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Given the tremendous potential of regenerative medicine to enhance human health and treat disease, Congress included a provision in the 21st Century Cures Act — a law passed in December 2016 to accelerate medical discovery and innovation — to support a Regenerative Medicine Innovation Project (RMIP). The RMIP aims to accelerate the field by supporting clinical research on adult stem cells while promoting the highest standards for protecting patient safety during the conduct of research. The RMIP is one of four Innovation Projects authorized under the Act; the others are the Precision Medicine Initiative (“All of Us”), the Beau Biden Cancer Moonshot, and the BRAIN Initiative.

�鶹��ý intends to commit total funds of up to $8,000,000 across the project periods of the FY 2023 FOAs. The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications. 

Through the relevant FOAs, �鶹��ý is accepting applications that propose UG3/UH3-Clinical Trials, U01-Preclinical Studies, and R34-Clinical Trial Planning Grants.

Awards will utilize the following funding mechanisms:

•  Investigator-Initiated Clinical Trials (UG3/UH3 - Clinical Trial Required)
• Investigator-Initiated Studies (Collaborative U01 – Clinical Trial Not Allowed)
•  Clinical Trial Planning Grant (R34 - Clinical Trials Not Allowed)

No.  This year, applications are being solicited for clinical trials, IND-enabling preclinical studies, and clinical trial planning activities.  

As stipulated in the 21st Century Cures Act, RMIP grantees must make non-Federal contributions to their projects in “an amount not less than $1 for each $1 of Federal funds provided in the award.” In other words, grantee contributions must be at least equal in value to the Federal dollars provided under the RMIP award. Applicants must identify the source, type, and amount of contribution(s) proposed to meet the matching requirement and explain how the value of any “in-kind” contributions was determined (see Q10).

In keeping with the 21st Century Cures Act, NIH expects award recipients to match the total federally awarded amount (normally direct plus indirect costs, but see also Q11 below).

Matching contributions may be monetary or “in-kind” (i.e., non-monetary contributions). Matching contributions may not be from Federal sources, however, or paid for with Federal dollars. They may be in the form of funding, or paid for by funds, from non-Federal sources such as private industry, foundations, and institutional funds (not derived from Federal grants or contracts).

“In-kind” contributions are non-monetary contributions. Acceptable forms of in-kind contributions include personnel time and effort, facilities and administrative (i.e., indirect) costs, equipment, and real estate. Importantly, to be eligible, in-kind contributions must not have been obtained with support from any Federal agency.

If the institution is forgoing all indirect cost reimbursement, and consequently the NIH award is only for direct costs, then the institution must match the direct cost amount (since the 21st Century Cures Act requires matching all federally awarded dollars).

No. Such revenue is considered “program income.” Program income is not an allowable source of matching dollars. Program income is gross income earned by a recipient, a consortium participant, or a contractor under a grant that was directly generated by the grant-supported activity or earned as a result of the award. Program income includes, but is not limited to, income from fees for services performed; charges for the use or rental of real property, equipment or supplies acquired under the grant; the sale of commodities or items fabricated under an award; charges for research resources; registration fees for grant-supported conferences, and license fees and royalties on patents and copyrights.

The 21st Century Cures Act only specifies that matching funds must be non-Federal in origin. Other policies, laws and regulations, however, may impose restrictions or requirements for funds originating from a foreign source. Before relying on such sources of money, investigators should first discuss the scenario with the appropriate agency contact listed at the end of the FOA, who can consult in turn with appropriate entities, including legal counsel, about the acceptability of the source and the requirements that may apply.

Matching contributions must be available in each budget period in an amount at least equal to the amount of Federal dollars awarded for that period. Any matching contribution provided in excess of a given budget period’s obligation may be credited toward the following budget period’s matching obligation.

For applications to the UG3/UH3 FOA, there are two budget periods: UG3 (up to one year) and UH3 (up to four years). For applications to all other FOAs, there is a single budget period: the period of the award.

An aim of the 21st Century Cures Act is to accelerate the development of regenerative medicine therapies, which the Act describes as including “cell therapy, therapeutic tissue engineering products, human cell and tissue products, and combination products using any such therapies or products…” RM research eligible for 21st Century Cures Act funding may encompass, for example, research on biologics (e.g., growth factors, cytokines) and biomaterials (e.g., extracellular matrix, scaffolds) that stimulate or support host adult stem cell growth, proliferation, differentiation, and function or otherwise directly act upon adult stems cells to support innate host healing mechanisms, treat disease, and/or restore function. RM research in this context is interpreted to include gene therapies that lead to a durable modification of adult stem cells.

No. Basic research is a critically important component of regenerative medicine research and is funded by other NIH programs. The 21st Century Cures Act requires that the RMIP funds be used “to award grants and contracts for clinical research to further the field of regenerative medicine using adult stem cells, including autologous stem cells” (see Q17 below).

Per the FOA, proposed projects will be considered clinical research if they involve: (1) human subjects and/or (2) material of human origin, such as cells, tissues, and specimens.

No. The 21st Century Cures Act stipulates that these funds are to be used for regenerative medicine research using adult stem cells. For the purpose of research conducted with the RMIP funds, adult stem cells may not be derived from human embryonic or fetal sources.

Research with human iPSCs is eligible for RMIP funding, provided the stem cells were not derived from embryonic or fetal cells.

Yes. Human neonatal stems cells (e.g., cells derived from foreskin) are considered adult stem cells for the purpose of this funding opportunity since they are not derived from fetal or embryonic sources.

Yes. Eligible projects encompass, for example, research on biologics (e.g., growth factors, cytokines) and biomaterials (e.g., extracellular matrix, scaffolds) that stimulate or support host (i.e., endogenous) adult stem cell growth, self-renewal, proliferation, differentiation, and function or otherwise directly act upon adult stems cells to support innate host healing mechanisms, treat disease, and/or restore function.

No. Research using only animal models would only be eligible if it entailed the testing of adult stem cells of human origin in those models. Research using only animal models and animal stem cells is not eligible because it is not “clinical research” as described in the FOAs.

Not necessarily. Certain types of clinical trials eligible for RMIP funding may not legally require IND authorization or IDE approval. Furthermore, three of the four award mechanisms being utilized are for research that does not involve a clinical trial (and hence, in those cases, an IND or IDE application is not required); the mechanisms being used for preclinical research are focused on late-stage or IND/IDE enabling research.  See also Q26 below.

Successful applicants must provide evidence of having had an  consultation and/or pre-IND consultation with FDA ideally by time of application, but no later than the time of award. Before transitioning from UG3 to UH3 phase, applicants must obtain an Investigational New Drug (IND) authorization or Investigational New Device Exemption (IDE) approval to administer the product to humans

Applicants should describe their , including the dates of any pre-IND meetings and other communications.

If the protocol is judged by the applicant to not require an IND/IDE, the applicant should provide a written explanation accompanied by documentation from FDA. Applicants are encouraged to consult with FDA early on in the process for an authoritative opinion that their product is exempt from the IND/IDE requirements by submitting a request for designation (RFD) to obtain a formal FDA determination of their cell product (see instructions at ). Please note that if the protocol is exempt from the requirement to file an IND or IDE application, RMIP applicants are required to provide to NIH — prior to award — a copy of a formal designation letter from FDA.

FDA is an essential partner and collaborator with NIH on the implementation of the RMIP. As such, FDA provides critical input on the state of regenerative medicine science, including the current knowledge gaps and technical, scientific, and operational challenges, especially with respect to regulatory science needs. NIH has worked with FDA on the development of the FOAs, including the design of the review criteria and process. FDA staff may participate as observers on the initial review panels assessing the scientific merits of the applications.

The RMIC is a resource that is being established and will be funded by NIH to catalyze the efficient development of safe and effective adult stem cell-based therapies and to further the field of regenerative medicine. The RMIC will offer services and resources to RMIP investigators to facilitate the conduct of their studies. Ultimately, the activities of the RMIC will also allow a deeper understanding of stem cell clinical products, in part by facilitating the correlation of cell characterization with clinical outcomes data. Toward these ends, it is anticipated that the RMIC will:

• Conduct in-depth and independent characterization of the source stem cell line and stem cell products being administered to research subjects (see Q30 and Q31)
• Provide storage and dissemination services for in-depth cell characterization results and clinical data

RMIP awardees will be expected to provide: (1) representative samples of the source stem cell line, (2) representative samples of the clinical-grade stem cell product, and when applicable (3) individual participant-level data emanating from an RMIP-funded clinical trial. Details about timeframes and procedures will be negotiated with individual recipients at the time of award.

While our understanding of stem cell biology is progressing rapidly, it is nonetheless widely acknowledged that a critical challenge in the development of stem cell therapies is the need for a more complete characterization of the biological attributes of stem cell products. Such in-depth characterization would enable a fuller understanding of how clinical outcomes may be related to particular cell characteristics and may inform future product development and enhance reproducibility of subsequent studies. Towards these ends, RMIP grantees will be asked to submit representative samples from their source cells, as well as the clinical-grade cell products derived from them, to an NIH-designated in-depth cell characterization platform provider for in-depth analysis of cell characteristics. The NIH-designated provider will conduct in-depth analyses of cell surface markers, -omics characteristics and other assays as appropriate. NIH recognizes that commercialization is important to developing products that will ultimately be made available to the public, and thus any proprietary information provided will be protected to the extent possible under the law.

Investigators will receive the in-depth cell characterization results on the cell samples that they provide. However, the biologic and clinical significance of various cell characteristics for efficacy and safety may not be known for some time, since making that correlation will require additional data, study and analysis. Thus, the primary purpose of conducting the cell characterization studies is to inform future research activities and the field at large. In-depth cell characterization assay results are not intended to inform clinical decisions during the conduct of the clinical trial, nor are they intended to factor into the normative oversight requirements and processes (e.g., FDA, DSMB, IRB) for the source study. Investigators may nonetheless consider what the results indicate relative to their scientific approach and whether any changes are warranted. In general, cell characterization assay results will be made available to the broader research community via the RMIC one year following the end of award (for preclinical studies) or the primary completion date (for clinical trials).

• The deidentified individual participant-level locked dataset will be shared via the RM Innovation Catalyst through controlled access as appropriate in compliance with applicable Federal laws, regulations, and policies according to the following schedule:
• Primary outcome data will be shared one year following the primary completion date.
• The full dataset will be shared two years following the primary completion date.

Applicants interested in these services should consult with the appropriate NIH Scientific/Research Contact listed in the FOA as early as possible in the application process to determine the suitability of these services for their cell development process, the mechanism(s) available to fund these product development services, and whether applicants need to budget for them in their application.

Not at this time. Initially, the RMIC will only be available to the RMIP awardees.  In the future, the role of the RMIC relative to other regenerative medicine studies may evolve.

No.

As with all grant applications submitted to NIH, RMIP applications will undergo two levels of peer review: an initial review of the proposal’s scientific and technical merits, and a second level of review by an advisory council regarding funding and research priorities. Initial peer review of RMIP applications will be conducted by a Special Emphasis Panel. Final funding decisions will be made by NIH leadership.

Please visit /rmi to find the FOAs, FAQs, and more. If you have questions about this initiative, you may also write to RMIP@nih.gov. Finally, you are strongly encouraged to discuss your application with the appropriate agency contact listed at the end of the FOA; early contact is important for developing a complete application and facilitating review.