Regenerative Medicine Innovation Project (RMIP) (U44 - Clinical Trial Not Allowed)

Purpose

The National Institutes of Health (NIH) participating Institutes and Centers (ICs), in coordination with the U.S. Food and Drug Administration (FDA), invite cooperative agreement (U44) applications to support small business research studies aimed at furthering the field of regenerative medicine (RM) using adult stem cells. These applications are expected to focus on innovative projects that propose solutions to widely recognized issues in the development of safe and effective RM therapies, contribute an enhanced understanding of stem cell product attributes, and promote data sharing. Emphasis will be given to projects that address critical issues in product development relevant for regulatory submissions. Areas of focus may include improved tools, methods, standards, or applied science that support a better understanding and improved evaluation of in-depth product characterization, manufacturing, potency, identity, quality, safety, in vivo function and integration, or effectiveness.

Toward these ends, the NIH will consider applications for late-stage preclinical research studies involving adult stem cells in the context of generating or supplementing the necessary evidence for clinical development, including, but not limited to, the submission of an Investigational New Drug (IND) or Investigational New Device Exemption (IDE) package; or to support such research conducted under an authorized IND or IDE. Successful applicants proposing the use of adult stem cells as a clinical intervention will be asked to make available representative samples of the source stem cell line and clinical-grade stem cell product for in-depth and independent characterization through the RM Innovation Catalyst.

This FOA utilizes the U44 activity code and will thereby support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies.

Background

This FOA, issued as part of the Regenerative Medicine Innovation Project (RMIP), represents one step in fulfilling a new statutory provision set forth in the 21st Century Cures Act.

Given the potential of RM to enhance human health and treat disease, in the 21st Century Cures Act Congress authorized a total of $30 million in fiscal years 2017 through 2020 for the funding of clinical research to further the field of RM using adult stem cells, including autologous cells. The 21st Century Cures Act stipulates that awards must be contingent upon the recipient procuring non-Federal contributions in an amount not less than $1 for each $1 of Federal funds (total Direct and Indirect/Facilities & Administrative (F&A) costs) provided in the award (i.e., a matching funds requirement). Additional information is provided in the FAQs and Matching Requirement section below.

Research projects responsive to this FOA are expected to involve both of the following: (1) human subjects or material of human origin, such as cells, tissues, and specimens; and (2) human stem cells that are not of embryonic or fetal origin. Research projects involving induced pluripotent stem (iPS) cells may be supported if the cells used to generate the iPS cells were not of fetal or embryonic origin. Applicable research on adult human stem cells may encompass, for example, research on biologics (e.g., growth factors, cytokines) and biomaterials (e.g., extracellular matrix, scaffolds) that stimulate host adult stem cell self-renewal, proliferation, differentiation, and/or function or otherwise directly act upon adult stems cells to support innate host healing mechanisms, treat disease, and/or restore function. Funding could be used, for example, for the appropriate chemistry, manufacturing, and controls development to support the production of such products for clinical trials using phase-appropriate current good manufacturing practices (cGMP). Funds may not be used for research involving human cells of embryonic or fetal origin.

This FOA seeks highly meritorious research projects proposing to explore and enable the development of safe and effective RM interventions. In addition to being subject to the standard NIH review criteria, applications submitted in response to this FOA will also be assessed according to the following criteria:

Regenerative Medicine Innovation Catalyst

To catalyze the efficient development of safe and effective adult stem cell-based therapies and further the field of RM, NIH intends to establish an RM Innovation Catalyst to provide critical services to RMIP awardees (for both non-clinical trial research and clinical trials). Toward these ends, the RM Innovation Catalyst will offer, at no cost, regulatory support services and may also provide assistance for the development of phase-appropriate clinical-grade product. Applicants interested in the services offered by the RM Innovation Catalyst are requested to contact their NIH Scientific/Research Contact as early as possible in the application process for further details regarding these services.

In addition, to inform future studies and ultimately advance the field, applicants will be expected to provide representative samples of the source stem cell line and clinical-grade stem cell product for in-depth characterization by the RM Innovation Catalyst. The RM Innovation Catalyst will:

The in-depth characterization assays conducted by the Catalyst will be performed in parallel with the study or post-hoc. Because in-depth characterization assays may identify cell attributes for which the clinical significance is not currently known, these results are not intended to inform decisions during the conduct of the study, nor are they intended to factor into the normative oversight requirements and processes for the source study. Assay results will be returned to the study investigators as they become available. In order to accelerate the field and inform oversight of future studies, assay results will be made available to the broader research community via the Catalyst one year following the end of award (or as appropriate).

See relevant FAQs for additional details.

Collection and Sharing of Resources

Materials

Awardees will be required to make available representative samples of the source stem cell line and clinical-grade stem cell product for in-depth and independent characterization. Details regarding the provision of stem cell samples will be communicated to awardees by NIH staff. Results of cell characterization will be provided to the study investigator when available and are anticipated to be made available to the research community one year following the end of award.

Research Examples

Applicants are strongly encouraged to submit research applications that demonstrate potential to catalyze sustained and accelerated development of the RM field through contributing to the knowledge critical for clinical testing, stem cell characterization and authentication, cGMP compliant stem cell production, in vivo stem cell tracking and monitoring, data standards development, and data sharing. It is expected that submitted applications will address the following:

Matching Requirement

An application funded under this announcement is required to match all federally awarded dollars (total costs: total Direct and Indirect/F&A costs) with at least an equal amount (1:1) of non-Federal contributions, as mandated by the 21st Century Cures Act. Qualifying non-Federal contributions may include state and local funding not originating from Federal funds, private-sector investments, in-kind contributions, and donations from foundations. See 45 CFR 75.306, as well as relevant FAQs, for additional details. The applicant will be required to demonstrate that funds and in-kind contributions are committed or available at the time of, and for the duration of, the award. Applications must identify the source, type, and amount of funds proposed to meet the matching requirement and explain how the value of in-kind contributions was determined.  Applications must also include letter(s) of support confirming that the required matching contributions (cash or in-kind contributions such as salary, consultant costs, equipment) are available. See additional details and instructions in in Section IV.2 and Section VI.3.

Definitions

Adult stem cells are defined, for the purpose of this FOA, as stem cells (including iPS cells) that are not of fetal or embryonic origin or derived from embryonic or fetal stem cells.

Total project budget is the total amount of financial resources allocated for the project. This includes Federal funds, as well as cash and in-kind contributions from non-Federal sources for direct and indirect expenses.

Total Federal budget is the Federal share of the total project budget.

Applications Not Responsive to this FOA

The following types of applications will be considered non-responsive to this FOA:

Consultation

Potential applicants to this FOA are strongly encouraged to consult with the Scientific/Research Contact(s) for the area of science for which they are planning to develop an application. Early contact is encouraged as it provides an opportunity for NIH staff to discuss the scope and goals of the project and to provide guidance to applicants.

For more information please refer to specific FAQs for the FOAs.

See Section VIII. Other Information for award authorities and regulations.

1. • Addresses critical issues relevant to clinical research and regulatory submissions including those related to product development. Areas of focus may include improved tools, methods, standards, or applied science that support a better understanding and in-depth characterization of product manufacturing, quality, safety, or effectiveness;
   • Helps to significantly advance the field of RM by addressing a well-recognized challenge in clinical development, including the development and evaluation of safe and effective RM products; and
   • Contributes to breadth/diversity of RM science.
   • Conduct in-depth and independent characterization of the source stem cell line and stem cell products being administered to research subjects
   • Provide a resource for sharing and analysis of clinical trial and cell product characterization data, thereby potentially enabling correlation of stem cell attributes with clinical outcomes (see Resource Sharing Plan)
   • Ultimately create a foundation for enhancing our understanding of clinical outcomes and refining production methods.
   • Preclinical studies that contribute to conducting clinical trials that address specific clinical indications;
   • Testing human adult stem cells in well-developed animal models;
   • Monitoring stem cell function and integration in vivo;
   • Methods for in-depth stem cell characterization and deep fingerprinting, and utilization of standards;
   • Interactions with FDA regarding a future IND or IDE application (such as having had a pre-IND meeting and other communications);
   • Further development of standards and cGMP for adult stem cell-based RM products;
   • Leveraging extant cell production facilities for product preparation and qualification; and
   • Contributing to a better and shared understanding of current technical and operational barriers as well as regulatory science issues and how to overcome them.
   • Any research using human embryonic or fetal stem cells. Such projects are non-responsive.
   • Applications that do not include a plan to make available representative samples of the source stem cell line and clinical-grade stem cell product for in-depth characterization by an NIH-designated core facility (RM Innovation Catalyst). Such applications are incomplete. See additional details and instructions in Section IV.2.
   • Applications that do not include a letter(s) of support confirming that the required matching contributions (cash; in-kind contributions such as salary, consultant costs, equipment) are available. Such applications are incomplete; see additional details and instructions in Section IV.2.
   •