It is critical that applicants follow the Research (R) 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 purpose of this FOA is to establish a Data Resource associated with clinical trials in cellular immunotherapy as a component of the Immuno-Oncology Translation Network (IOTN). Projects proposed should focus on establishing an efficient infrastructure to collect and analyze outcomes data of cellular immunotherapy trials (NCI-sponsored, investigator-initiated, or pharmaceutical company-sponsored) or with an FDA-approved agent and facilitating analysis of the observational data for the design of pre-clinical research in the Cancer Immunotherapy Consortium (CIC) and elsewhere, as well as inform design of future trials.

Organization of the Immuno-Oncology Translation Network

Four companion FOAs will support the establishment of the IOTN with the following components:

• Cancer Immunotherapy Consortium (CIC): The CIC will be composed of organ site-specific Cancer Immunotherapy Research Projects (U01, supported by RFA-CA-17-045) and Cancer Immunoprevention Research Projects (U01, supported by RFA-CA-17-046). The CIC will form an integrated network of multi-disciplinary, collaborative teams with the overarching goals of accelerating the development of improved immunotherapeutic strategies capable of eliminating established cancers or preventing cancers before they occur. Approximately, 10-12 U01s are expected to be awarded in FY18.
• Data Management and Resource-Sharing Center (DMRC): The DMRC (one U24 to be supported by FOA, RFA-CA-17-047) will provide overall support, and facilitate collaboration among the adult IOTN-funded components. The DMRC will also promote scientific outreach with other Cancer Moonshot initiatives and the larger scientific community.
• Cellular Immunotherapy Data Resource (CIDR): The CIDR (supported by this FOA, RFA-CA-17-048) will support a data registry for collecting outcomes of patients receiving cellular immunotherapies, that could be utilized for observational studies or inform subsequent pre-clinical studies and clinical trials.

Governance of the IOTN: The IOTN, including DMRC, CIDR, and the Cancer Immunotherapy and Immunoprevention Research Project components will be governed by the IOTN Steering Committee. (see Section VI: Terms and Conditions of Cooperative Agreement.)

The purpose of this specific FOA is to establish a Cellular Immunotherapy Data Resource (CIDR).

NCI convened the Blue Ribbon Panel (BRP) in 2016 to provide recommendations for achieving the Cancer Moonshot's ambitious goal of making a decade's worth of progress in cancer research in 5 years, now called the Beau Biden Cancer MoonshotSM Initiative. The BRP was charged with assessing the state of the science in specific areas and identifying major research opportunities that could uniquely benefit from the support of the Cancer Moonshot and could lead to significant advances in our understanding of cancer and in how to intervene in its initiation and progression. The recommendations focused on areas in which a coordinated effort could profoundly accelerate the pace of progress in the fight against cancer and were not intended to replace existing cancer programs, initiatives, and policies already underway. The BRP final report was approved by the National Cancer Advisory Board and included a recommendation for establishing a translational science network devoted exclusively to discovering and evaluating novel immune-based approaches to treat and prevent adult cancers. Implementation of the IOTN will address this BRP scientific priority.. The 21st Century Cures Act was signed into law in December 2016 dedicating new funds to support efforts associated with the Beau Biden Cancer MoonshotSM Initiative, including support for this FOA.

Cellular immunotherapy is a rapidly evolving field with enormous potential for hematologic malignancies, solid cancers, as well as viral infection-associated malignancies. T cell based adoptive cell therapy (ACT) includes the use of both tumor infiltrating lymphocytes (TILs) extracted from fresh tumor samples and peripheral blood lymphocytes that can be selected and then used either in their natural state or genetically modified.

Cellular product therapies have been used for treating patients with hematologic malignancies after relapse following conventional therapies, but such treatment using T cells in their natural state has seen limited success. On the other hand, recent advances using genetically modified T cells, either through altering the specificity of the T cell receptor (TCR) or through introducing antibody-like recognition via a chimeric antigen receptor (CAR) to direct the T cell against specific antigens on the malignant cell have shown great promise. Autologous T lymphocytes bearing a CAR directed against the B cell antigen CD19 has shown remarkable efficacy for reducing disease burden for B cell acute lymphoblastic leukemia (ALL), and chronic lymphocytic leukemia (CLL). Meanwhile, NY-ESO-1-specific T cell receptor (NY-ESO-1 TCR) engineered T cell therapy have also shown promising clinical responses and impressive benefits in patients with multiple myeloma. In contrast, genetically-directed cell therapies for solid tumors has had limited success and faces unique challenges because of inherent heterogeneity, limited accessibility and an immunosuppressive microenvironment. Recently, TIL therapy has seen remarkable successes for some patients with advanced cancer, particularly metastatic melanoma. Despite current successes, cellular immunotherapy clinical trials are only in the beginning of exploring the potential of ACT, and CAR-redirected T cells in particular, for treating cancer patients.

Success of clinical trials in cellular therapies is tempered by challenging, often life-threatening unique toxicities. An infrastructure to collect and analyze outcomes data across multiple cell therapies, both short and long-term, from multiple academic centers, regardless of their treatment institution or source of cells, has the potential to facilitate research, development, and implementation of these therapies. In fact, although short-term data from current trials are now collected, the Food and Drug Administration (FDA) has indicated requirements for following recipients of genetically modified cells for at least 15 years, to better understand the late effects of these therapies. Although pharmaceutical companies are undertaking pivotal clinical trials in this area, and obtaining rights to manufacture and commercialize cellular products for their trials, there is little incentive for companies to provide a national, centralized database resource to accomplish this mandate. Finally, a resource to aid investigators in the use of this data for observational research studies in cellular therapies, is also an important unmet need.

Overall Goals for the Cellular Immunotherapy Data Resource (CIDR):

Responsive applications must ensure that the CIDR provides the academic community, as well as relevant pharmaceutical partners, with an infrastructure for collection of high quality data, including demographics, primary tumor characteristics, course of cancer treatment, cellular product manufacturing details, adverse events and outcomes, from patients undergoing cellular therapies for treatment of malignancies in either clinical trials (NCI-sponsored, investigator-initiated, or pharmaceutical company-sponsored) or with an FDA-approved agent and indication, using either autologous T or natural killer (NK) cells, cellular vaccines, tumor-infiltrating lymphocytes (TILs) or genetically modified T cells (CARs).

Organization of the Cellular Immunotherapy Data Resource:

The CIDR is expected to focus on providing an infrastructure for data collection and data verification management from cellular therapies across the multiple sources as well as facilitating retrospective observational research studies using CIDR data.

This data resource must ensure/provide all of the following capabilities and functions (but additional relevant aspects should also be considered):

• The electronic process for data collection including the data forms for each of the various steps in a cell therapy procedure, e.g. pre-cellular therapy form, cell infusion form, and post-cellular therapy form, for capturing cell product characteristics, indications for use, clinical status, concomitant therapies, route and schedule of administration, infusion reactions, adverse events, key safety, and efficacy endpoints at key dates;
• Mechanism for payment to centers for forms submission;
• Data quality control procedures, via data validation and data auditing;
• Strategies to collect long-term data (over the 15-year period mandated by the FDA) from patients on genetically modified cellular therapies;
• Mechanisms for aggregation and integration, for management of data from various sources, such as patient clinical baseline and outcomes data from either academic centers or pharmaceutical companies, for purposes of data sharing;
• Work closely with NCI staff to establish common data elements, data standards, metadata requirements, controlled vocabularies, and quality control metrics for all CIDR data to ensure that the data are findable, accessible, interoperable, and reusable (FAIR) to ensure the data and results are maximally useful to the public;
• Integration of data elements construct into a variety of external data systems, including development of an Application Programming Interface (API) to facilitate interactions with other Cancer Moonshot data coordinating centers and components of the Cancer Data Ecosystem;
• Handling proprietary or patented information, blinded data from clinical trials, timelines for release of data for sharing with the scientific community, etc.;
• A web page for access to investigators for data submission forms and other CIDR information;
• A Scientific Working Committee and the procedures for the review, prioritization and implementation of the proposed observational studies requesting use of resource data; and
• Biostatistical support for analysis of the outcomes data and support of Working Committee-vetted observational studies.

The following scientific studies will be encouraged for utilizing CIDR outcomes data:

• Retrospective observational disease-specific studies to examine overall survival trends, toxicities, and other meaningful questions, for instance comparing differing technical directions associated with cell product manufacture;
• Linkage of clinical outcomes data for defined patient subsets, including racial/ethnic minorities, with genomic and immunobiological information to understand outcomes, toxicities, and survivorship issues, and to identify potential mechanisms underlying any observed difference between groups.

Specific Research Examples may include:

• Analysis of baseline and outcomes data from patients undergoing CD19-specific CAR-T cell treatment for B-cell acute lymphoblastic leukemia and/or other B cell malignancies for observational studies related to cellular product variations, toxicities and complications associated with treatment, persistence of the CAR-T cells and efficacy of treatment;
• Analysis of baseline and outcomes data from clinical trials testing neoantigen-specific T cell therapies for melanoma and/or other solid tumors for observational studies on cellular product variations, toxicities of treatment, persistence of T cells, and efficacy of treatment.

Governing and Administrative Structure: The CIDR should have appropriate organizational and managerial structures for the programmatic goals defined above. It is expected that the CIDR will have an overall PD/PI and a Director for the Data Registry and a Senior Biostatistician. In addition, it is anticipated that the CIDR will have an Executive Committee for providing scientific and policy advice to the Chief Scientific Director (the contact PD/PI) and Scientific Working Committee for the review, prioritization and implementation of research studies requesting use of resource data.

Pre-Application Teleconference

A technical assistance teleconference will be held for potential applicants. NIH staff will be available to answer questions related to this FOA. Time, date, and dial-in information for the call will be announced in an NIH Guide Notice.

Applicants are encouraged to reach out to the Scientific/Research Contact listed in Section VII below to ensure appropriate alignment of projects with available funding opportunities.

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

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:

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o 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)
• Eligible Agencies of the Federal Government
• 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).

Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

It is critical that applicants follow the Research (R) 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:

Vikram Devgan, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-6980
Email:vikram.devgan@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 and Other Resources: Applicants must provide evidence that the appropriate resources will be available for the design and implementation of the Data Resource for the CIDR.

Other Attachments: The applicants must provide the additional materials specified below to support their application:

• Attachment 1: Data collection Forms, organized as:
• Table of Contents
• Examples of Data collection forms, if available

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

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

Budgets should include sufficient funds to support travel for PD(s)/PI(s) and other CIDR members to attend an annual IOTN consortium meeting.

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, with the following additional instructions:

Specific Aims: Outline succinctly the overall strategic goals for the CIDR and the plans to achieve these goals.

Research Strategy: Standard sub-sections of Research Strategy are replaced by the new sub-sections A-B.

Sub-section A: CIDR Overview

In this sub-section describe:

• Overview of the composition and function of administrative and scientific bodies of the CIDR, such as an Executive Committee and Scientific Working Committee;
• Overview of the data collection operations proposed for the CIDR; and
• Any current data collection operations in place that provide a framework for the proposed resource.

Sub-section B: Data Registry program

In this sub-section, describe plans to:

• Construct, or optimize as required, appropriate data collection tools required for collection of data for cell therapies, such as pre-cellular therapy, cell infusion, and post-cellular forms for collection at key dates post-infusion, as well as a death form capturing causes of death and both disease-specific and product-specific information forms, for capture of data over at least a 15-year time span post therapy;
• Capture data associated with toxicities unique to cellular therapies, such as cytokine release syndrome;
• Implement or optimize a mechanism for electronic data submission;
• Validate and process data submitted by centers;
• Provide a mechanism for centers to view and download their processed data;
• Provide a mechanism for payment to centers for forms submission;
• Provide a mechanism for analysis and integration of center-specific data for purposes of data sharing;
• Handle proprietary or patented information, blinded data from clinical trials, and timelines for release of data for sharing with the scientific community;
• Construct a web page for general information and for research investigators to obtain data collection forms;
• Prioritize observational research requests for using integrated resource data; and
• Provide biostatistical expertise to investigators or investigator teams for observational research studies selected for further development.

Health Disparities: If applicable to the type of research being proposed, address how minority health or health disparity populations or data will be integrated into the proposed studies. Highlight, as relevant, any opportunities that, if implemented, can reduce the burden of cancer in the health disparities that currently exist. In this context, efforts are encouraged to address the needs of minority health disparity populations and those from urban and rural areas who are poor and medically underserved, who continue to suffer disproportionately from certain cancers and have higher morbidity and mortality rates.

Letters of Support: Letters of Collaboration with planned or current participating sites contributing data, if available, can be provided, and organized as a Table of Contents

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, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
• Addressing the Cancer Moonshot Public Access Pilot Program: Utilizing the provision outlined in the 21st Century Cures Act, NCI has established a data sharing policy for projects that are funded as part of the Beau Biden Cancer MoonshotSM Initiative that requires applicants to submit a Public Access and Data Sharing Plan that: (1) describes their proposed process for making resulting Publications and to the extent possible, the Underlying Primary Data immediately and broadly available to the public; and (2) if applicable, provides a justification to NCI if such sharing is not possible. NCI will give competitive preference and funding priority to applications with a data sharing plan that complies with the strategy described here. The data sharing plan will become a term and condition of award.
• Guiding Principles for Cancer Moonshot Biobanking Activities: The goal in developing these guiding principles is to accelerate research by a) increasing the availability of biospecimens for Cancer Moonshot-related and other biomedical research through facilitation of investigator to investigator sharing of biospecimens, and b) increasing the reproducibility of Cancer Moonshot research through improved biospecimen practices and corresponding annotation. These guiding principles also seek to facilitate, where possible, increased engagement of research participants through researchers' communication of aggregate research results and, in some cases, individual genomic findings that may be medically actionable for research participants. NCI will give competitive preference and funding priority to applications that conform to the "Guiding Principles for Cancer Moonshot Biobanking Activities" (http://biospecimens.cancer.gov/programs/cancermoonshot/principles) and are consistent with the "2016 NCI Best Practices for Biospecimen Resources" (https://biospecimens.cancer.gov/bestpractices/).

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.

It is anticipated that the terms of award will include, but not be limited to, the following:

In carrying out its stewardship of Beau Biden Cancer Moonshot initiatives, the National Cancer Institute (NCI) will monitor and evaluate progress to meet the expectations set forth by Congress in the 21st Century Cures Act.

Investigators will be expected to:

• Leverage, where feasible, technology from related NCI-sponsored informatics initiatives, for example the NCI Informatics Technology for Cancer Research (ITCR) program, which supports the development of informatics algorithms, tools, and resources across the continuum of cancer.
• Coordinate with and leverage, where feasible, the technology of the NCI Cancer Research Data Commons, a program that will provide infrastructure to make diverse cancer research data broadly available and to maximize their reuse and impact (The Next Generation Cancer Knowledge Network).

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 components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Applicants are required to follow the instructions for post-submission materials, as described in the policy.

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 resource 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 resource 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 resource address an important problem or a critical need in the field? Is the scope of activities proposed for the resource appropirate to meet those needs? Will successful completion of the aims bring unique advantages or capabilities to the research community?

Specific to this FOA: How well is the Database resource set up to provide a robust data registry for addressing the needs of the cellular immunotherapy investigator community? How well does the application anticipate the future needs for a data resource in the area of cellular immunotherapies for cancer?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the resource? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated experience and an ongoing record of accomplishments in establishing resource(s)? If the resource 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? Does the applicant has experience overseeing selection and management of subawards, if needed?

Specific to this FOA: How appropriate are the overall leadership of the proposed CIDR and the staff of CIDR operations and management for optimal functioning of the CIDR? Do the members of the team bring complementary and integrated expertise to the Resource?

Does the application propose novel approaches, organizational concepts, management strategies, or technologies? Are the concepts, approaches or technologies novel to one type of research program or applicable in a broad sense? Is a refinement, improvement, or new application of concepts, approaches or technologies proposed?

Specific to this FOA: How innovative are approaches, methodologies, and directions proposed for the collection of cell therapies data from clinical immunotherapy trials in cancer? Are directions and approaches for potential areas of observational research cutting-edge and novel?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the resource? 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 rescource 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: Are the methods for data collection and information technology adequately developed, well-integrated, feasible, and appropriate to the various scientific goals of the Resource? How suitable and well-reasoned are the proposed data submission goals? How appropriate and how well integrated are the data retrieval and data integration processes proposed? Does the application contain acceptable plans for addressing the NCI Cancer Moonshot? Public Access and Data Sharing Policy? How well is the CIDR (as proposed) structured for the optimal prioritization of research problems that can be addressed by observational studies? Are the Scientific Working Committees with associated biostatistical input structured for optimal and efficient consolidation of data and formulation of study proposals? How well-defined, appropriate and efficient are the proposed processes for proposal approval, study completion, and timely publication of the results?

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 institutional environment in which the resource will operate contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the resource proposed? Will the resource benefit from unique features of the institutional environment, infrastructure, personnel or collaborative arrangements?

Specific to this FOA: To what degree is the environment of the CIDR applicant institution(s) conducive to the goals of the CIDR, including enhancing the information technology required for data registry support? To what extent will these environment(s) help respond to the needs of the communities to be served by the Resource?

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 NCI, 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 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 Cancer Advisory Board. 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.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant's integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 "Federal awarding agency review of risk posed by applicants." This provision will apply to all NIH grants and cooperative agreements except fellowships.

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 Part 75, 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 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 PD(s)/PI(s) will have the primary responsibility for:

• Defining objectives and approaches, and to ensure scientific rigor in the planning, conducting, analyzing, and publishing results, interpretations, and conclusions of studies conducted under this program;
• Setting project milestones in consultation with NIH staff, and reporting progress and milestones or objectives to NIH staff;
• Coordinating efforts and cooperating with the other U01 and U24 components of the IOTN and with NIH Institute/Center (IC) Project Scientists. These actions may involve (but will not be limited to) participation in appropriate coordinating meetings and/or working groups, and/or teleconferences as needed;
• In addition to standard annual Research Performance Progress Report (RPPR) submissions, Principal Investigators may be expected to supply additional progress-related information;
• Leveraging, where feasible, technology from related NCI-sponsored informatics initiatives, for example The NCI Informatics Technology for Cancer Research (ITCR) program, which supports the development of informatics algorithms, tools, and resources across the continuum of cancer research;
• Coordinating with and leveraging, where feasible, the technology of The NCI Cancer Research Data Commons, a program that will provide infrastructure to make diverse cancer research data broadly available and to maximize their reuse and impact (cbiit.cancer.gov/ncip/cancer-data-commons);
• Maintaining the confidentiality of the information shared by the IOTN consortium, including, without limitation, unpublished data, protocols, data analysis, confidential exchanges between members of the IOTN consortium, as well as any confidential information received by third party collaborators;
• Annotating samples using Consortium-defined Common Data Elements (CDEs);
• Participating and presenting findings at annual grantee meetings convened by NIH IC Project Scientists through the DMRC;
• Adhering to a Consortium Communication Plan: A consensus Communication Plan will be drafted by the Steering Committee during the Kickoff Meeting of the IOTN Consortium. This plan will clearly spell out interactive requirements that all IOTN Consortium PD(s)/PI(s) are expected to follow, including:
• Participating in regular conference calls and contributing to various sub-committees and working groups;
• Participating and presenting findings at IOTN annual investigator meetings;
• Coordinating efforts with other members of the IOTN consortium;
• Meeting yearly milestones as defined by PD(s)/PI(s) and NIH IC Project Scientists at the time of award;
• Working with, cooperatively interacting with, and actively seeking input from NIH IC Project Scientists;
• Participating in NCI-coordinated evaluation of the IOTN program;
• Coordinating the activities of CIDR organizational components, including the Executive Committee; and
• Establish and maintain a Scientific Working Committee for the review, prioritization and implementation of the proposed observational studies requesting use of the resource.

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. IOTN PD(s)/PI(s) are also encouraged to organize and participate in collaborative activities and scientific or programmatic working groups.

In carrying out its stewardship of Beau Biden Cancer Moonshot initiatives, the NIH Project Scientists will monitor and evaluate progress toward meeting the expectations set forth by Congress in the 21st Century Cures Act. In addition to standard annual Research Performance Progress Report (RPPR) submissions, Principal Investigators may be expected to supply additional progress-related information.

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

In carrying out its stewardship of Beau Biden Cancer Moonshot initiatives, the National Cancer Institute (NCI) will monitor and evaluate progress to meet the expectations set forth by Congress in the 21st Century Cures Act.

NIH IC Project Scientists will be responsible for:

• Coordinating and facilitating interactions among the activities awarded under this initiative;
• Working closely with investigators on research projects to coordinate and facilitate interactions/collaborations between U24 and U01 awardees across the consortium;
• Assisting the awardees as a resource in facilitating their broader interactions with other NCI and NIH programs for leveraging and coordinating existing NIH/NCI resources and infrastructures, such as those within the NCI ITCR program and the NCI Cancer Research Data Commons;
• Assisting in avoiding unwarranted duplication of effort with other NCI efforts;
• Developing working groups and trans-project efforts as needed;
• Monitoring progress and direction of awardees and working groups as needed;
• Organizing and conducting regular meetings to share progress either by teleconference, videoconference, or face-to-face, as needed between the U01 and U24 awardees of the IOTN Consortium; and
• Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

Additional U24 (Resource-Related Research Projects) Specific Responsibility include:

• Meeting annually with other Moonshot U24 coordinating centers to help coordinate the sharing of data, research resources, tools/platforms, and access to newly established biorepositories across the Moonshot initiatives;
• Coordinating, to the extent permitted, the standardization, harmonization and sharing of data and research resources, tools/platforms, including access to newly established biorepositories.

Areas of Joint Responsibility include:

The CIDR will have an Executive Committee as a governing body. This committee will be composed of PD/PI (or PDs/PIs if multiple PD/PI option is used), Senior Administrator, Head of the Data Registry, and NCI Project Officers (Program Director and Project Scientist) for the CIDR. The committee will meet regularly by phone conference to evaluate:

• Status of forms development for data collection, with periodic consideration of revision or addition to data collection forms;
• Status of information technology development;
• Coordination with centers and programs for data collection associated with their cellular immunotherapy trials; and
• Coordination with other aspects and activities of the IOTN program.

A Steering Committee (SC) will serve as the main governing board of the program as described below.

Because a close interaction among the participating PD(s)/PI(s) and NIH staff will be required to develop consortium policies and meet Program goals, the SC will be the principal governing body of the IOTN. The awardee agrees to the role and authority of the SC for governance of IOTN consortium activities.

The SC will be composed of the following voting members:

• One representative from each U01 project award (a PD/PI or their designee) who will have one vote;
• One representative from each U24 (a PD/PI or their designee) who will have one vote;
• A representative of a patient advocacy group who will have one total vote;
• One NIH Project Scientist from each participating IC will have one vote;
• The remaining NIH IC Project Scientists will participate in SC meetings as non-voting members;
• Additional NIH staff members, serving in an advisory capacity, may participate in these meetings as non-voting members; and
• The Chair and co-Chair of the SC will be selected from the representatives of all awardees.

Primary responsibilities of the SC include, but are not limited to, the following activities:

• Attending monthly teleconference meetings;
• Establishing IOTN consortium policies and procedures, guidelines, and agreements;
• Establishing policies and procedures for collaborative projects, and protocols;
• Developing guidelines for the collection and distribution of specimen reference sets for collaborative research;
• All major scientific and policy decisions will be determined by voting policies as established by the SC. Specific activities may include, but are not limited to:
• Developing collaborative protocols;
• Identifying impediments to success and developing strategies to overcome them;
• Developing shared tools for disseminating information about the IOTN consortium;
• Facilitating communication and fostering collaboration across the IOTN consortium;
• Developing publication policies to facilitate collaborations and co-publications by consortium members; and
• Ensuring that the IOTN consortium leverages existing NIH resources and programs;
• NIH Project Scientists involved with the management of the IOTN will help the SC develop and draft sharing and operating policies that are in accordance with NIH guidelines;
• Serving as a nucleus for a broader outreach to the entire extramural immuno-oncology research community;
• Organizing agendas for annual Steering Committee meetings.
• The DMRC (U24) awardee PD(s)/PI(s) will be responsible for arranging annual grantee meetings at locations selected by the SC in consultation with the NCI; and
• The SC may decide to establish sub-committees for specific purposes. The NIH IC Project Scientists will serve on such sub-committees, as they deem appropriate;

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. It will have three members: 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 RPPR, 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.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

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 Center Telephone: 800-518-4726
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

Vikram Devgan, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-6980
Email: vikram.devgan@nih.gov

Referral Officer
National Cancer Institute (NCI)
Telephone: 240-276-6390
Email: ncirefof@dea.nci.nih.gov

Crystal Wolfrey
National Cancer Institute (NCI)
Telephone: 240-276-6277
Email: Crystal.wolfrey@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.