that asks for high-priority research at the intersection of HIV and substance use disorders with a team-based RM1 structure. It is explicitly designed for research programs that are difficult for a single R01 to handle because the biology, behavior, service delivery, implementation, and policy questions require several principal investigators with complementary expertise. The opportunity carries a total NIH commitment of $3.0M across FY 2025, 2026, and 2027 and is aimed at one to two awards. NIDA states that each individual award should not exceed $1.5M in direct costs per fiscal year and that the maximum project period is five years.

The most important distinction in practical terms is the structure requirement: this is not a standard single-PI grant. It is an RM1 team award and the NOFO requires teams of three to six PD/PIs with clearly integrated roles. That requirement is where many otherwise strong applications fail or get delayed. If your project is already planned as one PI doing a subset of established work, this is likely not the right mechanism.

Why this one matters for 2026 and 2027

The key dates list in the NIH page shows this opportunity with recurring review and award windows across 2026 and 2027. While the posted/updated lifecycle started earlier, the NOFO has an expiration update tied to NIH due-date changes (March 2026 notice context), and the latest known final date cycle appears at the 2027 milestones (2027-03-05 appears in the published sequence of due dates). For teams that were not ready during the first 2024/2025 windows, this NOFO still offers immediate planning value for teams targeting the 2026 cycle and then carrying into 2027.

This makes the opportunity especially relevant if your team is iterating through a high-risk, high-impact concept that needs stronger cross-disciplinary integration and if you can meet the MPI requirement without diluting ownership.

Key details at a glance

What this opportunity is exactly

The NOFO is designed to stimulate research that can open new HIV/AIDS pathways in the context of substance use. The statement of purpose is broad in topic but narrow in structure:

• It includes basic, epidemiologic, clinical, intervention, and implementation research.
• It prioritizes programs tied to prevention, treatment, and cure pathways among people who use addictive substances.
• It asks for a single, well-defined scientific objective rather than a portfolio of loosely related projects.

The same paragraph that defines the program also notes a hard mechanism-level fit rule: the initiative is open only to teams of three to six PD/PIs. In other words, you are being funded to build coordinated collaboration, not to scale a standard PI-driven R01 into many sub-aims.

The NOFO calls the RM1 structure “single focused, ambitious and challenging” and explicitly differentiates from parent R01 or P01-style approaches that often accept narrower project ownership models. If your question can be addressed by a single conventional proposal, the expected review fit is likely weaker than a mechanism crafted for complex team execution.

Who this opportunity is for

The applicant organization rules are broad but not unlimited:

• eligible U.S. entities include higher-ed, nonprofits (with and without IRS 501(c)(3) status), for-profits including small businesses, local governments, federal agencies, tribal governments (recognized or not), public housing authorities, regional organizations, and community/faith-based organizations.
• foreign organizations are explicitly excluded from eligibility.
• foreign components that support U.S. work are allowed.

Because this is a domestic rule, teams led by overseas institutions need to partner operationally with a U.S. applicant organization that can carry the registration and submission load.

At the project level, there is a very specific “team fit” demand:

• The 3–6 PI team should each provide a unique contribution.
• Leadership should not be effectively dominated by one investigator.
• The program expects clear synergy across disciplines, methods, and implementation pathways.

This is a good fit when:

• HIV team scientists need integration with addiction medicine, epidemiology, implementation science, social and behavioral science, health systems, and possibly computational or data science expertise.
• the project has to bridge laboratory questions with real-world care delivery and prevention systems.
• the proposed team can show that no single PI can complete all required work.

It is not a good fit when:

• one PI already has all expertise and the multi-PI list would be additive rather than transformative.
• the application remains descriptive or isolated by one discipline.
• the submission is mostly a technology platform or infrastructure proposal with weak linkage to HIV/SUD outcomes.

What the NOFO funds vs. what it excludes

Explicitly funded-type scope

The opportunity is intended for high-priority HIV and substance use work that should produce novel insight or practical changes across prevention, treatment, care continuity, or outcomes among people who use addictive substances. The NOFO’s language repeatedly emphasizes high ambition and potentially high-impact transformation, especially through integrated team design.

Examples of the favored direction include:

• work that combines HIV and SUD in one design, not simply a parallel HIV plus SUD side project;
• studies aimed at stronger mechanistic understanding of HIV infection and comorbidity in people with SUD;
• projects that connect data and interventions with end users (clinics, public health agencies, justice systems, community organizations) and show planned knowledge transfer.

Explicit non-responsive criteria (important)

The following are treated as non-responsive by the NOFO and can be disqualified before merit review:

• projects not aligned with NIH/HIV and substance-use priorities;
• proposals focused solely on alcohol exposure;
• projects only doing one of small-molecule/biologic/device treatment development;
• clinical trials focused only on early-phase safety/tolerability questions (without broader program fit);
• purely observational/epidemiologic designs when the ask is not broader than that;
• studies conducted outside the U.S.; and,
• projects where foreign organizations are submitting as eligible principal applicants (not allowed).

This is more than a bureaucratic note. In NIH terms, non-responsiveness can lead to withdrawal before review. If any element above is unclear in your draft, the first correction is scope rewrite, not formatting.

Timeline strategy for 2026/2027 planning

The official key-dates section shows recurring rounds across the two target years, with LOI due 30 days before each application due date and review/award milestones spread across the cycle. The practical interpretation for applicants is:

• build your LOI at least one submission cycle early;
• maintain registration well ahead of the LOI and submission deadlines because NIH systems can take weeks;
• avoid treating the final 2027 milestone as a “last chance” to build a complete draft.

Because multiple cycles appear in the same NOFO, teams can choose a submission strategy that matches readiness:

1. Early-cycle submit if your team has pilot data and clear governance.
2. Mid-cycle submit if you need one more institutional review layer.
3. Last-cycle submit only if your materials are truly ready and all cross-team documents are approved.

Given that the NOFO already includes 2026 windows and a 2027 close, many teams find value in using 2026 for piloting and 2027 for a stronger revised/renewed strategy while preserving alignment with the same opportunity statement.

Core application mechanics

This is submitted electronically only via NIH pathways.

1. You can use ASSIST, system-to-system institutional solutions, or Grants.gov Workspace for forms.
2. You must use NIH submission infrastructure correctly for on-time checks and validation.
3. All applicants must have completed required registrations (SAM, eRA Commons, and Grants.gov as applicable) before submission.

The NOFO repeatedly stresses that late registrations are not valid reasons for late submission, and NIH systems enforce many validation rules at upload time.

Registration and system requirements (often overlooked)

• SAM registration and renewals can take time.
• eRA Commons must identify at least one signing official and one PD/PI for the organization.
• grants.gov activity registration must be current and consistent with SAM.
• all organizations must ensure the same unique entity identifier is used across systems.

Required document strategy

The NOFO adds extra required components beyond the standard SF424(R&R):

• Team Management Plan (3 pages max)
• Timeline and Benchmarks for Success
• Organization Chart
• Infrastructure, partnerships and collaborations table

Each is submitted as Additional Project Information, and missing any of these is treated as incomplete. The NOFO language is explicit that incomplete applications can be withdrawn.

For RM1 applications, the quality of governance documentation matters almost as much as science. Reviewers look for:

• how the team makes decisions;
• conflict-resolution methods;
• fair allocation of work and credit;
• mechanisms for sharing data and knowledge between institutions.

Content constraints and process checks

The research strategy section has a specific page limit (15 pages), and all NIH page and format instructions in the SF424(R&R) guide must be followed. Given this NOFO’s “single transformative objective” orientation, overlong narratives can dilute quality. The better approach is often:

• concise significance section with explicit translational pathway,
• clearly mapped method package,
• pre-specified milestones tied to team coordination,
• and risk management tied to fallback plans.

Review lens: what evaluators reward

NIH peer review for this opportunity applies standard scientific review logic but with an explicit appetite for ambitious work. Key evaluation points include:

• Significance: importance, barrier removal, potential to advance HIV/SUD science;
• Innovation and audacity: reviewers expect risk where appropriate, provided rationale and feasibility are clear;
• Investigator strength: not just publication history, but whether all PD/PIs are necessary and effectively integrated;
• Team management quality: governance design, communication plan, credit sharing, and conflict prevention;
• Timeline realism: whether major outcomes are feasible in the requested project period.

The “innovative and risky” expectation means teams can propose approaches that are less incremental than typical R01 plans, but only if they also show strong internal logic and evidence generation plans.

Review and selection does not happen in isolation. After review, funding decisions depend on scientific merit, available funds, and alignment with NIDA priorities.

Practical preparation sequence (what to do now)

Phase 1: Fit and structure (now)

• Define one central question that cannot be solved by a single PI.
• Force each PI into a distinct role and map interdependencies.
• If you have only two people with strong fit, do not downsize this NOFO. Either expand to include missing expertise or shift to a non-RM1 mechanism.

Phase 2: Evidence and methods (next)

• Pull preliminary data that validates your central mechanism.
• Add implementation evidence if the hypothesis depends on care systems or policy translation.
• Explicitly tie substance use and HIV pathways in the same logic model.

Phase 3: Governance artifact build (parallel)

• Write the Team Management Plan as a real operating system, not a box-checking document.
• Include governance cadence, decision thresholds, milestone owners, escalation rules, and trainee roles.
• Prepare the organization chart to show functional relationships, not just titles.

Phase 4: Compliance packaging (final 4 weeks before LOI)

• Confirm all required identifiers and registrations are active.
• Pre-fill page limits and formatting checks.
• Build a required-doc matrix: Research Strategy, Multiple PD/PI plan, Team Management Plan, Timeline/Benchmarks, Organization Chart, Infrastructure table.
• Run a complete dry submission test if your institution supports non-live validation.

Phase 5: Submission and correction window

• Submit early enough to fix system flags before due date.
• Make sure all PD/PIs have valid eRA Commons credentials in the Senior/Key Person Profile.
• If system validation blocks due to warnings, correct and re-submit before deadline; late corrections are not treated as on-time.

Common mistakes teams make

1. Treating RM1 as a renamed R01
   • This is the most frequent conceptual error. RM1 requires real team complexity and one shared goal, not a list of independent aims.
2. Under-developing governance artifacts
   • Failing to provide clear team management details can hurt review quality and cause compliance risk.
3. Missing domestic execution clarity
   • Because foreign orgs are not eligible and U.S. execution is expected, teams with overseas collaborators must define where each activity is performed.
4. Proposing only one-off translational step
   • Proposals that are only treatment-development or early safety trials can be filtered out as non-responsive unless tightly integrated with broader program goals.
5. Treating LOI as optional admin detail
   • LOI is not required by policy, but NIH expects it and it strongly helps review planning. Skipping it can reduce administrative preparedness.
6. Ignoring registration lead time
   • SAM/eRA/Grants.gov timing is often the difference between on-time submission and forced correction loops.

FAQ

Is this limited to clinical trials only?

No. Clinical trials are optional. The mechanism is broad and can include basic, epidemiologic, clinical, intervention, and implementation work.

Must I propose a new technology project?

No. In fact, proposals focused only on developing new technologies, drugs, or devices are explicitly disfavored unless they serve the HIV/SUD integrated goals of this NOFO and are not isolated from the broader scientific and translational objective.

Can one small business apply?

Yes, small businesses are listed among eligible applicant organizations. Eligibility is organization-level; funding is still competitive and review-focused.

Are outside collaborators required to be in the U.S.?

The NOFO states non-domestic organizations are not eligible to apply. Foreign components can support U.S. research, but the applicant and project execution must align with domestic eligibility rules.

Can early-career investigators lead?

They can participate as part of the team if the team structure and evidence are strong, but the NOFO is explicitly complex. The strongest applications usually involve established and emerging investigators with complementary strengths.

How many applications can we submit?

The NOFO allows more than one if scientifically distinct. Overlapping applications cannot be simultaneously active in ways prohibited by NIH overlap policy.

Official links to review before writing

• Program page (official): https://grants.nih.gov/grants/guide/rfa-files/RFA-DA-25-060.html
• Application guide and NIH systems instructions: https://grants.nih.gov/grants/forms/other/How%20to%20Apply%20%E2%80%93%20Application%20Guide%20_%20NIH.html
• NIH Grants Policy Statement: https://grants.nih.gov/grants/policy/nihgps
• ASSIST instructions and support contacts: https://era.nih.gov/need-help
• Grants.gov support: https://www.grants.gov
• NIH clinical trials registration and reporting guidance: https://grants.nih.gov/policy/clinical-trials/reporting/index.htm

Official contact points

The NOFO lists multiple NIH contacts for application submission and technical questions, including the eRA Service Desk, general grants support, and NIDA scientific contacts. For fast, clean communication, use the contact channels marked for submission systems and research content questions on the official NIH page and capture your reference number in all follow-ups.

Bottom line

RFA-DA-25-060 is still one of the few NIH opportunities in this cycle that formally rewards deeply integrated, high-risk HIV/SUD science through an explicitly team-science mechanism. If your idea is ambitious, if your team is already interdependent, and if you can document governance at submission quality, this is a serious fit. If your concept is not yet integrated across at least three strong PI perspectives, your best move is to strengthen team design first, then return to the mechanism.