Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

The National Institute of Dental and Craniofacial Research (NIDCR) is firmly committed to facilitating clinical translation of the most promising scientific and technological advances in tissue engineering and regenerative medicine (TE/RM) to safely and effectively regenerate and reconstruct dental, oral and craniofacial (DOC) tissues. Toward achieving this goal, NIDCR will establish a multidisciplinary DOC Tissue Regeneration Consortium (DOCTRC) that will conduct pre-clinical studies leading to submission of Investigational New Drug (IND)/Investigational Device Exemption (IDE) applications to the U.S. Food and Drug Administration (FDA). This Consortium will develop safe, predictive and effective clinical strategies for regeneration and reconstruction of functional tissues of the human DOC complex, including vascularized and innervated craniofacial bone and musculoskeletal complex, periodontium, oral mucosa, tooth, cartilage, salivary gland and temporomandibular joint (TMJ). The DOCTRC will be built through a three-stage process. One year of support was provided under RFA-DE-15-005 though the R34 Planning Grant funding mechanism to develop an overall vision, roadmap, organizational structure, operational procedures and detailed plans for establishing centralized Resource Centers (RCs) that will bring together interdisciplinary teams of biologists, bioengineers, clinicians and other technical and regulatory experts to work toward a common goal of facilitating translation of DOC TE/RM technologies to clinic. Ten individual R34 Planning Grants were awarded in September 2015.

The current FOA will support activities in Stage 2, namely, development and establishment of the Resource Centers (RCs), which will serve as an integrative hub(s) for the DOCTRC. The ultimate goal of the DOCTRC effort, which will be achieved by the end of Stage 3, will be the development of TE/RM products, including combination products, based on cells, biologics and/or devices and associated protocols ready for the initiation of clinical trials. In this FOA, the teams of biologists, bioengineers, clinicians, regulatory and industrial experts and other professionals developed in Stage 1 will compete for the RCs through Resource-Related Research Projects Cooperative Agreement mechanism (U24) for a project period of up to three years. On the basis of peer review assessment and programmatic considerations, NIDCR will select 1-3 most meritorious teams to establish the RCs. The goals of the RCs will be to 1) develop a robust infrastructure to deliver uniform high-quality clinical and technical support, research capacity and regulatory and commercial expertise for pre-clinical activities of the DOCTRC and 2) organize, recruit and integrate several Interdisciplinary Translational Project (ITP) teams into the RC. The ITP teams will pursue development of specific TE/RM approaches for regeneration of functional DOC tissues, and will utilize synergistic and complementary expertise of the RCs in achieving their objectives. While the exact strategy for recruiting the ITP teams will be determined by the RCs themselves, complementarity of expertise between the RCs and the ITPs and the ability of the RC to provide all the necessary infrastructure support for the particular ITP must be taken into consideration. In order to effectively support the ITPs, the RCs will improve, optimize, validate and standardize tools and technologies for DOC tissue regeneration in the following areas: (i) cells, biomaterials and devices; (ii) disease and injury-relevant large animal models; (iii) functional assays and endpoints; (iv) quality control, scale up and manufacturing; (iv) interactions with FDA and Intellectual Property (IP) protection support; and (v) products commercialization and interactions with industry. To successfully compete for inclusion in the future Stage 3 of the DOCTRC, the RCs and the ITP teams must establish productive collaborations by the completion of Stage 2, and demonstrate their capacity to function as teams to advance the most likely to succeed TE/RM products through the translational pipeline. If more than one RC is awarded, productive collaborations between different RCs in areas of complementary expertise are highly encouraged during Stage 2.

To meet the demands of the accelerated translational timeline of the DOCTRC, the future awardees of this FOA will employ those innovative TE/RM tools and strategies that have been tested previously in small or large animal models, have already demonstrated a significant translational potential and would utilize either established or minimally-modified animal models.

Stage 3, Consortium Stage, will be solicited through a future FOA where the RCs and their ITP teams will compete for the final stage to establish the DOCTRC. Only members of prior established RCs will be able to apply for Stage 3 FOA. The successful RCs will form the nucleus of the Consortium , and they will be able to attract additional ITPs through the selection and approval process that will be outlined in Stage 3 FOA. The duration of stage 3 will be four to five years. The ITP teams will continue to leverage resources developed by the RCs during stage 2, and will work in close collaboration with the RCs while seeking advice from clinicians, FDA and industrial partners in advancing specific TE/RM technologies. During Stage 3, the DOCTRC will complete validation, manufacturing, and preclinical testing of the most promising TE/RM products and will develop INDs/IDEs for submission to FDA. The outcome of the DOCTRC will be TE/RM products and associated protocols ready for initiation of clinical trials.

Over the years, many promising scientific and technological advances have emerged from the NIDCR and NIH funded TE/RM research. These include scaffolds that can guide functional maturation of engineered constructs in vitro and facilitate tissue regeneration in vivo. Such scaffolds can be designed to deliver active biomolecules to cells, degrade at a pre-determined rate, control inflammatory responses, and exhibit many other useful characteristics. Further, substantial progress has been made in isolating and characterizing DOC tissue-specific stem and progenitor cells, developing functional assays for testing safety and efficacy of TE/RM products, and generating cell tracking and tissue imaging modalities for monitoring tissue regeneration in vivo. However, despite this progress, only a few TE/RM-based therapies for DOC and other tissues have reached the stage of clinical trials and commercialization.

NIDCR carried out a comprehensive analysis of the nature of obstacles interfering with TE/RM translation, and on the basis of this analysis, generated a plan to establish a translation-targeted DOCTRC. One of the key features to ensure the success of DOCTRC in advancing TE/RM products to the clinic will be a strong alignment between specific clinical needs for DOC tissue regeneration and the available tools and technologies that have matured sufficiently in discovery research to support these particular needs. Achieving this alignment will require robust interdisciplinary and multidisciplinary partnerships among practicing clinicians, biologists, bioengineers, regulatory and industrial experts and other technical professionals. In these partnerships, there is a need for clinicians to define areas of clinical needs and to establish product design criteria. On the basis of these recommendations, the technical and regulatory experts of the DOCTRC will develop specific technical strategies and products to meet these needs.

Given a multitude of the available TE/RM-based biomaterials, scaffolds, cell sources, functional assays, animal models and other experimental tools, an initial stage will be needed before specific products and protocols can be advanced through the translational pipeline for preclinical testing. For example, it will be necessary to conduct side-by-side qualitative and quantitative comparisons, and to standardize, optimize and validate the available materials, cells and protocols in DOC disease and injury-relevant large animal models with respect to their safety, efficacy, and other functional outcome parameters. This work will allow the identification of those strategies that are most likely to fulfill clinical needs and succeed in the clinical settings. Moreover, effective scale up, Good Manufacturing Practices (GMP) protocols and Standard Operating Procedures (SOPs) preliminary IP protection and commercialization plans will need to be developed before the products can be effectively advanced toward clinical trials. The DOCTRC will systematically address these issues during its second stage while the third stage will focus on advancing specific most likely to succeed products and protocols toward clinical trials, IND/IDE submissions and development specific commercialization and IP protection plans, among other activities.

This FOA for Stage 2 DOCTRC encourages applications for Resource-Related Research Projects Cooperative Agreement mechanism (U24) from multidisciplinary groups of investigators who have developed robust, rigorous and realistic plans for establishing partnerships that will function as collaborative RCs. It is expected that substantial prior RC planning activities, including meetings, conferences and consultations among key multidisciplinary professionals that will form the nucleus of the RC, and of prior interactions with NIDCR Program Officials regarding these plans would have occurred prior to submission of applications to this FOA. Prior involvement in advancing TE/RM products and technologies to clinical trials, and history of prior collaboration among team members are desired. Multiple Program Director/Principal Investigator (multiple-PD/PI) applications are strongly encouraged. Specific requirements for applications submitted in response to this FOA are outlined below:

• This FOA will not support clinical trials or first in human clinical studies; projects that have sufficiently matured to enter these clinical phases should utilize other appropriate funding mechanisms available at NIDCR.
• This FOA will not support discovery research. Approaches and technologies to be pursued by the RCs and the ITPs must be sufficiently mature to show significant promise in animal models, and must demonstrate feasibility and readiness to be advanced toward clinical trials.
• Launching of collaborations with ITP teams and selection of technologies to be advanced toward clinical trials must take place during the course of Stage 2. Few of the selected technologies may originate from the members of the RC. However, the RC must attract additional ITPs from the outside of their own RC.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

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)

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) 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.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. 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 DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

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.

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

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. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

Applicants must obtain the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

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 IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Yasaman Shirazi, PhD
Chief, Scientific Review Branch
NIDCR, NIH
6701 Democracy Blvd., Rm. 662
Bethesda, MD 20892-4878 (20817 for express deliveries)
Telephone: 301-594-5593
Email: yasaman.shirazi@nih.gov

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

Facilities & Other Resources. Highlight the following:

• Facilities in place to establish the RC;
• Availability of resources at home institutions to support the function of the RC;

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

PD(s)/PI(s) are expected to collectively provide at least 3 person-months (25% FTE) to the Program; increased effort is expected if the PD(s)/PI(s) plan to also lead a research project within the RC; the amount of this increased effort should be commensurate with the specific needs of the research project.

Applicants should budget to travel to annual DOCTRC retreats. An inaugural retreat will take place in the winter/spring 2017 at NIDCR site in Bethesda, MD

All instructions in the SF424 (R&R) Application Guide must be followed. Support for the ITP teams must be provided via sub-awards from the parent grant. Facilities and Administrative (F&A) costs of each sub-award do NOT count towards any direct costs cap of the parent award.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Research Strategy: The Research Strategy should address the elements specified in Section I (see Scope subsection of this FOA). The description of the RC activities should be captured under the following areas:

• Rationale for establishing the RC and RC's objectives and goals
• Overall vision for the RC that will support goals and specific objectives of the DOCTRC, as well as collaborations with external ITPs and among different RCs;
• Organizational and administrative structure of the RC;
• Leadership and communication plans within RC and among RCs, and plans for dealing with geographical distances among collaborators, if applicable;
• Collaborations and communications within the RC with a particular emphasis on interdisciplinary collaborations, among scientists, clinicians, industry and FDA;Evidence of presence of an aggregate interdisciplinary expertise on the team that includes clinicians, biologists, bioengineers, chemists, material scientists, and other proffessionals, as needed for achieving the goals of the FOA.
• Supporting documented evidence of prior substantial RC planning activities, including meetings, conferences and consultations among key multidisciplinary professionals that will constitute the nucleus of the RC. Also, evidence of prior interactions with NIDCR Program Officials regarding these plans is highly desirable.
• Strategies for defining clinical needs for the RC, and a plan for recruiting practicing physicians and dentists to the RC who will drive the development of TE/RM products;
• Strategies for attracting to the RCs team members with solid track record in needed areas of expertise; ;
• Strategies for interactions with industry and FDA and for submitting IND/IDE submissions;
• Technical focus areas of the RC that have been selected on the basis of prior promising results in small and large animal models, and relevance of these focus areas to clinical needs;
• Strategies for prioritization of clinical needs;
• Comparative evaluation of potential effectiveness for the therapies under development with those of existing gold standards currently available in clinical practice;
• Statistical methods, functional assays, power analysis;
• Human disease-relevant animal models with emphasis on large animal models; derivation of new animal models, as needed;
• SOPs and protocol development;
• Validation, standardization and quality control of TE/RM materials and products, transportation/storage of the product(s), path forward within IP space;
• Personnel training;
• Strategies for establishing collaborations with ITPs that include considerations of expertise complementarity between the RCs and the ITPs and the ability of the RCs to provide all the necessary infrastructure support for the particular ITP, among other considerations
• Plans for establishing balance between specific projects driven by internal RC investigators and projects from external ITPs;
• Milestones and timelines, including monitoring; overcoming obstacles;
• Strategies for achieving successful transition from Stage 2 to Stage 3

The listed examples only serve to illustrate the areas that should be addressed in applications. Applicants can expand on these examples, and introduce additional elements into their applications to facilitate building functional RC infrastructure

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

• All applications should address Resource and Data Sharing Plans.

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing PHS Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

All instructions in the SF424 (R&R) Application Guide must be followed.

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

This initiative is not subject to intergovernmental review.

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by NIDCR, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Consultation with NIDCR Program staff at least 10 weeks prior to the application due date is strongly encouraged for submission of applications in response to this FOA. The NIDCR staff will consult on whether the proposed application meets the goals of the FOA. NIDCR staff will not evaluate the technical and scientific merits of the proposed application; technical and scientific merit will be determined during peer review using the review criteria indicated in this FOA.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Does the project address an important problem or a critical barrier to progress in the field? Is there a strong scientific premise for the project? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Specific to this FOA: Is the rationale for establishing the proposed RC well-justified, and the proposed RC goals and objectives adequately defined? Is there a clear statement of the focus and specific technical areas to be addressed? Does the application provide justification for selecting the proposed organizational and administrative infrastructure of the RC? Is there sound clinical, biological and technical data to support selection of the particular infrastructure of the RC?

Does the application provide evidence that the clinical needs identified by practicing physicians and dentists will drive the development of specific TE/RM products pursued by the RC?

Will the proposed RC infrastructure effectively support the goals and the specific objectives of the DOCTRC, to conduct pre-clinical studies leading to the submission of IND/IDE applications to FDA to develop safe, predictive and effective clinical strategies for regeneration of functional tissues of the human DOC complex?

Is there a high likelihood that the proposed RC infrastructure can support collaborations with external ITPs and collaborations between different RCs?

Does the application describe how achieving of the goals of Stage 2 will position the RC and the ITPs to successfully compete for Stage 3?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Specific to this FOA: Has the team provided evidence of substantial prior planning activities, including meetings, conferences and consultations among key multidisciplinary professionals that will constitute the nucleus of the RC? Is the team appropriately qualified and well-suited for the proposed RC and have experience advancing TE/RM products to clinical trials? Is there a history of prior collaboration between the members of the team? ? Does the team include practicing physicians and dentists who manage patient care on a regular basis? Do members of the team have a proven track record in the areas to be addressed by the RC?

Is there a plan in place for attracting ITPs to the RC? Is there evidence of a balance between specific projects driven by internal RC investigators and projects from external ITPs? Is a plan in place to attract industrial partners on the team? Is a plan in place to ensure proper training of the technical personnel of the RC?

Will the interdisciplinary composition of the RC promote productive collaborations within the RC and forge collaborations with ITP teams and other RCs? Are the communication and collaboration plans within the RC adequately described? Is there an evidence of an effective leadership plan?

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Specific to this FOA: Are functional assays, DOC disease-relevant animal models, scale up, GMP-grade manufacturing strategies and other technical features of the RC based on innovative state-of-the-art principles? Are the overall infrastructure and organizational/managerial configuration of the RC built on innovative principles that will enhance RC function?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

Specific to this FOA

Will the proposed RC employ TE/RM tools and strategies that have been tested previously in small or large animal models, and have already demonstrated significant translational potential, feasibility and readiness to advance through the translational pipeline? Will the proposed RC infrastructure effectively support the general goals and the specific objectives of the DOCTRC, to conduct pre-clinical studies leading to the submission of IND/IDE applications to FDA to develop safe, predictive and effective clinical strategies for regeneration of functional tissues of the human DOC complex?

Does the application present a detailed description of the activities to be conducted and completed during Stage 2, including milestones, timelines and plans for overcoming obstacles and barriers? Are milestones and timelines realistic and feasible?

Does the application address the availability of human disease-relevant animal models, and plans for deriving new animal models, if needed, particularly large animal models to be employed by the RC?

Does the application describe procedures for side-by-side evaluations of technologies and functional assays to be used for measuring outcomes of these comparisons? Does the application outline strategies for comparative evaluation of potential effectiveness for the therapies under development with those of existing gold standards currently available in clinical practice?

Does the application provide plans for prioritization of clinical needs?

Does the application describe specific plans for attracting external ITPs into the RC? Does the application describe specific plans for collaboration with other RCs?

Are the proposed approaches and methodologies to be employed by the RC scientifically/technically sound, and can they be executed realistically within the duration of Stage 2?

Are appropriate technical plans included to address quantitative side-by-side comparison, standardization, functional validation, quality control GMP-grade manufacturing and transportation/storage of the TE/RM products to be developed by the RC? Are the SOPs realistic and sound?

Does the application present a detailed description of the interdisciplinary interactions between clinical, technical, regulatory and industrial components of the RC?

Does the application provide appropriate discussion of plans for interactions with FDA and preparation of IND/IDE submissions? Does the application address plans for interactions with industrial partners? Is the appropriate discussion of IP issues provided? Does the application include discussion of detailed milestones and timelines? Is there evidence that the proposed timelines and milestones are feasible and appropriate for achieving the goals of the project? Does the application include discussion of how the proposed RC and collaborating ITPs will position themselves for competing for Stage 3 by the end of Stage 2?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

Specific to this FOA: Are adequate facilities in place to establish the RC? Are there adequate plans for the development of an effective organizational structure and a communication plan, including plans for managing geographical distances, between different components of the RC, between the RC and ITPs and between different RCs? Does the application provide evidence for the availability of resources at home Institutions to support the function of the RC?

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Not Applicable

Not Applicable

Not Applicable

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Not Applicable

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by{NIDCR Special Emphasis panel (SEP)}, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
• Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Dental and Craniofacial Research Council. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH s purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

The Program Directors/Principal Investigators PD(s)/PI(s) will have the primary responsibility for:

• Defining the research plan and goals;
• Defining the organizational and administrative structure of the RC;
• Defining leadership and communication plans of the RC
• Overseeing the execution of all aspects of the projects and coordinating/overseeing research design;
• Coordinating among collaborating interdisciplinary groups within the RC and among different RCs;
• Ensuring compliance with the mandatory regulations (including protection of human subjects);
• Overseeing establishment and maintenance of appropriate quality control procedures, SOPs, and other technical aspects of the RC function;
• Establishing collaborations with ITPs;
• Overseeing final data analysis and interpretation and preparation of publications;
• Cooperating with NIDCR programmatic, technical and administrative staff;
• Administratively managing the U01 award;
• Participating in monthly periodic teleconferences (as needed); and
• Ensuring and overseeing the timely sharing of results, resources, methods etc. with collaborators and scientific community;
• Adhering to timelines and milestones and overcoming obstacles;
• Timely submission of annual Research Performance Progress Reports (PPPRs). This U01 will require additional midyear Progress Reports.

The PDs/PIs agree to accept assistance, coordination, cooperation and participation of NIDCR staff in scientific management of the project in accordance with the terms formally and mutually agreed upon prior to the award.

Publications: The PDs/PIs will be responsible for the timely submission of all abstracts, manuscripts and reviews (co)authored by members of the cooperative agreement award and supported in part or in total under this Agreement. Publications or oral presentations of work performed under this Agreement are the responsibility of the PDs/PIs and will require appropriate acknowledgement of NIDCR support.

The PDs/PIs are expected to maintain significant effort commitment: collectively not less than that stated in the application- at least 3 person-months (25% FTE) during the funded period of the project.

Awardees will be expected to develop and implement common, uniform standard operating procedures (SOP) and technical formats for depositing data into public databases. Data generating methods and analysis algorithms shall be described in sufficient detail to enable duplication by other investigators.

Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

NIH staff will have a substantial programmatic involvement that is above and beyond the normal stewardship role in awards as described below:

A designated NIDCR Program Director(s) acting as a Project Scientist(s) (PS) will have the following responsibilities:

• Serving as a liaison/facilitator between the awardee and other government agencies;
• Serving as a resource of scientific and policy information related to the goals of the awardee's research;
• Providing policy assistance and feedback to the awardees as appropriate;
• Facilitating coordination of project activities during the course of the project;
• Assisting the awardee with access to other NIDCR-supported resources and services.
• Monitoring progress of the RC as a whole and of the specific studies through the evaluation of semi-annual progress reports that awardees will be providing to NIDCR during the funding phase. The progress will also be monitored via regular teleconferences between the awardees and the programmatic team;
• Negotiating project specific timelines and milestones with grantees during the funding phase;
• Conducting periodic site visits or discussions with awardee research teams as needed;
• Facilitating interactions/collaborations between the awardees and other NIH-sponsored programs, investigators, or organizations that may contribute to the project goals; and
• Monitoring the adherence of the awardees to the approved resource and data sharing plans.

Additionally, NIDCR Program Official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

The NIDCR will adjust funding, withhold, suspend, or terminate the support to the awardee if the team is unable to meet the negotiated milestones set forth in these Terms and Conditions of Award or the performance of the team is deemed to be significantly low that the aims will not be met within the time frame of the cooperative agreement. Continuous funding will depend upon meeting milestones negotiated for the projects.

Areas of Joint Responsibility include:

None; all responsibilities are divided between awardees and NIH staff as described above.

Additional notes:

NIDCR will assemble an External Expert Panel to assess and evaluate progress of the RCs on an annual basis and provide input to enhance performance and coordination of the RCs as appropriate. Awardees are expected to plan and budget for an annual meeting either at the NIH or at other venues to discuss progress of their projects.

RC Steering Committee(s) will be established to direct the overall efforts of the RC(s) and the ITPs. The steering committee(s) will be composed at a minimum of PDs/PIs of each of the RC(s) and a NIH Project Scientist serving as the representative of the NIH. The RC(s) Steering Committee(s) will make recommendations related to all aspects of the RC(s) development and function, and will monitor the progress of funded projects. If more than one RC is funded, periodic interactions between the steering committees will be implemented.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. The three members will be: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact CenterTelephone: 800-518-4726
Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-710-0267

Nadya Lumelsky, PhD
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-7703
Email: nadyal@nidcr.nih.gov

Yasaman Shirazi, PhD
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-5593
Email: yasaman.shirazi@nih.gov

Diana Rutberg, MBA
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-4798
Email: rutbergd@mail.nih.gov

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.