of Health and Human Services
National Institutes of Health (NIH), (http://www.nih.gov)
National Cancer Institute (NCI), (http://www.nci.nih.gov)
Title: Memory T Lymphocytes in
Cancer Immunology (R21)
Update: The following update relating to this announcement has been issued:
APPLICATIONS MAY NOT BE SUBMITTED IN PAPER FORMAT.
This FOA must be read in conjunction with the application guidelines included with this announcement in Grants.gov/Apply for Grants (hereafter called Grants.gov/Apply).
A registration process is necessary before submission and applicants are highly encouraged to start the process at least four weeks prior to the grant submission date. See Section IV.
Program Announcement (PA) Number: PA-06-349
Catalog of Federal Domestic Assistance Number(s)
Release/Posted Date: April 13, 2006
Opening Date: May 2, 2006 (Earliest date an application may be submitted to Grants.gov)
NOTE: On time submission requires that applications be successfully submitted to Grants.gov no later than 5:00 p.m. local time (of the applicant institution/organization).
Letters of Intent Receipt Date(s): Not applicable.
Application Submission Date(s): Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm.
Peer Review Date(s): Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm.
Council Review Date(s): Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm.
Earliest Anticipated Start Date(s): Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm.
Additional Information To Be Available Date (URL Activation Date): Not applicable.
Expiration Date: May 2, 2009 (now May 8, 2009 per NOT-OD-07-093)
Due Dates for E.O. 12372
Additional Overview Content
Table of Contents
Part I Overview Information
Part II Full Text of Announcement
Section I. Funding Opportunity Description
1. Research Objectives
Section II. Award Information
1. Mechanism of Support
2. Funds Available
Section III. Eligibility Information
1. Eligible Applicants
A. Eligible Institutions
B. Eligible Individuals
2. Cost Sharing or Matching
3. Other - Special Eligibility Criteria
Section IV. Application and Submission Information
1. Request Application Information
2. Content and Form of Application Submission
3. Submission Dates and Times
A. Submission, Review, and Anticipated Start Dates
1. Letter of Intent
B. Sending an Application to the NIH
C. Application Processing
4. Intergovernmental Review
5. Funding Restrictions
6. Other Submission Requirements
Section V. Application Review Information
2. Review and Selection Process
A. Additional Review Criteria
B. Additional Review Considerations
C. Sharing Research Data
D. Sharing Research Resources
3. Anticipated Announcement and Award Dates
Section VI. Award Administration Information
1. Award Notices
2. Administrative and National Policy Requirements
Section VII. Agency Contact(s)
1. Scientific/Research Contact(s)
2. Peer Review Contact(s)
3. Financial/Grants Management Contact(s)
Section VIII. Other Information - Required Federal Citations
Part II - Full Text of Announcement
1. Research Objectives
This Funding Opportunity Announcement (FOA) is intended to advance the area of anti-tumor immunity by promoting basic research studies that are focused on memory T lymphocytes, and the cells and molecules with which they interact. The overarching objective is to ultimately improve the prospects for the development and application of vaccines and immunotherapies that can be used to successfully prevent and treat cancers in humans.
Understanding and exploiting the induction of long-lasting antigen-specific T lymphocyte immunity to human tumors is one of the major challenges faced by cancer immunology research. Long-lasting T cell immunity to any antigen requires both an initial primary response to generate specific effector T cells, and the subsequent generation of memory T cells that stay quiescent for a long time but are capable of re-activation upon host re-encounter with the antigen. Memory T cells, like effector T cells, belong to a heterogeneous class of lymphocytes. Memory T cells are defined based on phenotypic and/or functional criteria, although specific definitions vary among different investigators. The relationship between effector and memory T cells is not yet fully understood. The generation of effector cells is a necessary step, but is not sufficient for the induction of long-lasting anti-tumor immunity. Also important are the emergence of memory T cells, their maintenance, and their re-activation upon the re-exposure to antigen. The requirements for steps involving memory T cells may differ from those for the induction of primary effector T cell responses. Given the potential anti-tumor effects, a deeper understanding of the biological processes underlying effective immune memory responses is needed and is worthy of detailed exploration.
There is the particular need to know more about tumor antigens that are capable of initiating memory cell responses, and about the mechanisms that drive T cells into the memory cell differentiation pathway, while overcoming growth inhibitory signals present in the tumor microenvironment. The roles of the cytokines and growth factors in these processes need to be elucidated. It is important to understand how memory cells are maintained in a quiescent state and how they resume proliferation after long dormancy. Such re-activation may be a critical step in response to the re-emergence of tumor growth from residual disease depots.
Recent advances and successes in cancer immunotherapy research and practice are in significant part a derivative of increasing multidisciplinary knowledge and novel technological capabilities at the interface of tumor immunology, biology, and genetics. The progress to date justifies continued and intensified research efforts to understand the fundamental properties of the immune system and to apply that understanding to elicit desirable tumor-directed immune responses. Recognizing the need and timeliness to stimulate research on cancer immunology related to memory T cell generation and their subsequent responses, the National Cancer Institute announces two parallel FOAs of identical overall objectives and scientific scope.
Who should consider this FOA?
Background and Overall Objectives
Antigen presentation to T cells for induction of effective memory immune responses.
Over the last several years, biochemical and genetic screening systems have allowed identification and characterization of candidate antigens and epitopes for a number of tumor types (e.g., melanoma and renal cell carcinoma). These epitopes have been predominantly MHC Class I-restricted and recognized by CD8+ T cells. The identification and characterization of MHC Class II-restricted epitopes recognized by CD4+ T cells has lagged behind, due to greater technical requirements of the antigen-screening strategies for these epitopes. Potential sources of candidate tumor antigens are expanding. Accordingly, efforts are needed to identify antigens derived not only from the dominant clonal tumor cells, but also from tumor stem cells. Another potential source of target antigens is the constellation of non-transformed tumor stromal cells, since these cells may be required for tumor survival and growth. Studies designed to investigate the generation, maintenance, and function of T cell responses to these types of authentic tumor antigens, rather than to highly immunogenic “model” antigens, are therefore very timely and will be necessary to address such critical issues as T cell tolerance to authentic tumor antigens and the potential repertoire of T cells that can recognize authentic tumor antigens.
Because many (or most) authentic tumor antigens are self-antigens, T cell responses to such tumor antigens may be impaired by previous exposure to the antigens in the host. The requirements for developing and optimizing protocols for effective antigen presentation to T cells for memory cell generation may therefore be unique for anti-tumor responses. In addition, recent findings suggest that antigen presentation requirements may be different for effector T cell and memory T cell generation. Studies designed to investigate tumor antigen presentation will necessarily build on what is known for presentation of non-self antigens, but must also address the unique challenges of mounting an effective memory T cell response to these self antigens.
The success or failure of strategies aimed at generating persistent memory T cell responses to authentic tumor antigens is likely to depend on three key strategic choices: (1) the selection of the antigen presenting cell (APC) type, (2) antigen source/form, and (3) the handling of APCs (including approaches to loading APCs with antigen) to optimize their immunogenicity.
1. Type of APC. Hemopoietic dendritic cells (DCs) are now recognized as the most potent class of APC and, therefore, are most likely to be used as APCs. However, DCs are a heterogeneous cell category, with distinct maturation stages and differentiated subsets. Therefore, for reproducible immunotherapy protocols, it needs to be clarified which DC sub-types are effective under various tumor antigen immunization conditions.
2. Antigen source
/form. Available strategic options are
diverse and include: (a) an isolated antigenic peptide; (b) full-length
antigenic protein; (c) cDNA encoding an antigenic protein; (d) cDNA encoding a
fusion protein (containing both an antigenic peptide and additional epitopes to
augment the immune response); (e) mRNA for an antigenic protein; (f) tumor cell
lysates; or (g) killed tumor cells. Each of these strategies has been used in
immunotherapy protocol models and each has its advantages and disadvantages. Further
investigations need to define which of these strategies would be optimal for
inducing memory T cell responses.
3. APC handling. Approaches and procedures to activating the APCs need also to be optimized for memory T cell generation. APCs can be isolated from the host, loaded with tumor antigen in vitro, and then re-administered into the host (adoptive cell transfer). Alternatively, the APCs can be loaded in vivo by injecting the antigen into the host. The in vitro option may provide more flexibility with respect to additional manipulations of the APCs, such as adjuvant treatment to enhance activation and increase their immunogenicity. Conversely, the in vivo option may lead to superior DC trafficking and homing to the relevant lymphoid tissues for initiation of the T cell activation process and memory T cell generation.
Studies of the expanding array of inhibitory signals that affect T cell activation in vivo are also warranted. Some of these signals originate outside of the immune system, such as those from tumor cells or other cells in the tumor microenvironment. Other inhibitory effects arise from the activities of subsets of immune cells, such as CD25+ regulatory T cells or immature DCs. Responding T cells also generate normal intrinsic inhibitory signals, such as those initiated by CTLA-4. Blockade of inhibitory cells and/or signals can be combined with either active anti-tumor immunization or adoptive transfer of in vitro-generated anti-tumor T cells. Impressive results from such combination therapies have been observed in the clinic and in animals. The relationship of these therapeutic successes to successful memory T cell generation may be a key for the design of future cancer immunotherapies.
Generation of tumor-directed T cell memory in vitro for adoptive T cell transfer. Recent successes in the use of in vitro activation followed by in vivo re-infusion of tumor-specific T cells for the treatment of melanoma in humans and in animal models raise the possibility that this strategy may be explored for other tumor types as well. Various parameters requiring optimization for memory T cell generation in vitro correspond directly to those required for active immunization of anti-tumor memory T cell responses in vivo. However, the flexibility in manipulations of T cells in vitro may facilitate generating optimal anti-tumor immunity (including long-lasting memory T cells) that would not be possible with purely in vivo immunization strategies. Memory T cell generation, either in vitro before re-infusion or in vivo in the patient after re-infusion, could ultimately lead to improved immunotherapy. It remains to be determined which of these two strategies would be more efficacious.
Decisions regarding tumor antigen and DC preparation for in vitro T cell activation protocols may be influenced by whether the selected T cell populations to be stimulated and expanded in vitro have previously encountered the target antigen in vivo, and by the nature and outcome of that encounter. The possibility that the most relevant antigen-specific T cells have been deleted, anergized, and/or otherwise incapacitated by normal self-tolerance and/or tumor-induced immunosuppression in vivo will also directly impinge on the in vitro activation strategy. This latter scenario is one in which in vitro activation of T cells may provide opportunities not available with in vivo immunization strategies. For example, flexibility in the source of T cells (e.g., blood, lymph node(s), or tumor-infiltrating cells) to be used for the in vitro activation regimen may facilitate collection and/or enrichment of T cells with desirable activation or re-activation capacities. Purification of T cells for in vitro stimulation would also remove tumor cells from the activation environment. This eliminates the adverse possibility of re-creating of the patient’s own ineffective in vivo anti-tumor T cell priming process. Instead, in the absence of tumor cells, the immune response may be skewed toward desirable memory T cell generation. After the primed T cells of the effector and/or memory sub-types are generated, they are suitable for adaptive cell transfer. However after their re-administration to patients, additional interventions are needed to promote the continued survival and function of the memory cells in vivo. Possible strategies that should be investigated include such cytokine supplementation, periodic boosting with an appropriate antigen-expressing APC population, and elimination or dampening of regulatory cell populations.
Scope of Specific Objectives
The over-arching goal of research applications in response to this FOA should be closing the gaps, outlined in the preceding section, in our existing knowledge of memory T cell function in antitumor immunity. The expected outcomes should be relevant to, and ultimately useful for, improving cancer immunotherapy. Studies on the general properties of immune cells and responses, not clearly directed at cancer immunology, will be considered non-responsive to this FOA.
The proposed research may include investigations of T memory cell differentiation, maintenance, and re-activation. Investigations may entail both human and animal studies, and both in vitro and in vivo models. Innovative uses of existing technologies and reagents, as well as the development of new technologies and reagents, are encouraged.
The following topical areas are of high interest, but other relevant innovative projects are also encouraged.
for policies related to this announcement.
1. Mechanism of Support
This FOA will use the NIH Exploratory/Developmental Research Grant (R21) award mechanism. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project.
This FOA uses just-in-time concepts. It also uses the modular budget formats (see the “Modular Applications and Awards” section of the NIH Grants Policy Statement. Specifically, if you are submitting an application with direct costs in each year of $250,000 or less (excluding consortium Facilities and Administrative [F&A] costs), use the PHS398 Modular Budget component provided in the SF424 (R&R) Application Package and SF424 (R&R) Application Guide (see specifically Section 5.4, “Modular Budget Component,” of the Application Guide).
Exploratory/developmental grant support is for new projects only; competing renewal (formerly “competing continuation”) applications will not be accepted. Up to two resubmissions (formerly “revisions/amendments") of a previously reviewed exploratory/developmental grant application may be submitted. See NOT-OD-03-041, May 7, 2003.
2. Funds Available
Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the NCI provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds and the submission of a sufficient number of meritorious applications.
The total project period for an application submitted in response to this funding opportunity may not exceed 2 years. Although the size of award may vary with the scope of research proposed, it is expected that applications will stay within the budgetary guidelines for an exploratory/developmental project; direct costs are limited to $275,000 over an R21 2-year period, with no more than $200,000 in direct costs allowed in any single year. Applicants may request direct costs in $25,000 modules, up to the total direct costs limitation of $275,000 for the combined 2-year award period. NIH grants policies as described in the NOT-OD-05-004.
1. Eligible Applicants
1.A. Eligible Institutions
You may submit an application(s) if your organization has any of the following characteristics:
1.B. Eligible Individuals
individual with the skills, knowledge, and resources necessary to carry out the
proposed research as the Project Director/Principal Investigator (PD/PI) 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.
2. Cost Sharing or Matching
Not applicable. This program does not require cost sharing as defined in the current NIH Grants Policy Statement.
3. Other-Special Eligibility Criteria
Applicants may submit more than one application, provided each application is scientifically distinct.
To download a SF424
(R&R) Application Package and SF424 (R&R) Application Guide for
completing the SF424 (R&R) forms for this FOA, link to http://www.grants.gov/Apply/ and follow
the directions provided on that Web site.
A one-time registration is required for institutions/organizations at both:
PDs/PIs should work with their institutions/organizations to make sure they are registered in the eRA Commons.
Several additional separate actions are required before an applicant institution/organization can submit an electronic application, as follows:
1) Organizational/Institutional Registration in Grants.gov/Get Started
3) Project Director/Principal Investigator (PD/PI) Registration in the NIH eRA Commons: Refer to the NIH eRA Commons System (COM) Users Guide.
Note that if a PD/PI is also an NIH peer-reviewer with an Individual DUNS and CCR registration, that particular DUNS number and CCR registration are for the individual reviewer only. These are different than any DUNS number and CCR registration used by an applicant organization. Individual DUNS and CCR registration should be used only for the purposes of personal reimbursement and should not be used on any grant applications submitted to the Federal Government.
Several of the steps of the registration process could take 4 weeks or more. Therefore, applicants should immediately check with their business official to determine whether their organization/institution is already registered in both Grants.gov and the Commons. The NIH will accept electronic applications only from organizations that have completed all necessary registrations.
1. Request Application Information
Applicants must download the SF424 (R&R) application forms and SF424 (R&R) Application Guide for this FOA through Grants.gov/Apply.
Only the forms package directly attached to a specific FOA can be used. You
will not be able to use any other SF424 (R&R) forms (e.g., sample forms,
forms from another FOA), although some of the "Attachment" files may
be useable for more than one FOA.
For further assistance, contact GrantsInfo; Telephone: 301-435-0714, Email: GrantsInfo@nih.gov.
Telecommunications for the hearing impaired: TTY 301-451-5936.
2. Content and Form of Application Submission
The SF424 (R&R) Application Guide is critical to submitting a complete and accurate application to NIH. There are fields within the SF424 (R&R) application components that, although not marked as mandatory, are required by NIH (e.g., the “Credential” log-in field of the “Research & Related Senior/Key Person Profile” component must contain the PD/PI’s assigned eRA Commons User ID). Agency-specific instructions for such fields are clearly identified in the Application Guide. For additional information, see “Tips and Tools for Navigating Electronic Submission” on the front page of “Electronic Submission of Grant Applications.”
The SF424 (R&R) application is comprised of data arranged in separate components. Some components are required, others are optional. The forms package associated with this FOA in Grants.gov/APPLY will include all applicable components, required and optional. A completed application in response to this FOA will include the following components:
SF424 (R&R) (Cover component)
Research & Related Project/Performance Site Locations
Research & Related Other Project Information
Research & Related Senior/Key Person
PHS398 Cover Page Supplement
PHS398 Research Plan
PHS398 Modular Budget
PHS398 Cover Letter File
Research & Related Subaward Budget Attachment(s) Form
Note: While both budget components are included in the SF424 (R&R) forms package, the NIH R21 uses ONLY the PHS 398 Modular Budget. (Do not use the detailed Research & Related Budget.)
Several special provisions apply to applications submitted by foreign organizations:
Proposed research should provide special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions in other countries that are not readily available in the United States or that augment existing U.S. resources.
3. Submission Dates
See Section IV.3.A for details.
3.A. Submission, Review, and Anticipated Start Dates
Letter of Intent Receipt Date(s): Not applicable
Application Submission Date(s): http://grants.nih.gov/grants/funding/submissionschedule.htm
Peer Review Date(s): http://grants.nih.gov/grants/funding/submissionschedule.htm
Council Review Date(s): http://grants.nih.gov/grants/funding/submissionschedule.htm
Earliest Anticipated Start Date(s): http://grants.nih.gov/grants/funding/submissionschedule.htm
3.A.1. Letter of Intent
A letter of intent is not required for the funding opportunity.
3.B. Sending an Application to the NIH
To submit an application in response to this FOA, applicants should access this FOA via http://www.grants.gov/Apply and follow steps 1-4. Note: Applications must only be submitted electronically. PAPER APPLICATIONS WILL NOT BE ACCEPTED.
3.C. Application Processing
Applications may be submitted to Grants.gov on or after the opening date and must be submitted no later than 5:00 p.m. local time (of the applicant institution/organization) on the application submission date(s). (See Section IV.3.A. for all dates.) If an application is not submitted by the submission date(s) and time, the application may be delayed in the review process or not reviewed.
Once an application package has been successfully submitted through Grants.gov, any errors have been addressed, and the assembled application has been created in the eRA Commons, the PD/PI and AOR/SO have two business days to view the application image.
Both the AOR/SO and
PD/PI will receive e-mail notifications when the application is rejected or the
application automatically moves forward in the process after two days.
Upon receipt applications will be evaluated for completeness by the Center for Scientific Review (CSR), NIH. Incomplete applications will not be reviewed.
There will be an acknowledgement of receipt of applications from Grants.gov and the Commons. Information related to the assignment of an application to a Scientific Review Group is also in the Commons.
The NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial merit review unless the applicant withdraws the pending application. The NIH will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of an application already reviewed with substantial changes, but such application must include an “Introduction” addressing the previous critique. Note such an application is considered a "resubmission" for the SF424 (R&R).
4. Intergovernmental Review
This initiative is not subject to intergovernmental review.
5. Funding Restrictions
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. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new award if such costs: are necessary to conduct the project, and would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new award.
The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project. See the NIH Grants Policy Statement.
6. Other Submission Requirements
The NIH requires the PD/PI to fill in his/her Commons User ID in the “PROFILE – Project Director/Principal Investigator” section, “Credential” log-in field of the “Research & Related Senior/Key Person Profile” component. The applicant organization must include its DUNS number in its Organization Profile in the eRA Commons. This DUNS number must match the DUNS number provided at CCR registration with Grants.gov. For additional information, see “Tips and Tools for Navigating Electronic Submission” on the front page of “Electronic Submission of Grant Applications.”
Renewal (formerly “competing continuation” or “Type 2”) applications are not permitted.
All application instructions outlined in the SF424 (R&R) application are to be followed, with the following requirements for R21 applications:
Note: While each section of the Research Plan needs to be uploaded separately as a PDF attachment, applicants are encouraged to construct the Research Plan as a single document, separating sections into distinct PDF attachments just before uploading the files. This approach will enable applicants to better monitor formatting requirements such as page limits. All attachments must be provided to NIH in PDF format, filenames must be included with no spaces or special characters, and a .pdf extension must be used.
Plan for Sharing Research Data
Plan for sharing research data is not required for this FOA.
Sharing Research Resources
NIH policy requires that grant awardee recipients make
unique research resources readily available for research purposes to qualified
individuals within the scientific community after publication (see the NIH
Grants Policy Statement at http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm#_Toc54600131).
Investigators responding to this funding opportunity should include a sharing
research resources plan addressing how unique research resources will be shared
or explain why sharing is not possible.
The adequacy of the resources sharing plan and any related data sharing plans will be considered by Program staff of the funding organization when making recommendations about funding applications. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each Non-Competing Grant Progress Report (PHS 2590). See Section VI.3., “Reporting.”
1. Criteria (Update: Enhanced review criteria have been issued for the evaluation of research applications received for potential FY2010 funding and thereafter - see NOT-OD-09-025).
Only the review criteria described below will be considered in the review process.
2. Review and Selection
Applications submitted for this funding opportunity will be assigned to the NIH ICs on the basis of established PHS referral guidelines.
Appropriate scientific review groups convened in accordance with the standard NIH peer review procedures (http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific and technical merit.
As part of the initial merit review, all applications will:
Applications submitted in response to this funding opportunity will compete for available funds with all other recommended applications. The following will be considered in making funding decisions:
The NIH R21 exploratory/developmental grant is a mechanism for supporting novel scientific ideas or new model systems, tools, or technologies that have the potential to significantly advance our knowledge or the status of health-related research. Because the Research Plan is limited to 15 pages, an exploratory/developmental grant application need not have extensive background material or preliminary information as one might normally expect in an R01 application. Accordingly, reviewers will focus their evaluation on the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Reviewers will place less emphasis on methodological details and certain indicators traditionally used in evaluating the scientific merit of R01 applications, including supportive preliminary data. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Preliminary data are not required for R21 applications; however, they may be included if available.
The goals of NIH supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application.
that an application does not need to be strong in all categories to be judged
likely to have major scientific impact and thus deserve a high priority score.
For example, an investigator may propose to carry out important work that by
its nature is not innovative but is essential to move a field forward.
Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge or clinical practice be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?
Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics?
Innovation: Is the project original and innovative? For example: Does the project challenge existing paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area?
Investigators: Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the PD/PI and other researchers? Does the investigative team bring complementary and integrated expertise to the project (if applicable)?
Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support?
Additional Review Criteria:
In addition to the above criteria, the following items will continue to be considered in the determination of scientific merit and the priority score:
Protection of Human Subjects from Research Risk: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. See item 6 of the Research Plan component of the SF424 (R&R).
Inclusion of Women, Minorities and Children in Research: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated. See item 7 of the Research Plan component of the SF424 (R&R).
Care and Use of Vertebrate Animals in Research: If vertebrate animals are to be used in the project, the five items described under item 11 of the Research Plan component of the SF424 (R&R) will be assessed.
Biohazards: If materials or procedures are proposed that are potentially hazardous to research personnel and/or the environment, determine if the proposed protection is adequate.
2.B. Additional Review Considerations
Budget and Period of Support: The reasonableness of the proposed budget and the appropriateness of the requested period of support in relation to the proposed research may be assessed by the reviewers. Is the percent effort listed for the PD/PI appropriate for the work proposed? Is each budget category realistic and justified in terms of the aims and methods?
Sharing Research Data
Sharing Research Resources
NIH policy requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (see the NIH Grants Policy Statement at http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm#_Toc54600131). Investigators responding to this funding opportunity should include a sharing research resources plan addressing how unique research resources will be shared or explain why sharing is not possible.
Program staff will be responsible for the administrative review of the plan for sharing research resources.
adequacy of the resources sharing plan and any related data sharing plans will
be considered by Program staff of the funding organization when making
recommendations about funding applications. The effectiveness of the resource
sharing will be evaluated as part of the administrative review of each Non-Competing Grant
Progress Report (PHS 2590), See Section VI.3.,
3. Anticipated Announcement and Award Dates
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 NIH eRA Commons.
the application is under consideration for funding, NIH will request
"just-in-time" information from the applicant. For details,
applicants may refer to the NIH
Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards,
Subpart A: General.
A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official.
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. See Section IV.5., “Funding Restrictions.”
2. Administrative and National Policy Requirements
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.
When multiple years are involved, awardees will be required to submit the Non-Competing Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.
encourage your inquiries concerning this funding opportunity and welcome the
opportunity to answer questions from potential applicants. Inquiries may fall
into three areas: scientific/research, peer review, and financial or grants
1. Scientific/Research Contacts:
Susan A. McCarthy, Ph.D.
Division of Cancer Biology
National Cancer Institute
6130 Executive Blvd., EPN Room 5058
Bethesda, MD 20892-7380 (for U.S. Postal Service express or regular delivery)
Rockville, MD 20852 (for express/courier delivery)
Telephone: (301) 496-7815
2. Peer Review Contacts:
3. Financial or Grants
Office of Grants Administration
National Cancer Institute
6120 Executive Blvd., EPS Room 243
Bethesda, MD 20892-7148 (for U.S. Postal Service express or regular delivery)
Rockville, MD 20852 (for express/courier delivery)
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Section VIII. Other Information
Required Federal Citations
Use of Animals in Research:
Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf) as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm) as applicable.
Human Subjects Protection:
Federal regulations (45 CFR 46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).
Data and Safety Monitoring Plan:
Data and safety monitoring is required for all types of clinical trials, including physiologic toxicity and dose-finding studies (phase I); efficacy studies (Phase II); and efficacy, effectiveness, and comparative trials (Phase III). Monitoring should be commensurate with risk. The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risks to the participants (“NIH Policy for Data and Safety Monitoring,” NIH Guide for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).
Sharing Research Data:
Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing).
Investigators should seek guidance from their institutions, on issues related to institutional policies and local institutional review board (IRB) rules, as well as local, State, and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score.
Access to Research
Data through the Freedom of Information Act:
The Office of Management and Budget (OMB) Circular A-110 has been revised to provide access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are: (1) first produced in a project that is supported in whole or in part with Federal funds; and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this funding opportunity in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award.
Sharing of Model Organisms:
NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time, the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh-Dole Act (see the NIH Grants Policy Statement. Beginning October 1, 2004, all investigators submitting an NIH application or contract proposal are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.
Inclusion of Women And Minorities in Clinical Research:
It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research” (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the SF424 (R&R) application; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.
Inclusion of Children as Participants in Clinical Research:
The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all clinical research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them.
All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects (http://grants.nih.gov/grants/funding/children/children.htm).
Required Education on the Protection of Human Subject Participants:
NIH policy requires education on the protection of human subject participants for all investigators submitting NIH applications for research involving human subjects and individuals designated as key personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.
Human Embryonic Stem Cells (hESC):
Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov). It is the responsibility of the applicant to provide in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s) to be used in the proposed research. Applications that do not provide this information will be returned without review.
NIH Public Access Policy:
NIH-funded investigators are requested to submit to the NIH manuscript submission (NIHMS) system (http://www.nihms.nih.gov) at PubMed Central (PMC) an electronic version of the author's final manuscript upon acceptance for publication, resulting from research supported in whole or in part with direct costs from NIH. The author's final manuscript is defined as the final version accepted for journal publication, and includes all modifications from the publishing peer review process.
NIH is requesting that authors submit manuscripts resulting from: 1) currently funded NIH research projects; or 2) previously supported NIH research projects if they are accepted for publication on or after May 2, 2005. The NIH Public Access Policy applies to all research grant and career development award mechanisms, cooperative agreements, contracts, Institutional and Individual Ruth L. Kirschstein National Research Service Awards, as well as NIH intramural research studies. The Policy applies to peer-reviewed, original research publications that have been supported in whole or in part with direct costs from NIH, but it does not apply to book chapters, editorials, reviews, or conference proceedings. Publications resulting from non-NIH-supported research projects should not be submitted.
For more information about the Policy or the submission process, please visit the NIH Public Access Policy Web site at http://publicaccess.nih.gov/ and view the Policy or other Resources and Tools, including the Authors' Manual.
Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information," the "Privacy Rule," on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR).
Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.
URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site.
Healthy People 2010:
The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This PA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.
Authority and Regulations
This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. 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 Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.
Loan Repayment Programs:
NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The LRP is an important component of NIH's efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40 hour week) for 2 years to the research. For further information, please see: http://www.lrp.nih.gov.
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NIH Funding Opportunities and Notices
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