The Common Fund Venture Program is a new area of Common Fund support that provides a framework for development of short-term Common Fund initiatives that embrace bold approaches and are responsive to the shared priorities of NIH Institutes, Centers, and the Office of the Director.

Venture initiatives are Common Fund investments and so must meet Common Fund criteria, as expressed below. However, additional criteria also apply, emphasizing brief, modest investments that can be implemented quickly in response to emerging opportunities. Venture investments should be lightweight and nimble while having a strong potential to accelerate science quickly.

What makes Venture initiatives special?

• They are Bold: they are daring investments with potential for significant, outsized impact
• They are Nimble: they can be implemented rapidly in response to scientific opportunity
• They are Focused: they are limited to three years, up to $5 million annually to invest in a clearly defined research topic

What makes Venture initiatives consistent with the Common Fund?

• Common Fund criteria will apply to Venture investments, with accelerated timelines and nimble project management. Venture initiatives will be:
  • Transformative: projects have strong potential for exceptionally high and broadly applicable impact in biomedical/behavioral research
  • Catalytic: projects are time-limited investments of 10 years or less, designed to capitalize on new scientific knowledge or breakthroughs to accelerate and enable subsequent research
  • Goal-driven: projects include defined goals to develop specific deliverables (such as new knowledge, data sets, resources, methods, or technologies)
  • Synergistic: projects advance the missions of multiple ICOs, and are relevant to multiple diseases or conditions
  • Novel: projects pursue innovative solutions to specific scientific challenges important to the NIH mission but that no other entity is likely or able to address
• Venture initiatives are not:
  • Pilot programs to prepare for larger Common Fund investments
  • A means to address high-priority projects for individual ICOs
  • Support for exploratory, open-ended research without specific goals and milestones
• Governance:
  • Ideas for new Venture initiatives are submitted through the ICO Directors to the Office of Strategic Coordination, which oversees the NIH Common Fund, leveraging public input as appropriate. Initiative idea submissions can derive from any areas of biomedical and behavioral research. All proposals are evaluated for responsiveness to the Common Fund and Venture criteria, and are considered by the Venture Board, made up of ICO Directors. Promising ideas are recommended by the Board for full development. The NIH Director provides final approval. Updates on the progress of each Venture initiative will be described on their individual website. 

What is the Venture Advancing Non-Invasive Optical Imaging Approaches for Biological Systems (NIOI) Initiative? 

The Common Fund Advancing Non-Invasive Optical Imaging Approaches for Biological Systems (NIOI) Venture Initiative aims to develop next-generation non-invasive or minimally invasive optical imaging techniques to overcome the problem of light scattering in biological systems. Enhanced imaging techniques can make possible earlier detection of conditions, more precise evaluation of cellular and tissue health, and advancements in non-invasive or minimally invasive procedures, ultimately improving patient outcomes and reducing the need for more invasive methods. 

What is the title of this Notice of Funding Opportunity (NOFO)?

In Vivo Non-Invasive Optical Imaging Approaches for Biological Systems (UG3/UH3 Clinicals Trial Not Allowed)

What is the Announcement Number of this NOFO?

RFA-RM-24-012

What is the purpose of this announcement?

The purpose of this announcement is to invite applications from eligible organizations to support the development of next-generation non-invasive or minimally invasive optical imaging techniques to overcome light scattering limitations, resulting in high spatial and temporal resolution optical images at significantly greater depths within biological tissues than is currently possible.

Whom can I reach out to with questions about this announcement?

All questions are welcome. Please reach out to Jonathan D. Pollock, Ph.D. ([email protected]). Please also reach out to Pam Fleming ([email protected]) with any financial/grants management questions.

How can I follow the NIOI initiative?

Please consider signing up for the NIOI listserv. You can also follow the Common Fund X account for details about this initiative as well as other Common Fund programs: @NIH_CommonFund.

Can we expect the same Venture initiative request for applications a year from now, or will the opportunity be issued only once?

We do not anticipate reissuing this NOFO next year. The NIOI initiative is a one-time opportunity that will fund projects in fiscal year 2026 with the level of funding in Year 2 and Year 3 contingent upon scientific progress and congressional appropriation of funding. If funding for awarded projects were to go beyond the three-year period, it would be through a different program at individual NIH ICs but not the Common Fund.

*Letters of Intent are strongly encouraged. They are of great help in organizing reviews and can let  program officials inform applicants about changes in the funding opportunity and may inform applicants about whether the proposal will be responsive to the NOFO.

What organizations are eligible?

• Higher Education Institutions
  • Public/State Controlled Institutions of Higher Education
  • Private Institutions of Higher Education
• The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:
  • Hispanic-serving Institutions
  • Historically Black Colleges and Universities (HBCUs)
  • Tribally Controlled Colleges and Universities (TCCUs)
  • Alaska Native and Native Hawaiian Serving Institutions
  • Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)
• Nonprofits Other Than Institutions of Higher Education
  • Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
  • Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• For-Profit Organizations
  • Small Businesses
  • For-Profit Organizations (Other than Small Businesses)
• Federal Government
  • Eligible Agencies of the Federal Government
  • U.S. Territory or Possession

Will foreign institutions be eligible?

• Non-domestic (non-U.S.) Entities (Foreign applicants) are not eligible to apply.
• Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
• Foreign components, as defined in the NIH Grants Policy Statement, are allowed.
  • An investigator from a foreign institution can be a collaborator but cannot submit applications as a principal investigator unless this foreign institution is a component of a US Organization.  

Can an NIH Intramural Research Program (IRP) investigator submit an application for the NIOI initiative?  

No. IRP investigators cannot apply as the prime recipient for the NIOI initiative.  

Can NIH IRP investigators participate as collaborators with the lead recipient for the NIOI initiative? 

• Yes. NIH IRP investigators can participate in the Venture Program NIOI initiative, with certain limitations. Intramural investigators may collaborate with extramural investigators when both have expertise that could contribute to the goals of the program.  
• For projects that involve IRP investigators, separate letters originating from and signed by each participating IRP investigator’s Scientific Director must be included in the application, in accordance with the NIH Intramural Sourcebook. The letter(s) must describe the intramural aim(s) and include the requested budget and justification for the intramural activity.
• The number of person months and justification for all federal employees who will be committed to the project must be included in the letter, in accordance with the NIH Intramural Sourcebook. This will allow the reviewers to evaluate the suitability of proposed staff to conduct the work.

Can NIH IRP investigators request salary funds for their effort in the project?

No. No support may be requested from any federal agencies, including the NIH intramural program, for salary or related fringe benefits for career, career conditional or other federal employees (civilian or uniformed series) with permanent appointments under existing position ceilings or any costs related to administration of facilities support.

Can NIH IRP investigators request funds for the project other than their salary? 

• Funds may be requested for IRP investigator participation and are limited to the costs required for carrying out the proposed work, provided those costs can be specifically identified with the Venture Program NIOI initiative.
• Costs may include:
  • Salary for staff to be specifically hired under a temporary appointment for the project
  • Consultant costs
  • Equipment
  • Supplies
  • Travel
  • Other items typically listed under Other Expenses.

Where in the application should IRP investigators include a budget request and justification?

IRP investigator costs must not be included in the application budget request or budget justification to RFA-RM-24-012.  Instead, a specific IRP budget request must be included in the letter(s) from the Scientific Director(s).  

In which sections of the application should IRP investigator participation be described? 

Include IRP investigator participation in the Research Strategy, Leadership Plan, Milestone and Deliverables, Biosketches, Plan for Enhancing Diverse Perspectives, and PHS Human Subjects and Clinical Trials Information.  Information (if relevant) for all other sections (Equipment and Facilities, Institutional Letter of Support, Budget and Budget Justification, Resource Sharing Plan, Data Management and Sharing Plan) should be provided in the Letter from the IRP investigator’s Scientific Director.

How are funds requested for the IRP investigator and/or related to IRP participation provided if the project is selected for funding? 

The project budget, including for the IRP investigator and/or IRP participation, will be determined prior to award.  For projects selected for funding, IRP investigator funds will be issued through an Interagency Agreement (IAA) and terms and conditions of funding included in an associated Memo of Understanding (MOU).

Can other federal agencies of the US Government apply to the NIOI initiative through Research Opportunity Announcement RFA-RM-24-012? 

Yes, other federal agencies of the US Government may apply to the NIOI initiative EXCEPT for NIH investigators, who cannot apply as the prime recipient.  See FAQs for participation of Intramural Research Program investigators as collaborators. 

Are foreign partners allowed? 

Foreign partners are allowed as sub-awardees, but they cannot be the primary awardee. You must justify why the foreign partner brings a unique component that you would not find in the U.S.

Are industry partners encouraged?

Industry partners are encouraged. 

Can a team be made up of industry partners only?

Yes. There is no requirement to make academic or non-profit partners a part of the team. Regardless of the make-up of the project team, applicants must demonstrate that they possess the experience and skillsets required to ensure success. 

Are applications with multiple PIs permitted? 

Yes. For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide. Moreover, inclusion of PIs with diverse expertise (e.g., engineering, biology, clinical) toward the completion of the aims of the projects are highly encouraged.  

Can an organization submit more than one application? 

Applicant organizations may submit more than one application, provided that each application is scientifically distinct. The NIH will not accept duplicate or highly overlapping applications under review at the same time. 

Can PIs submit multiple proposals?

PIs are welcome to submit multiple proposals so long as the scientific focus is unique for each proposal submitted. As such, the submission of multiple proposals is not encouraged or discouraged.

If we are not academic PIs, can we apply? 

You do not have to be a part of academia to be eligible to apply. Academia, industry, and non-profit entities are eligible per the eligibility requirements stated in the NOFO. Individual persons cannot apply. 

 Will I lose my early-stage investigator (ESI) or new investigator (NI) status for a future R01 submission for myself if I am awarded a grant under this NOFO? 

Yes, being awarded the UG3/UH3 NIOI will remove ESI and NI status for PDs/PIs because UG3/UH3 award is considered a substantial NIH independent research award. An ESI is a Program Director / Principal Investigator (PD/PI) who has completed their terminal research degree or end of post-graduate clinical training, whichever date is later, within the past 10 years and who has not previously competed successfully as PD/PI for a substantial NIH independent research award. A NI is a PD/PI who has not previously competed successfully for a substantial research award from NIH. See the list of NIH awards that a PD/PI can hold and still be considered an ESI or NI.  

Is it mandatory to have partners from industry?

No, it is not mandatory, but we want to see an interdisciplinary team with expertise in all relevant areas of research and development included in the project, including commercial development. This does not have to necessarily come from industry partners if all components are met from academia or a non-profit organization.

Are there specific medical areas of interest or priority for this RFA? For instance, neurological sciences, cancer, cardiovascular conditions, etc.

No. The priority of the RFA is to achieve significant increase in optical depth without losing spatial and temporal resolution.

Can I apply for this opportunity without submitting a Letter of Intent (LOI)?

Yes. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NIH staff to estimate the potential review workload and plan the review. 

Letters of intent are strongly encouraged. These letters assist review in identifying reviewers and conflicts. The letters of intent also keep applicants informed of any changes in the RFA and provide feedback about whether the proposed aims are within scope of the RFA. 

What is the budget for this opportunity?

The Common Fund Venture Initiative may allocate up to $4,900,000 total (direct + F&A) costs per year for all awards. Support of 3 projects is anticipated. 

The funding decisions will consider (1) the scientific and technical merit of the proposed project as determined by scientific peer review, (2) availability of funds and (3) relevance of the proposed project to programmatic priorities. Institutions with an established Facilities and Administrative (F&A) rate should use their federally approved rate to calculate indirect costs for non-compute expenses.

What is the typical budget size for a team with one PI or a team with a PI and clinician?

The application budget should reflect the proposed activities and personnel. The awarded budget size is dependent on the objectives proposed in the application and subsequently determined prior to award issuance.   

Is the funding $5M per award? Or total budget for three awards is $5M?

The total amount budgeted by NIH for the initiative is $4.9 million each year for each of the 3 Years or a total of $15.7 Million total over 3 years. You may request as much as $4.9 million in total cost for each of the 3 years.  However, we expect to fund 3 awards (i.e., $1.633 million in total cost for each of the 3 years). You should ask for what you need in your proposal and justify it. 

Is major equipment allowed in the budget? Is institutional commitment as matching allowed for this?

Yes and yes.

What is the maximum dollar amount per proposal?  Is there a $500k per year limit as with R01s?

There is no limit. The application budget should reflect the proposed activities and personnel. The awarded budget size is dependent on the objectives proposed in the application and subsequently determined prior to award issuance.  NIH expects to fund 3 applications.

What is the expected duration of the project?

The expected project duration is three years. Provide a timeline (Gantt chart) and milestones for each year of the three-year application. Milestones must be specific, quantifiable, and scientifically justified. 

Do one of the milestones have to focus on implementation and deployment of the technology?

Yes, at the level of demonstration, not validation. At the end of the three-year performance period, we expect demonstration in an appropriate mammalian animal model or human patients.

Is a timeline (Gantt chart) including milestones required?

Yes, a Gantt chart and milestones are required by this NOFO.  Milestones are goals that create go/no-go decision points in the project and must include clear and quantitative objective criteria for success. Yearly quantitative milestones are required to provide clear indicators of a project's continued progress or emergent difficulties and will be used to evaluate the application not only in peer review but also in consideration of the awarded project for funding non-competing award years. The application must include well-defined milestones, e.g., appropriate objective performance targets, quantitative for go/no go decision points such as an appropriate level of detection and coefficient of variation, or sensitivity and specificity; and timelines for assessing progress in both the UG3 and UH3 phases, including specific milestones for progressing from the UG3 phase to the UH3 phase. Milestones and timelines for each stage and year must be provided in a separate heading and should:

• Provide appropriately detailed (quantitative) criteria by which milestone achievement will be assessed.
• Provide a detailed timeline for the anticipated attainment of each milestone and the overall goal.
• Identify any impediments that could require an addendum to the research plan, milestones, or timeline with a discussion of alternative approaches.

Transition from UG3 to UH3: An administrative review will be conducted by NIH Program staff to decide whether a project will be considered for transition from the UG3 phase to the UH3 phase. To be eligible for transition, a project must have met the stated milestones of the UG3 Phase.
 

What are the important dates for the full application?

Applications must be submitted via Application Submission System & Interface for Submission Tracking (ASSIST) by March 7, 2025 at 5:00 pm (based on the local time of the applicant organization). Applications received past this date and time will not be accepted. 

Which applications will be reviewed? Which will not be reviewed?

Applications will only be accepted from entities listed in the Eligible Organizations section of this Announcement, who meet the criteria listed in the Eligibility Requirements. Applications submitted from organizations not included in the Eligibility section will not be reviewed. Applications that are deemed non-responsive or incomplete will not be reviewed.

How do I register to the NIH eRA Commons ASSIST system?

• Applicants must submit via the NIH eRA Commons ASSIST system no later than March 7, 2025 by 5:00 PM local time of applicant organization. Use RFA-RM-24-012 in the Funding Opportunity Announcement field. Here are instructions for submitting via the NIH eRA ASSIST system. Technical assistance is available from the eRA Service Desk.
• To submit a full application via ASSIST, the applicant organization must be registered in eRA Commons. If you are invited to submit a full application, you must be registered in eRA Commons, which may take six (6) weeks or more to complete, applicants should therefore begin the registration process as soon as possible.
• On the eRA Commons home page, select the “Register Organization” link for more details.
• To complete registration, if you have not done so already, you may need to register for the following:
  • System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
    • NATO Commercial and Government Entity (NCAGE) Code – Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
    • Unique Entity Identifier (UEI)- A UEI is issued as part of the SAM.gov registration process. SAM registrations prior to fall 2021 were updated to include a UEI. The same UEI must be used for all registrations, as well as on the other transactions application.
  • eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their full SAM and Grants.gov registrations; all registrations must be in place by time of submission of the full application. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
  • Grants.gov – Applicants must have an active SAM registration in order to complete the Grants.gov registration.
• If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance.

How do I submit my application?

All applications must be submitted electronically. Applicants should follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise [in this FOA (Section IV. Application and Submission Information) or in a Notice from NIH Guide for Grants and Contracts].

On what basis are applications selected for funding? 

Applications will be selected for funding based on scientific merit, current NIH program research priorities, and availability of funds. Applicants are highly encouraged to discuss potential research aims with program officials to determine fit with programmatic research priorities. 

Where will my application be reviewed? Is there any specific study section? 

Applications will be evaluated for scientific and technical merit via a special emphasis panel convened by the Center for Scientific Review in accordance with NIH peer review policy and procedures, using the stated review criteria. The assignment to a Scientific Review Group will be shown in the eRA Commons. 

Will NIH provide feedback on my application?

As part of the scientific peer review, all applications will receive a written critique in the form of a Summary Statement. NIH will not accept an appeal of the initial peer review or funding decision outcomes.

Do we need to specify the NIH Institute or Center when submitting?

No, this is a Common Fund Initiative, with collaboration across multiple NIH Institutes and Centers. Please specify that you are responding to Opportunity Number RM-24-012, In Vivo Non-Invasive Optical Imaging Approaches for Biological Systems (UG3/UH3 Clinical Trials Not Allowed). 

Do I need to show case in-vivo studies during the UH3 phase? Does it have be human studies? 

During the UH3 phase, applications will need to demonstrate the capability of the system for in-vivo imaging in either human or other mammalian animal models. Applicants proposing the use of non-mammalian tissue or non-mammalian organisms will not be considered responsive to the NOFO and the application will be withdrawn prior to review. 

Would I be eligible to apply if it becomes necessary to cut the tissue to increase the penetration depth of the optical imaging? 

The imaging modality should independently demonstrate its deep tissue imaging capabilities non-invasively, without requiring incisions or tissue perturbations. Applicants that propose a device that relies on surgical manipulation of the tissue to achieve increased imaging depth will not be considered and the application will be withdrawn prior to review.

What wavelengths can be used for the imaging technology?  

Light in the ultraviolet to infrared range can be used. Applicants that propose the use of gamma-rays, x-rays, microwaves, or radio waves will not be considered responsive to the NOFO and the application will be withdrawn prior to review. 

How will projects be selected for the UH3 Phase? 

The Research Performance Progress Report submitted toward the end of year 2 will be reviewed administratively by NIH Program staff. Projects must meet the stated milestones of the UG3 phase to be eligible for the UH3 Phase, for funding of the third and final budget period.   

How are Intellectual Property (IP) rights handled – is anything funded intended to be open access?

Generally speaking, any IP will be retained by the recipient, but NIH is granted licensing rights. Recipients of awards are expected to comply with NIH Data Sharing and Management Plans, Resource Sharing plans, comply with NIH Public Access policy, and report inventions in iEdison. 

 For background regarding legislative authority concerning intellectual property rights: The Bayh–Dole Act is US legislation dealing with intellectual property arising from federally funded research. This Act encourages researchers to patent and market their inventions by guaranteeing patent rights. This Act automatically grants first rights to a patent for an invention fully or partially funded by a federal agency to the awardee organization. To obtain these benefits, however, the inventor and the organization have several reporting requirements that protect the rights of the government. For more information on the Bayh-Dole Act and NIH’s Role, please read Guide Notice NOT-95-003.

When will the first funding period open? 

We anticipate NIOI projects to be funded starting in FY26, with maximum 3-year project periods. The start date is anticipated to be no earlier than December 1, 2025, but no later than July 30, 2025. All key dates can be found on pp. 1 and 2 of the NOFO RFA-RM-24-012.

How many awards do you anticipate to fund?

We anticipate funding 3-4 awards in FY2026.

Are this initiative’s full application requirements similar to the standard R01 with respect to significance, innovation, and approach sections?

The RFA-RM-24-012 NOFO outlines the requirements for the full application.

How many specific aims would be appropriate?

This is completely dependent on the proposal. The proposed research activities will need to be commensurate with the budget request and within the 3-year period of performance.

Does the device need to generate an image (i.e. a visual representation of a likeness of an object, not a spectroscopic measurement)?

Both visual and/or spectroscopic representations will be considered as long as the technology can demonstrate significantly higher imaging depth and the captured information is clinically and biologically relevant.

What is meant by achieving a significant increase in penetration depth for optical imaging?  

The proposed technology must be able to obtain images at much greater depth in tissue beyond the current capabilities of optical technologies while maintaining or improving other performance features such as spatial and temporal resolution and contrast. Such improvements are understood to be specific to a given approach and technique, and the current state-of-the-art should be referenced. The proposer should also explicitly state and justify the degree of expected improvements.

Does technology or device need to capture images across all multiple scales from subcellular to whole tissue?  

This would be ideal. However, the significant improvements in imaging depth while maintaining or improving other performance features such as spatial and temporal resolution, either at the cellular level or whole tissue, is responsive to the RFA.  

What is meant by minimally invasive technical strategies?

We use “minimally invasive” to define strategies where impacts to tissues for resolving or accessing a given target or target type are minimum. For example, intravenous injections of agents that increase imaging depth and provide contrast are examples of minimally invasive techniques. Another example of minimally invasive technique is use of  imaging probe that does not penetrate the tissue but is brought in proximity to the tissue via an endoluminal approach (like bronchoscopy or endoscopy). Mechanical penetration of imaging probe (e.g. fiber) to increase imaging depth is not responsive to this NOFO. Removal of a portion of the skull to view the brain or cutting tissue to expose underlying structures are examples of invasive techniques and will not be considered responsive.  

As stipulated in the research strategy, “Development of the device must first demonstrate a significant increase in tissue depth non-invasively by optical means; following development, the device may be used in applications that are non-invasive, minimally invasive, or in surgical settings.” Meaning that once the capabilities according to the program criteria (increasing the imaging depth non-invasively or minimally invasively as defined above) have been demonstrated during the UG3 and UH3 phase, the technology then can be used in different settings, including but not limited to surgical operations during UH3. 

Would I be eligible to apply if it becomes necessary to cut the tissue to increase the penetration depth of the optical imaging? 

No. The imaging modality should independently demonstrate its deep tissue imaging capabilities non-invasively, without requiring incisions or tissue perturbations. However, demonstrations conducted during surgical procedures, where tissue is already being incised as part of the operation, would also be acceptable. Applicants that propose a device that relies on surgical manipulation of the tissue and transgenic approaches to achieve increased imaging depth will not be considered and the application will be withdrawn prior to review.

Is insertion of a thin fiber optic probe considered minimally invasive?

The imaging probe (e.g., fiber) should not penetrate tissue. Mechanical means to increase depth are not responsive to the NOFO. An imaging probe that does not penetrate the tissue but is brought in proximity to the tissue via an endoluminal approach (like bronchoscopy or endoscopy) is appropriate. 

Can I propose a transgenic animal or a virus to express an imaging probe?

No. You cannot use a transgenic animal or a virus to express an imaging probe to achieve image resolution of the target structure(s), Applications that propose a device that relies on transgenic approaches to achieve increased imaging depth will not be considered, and the application will be withdrawn prior to review. 

Can I propose the use of gamma-rays, microwaves to deeply image tissue?

No. This NOFO will support projects that develop novel in vivo optical imaging utilizing light as the imaging modality. Here, light is defined as radiation ranging from ultraviolet to infrared on the electromagnetic spectrum.  Applicants that propose the use of gamma-rays, x-rays, microwaves, or radio waves will not be considered responsive to the NOFO and the application will be withdrawn prior to review.

Can I propose the use of non-mammalian organisms such as zebrafish?

No. Applicants proposing the use of non-mammalian tissue or non-mammalian organisms will not be considered responsive to the NOFO and the application will be withdrawn prior to reviews.

The RFA states, “By the close of the third year of funding support, it is expected that developed technologies will have been evaluated for performance in a relevant biological system and will have demonstrated the capability to effectively capture images across multiple scales (e.g. subcellular to cellular or cellular to tissue) relevant to the tissue of interest.” Does expected mean required?

No.  Expected means something that is anticipated while required means something is obligatory or must be done.  The ability to capture across multiple scales is an aspirational goal of the RFA. Ultimately, the milestone requirement is to be negotiated just before time of award. As stated in Section IV. Application and Submission Information under the research strategy section for the UH3 phase: 

“Further refinement of the relevant optical imaging technology and relevant algorithm and testing the platform in appropriate in-vivo animal or human model. By the conclusion of the three-year period of performance supported by NIOI, in vivo demonstrations of the technology must have been conducted in appropriate biological model systems. Demonstrate technology performance in appropriate in vivo animal or human models, non-invasively or minimally invasively. Include quantitative tests that achieve the proposed metrics and are relevant to the technology and tissue of interest.  Evaluate performance against at least one comparable system in routine current use for research and/or clinical imaging.  Clearly demonstrate a significantly increased imaging depth at relevant biological temporal and spatial resolution for in vivo studies, and any other appropriate quantitative metrics of interest. Demonstrate the reproducibility and repeatability of relevant measurements such as field of view, spatial and temporal resolution, and imaging depth. Provide milestones for year 3 under Milestone and Timeline plan.”

Are photoacoustic techniques permitted? If so, are there any specific resolution requirements? 

Yes, photoacoustic techniques are permitted, provided the technology uses light in the spectrum from infrared to ultraviolet to significantly increase the ability to resolve images at greater depth.  Applicants must propose methods that significantly increase the image depth at temporal and spatial performance parameters currently achieved by a photoacoustic technique or a competing technology for imaging tissues. As a reminder, the current state of the art should be referenced, and the proposer should explicitly state and justify the degree of expected improvement.

How novel must the new technology developments be to be eligible for this NOFO? Specifically, would relatively minor advancements in imaging technologies be eligible? 

Yes, relatively minor advancements in imaging technologies are eligible, provided the proposed minor advance significantly increases optical depth, that overcomes issues such as optical aberrations and motion artifacts that have prevented 3 photon imaging from achieving depths greater that 1.4 mm.  However, there may be other highly innovative and competitive technologies that achieve greater imaging depth than can be achieved with minor technological advances in 3 photon microscopies. Thus, to be competitive the proposed technology must be significant better that the current state of the technology. Please note that extending tissue imaging depth for a given optical modality should demonstrate meaningful clinical and translational impact. Furthermore, the unique aspects of the approach and improvements should be clearly articulated, highlighting how it stands out and remains competitive with respect to the current state-of-the-art technologies.

Does it matter what tissue I might use? 

Other than the requirement that it is a mammalian tissue or organism, the choice of biological tissue you use to develop or test the device is your decision. However, it is important to provide a clear justification for the choice and evidence that it can effectively demonstrate the capabilities of the technology in terms of imaging depth without a loss of spatial or temporal resolution.  

Do competing optical imaging technologies for deep tissue imaging need to achieve significantly greater depth than what can be currently achieved with the current state-of-the-art deep optical imaging technology?

Yes. The benchmark is the current methods or state-of-the-art technologies that can achieve the greatest optical image depth with the greatest spatial, temporal, and contrast resolution at different scales. 

Does the device or technology need to capture physiological events in real-time?  

Yes. The proposed device or technology must capture relevant physiological changes at the timescales relevant to biological events (e.g., heartbeat, action potential). 

When will the successful applicant have to demonstrate that the technology can obtain in vivo optical images non-invasively at a significant objective increase in penetration depth while maintaining or improving other performance features such as spatial and temporal resolution and contrast?

By the conclusion of the three years of performance supported by NIOI, in vivo demonstrations of the approaches in appropriate biological model systems must have been conducted and compared for performance evaluation against at least one comparable system in routine current use for research and/or diagnostic imaging.

Is in vivo optical tissue clearance using chemicals allowed?  

Yes, under the auspices of “minimally invasive”, chemical adjuvants or contrast agents can be used to significantly improve optical performance if they can be demonstrated to avoid toxic side effects. Note, however, that translation to humans may be ultimately hindered and this may impact review for alignment with program goals. 

At the end of the funding period, does the device require proof of concept in human beings? Is the focus of the funding opportunity on in vivo human imaging, or can it be any model mammalian organism?

No, the device does not require proof of concept in humans but can be demonstrated in any model mammalian organism or tissue. However, the instructions to applicants state, “Explain how the proposed device would significantly advance biomedical and clinical research, and how the technology would be used by other investigators and broader community.” It is up to the proposer to outline the reasonable transition of the technology to advanced development and application.

Does the non-invasive optical imaging initiative require 3D image reconstruction of tissue or cells?   

No. However, rapid 3D image reconstruction of tissue that exceeds the current acquisition/reconstruction speed for creating 3D optical images is encouraged. 

Are multidisciplinary teams encouraged? 

Yes. The NIOI initiative requires innovation and integration across multiple disciplines, such as engineering, physics, biology, and physiology. This notice strongly encourages the assembly of a team with the required diverse expertise and perspectives that demonstrate evidence of past productive collaboration and/or commitment to realizing the goals of the effort as a team. 

What award mechanism is used for In Vivo Non-Invasive Optical Imaging Approaches for Biological Systems (UG3/UH3 Clinical Trials Not Allowed)?  

NIOI will use a two-stage, phased award mechanism to develop and validate integrated approaches for non-invasive or minimally invasive, in vivo optical-based imaging. Phase I (UG3, years 1-2) is expected to encompass designing hardware integrating novel forms of optical imaging data acquisition and processing and developing prototypes that overcome light-scattering barriers in complex biological systems. Phase II (UH3, year 3) will focus on optimization and performance testing. By the conclusion of the three years of performance supported by NIOI, in vivo demonstrations of the technology must have been conducted in appropriate biological model systems.

Thus, by the end of the third year of performance, the principal investigator and the research team will need to demonstrate the technology performance in appropriate in vivo mammalian animal or human models, non-invasively or minimally invasively. Include quantitative tests that achieve the proposed metrics relevant to the technology and tissue of interest.  Evaluate performance against at least one comparable system in routine current use for research and/or clinical imaging.  Clearly demonstrate a significantly increased imaging depth at relevant biological temporal and spatial resolution for in vivo studies, and any other appropriate quantitative metrics of interest. Demonstrate the reproducibility and repeatability of relevant measurements such as field of view, spatial and temporal resolution, and imaging depth. Provide milestones for year 3 under the Milestone and Timeline plan.

Transition from UG3 to UH3: An administrative review of each funded UG3 project will be conducted by NIH Program staff in year two to decide whether it will be considered for transition from the UG3 phase to the UH3 phase.  To be eligible for transition, a project must have successfully met the stated milestones of the UG3 Phase.

What is a cooperative agreement mechanism?

A cooperative agreement mechanism is a hybrid between a contract and a grant that is milestone driven with significant input from NIH Staff.

Are this initiative’s full application requirements similar to the standard R01 with respect to significance, innovation, and approach sections?

The RFA-RM-24-012 NOFO outlines the requirements for the full application. Arrange the Research Strategy for each phase by significance, innovation and approach as per Research (R) instructions in the How To Apply - Application Guide, following the RFA instructions. 

How many specific aims would be appropriate?

This is completely dependent on the proposal. The proposed research activities will need to be commensurate with the budget request and within the 3-year period of performance.

What must be included in the research strategy?

• Describe the conceptual design, technical specifications, engineering requirements, theoretical underpinnings, and applications of the proposed device, which must achieve significant increase in penetration depth compared to the current capabilities of optical imaging technology and must achieve temporal and spatial resolution relevant to the tissue and biological system of interest.
• Development of the device must first demonstrate a significant increase in tissue depth non-invasively by optical means; following development, the device may be used in applications that are non-invasive, minimally invasive, or in surgical settings.
• Describe how the proposed device with improved depth of imaging captures relevant physiological changes and timescales for biological events (e.g., heartbeat, action potentials).
• Explain how the proposed device would significantly advance biomedical and clinical research, and how the technology would be used by other investigators and broader community.  
• Discuss the materials and fabrication expertise needed to achieve the goals of the project.  
• Describe whether the device can be assembled from existing components or technologies, or if new technologies will need to be developed.
• Provide a description of any necessary software or algorithms to be implemented or developed for the project to succeed.
• Provide evidence that technology practice and distribution can be pursued when covered and/or built upon third party patent claims.
• Discuss and justify expertise and subcontracts needed to engineer and/or test the device in biological systems.
• Explain the methods and metrics needed to validate the components, algorithms, and prototype.
• Provide plans to demonstrate that the technology produces reproducible and reliable data in biological systems. 

How should I divide the approach in the research plan to address the following goals?

Divide the approach as indicated below to address the following goals:

Year 1/UG3 Phase:

Conceptualization, design, and modification of non-invasive optical imaging technology and algorithms.

Provide device prototype designs, plans for the construction of or acquisition of components, relevant algorithms, and necessary expertise to demonstrate the proof-of-concept capabilities (phantoms, simulations, etc.) based on relevant quantitative metrics of the technology of interest such as depth of interrogation, resolution, and optical biomarkers. Clearly define the performance metrics compared to the relevant existing state-of-the-art technologies. Provide milestones for year 1 under Milestone and Timeline plan.

Year 2/UG3 Phase: continued:

Development, of prototype technology and demonstration in relevant tissue models.

Demonstrate the accuracy and reliability of the technology to non-invasively image the relevant tissue at significantly higher depth. Include quantitative metrics based upon specific optical modalities such as sensitivity, specificity, resolutions, and signal-to-noise ratios, field of view etc. Include demonstration of the reproducibility and repeatability of the measurements.

Specify clear, appropriate, and measurable milestones under Milestone and Timeline plan (see below). Milestones must be achieved prior to transitioning to the UH3 phase. Milestones will be used as criteria by NIH Program staff to evaluate whether the project has successfully completed the UG3 phase and can be awarded support for the UH3 phase. Transition to the UH3 phase is subject to administrative review by Program staff and availability of funds.

Year 3/UH3 Phase:

Further refinement of the relevant optical imaging technology and relevant algorithm and testing the platform in appropriate in-vivo animal or human model.

By the conclusion of the three-year period of performance supported by NIOI, in vivo demonstrations of the technology must have been conducted in appropriate biological model systems.

Demonstrate technology performance in appropriate in vivo animal or human models, non-invasively or minimally invasively. Include quantitative tests that achieve the proposed metrics and are relevant to the technology and tissue of interest.  Evaluate performance against at least one comparable system in routine current use for research and/or clinical imaging.  Clearly demonstrate a significantly increased imaging depth at relevant biological temporal and spatial resolution for in vivo studies, and any other appropriate quantitative metrics of interest. Demonstrate the reproducibility and repeatability of relevant measurements such as field of view, spatial and temporal resolution, and imaging depth. Provide milestones for year 3 under the Milestone and Timeline plan.

How will projects be selected for the UH3 Phase? 

The Research Performance Progress Report submitted toward the end of year 2 will be reviewed administratively by NIH Program staff.  Projects must meet the stated milestones of the UG3 phase to be eligible for the UH3 Phase, for funding of the third and final budget period.  

Does the NOFO require commercialization?

No.  Detailed plans for partnerships to continue technology maturation beyond the NIOI project period, including but not limited to commercialization, startups, follow-on funding from advanced developers, etc., are encouraged.

How are Intellectual Property (IP) rights handled? Is anything funded intended to be open access?

Generally speaking, any IP will be retained by the recipient, but NIH is granted licensing rights. Recipients of awards are expected to comply with NIH Data Sharing and Management Plans, Resource Sharing plans, NIH Public Access policy, and to report inventions in iEdison.  

The Bayh–Dole Act is US legislation dealing with intellectual property arising from federally funded research. This Act encourages researchers to patent and market their inventions by guaranteeing patent rights. This Act automatically grants first rights to a patent for an invention fully or partially funded by a federal agency to the awardee organization. To obtain these benefits, however, the inventor and the organization have several reporting requirements that protect the rights of the government. For more information on the Bayh-Dole Act and NIH’s Role, please read Guide Notice NOT-95-003.

Do I need to showcase in vivo studies during the UH3 phase? Do they have to be human studies? 

During the UH3 phase, applications will need to demonstrate the capability of the system for in vivo imaging in either human or other mammalian animal models. Applicants proposing the use of non-mammalian tissue or non-mammalian organisms will not be considered responsive to the NOFO and the application will be withdrawn prior to review.

Does the NOFO require both a resource sharing plan and a Data Management Sharing Plan?

Yes. 

Does proof of concept have to be performed in human beings to be responsive?

No.

Would preclinical applications (e.g., drug discovery) be eligible or should it be translational?

Drug discovery applications are not responsive. The device should ultimately have translational significance. Per research strategy you are asked to “Explain how the proposed device would significantly advance biomedical and clinical research, and how the technology would be used by other investigators and broader community.”

What does "Biological Systems" mean. Is proposing an instrument for non-invasive measurement of neuronal activities in humans responsive?

Yes. The requirement is to achieve a radical increase in optical depth in any mammalian tissue or organism.

Do you expect the proposed technology to be applied for all ages of human subjects?

The NIOI initiative is looking for breakthrough solutions to radically increase imaging depth across the human life span.

Can you comment on the expectation for preliminary data for the proposed technology?

Preliminary data is always helpful in supporting feasibility. However, the UG3/UH3e cooperative agreement mechanism with milestones also facilitates risk-taking. 

Would this NOFO support a pilot clinical study? I understand clinical trials not supported.

No.

Should discussion of alternative approaches be included in the milestones and Timeline Plan original document? 

Milestones can be written as go, no-go decisions points for proceeding with an alternative strategy. 

Is there a preference for a radical new approach demonstrated to a limited 3-year level or a relatively new approach that can be developed to a much more mature level in 3 years? 

Radical and novel approaches are encouraged.  The cooperative agreement mechanism allows for greater risk to be taken because projects are milestone driven.  If a milestone is not reached, the milestone can be re-negotiated or the project may be stopped.  

This Venture initiative is meant to be: 

• Transformative: projects have strong potential for exceptionally high and broadly applicable impact in biomedical/behavioral research
• Catalytic: projects are time-limited investments of 10 years or less, designed to capitalize on new scientific knowledge or breakthroughs to accelerate and enable subsequent research
• Goal-driven: projects include defined goals to develop specific deliverables (such as new knowledge, data sets, resources, methods, or technologies)
• Synergistic: projects must advance the missions of multiple ICOs and be relevant to multiple diseases or conditions
• Novel: projects pursue innovative solutions to specific scientific challenges important to the NIH mission but that no other entity is likely or able to address

For validation of the depth improvement, can simulations, phantoms, animal, and/or in vivo human tests all be considered?

Yes.

Do we need to include specific biological questions that the proposed technology can solve and demonstrate them?

There is no requirement to answer a specific biological question.

Would an increase in the order of non-linearity of a microscopic method, such as going from two-photon to three-photon microscopy, and hence increasing the depth of sampling, be responsive in the context of preclinical brain imaging applications? 

Any approach that can significantly increase the optical imaging depth is responsive. 

Is AI algorithm development for imaging analysis in the scope of this funding opportunity?

Yes.

Can you please help clarify why laparoscopy is considered as invasive while endoscopy is not?

Endoscopy is minimally invasive as it does not involve physical penetration of tissue to access the imaging targets. Laparoscopic approaches involve penetration of the abdominal cavity from the outside and are thus invasive and out-of-scope. 

Are Plans for Enhancing Diverse Perspectives (PEDPs) required?

No, they are not required at this time.