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) (http://www.cancer.gov/)

Title: The Biology of Estrogen Receptor-Negative Breast Cancer in Various Racial and Ethnic Groups (U01)

Announcement Type
New

Request For Applications (RFA) Number: RFA-CA-09-026

Catalog of Federal Domestic Assistance Number(s)
93.396

Key Dates
Release Date: August 13, 2009
Letters of Intent Receipt Date: December 5, 2009
Application Receipt Date: January 5, 2010
Peer Review Date: May 2010
Council Review Date: August 2010
Earliest Anticipated Start Date: September 2010
Additional Information To Be Available Date (Url Activation Date): Not Applicable
Expiration Date: January 6, 2010

PRE-APPLICATION MEETING

NCI will hold a pre-application teleconference on Monday, September 28th from 2-3 pm to which all prospective applicants are invited. NCI program and review staff members will make presentations to explain the goals and objectives of this initiative, discuss the application peer review process, and to answer questions from the attendees. An NCI Grants Management Specialist will be available to answer financial questions. Participating in the teleconference is neither required nor necessary for a successful application. It is intended to be an opportunity to clarify the objectives of the initiative.

For update on this pre-application teleconference, please send an email to sathyamn@mail.nih.gov in the first week of September. Updated information will also be available on the Division of Cancer Biology website (http://dcb.nci.nih.gov/).

Due Dates for E.O. 12372

Not Applicable

Additional Overview Content

Executive Summary

• Purpose.The purpose of this funding opportunity announcement (FOA) is to promote the systematic study of the biology of estrogen receptor (ER)-negative human breast cancers, the characterization of their molecular features, the signaling pathways and networks that support their growth, as well as to identify differences in the biology of ER-negative breast tumors among racial and ethnic groups. The information will be crucial in developing early detection and intervention strategies. This initiative will support studies on: the basic biology of ER-negative breast cancers and delineation of differences that exist between ER-positive and ER-negative breast cancers; the identification of the subtypes or heterogeneity that exist within ER-negative breast cancers; and the determination of whether the biology of ER-negative breast tumors differs across racial and ethnic groups. In order to address these goals, the National Cancer Institute (NCI) solicits applications from collaborative teams of interdisciplinary investigators focused on characterizing the biologic drivers, including genetic, epigenetic, molecular, and cellular factors, of ER-negative human breast cancer development and progression.
• Mechanism of Support. This FOA will utilize the NIH U01 cooperative agreement mechanism.
• Funds Available and Anticipated Number of Awards. The NCI expects to commit approximately $10 million for 5 years to fund up to three awards.
• Budget and Project Period. An applicant may request a project period of up to 5 years and a budget (total cost) of up to $667,000 per year.
• Eligible Institutions/Organizations. Institutions/organizations listed in Section III, 1.A. are eligible to apply.
• Eligible Project Directors/Principal Investigators (PDs/PIs). Individuals with the skills, knowledge, and resources necessary to carry out the proposed research are invited to work with their institution/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.
• Number of PDs/PIs. More than one PD/PI (i.e., multiple PDs/PIs) may be designated on the application.
• Number of Applications. Applicant institutions may submit more than one application, provided they are scientifically distinct and are proposed by different research teams (different PD/PIs and key personnel).
• Resubmissions. Resubmission applications are not permitted in response to this FOA.
• Renewals. Renewal applications are not permitted in response to this FOA.
• Special Date(s). This FOA uses non-standard due dates. See Receipt, Review, and Anticipated Start Dates.
• Application Materials. See Section IV.1 for application materials.
• Hearing Impaired. Telecommunications for the hearing impaired are available at: TTY 301-451-5936.

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(s) 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. Address to Request Application Information
2. Content and Form of Application Submission
3. Submission Dates and Times
A. Receipt, Review and Anticipated Start Dates
1. Letter of Intent
B. Sending an Application to the NIH
C. Application Processing
D. Application Assignment
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. Resource Sharing Plan(s)
3. Anticipated Announcement and Award Dates

Section VI. Award Administration Information
1. Award Notices
2. Administrative and National Policy Requirements
A. Cooperative Agreement Terms and Conditions of Award
1. Awardee and Principal Investigator Rights and Responsibilities
2. NIH Responsibilities
3. Collaborative Responsibilities
4. Arbitration Process
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 promote the systematic study of the biology of ER-negative (ER -) human breast cancers, the characterization of their molecular features, and the signaling pathways and networks that support their growth, as well as to identify differences in the biology of ER-negative breast tumors among racial and ethnic groups. The information will be crucial in developing early detection and intervention strategies.

This FOA solicits applications from collaborative teams of interdisciplinary investigators focused on characterizing the biologic drivers, including genetic, epigenetic, molecular, and cellular factors, of ER-negative human breast cancer development and progression.

Specifically, this initiative will support research projects focused on three main areas (which may be combined):

• Basic biology of ER-negative breast cancers and delineation of differences that exist between ER-positive (ER +) and ER - breast cancers;
• Identification of the subtypes or heterogeneity that exist within ER-negative breast cancers; and
• Determination of whether the biology of ER-negative breast tumors differs among racial and ethnic groups.

To be responsive to this FOA, proposed projects must combine the use of human samples as well as models relevant to human breast cancers.

Background

Breast cancer is the most common cancer in women and the second leading cause of cancer death among women in the United States (U.S.). In 2008, the American Cancer Society estimated about 182,460 new cases of breast cancer diagnosed in U.S. women and about 40,480 deaths from the disease. Significant disparities exist with regard to breast cancer incidence and mortality among racial and ethnic groups for which clinical data are available. Specifically, while the incidence of breast cancer in African-American women (AA) is lower than that of non-Hispanic whites (NHW), the overall breast cancer mortality rate is higher among AA.

Breast cancers exhibit heterogeneity at the clinical, microscopic, and molecular level. Breast tumors are staged clinically based on tumor size, presence of nodal metastasis and distant metastasis (TNM classification). An important classification of breast tumors is based on the presence or absence of the estrogen receptor. While the majority of breast cancers are ER-positive, approximately 30% are ER-negative. The presence of the estrogen receptor and the growth factor receptor Her 2 allows oncologists to choose targeted therapy. Patients with ER-positive breast cancer receive hormonal therapy using either tamoxifen or aromatase inhibitors and have a better prognosis. The presence of Her 2 allows the targeting of breast tumors with the HER 2 receptor-specific drugs, herceptin or lapatinib. However, the treatment of patients with tumors that are both ER-negative and Her 2-negative (HER 2 -) is a challenge. Given the lack of targeted therapies, the main options for ER -/HER 2 - breast cancer patients are limited to conventional cytotoxic chemotherapy.

Gene expression profiling has allowed researchers to gain new insights into the cell biology of breast cancers, providing biologically sound and clinically useful classification of tumors that can be used to stratify patients and decide treatment options. This knowledge has enabled the sub classification of breast cancer into five subtypes:

1. Luminal A (ER + /PR +/Her2 -);

2. Luminal B (ER + /PR +/Her2 +);

3. Her2+ (ER - /Her2 +);

4. Basal (ER -/PR -/Her2 -); and

5. Unclassified (ER -/PR -/Her2 -/CK5/6 -/Her1 -) cancers.

In general, the ER-negative tumors are far more aggressive and have a poorer clinical outcome. Among the ER-negative tumors, the basal type exhibits the strongest differential association with race and age.

The elevated mortality rate among AA women may be partially explained by the higher incidence of ER-negative breast tumors in this population relative to NHW. Notably, 45% of pre-menopausal AA women diagnosed with breast cancer have ER-negative breast tumors as compared to 30% in NHW breast cancer patients. ER-negative breast tumors tend to be poorly differentiated and aggressive (with a higher propensity for visceral and brain metastasis). Consequently, these tumors are less amenable to therapy and generally have a poor clinical outcome.

Challenges and New Research Opportunities in ER - Breast Cancer

Given the clinical needs, further efforts are highly warranted to understand better the biological complexity of ER-negative breast tumors and to delineate their unique features. Understanding the biologic basis for this disease will provide a foundation for making substantive advances in minimizing risk, identifying targets, developing preventive and therapeutic interventions for ER-negative breast cancer, and understanding how genetic susceptibility may be influenced by race and ethnicity. Eventually, such efforts may be expected to pave way to targeted therapies aimed at ER-negative cancers.

Research efforts in this area are now facilitated by the availability of clinically annotated archived and/or fresh tumor samples and existing breast cancer cohorts. In addition, recent technological advances in tissue-specific targeting and conditional knockout strategies have allowed the development of novel genetically engineered animal models. Extensive efforts were devoted to comparing the gene expression profiles of mouse mammary tumors and human breast cancers. It has been shown that the molecular biology of mammary tumors derived from mouse models with dysfunctional p53, mutated Brca1 or Brca2, loss of Rb, and expression of T-antigen is similar to that of human basal-like breast cancer. In addition to the novel in vivo models of the disease, there are well-characterized human breast cancer cell lines with the defined status of ER and HER 2 (i.e., ER +, ER , and Her2 +/-). Research on ER-negative breast cancer may also benefit from the recent advances in heterotypic 3-D cultures that may allow researchers to address in vitro specific biological questions that previously required in vivo studies. Furthermore, new technologies that have emerged (such as highly sensitive imaging modalities, high-throughput molecular techniques, and laser capture micro-dissection) enable the molecular analysis of complex samples including tumor, tumor-associated stroma as well as surrounding normal cells.

Specific Research Objectives and Scope of this FOA

This FOA will support studies in the following priority areas: (a) delineate novel mechanisms that uniquely identify ER-negative breast cancer pathways and provide a mechanistic understanding of ER-negative breast cancer; (b) compare the biology of ER-negative tumors in racial and ethnic groups to determine whether there are differences at the molecular or signaling pathways level; (c) identify subtypes or heterogeneity that exist within ER-negative breast cancers. Combined focus on more than one area is allowed and encouraged.

Research projects proposed in response to this FOA must be relevant to ER-negative human breast cancer and should focus on the mentioned priority areas (It is expected that the proposed projects will take advantage of the current availability of unique reagents, experimental models, and recent technological advances (e.g., in imaging technologies, various omics approaches, and other high-throughput methods).

To be responsive to this FOA, proposed projects must combine the use of human samples as well as models relevant to human breast cancers.

Possible research topics include (but are not limited to) the following examples:

• Identifying biomarkers that uniquely differentiate ER +/Her2 + tumors from ER -/Her2 + tumors;
• Identifying key gene sets that are differentially altered in ER-positive and ER-negative tumors (genetic and/or epigenetic alterations);
• Identifying differences in the signaling cascades of ER-negative/Her2- and ER-negative/Her2 + breast tumors;
• Understanding the mechanism(s) of ER-negative tumor progression by identifying signaling pathways that drive the ER-negative phenotype and by characterizing and identifying critical growth regulators for these ER-negative breast cancer cells;
• Characterizing at the molecular level both epithelial and stromal cells in ER-negative tumors using multiple approaches, such as gene expression and/or genetic/epigenetic changes;
• Delineating ER-negative breast cancer subtypes;
• Determining whether the ER-negative phenotype is already evident in premalignant lesions, identifying factor(s) that may predispose premalignant lesions to become ER-negative breast tumors and establishing how early in tumorigenesis can such factors can be detected;
• Identifying and characterizing the progenitor cells that give rise to ER-negative tumors (e.g., are the progenitor cells the same or different for ER -positive and ER-negative tumors?);
• Determining whether estrogen plays an indirect role in ER-negative breast tumors;
• Establishing or optimizing models (e.g., three-dimensional, organotypic, and/or genetic models) to accurately reflect the properties of human ER-negative breast cancer to investigate the biology of ER-negative breast cancer;
• Defining the role of tumor-associated stroma in contributing to ER-negative tumor progression (e.g., compared with ER-positive tumors, how does the microenvironment of ER-negative tumors vary among subtypes and/or racial and ethnic groups?); and
• Determining whether the signaling pathways in ER-negative breast tumors differ among racial and ethnic groups.

Investigators are encouraged to use human tissue samples, complemented with experimental models relevant to ER-negative human breast cancer. In their selection of tumor samples and experimental design, investigators are encouraged to consider addressing the biological basis of the racial and/or ethnic disparity associated with ER-negative breast cancer. Projects proposing to use only animal models or non-human tumor samples would not be responsive to this FOA.

Clinical data pointing to disparities in the context of ER-negative breast cancers are largely limited to AA women. Nonetheless, studies proposed in response to this FOA may include other racial/ethnic minorities if justified by other available clinical data and the availability of appropriate clinical samples. .

Clinical trials with ER-negative breast cancer patients are beyond the scope of this FOA. Proposals for evaluating environmental predictors of ER-negative tumors in population-based studies are also beyond the scope of the FOA.

The NCI anticipates that this program will generate new scientific information on ER-negative human breast tumors, reagents, methods, and other resources that will better inform clinical treatment as well as prevention strategies.

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

Section II. Award Information

1. Mechanism of Support

This funding opportunity will use the NIH U01 cooperative agreement funding mechanism. In the cooperative agreement mechanism, the Project Director/Principal Investigator (PD/PI) retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the Section VI. 2. Administrative Requirements, "Cooperative Agreement Terms and Conditions of Award.

This FOA uses Just-in-Time information concepts. It also uses non-modular budget formats described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/phs398/phs398.html).

2. Funds Available

• NCI expects to commit a total of $2million in FY 2010 for this funding opportunity.
• Up to three awards are anticipated to be made, depending on the availability of funds and the number of meritorious applications.
• The requested total cost amount for individual applications may not exceed $667,000 per year.
• The maximum term of any award will be 5 years.

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 receipt of a sufficient number of meritorious applications.

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.

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

The following organizations/institutions are eligible to apply:

• Public/State Controlled Institutions of Higher Education;
• Private Institutions of Higher Education;
• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education);
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education);
• Small Businesses;
• For-Profit Organizations (Other than Small Businesses);
• State Governments;
• U.S. Territories or Possessions;
• Regional Organizations;
• Eligible Agencies of the Federal Government; and
• Units of Local Governments.

Foreign institutions are not eligible to apply. However, investigators from Foreign institutions may participate (under subcontractual arrangements) on an application submitted by a PI from an eligible institution within the U.S.

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research as the PD/PI is invited to work with his/her institution 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.

More than one PD/PI, or multiple PDs/PIs, may be designated on the application for projects that require a team science approach and therefore clearly do not fit the single-PD/PI model. Additional information on the implementation plans, policies and procedures to formally allow more than one PD/PI on individual research projects is available at http://grants.nih.gov/grants/multi_pi. All PDs/PIs must be registered in the NIH eRA Commons prior to the submission of the application (see http://era.nih.gov/ElectronicReceipt/preparing.htm for instructions).

Although the thrust of this U01 is to encourage multidisciplinary approaches, the decision of whether to apply for a grant with a single PD/PI or multiple PDs/PIs is the responsibility of the investigators and applicant organizations, and should be determined by the scientific goals of the project. Applications for grants with multiple PDs/PIs will require additional information, as outlined in the instructions below. When considering multiple PDs/PIs, please be aware that the structure and governance of the PD/PI leadership team as well as the knowledge, skills and experience of the individual PDs/PIs will be factored into the assessment of the overall scientific merit of the application. Multiple PDs/PIs on a project share the authority and responsibility for leading and directing the project, intellectually and logistically. Each PD/PI is responsible and accountable to the grantee organization, or, as appropriate, to a collaborating organization, for the proper conduct of the project or program, including the submission of required reports. For further information on multiple PDs/PIs, please see http://grants.nih.gov/grants/multi_pi.

2. Cost Sharing or Matching

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

3. Other-Special Eligibility Criteria

Resubmissions. Resubmission applications are not permitted in response to this FOA.

Renewals. Renewal applications are not permitted in response to this FOA.

Number of Applications. Applicant institutions may submit more than one application, provided they are scientifically distinct and are proposed by different research teams (different PD/PIs and key personnel).

Section IV. Application and Submission Information

1. Address to Request Application Information

The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. Applicants must use the currently approved version of the PHS 398. For further assistance, contact GrantsInfo -- Telephone: (301) 710-0267; Email: GrantsInfo@nih.gov.

Telecommunications for the hearing impaired: TTY 301-451-5936.

2. Content and Form of Application Submission

Applications must be prepared using the current PHS 398 research grant application instructions and forms. Applications must have a D&B Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

The title and number of this funding opportunity must be typed in item (box) 2 only of the face page of the application form and the YES box must be checked.

SPECIAL INSTRUCTIONS

Applications with Multiple PDs/PIs

When multiple PD/PIs are proposed, use the Face Page-Continued page to provide items 3a 3h for all PD/PIs. NIH requires one PD/PI be designated as the contact PD/PI for all communications between the PD/PIs and the agency. The contact PD/PI must meet all eligibility requirements for PD/PI status in the same way as other PD/PIs, but has no special roles or responsibilities within the project team beyond those mentioned above. The contact PD/PI may be changed during the project period. The contact PD/PI should be listed in block 3 of Form Page 1 (the Face Page), with all additional PD/PIs listed on Form Page 1-Continued. When inserting the name of the PD/PI in the header of each application page, use the name of the Contact PD/PI, et. al. The contact PD/PI must be from the applicant organization if PD/PIs are from more than one institution.

All individuals designated as PD/PI must be registered in the eRA Commons and must be assigned the PD/PI role in that system (other roles such as SO or IAR will not give the PD/PI the appropriate access to the application records). Each PD/PI must include their respective eRA Commons ID in the eRA Commons User Name field.

All projects proposing Multiple PDs/PIs will be required to include a new section describing the leadership plan approach for the proposed project.

Multiple PD/PI Leadership Plan: For applications designating multiple PDs/PIs, a new section of the research plan, entitled Multiple PD/PI Leadership Plan must be included. A rationale for choosing a multiple PD/PI approach should be described. The governance and organizational structure of the leadership team and the research project should be described, and should include communication plans, process for making decisions on scientific direction, and procedures for resolving conflicts. The roles and administrative, technical, and scientific responsibilities for the project or program should be delineated for the PDs/PIs and other collaborators.

If budget allocation is planned, the distribution of resources to specific components of the project or the individual PDs/PIs should be delineated in the Leadership Plan. In the event of an award, the requested allocations may be reflected in a footnote on the Notice of Award (NoA).

Additional information is available in the PHS 398 grant application instructions.

3. Submission Dates and Times

Applications must be received on or before the receipt date described below (Section IV.3.A). Submission times N/A.

3.A. Receipt, Review, and Anticipated Start Dates
Letters of Intent Receipt Date: December 5, 2009
Application Receipt Date: January 5, 2010
Peer Review Date: May 2010
Council Review Date: August 2010
Earliest Anticipated Start Date: September 2010

3.A.1. Letter of Intent

Prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed research;
• Name(s), address(es), and telephone number(s) of the Principal Investigator(s);
• Names of other key personnel;
• Participating institutions; and
• Number and title of this funding opportunity.

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NCI staff to estimate the potential review workload and plan the review.

The letter of intent is to be sent by the date listed in Section IV.3.A.

The letter of intent should be sent to:

Neeraja Sathyamoorthy, Ph.D.
Division of Cancer Biology
National Cancer Institute
6130 Executive Boulevard, EPN Suite 5000, MSC 7364
Bethesda, MD 20892-7364
Telephone: (301) 435-1878
FAX: 301-480-0864
Email: sathyamn@mail.nih.gov

3.B. Sending an Application to the NIH

Applications must be prepared using the forms found in the PHS 398 instructions for preparing a research grant application. Submit a signed, typewritten original of the application, including the checklist, and three signed photocopies in one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710 (U.S. Postal Service express or regular mail)
Bethesda, MD 20817 (for non-USPS delivery)

Personal deliveries of applications are no longer permitted (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-040.html).

At the time of submission, two additional copies of the application and all copies of the appendix material must be sent to:

Referral Officer
Division of Extramural Activities
National Cancer Institute
6116 Executive Boulevard, Room 8041, MSC 8329
Bethesda, MD 20892-8329 (for U.S. Postal Service regular or express mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: (301) 496-3428
FAX: (301) 402-0275
Email: ncirefof@dea.nci.nih.gov

3.C. Application Processing

Applications must be received on or before the application receipt date described above (Section IV.3.A.). If an application is received after that date, the application may be delayed in the review process or not reviewed. Upon receipt, applications will be evaluated for completeness by the CSR and for responsiveness by the reviewing Institute Incomplete and/or non-responsive applications will not be reviewed.

The NIH will not accept any application in response to this funding opportunity that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to a funding opportunity, it is to be prepared as a NEW application. That is, the application for the funding opportunity must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application.

Information on the status of an application should be checked by the Principal Investigator in the eRA Commons at https://commons.era.nih.gov/commons/.

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. The Grants Policy Statement can be found at 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: 1) are necessary to conduct the project; and 2) 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 at http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part6.htm.)

6. Other Submission Requirements

Applicants should demonstrate in the application their ability to meet:

• Research Objectives and Scope defined in Section I of the FOA;
• Data, Software and Model sharing requirements as outlined in Section IV.6. Other Submission Requirements; and
• Other Investigator responsibilities described in Section VI.2. A Cooperative Agreement Terms and Conditions of Award.
  

Research Plan Page Limitations

The page limit for items 2-5 of the PHS 398 Research Plan is 25 pages.

The applicant should identify clearly in the Project Summary and more fully in the Research Plan the specific questions that will be addressed in order to:

• Fully understand the biological complexity of ER-negative human breast cancer;
• Delineate novel mechanisms that uniquely identify ER-negative breast cancer pathways and provide a mechanistic understanding of the disease;
• Compare the biology of ER-negative tumors in racial and ethnic groups to determine whether there are differences at the molecular or signaling level.

The synergies to be achieved through the establishment of multi-disciplinary teams and novel collaborations should be fully described. It is anticipated that the application projects will be multi-disciplinary and draw on a variety of resources.

ADDITIONAL REQUIREMENTS:

Applicants must budget for travel and per diem expenses for the PI and a senior co-investigator to attend an annual meeting of investigators funded by this FOA.

Appendix Materials

All paper PHS 398 applications must provide appendix material on CD only, and include five identical CDs in the same package with the application (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-031.html).

Do not use the Appendix to circumvent the page limitations of the Research Plan component. An application that does not observe the required page limitations may be delayed in the review process.

Resource Sharing Plan(s)

NIH considers the sharing of unique research resources developed through NIH-sponsored research an important means to enhance the value of, and advance research. When resources have been developed with NIH funds and the associated research findings published or provided to NIH, it is important that they be made readily available for research purposes to qualified individuals within the scientific community. If the final data/resources are not amenable to sharing, this must be explained in Resource Sharing section of the application. See http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm.

(a) Data Sharing Plan: Investigators seeking $500,000 or more in direct costs in any year are expected to include a brief 1-paragraph description of how final research data will be shared, or explain why data-sharing is not possible. Applicants are encouraged to discuss data-sharing plans with their NIH program contact. See Data-Sharing Policy or http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html.

(b) Sharing Model Organisms: Regardless of the amount requested, all applications where the development of model organisms is anticipated are expected to include a description of a specific plan for sharing and distributing unique model organisms and related resources, or state appropriate reasons why such sharing is restricted or not possible. See Sharing Model Organisms Policy and NIH Guide NOT-OD-04-042.

(c) Genome-Wide Association Studies (GWAS): Regardless of the amount requested, applicants seeking funding for a genome-wide association study are expected to provide a plan for submission of GWAS data to the NIH-designated GWAS data repository, or provide an appropriate explanation why submission to the repository is not possible. A genome-wide association study is defined as any study of genetic variation across the entire genome that is designed to identify genetic associations with observable traits (such as blood pressure or weight) or the presence or absence of a disease or condition. For further information see Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088, and http://grants.nih.gov/grants/gwas/.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process.

2. Review and Selection Process

Applications that are complete and responsive to the FOA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the National Cancer Institute and in accordance with NIH peer review procedures (http://grants1.nih.gov/grants/peer/), using the review criteria stated below.

As part of the scientific peer review, all applications will:

• Undergo a selection process in which only those applications deemed to have the highest scientific and technical merit, generally the top half of applications under review, will be discussed and assigned an impact/priority score;
• Receive a written critique; and
• Receive a second level of review by National Cancer Advisory Board.

The following will be considered in making funding decisions:

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

The mission of the NIH is to support science in pursuit of knowledge about the biology and behavior of living systems and to apply that knowledge to extend healthy life and reduce the burdens of illness and disability. As part of this mission, applications submitted to the NIH for grants or cooperative agreements to support biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system. .

U01 Review Criteria as applicable to this FOA are presented below.

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

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

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

In addition, specific to this FOA: Does the project involve a rigorous analysis of ER-negative human breast cancers which will lead to a mechanistic understanding of its biology Will it be able to inform whether biologic differences exist among racial and ethnic groups?

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

In addition, specific to this FOA: Does the applicant team provide full multi-disciplinary expertise needed for the proposed research project?

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

Approach. Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?

In addition, specific to this FOA: Do the investigators have access to clinically annotated ER-negative human breast cancer samples? Do these samples include various racial and ethnic groups?

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

2A. Additional Review Criteria

As applicable for the project proposed, reviewers will consider the following additional items in the determination of scientific and technical merit, but will not give separate scores for these items.

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

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption; 2) human subjects involvement and characteristics; and 3) sources of materials.

Inclusion of Women, Minorities, and Children. When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children.

Vertebrate Animals. The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia.

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

2B. Additional Review Considerations

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

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

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

Resource Sharing Plans: Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan (http://grants.nih/gov/grants/policy/data_sharing/data_sharing_guidance.htm); 2) Sharing Model Organisms (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-04-042.html) and 3) Genome Wide Association Studies (GWAS) (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-088.html)..

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 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 email notification from the awarding component to the grantee business official (designated in item 14 on the Application Face Page). If a grantee is not email enabled, a hard copy of the NoA will be mailed to the 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 also 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 (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part4.htm) and Part II Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part9.htm).

The following Terms and Conditions will be incorporated into the award statement and will be provided to the Principal Investigator as well as to the appropriate institutional official, at the time of award.

2.A. Cooperative Agreement Terms and Conditions of Award

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

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the U01 as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

These Terms and Conditions of Award apply to all individual in the investigators funded by this U01. All the awardee institution(s), principal investigators (PIs/PDs) and other key personnel must agree to collaborate on the goals of this initiative on The Biology of Estrogen Receptor Negative Breast Cancer in Various Racial and Ethnic Groups .

2. A.1. Awardee and Principal Investigator Rights and Responsibilities

The PDs/PIs have primary authority and responsibility to define objectives and approaches, and to plan, conduct, analyze, and publish results of studies conducted under this program. The PDs/PIs assume responsibility and accountability to the applicant organization officials and to the NCI for the performance and proper conduct of the research supported by the U01 in accordance with these terms and conditions of the award.

Specific rights and responsibilities of the U01 awardees will include the following:

• The PD(s)/PI(s) for each U01 award will have the primary authority and responsibility for the project as a whole, including defining the research objectives, conducting specific studies, analysis and interpretation of research data, and preparation of publications;
• Representatives of each U01 award will be expected to work with the NCI Project Scientist on the coordination of research program activities. These actions may involve (but will not be limited to) the participation in the appropriate meetings and/or working groups, and/or teleconferences as needed;
• One PD/PI and a co-investigator from each funded U01 projects will participate in the annual consortium meeting ;
• In addition to providing standard annual progress reports (see Section VI.3. Reporting), each U01 awardee will be responsible for providing other relevant information to the NCI Project Scientist, and coordinate and cooperate with NCI staff and other members of the Program; and
• Each U01 awardee will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.
• Principal Investigators will be responsible for adhering to the data and resource sharing plans and policies. The awardees are expected to make data, software and models that they develop under their U01 award, available to other U01 awardees and to the general research community.

2. A.2. NIH Responsibilities

A designated NCI Program Director, acting as a Project Scientist/Coordinator, will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below. Additional NCI Program Directors may also become substantially involved (as Project Scientists/Coordinators).

The main NCI responsibilities include the following activities. Specifically, the NCI Project Scientists/Coordinators will:

• Coordinate and facilitate the interactions among the U01 awardees under this initiative;
• Serve as liaison between the research awardees and NCI staff members and investigators involved in the program, facilitating interactions and scientific integration between the U01 awardees;
• Promote and help coordinate collaborative research efforts that involve interactions with other NCI-sponsored programs, projects, and centers;
• Participate in program meetings;
• Review all major transitional changes that the awardees might propose (e.g., a change in partnering institution) and advice on their appropriateness prior to implementation to assure consistency with the goals of this FOA;
• Provide technical assistance and advice to the awardees as appropriate;
• Assist in the interaction between the U01 awardees and investigators at other institutions, as appropriate for the program;
• Assist in avoiding unwarranted duplication of effort with other NIH initiatives;
• Monitor institutional commitments and resources available to the awardees;
• Suggest reprogramming efforts, including options to modify projects/programs when certain objectives of this FOA are not met. Specifically, the NCI Project Scientist may recommend withholding of support, suspension, or termination of a U01 award for lack of adherence to required policies and/or procedures;
• Develop working groups and trans-project efforts as needed; and
• Organize and conduct regular meetings to share progress either by teleconference, videoconference, or face-to-face, as needed between the awardees.
• Review the scientific progress of individual U01 grants.

The NCI Project Scientist and other substantially involved NIH staff members will not attend peer review meetings of renewal (competing continuation) and/or supplemental applications. If such participation is essential, these individuals will seek NCI waiver according to the NCI procedures for management of conflict of interest.

Additionally, an NCI Program Director acting as the Program Official will be responsible for the normal scientific and programmatic stewardship of the awards and will be named in the award notice. A Program Official may also have substantial programmatic involvement (e.g., as a Project Scientist). In that case, the individual involved will not attend peer review meetings of renewal (competing continuation) and/or supplemental applications, or will seek NCI waiver.

2.A.3. Collaborative Responsibilities

The NCI Project Scientist and the PDs/PIs of the U01 awards funded under this FOA will be jointly responsible for the coordination of intra-program activities and the scientific integration across individual projects.

The NCI Project Scientist and PDs/PIs will organize and attend an annual meeting of the awardees of this initiative.

2.A.4. Dispute Resolution

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

3. Reporting

When multiple years are involved, awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and Financial Status Report are required when an award is relinquished when a recipient changes institutions or when an award is terminated. The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

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

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 Contact:

Neeraja Sathyamoorthy, Ph.D.
Division of Cancer Biology
National Cancer Institute
6130 Executive Boulevard, EPN Suite 5000, MSC 7364
Bethesda, MD 20892-7364
Telephone: (301) 435-1878
FAX: 301-480-0864
Email: sathyamn@mail.nih.gov

2. Peer Review Contact:

Referral Officer
Division of Extramural Activities
National Cancer Institute
6116 Executive Boulevard, Room 8041, MSC 8329
Bethesda, MD 20892-8329 (for U.S. Postal Service regular or express mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: (301) 496-3428
FAX: (301) 402-0275
Email: ncirefof@dea.nci.nih.gov

3. Financial or Grants Management Contact:

Kent Hevner
Grants Management Specialist
National Cancer Institute
Fairview Center Building, Suite 300
1003 West 7th Street
Frederick, MD 21701-4106
Phone: (301) 846-1016
Fax: (301) 451-5391
E-mail: kent@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 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 http://grants.nih.gov/grants/policy/nihgps_2003/index.htm). All investigators submitting an NIH application or contract proposal, beginning with the October 1, 2004 receipt date, 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 new PHS Form 398; 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 and 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 and 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.

NIH Public Access Policy Requirement:
In accordance with the NIH Public Access Policy (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-033.html) investigators must submit or have submitted on their behalf their final, peer--reviewed manuscripts that arise from NIH funds and are accepted for publication as of April 7, 2008 to PubMed Central (http://www.pubmedcentral.nih.gov/), to be made publicly available no later than 12 months after publication. As of May 27, 2008, investigators must include the PubMed Central reference number when citing an article in NIH applications, proposals, and progress reports that fall under the policy, and was authored or co-authored by the investigator or arose from the investigator’s NIH award. For more information, see the Public Access webpage at http://publicaccess.nih.gov/.

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. 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. 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% of their time (at least 20 hours per week based on a 40 hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov.