Part I Overview Information

Department of Health and Human Services

Participating Organizations
National Institutes of Health (NIH) (http://www.nih.gov)

Components of Participating Organizations
National Cancer Institute (NCI/NIH) (http://www.nci.nih.gov)

Title: Exfoliated Cells and Circulating DNA in Cancer Detection and Diagnosis(R21)

Announcement Type

This funding opportunity announcement (FOA) is a r eissue of PA-06-423, which was previously released May 18, 2006.

Update: The following update relating to this announcement has been issued:

NOTICE: Applications submitted in response to this Funding Opportunity Announcement (FOA) for Federal assistance must be submitted electronically through Grants.gov (http://www.grants.gov) using the SF424 Research and Related (R&R) forms and the SF424 (R&R) Application Guide.

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 4 weeks prior to the grant submission date. See Section IV.

Program Announcement (PA) Number: PA-06-499


A compatible version of Adobe Reader is required for download. For Assistance downloading this or any Grants.gov application package, please contact Grants.gov Customer Support at http://grants.gov/CustomerSupport.
Catalog of Federal Domestic Assistance Number(s)
93.393, 93.394

Key Dates
Release Date: July 28, 2006
Opening Date: September 1, 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).
Application Submission Date(s): Standard dates apply, please see http://grants.nih.gov/grants/funding/submissionschedule.htm for details.
Peer Review Date(s): Standard dates apply, please see http://grants.nih.gov/grants/funding/submissionschedule.htm for details.
Council Review Date(s): Standard dates apply, please see http://grants.nih.gov/grants/funding/submissionschedule.htm for details.
Earliest Anticipated Start Date(s): Standard dates apply, please see http://grants.nih.gov/grants/funding/submissionschedule.htm for details.
Additional Information To Be Available Date (URL Activation Date): Not applicable.
Expiration Date: July 2, 2009 (now September 8, 2009 per NOT-OD-07-093)
  
Due Dates for E.O. 12372
Not Applicable

Additional Overview Content

Executive Summary

The NCI solicits grant applications aimed at the development of novel technologies for capturing, enriching, and preserving exfoliated abnormal cells from body fluids or effusions as well as methods for concentrating the tumor-derived sub-cellular material for use in biomarker studies.  In body fluids, such as sputum, exfoliated tumor cells are a minor component compared to normal cells. As a result, the detection of exfoliated abnormal cells by routine cytopathology is often limited by the small number of atypical cells present in a given specimen. New enrichment methods are necessary to facilitate the detection of small numbers of exfoliated tumor cells and tumor-derived sub-cellular materials in biological fluids.

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
1. Criteria
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
3. Reporting

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

Section I. Funding Opportunity Description

1. Research Objectives

PURPOSE

The purpose of this Funding Opportunity Announcement (FOA) is to develop novel technologies for capturing, enriching, and preserving exfoliated abnormal tumor cells and macromolecules in body fluids or effusions and to develop methods for concentrating the content of such specimens that originated from tumor or a pre-neoplastic lesion for biomarker studies. In the context of this FOA, the term “exfoliation” denotes not only the whole tumor cells, but also cellular materials, such as DNA and proteins.

In body fluids, such as sputum, the number of exfoliated tumor cells is often small compared to the number of non-neoplastic cells. Because few atypical cells may be present in the specimen, the detection of exfoliated abnormal cells by routine cytopathology is often limited. Another difficulty pertains to separating dysplastic cells from non-specific and degenerating cells.  Furthermore, exfoliated tumor cells and their sub-cellular components are accompanied by normal cells, bacteria, cellular debris, and other interfering matter which make molecular analysis difficult without physical separation of the neoplastic cells. Thus, the development of efficient enrichment methods is necessary to enable the routine detection of small numbers of exfoliated cells and small amounts of cellular materials in biological fluids for molecular analysis.

Enriched abnormal exfoliated cells and biomolecules will enable genomic, proteomic, and epigenomic analyses to detect cancer-specific alterations in expressed genes, protein/peptide profiles, and epigenetic markers. The ability to carry out such enrichment and analyses in a routine way using body fluids may lead to improvements in cancer detection. For example, analysis of tumor markers enriched from urine specimens may facilitate the detection of bladder cancer.

The long-term goal, this initiative is to facilitate the development of panels of well-characterized biomarkers derived from exfoliated cells that can be sampled in the clinical setting. These methodologies will be tested and validated in future population-based clinical trials, and integrated into a comprehensive information system that will be developed under the Early Detection Research Network (EDRN).

NOTE ON SELECTION OF MOST APPROPRIATE FOA:

In addition to this FOA, the “Circulating Cells in Cancer Detection” initiative comprises two other FOAs of identical scientific scope.  Applicants planning projects that have potential for commercializable products or services are encouraged to consider two parallel FOAs of similar scientific scope that solicit applications under the SBIR and STTR mechanisms RFA (RFA-CA-07-027 and RFA-CA-07-028, respectively).  The SBIR/STTR mechanisms are appropriate not only for exploratory (Phase I) projects, but also for further development of technologies/applications for which proofs-of-concept have been achieved (Phase II); or for projects that combine both Phase I and Phase II efforts in one application/award (“Phased Innovation” or “Fast-Track” awards).  

Please refer to the NIH Guide Notice NOT-CA-06-034 (http://grants.nih.gov/grants/guide/notice-files/NOT-CA-06-034.html) for the cross-comparison and the outline of the characteristics and requirements for all three partner FOAs.

BACKGROUND

More than 80 percent of human tumors originate from epithelial cells, often at a mucosal surface, and are clonal in origin (e.g., colon, lung, prostate, oral cavity, esophagus, stomach, uterine cervix, bladder). Their development often becomes apparent when tumor cells exfoliate spontaneously into sputum, urine, or even into various effusions. The molecular and genetic abnormalities within these exfoliated cells could be used to detect and identify precancerous lesions or very early stage cancer if highly sensitive technologies were clinically available to identify the few abnormal cells among millions of normal cells. Polymerase chain reaction (PCR)-allows for the analysis of DNA from rare neoplastic cells in body fluids. For example, detection of widespread microsatellite instability (MSI), monitored as expansion or elimination of marker elements of repetitive DNA may be applicable to exfoliated cells from a variety of tumors. Mutations in cancer relevant genes have been detected using the stools of patients with colorectal cancer (ras), in the urine of patients with bladder cancer (p53), and in the sputum of patients with lung cancer (p53). As these assays are complex and technically challenging, they depend on the development of novel technologies for isolating and enriching cells or subcellular materials/biomolecules of interest.

Abnormal exfoliated cells can be routinely identified by cytological examination of brushings and fluids, for instance, from bronchi, pancreatic ducts, voided urine, and effusions. Currently, fluids are usually processed by centrifugation or membrane filtration. However, the ability to detect abnormal exfoliated cells, including cancer cells, by routine cytopathological examination is limited by the very small number of abnormal cells compared to the number of normal cells. In addition, differences between abnormal and normal cells in terms of cellular and nuclear morphology may be minimal. This situation is common of cytological examinations of urine cytology, in which many low-grade papillary lesions are often missed. New PCR-based methods may substantially enhance detection sensitivity, but current technologies for isolating exfoliated cells and their components tend to be too cumbersome and/or specialized for routine use in the clinic.

The cellular and molecular changes that eventually lead to tumor emergence may be progressing over a number of years in an apparently random manner. The progressive accumulation of genetic and epigenetic aberrations gives rise to precancerous cell populations and, finally, to the clonal selection of subpopulations with the malignant phenotype. The progression of preneoplastic changes to cancer often requires extended time. For example, it takes on average 15 to 20 years for a small adenomatous polyp to become malignant.  Nevertheless, prior to the appearance of a morphologically identifiable precancerous or cancerous lesion, numerous genetic and molecular alterations would have already occurred.  The stochastic nature of molecular events in different cells confers genetic heterogeneity. The resulting abnormalities increase the chances for the selection of aggressive phenotypes but also offer a window of opportunity to detect precancerous and/or early malignant cells based on aberrant status of specific genetic and/or molecular biomarkers associated with the progression of the neoplastic process.

Identification of the neoplastic lesions before they reach advanced stages should increase the chances for a complete eradication of these lesions by allowing an earlier therapeutic intervention.  This principle has been well-demonstrated in cervical neoplasia, in which early detection of dysplastic exfoliated cells can result in a 70 percent or greater reduction in the cervical cancer mortality. For this reason, intensive efforts focus on the identification and characterization of molecular and genetic biomarkers of future malignancy. The small size of precancerous lesions and their cellular and genetic heterogeneity, however, pose significant methodological challenges in the early detection of such abnormalities.

Most importantly, cancer screening assays using biological fluids must be able to detect a small number of abnormal cells/biomolecules among a large number of their normal counterparts. Approaches to detect and analyze precancerous and cancerous cells and their aberrant component in biologic fluids, depend upon: (i) the type of biological fluid (e.g., sputum, bronchial washing cervical brushing, voided urine, etc.); and (ii) the form of analysis to be performed (e.g., cytopathological analysis, morphometric analysis, molecular biomarkers for specific receptors or genetic changes, fluorescence in situ hybridization [FISH]- or PCR-based analyses). All of these approaches require an enrichment of atypical epithelial cells or their respective biomolecules. The cell enrichment methods currently used rely primarily on various centrifugation techniques (e.g., cytospin, density gradient cell fractionation) and/or on antibody-based selection combined with mechanical separation (flow-assisted cell sorting [FACS], magnetic-assisted cell sorting [MACS], etc.). One type of enrichment operation can be sequentially added to another to improve the yield and degree of enrichment. Nonetheless, one needs enrichment factors of 1 to 10,000 or 1 to million to ensure adequate sensitivity and/or specificity required for detecting precancerous cells in body fluids.

Analogous enrichment must be accomplished if abnormal biomolecules derived from preneoplastic and neoplastic cells are to be analyzed. Quite often, stored plasma or serum samples are the only patient biospecimens that are available for analysis. Whereas such samples from normal/healthy individuals typically contain only very small amounts of DNA, increased amounts of extracellular DNA have been found in plasma or serum samples from cancer patients. This circulating DNA appears to correspond to chromatin fragments released into plasma from dying tumor cells. Circulating DNA has been shown to reflect the characteristics of the tumor DNA, including molecular changes, such as methylation, point mutations, and microsatellite instability. Hence, circulating DNA offers a valuable source of biomarkers that can be used for early detection of cancer and during the follow-up of the disease. To utilize this potential, however, technologies need to be developed that would be capable of isolating circulating DNA from typical biospecimens in quantities sufficient for the analysis of biomarkers.

GOALS AND SCOPE

The primary purpose of this initiative is to encourage the development of high-throughput technologies to facilitate the isolation and enrichment of exfoliated cells and subcellular materials. In pursuit of these goals, the NCI solicits R21 applications that are focused on at least one the following areas:

The R21 mechanism is intended to encourage new exploratory and developmental research projects that may involve considerable risk but may lead to a breakthrough in a particular area, or to the development of novel techniques, agents, methodologies, models, or applications that could have a major impact on a field of biomedical, behavioral, or clinical research.

Applications for R21 awards should describe projects distinct from those supported through the traditional R01 mechanism.  For example, long-term projects, or projects designed to increase knowledge in a well-established area, will not be considered for R21 awards.  Applications submitted under this mechanism should be exploratory and novel.  These studies should break new ground or extend previous discoveries toward new directions or applications. 

See Section VIII, Other Information - Required Federal Citations for policies related to this announcement.

Section II. Award Information

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” information 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 two-year award period. 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.

F&A costs requested by consortium participants are not included in the direct cost limitation. See NOT-OD-05-004, November 2, 2004.  

Section III. Eligibility Information

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

Any 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.

Applicants may submit more than one application, provided each application is scientifically distinct.

2. Cost Sharing or Matching

Not applicable. This program does not require cost sharing as defined in the current NIH Grants Policy Statement.

Section IV. Application and Submission Information

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

2) Organizational/Institutional Registration in the eRA Commons

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.

Note: 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, e-mail: GrantsInfo@nih.gov.

Telecommunications for the hearing impaired: TTY 301-451-0088.

2. Content and Form of Application Submission

Prepare all applications using the SF424 (R&R) application forms and in accordance with the SF424 (R&R) Application Guide (MS Word or PDF).

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:

Required 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 Checklist

PHS398 Modular Budget

Optional Components:

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 PHS398 Modular Budget. (Do not use the detailed Research & Related Budget.)

Foreign Organizations

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 and Times

See Section IV.3.A for details.

3.A. Submission, Review, and Anticipated Start Dates

Application Submission Date(s): Standard dates apply, please see http://grants.nih.gov/grants/funding/submissionschedule.htm for details.
Peer Review Date(s): Standard dates apply, please see http://grants.nih.gov/grants/funding/submissionschedule.htm for details.
Council Review Date(s): Standard dates apply, please see http://grants.nih.gov/grants/funding/submissionschedule.htm for details.
Earliest Anticipated Start Date(s): Standard dates apply, please see http://grants.nih.gov/grants/funding/submissionschedule.htm for details.

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 on or after the opening date and must be successfully received by Grants.gov no later than 5:00 p.m. local time (of the applicant institution/organization) on the application submission/receipt date(s). (See Section IV.3.A. for all dates.) If an application is not submitted by the receipt 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 the Authorized Organization Representative/Signing Official (AOR/SO) have two business days to view the application image.

·        If everything is acceptable, no further action is necessary. The application will automatically move forward for processing by the Division of Receipt and Referral, Center for Scientific Review, NIH, after two business days.

·        Prior to the submission deadline, the AOR/SO can “Reject” the assembled application and submit a changed/corrected application within the two day viewing window. This option should be used if the AOR/SO determines that warnings should be addressed. Reminder: warnings do not stop further application processing. If an application submission results in warnings (but no errors) it will automatically move forward after two business days if no action is taken.  Please remember that some warnings may not be applicable or may need to be addressed after application submission.

·        If the two day window falls after the submission deadline, the AOR/SO will have the option to “Reject” the application if, due to an eRA Commons or Grants.gov system issue, the application does not correctly reflect the submitted application package (e.g., some part of the application was lost or didn’t transfer correctly during the submission process). The AOR/SO should first contact the eRA Commons Helpdesk to confirm the system error, document the issue, and determine the best course of action. NIH will not penalize the applicant for an eRA Commons or Grants.gov system issue.

·        If the AOR/SO chooses to “Reject” the image after the submission deadline for a reason other than an eRA Commons or Grants.gov system failure, a changed/corrected application still can be submitted but it will be subject to the NIH late policy guidelines and may not be accepted. The reason for this delay should be explained in the cover letter attachment.

·        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, 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:

Guidelines for Milestones. Milestones should be clearly stated and presented in a quantitative manner, such as numerical specifications of sensitivity and specificity or a count of some desired kind of a specific molecule, etc.  Milestones must summarize the concrete parameters that the applicant expects to accomplish in a verifiable way and in the prescribed time frame, not general long-term potential capabilities of the technology.  Specific aims, as such, may not be regarded as milestones (unless they include appropriate quantitative end points).  In general, it is expected that the applicants provide milestones for each specific aim.

Warning: Please be sure that you observe the direct cost, project period, and page number limitations specified above for this FOA. Application processing may be delayed or the application may be rejected if it does not comply with these requirements.  

Note: While each section of the Research Plan component needs to be uploaded separately as a PDF attachment, applicants are encouraged to construct the Research Plan component 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

Not applicable.

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  http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.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.”

Section V. Application Review Information

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 Process

Applications submitted for this funding opportunity will be assigned to the ICs on the basis of established U.S. Public Health Service (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 NIH 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.

Note 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?

2.A. 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?

2.C. Sharing Research Data

Not applicable.

2.D. 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  http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.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.

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.”
 

3. Anticipated Announcement and Award Dates  

Not Applicable.

Section VI. Award Administration Information

1. Award Notices

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.

If 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 e-mail 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.

3. Reporting

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.

The NCI is developing a policy that will require Clinical Terms of Awards for clinical studies and trials when they are a component of the proposed research. The policy will require that studies be monitored commensurate with the degree of potential risk to study subjects and the complexity of the study. The new policy will be posted in the NIH Guide within a few weeks. All funded applicants will be expected to adhere to the new policy.

Section VII. Agency Contacts

We 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 management issues.

1. Scientific/Research Contacts:

Padma Maruvada, Ph.D.
Division of Cancer Prevention
National Cancer Institute
6130 Executive Boulevard, EPN Room  3144, MSC 7362
Bethesda, MD 20892-7362 (for U.S. Postal Service regular or express mail

Rockville, MD 20852 (for express/courier delivery)
Telephone: (301) 496-3893
Fax: (301) 402-8990
E-mail: maruvadp@mail.nih.gov

Or

Sudhir Srivastava, Ph.D., M.P.H.
Division of Cancer Prevention
National Cancer Institute
Executive Plaza North, EPN 3142, MSC 7362
Bethesda, MD 20892-7362 (for U.S. Postal Service express or regular mail)
Rockville, MD 20852 (for express/courier delivery)
Telephone: (301) 496-3983
Fax: (301) 402-8990
E-mail: ss1a@nih.gov

2. Peer Review Contacts:

Not applicable.

3. Financial or Grants Management Contacts:


Romy Mondesir Reis
Office of Grants Administration
National Cancer Institute
6120 Executive Boulevard, EPS Room 243, MSC 7148
Bethesda, MD  20892-7148
Telephone:  (301) 496-2834
Fax:  (301) 496-8601
E-mail:  reisr@mail.nih.gov

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 (45CFR46) 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 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); 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 (http://publicaccess.nih.gov/publicaccess_manual.htm).

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 Web site (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. For publications listed in the appendix and/or Progress report, internet addresses (URLs) must be used for publicly accessible on-line journal articles.  Unless otherwise specified in this solicitation, Internet addresses (URLs) should not be used to provide any other information necessary for 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 FOA 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 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 NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

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 percent 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.

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices

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