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: Limited Competition: Cooperative Family Registry for Epidemiologic Studies in Colon Cancer (C-CFR)(U24)

Announcement Type
This is a reissue of RFA-CA-02-501,which was released on August 29, 2001.

Request For Applications (RFA) Number: RFA-CA-08-502

Catalog of Federal Domestic Assistance Number(s)
93.393

Key Dates
Release Date: October 18, 2007
Letters of Intent Receipt Date: December 10, 2007
Application Receipt Date: January 10, 2008
Peer Review Date(s): February/March 2008
Council Review Date: October 2008
Earliest Anticipated Start Date: September 2008
Additional Information To Be Available Date (URL Activation Date): Not Applicable.
Expiration Date: January 11, 2008

Due Dates for E.O. 12372

Not Applicable

Additional Overview Content

Executive Summary

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 and 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
A. Cooperative Agreement Terms and Conditions of Award
1. 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 National Cancer Institute (NCI) requests limited competition applications from the current participating institutions of the Colon Cancer Family Registry (C-CFR). The applicants are expected to propose the continued support and restructuring of the six core activities (referred to as Cores ) constituting this infrastructure: Recruitment; Molecular Characterization; Follow-up and Clinical Data; Biospecimen; Data Management and Informatics; and Administrative and Coordination. Through this FOA, the NCI invites competing continuation applications for the support of the C-CFR infrastructure using the NIH U24 cooperative agreement mechanism.

Background

The C-CFR is an international consortium of six registries and an Informatics Support Center (ISC, separately funded). This consortium, which involves recruitment by more than 23 institutions in three countries (United States, Canada, and Australia), is now dedicated to establishing a comprehensive collaborative infrastructure for interdisciplinary studies in the genetics, epigenetics, and epidemiology of colorectal cancer (CRC). This scope encompasses studies of descriptive epidemiology, familial aggregation, familial risks and segregation analyses, mapping of new CRC genes (linkage and genome-wide association studies, including fine mapping of regions identified in linkage and association studies), gene characterization of the mismatch repair (MMR) genes and other genes as they are identified), as well as gene-gene and gene-environment interactions, behavioral research, molecular pathology, screening, and clinical outcomes.

The C-CFR awards are not intended to support research directly, but rather to create and maintain an infrastructure promoting hypothesis-driven research. This goal is realized through the specific Core activities listed above. During the current funding period, the awardees were also required to: a) develop a strong hypothesis-driven strategic research vision to guide the establishment and development of the infrastructure capable of addressing unique scientific questions pertinent to individuals at high risk of colon cancer; b) to perform pilot and feasibility studies; and c) cooperate with the NCI to enable further research and access to the data and samples collected from the participating families to the scientific community at large.

To date the C-CFR has established a unique and valuable resource for a wide variety of studies on the etiology and prevention of CRC. A total of 12,249 families are currently enrolled in the C-CFR, of which 293 are African American and 167 Japanese American. Currently, the accrual of data and specimens from Hispanic American and other minority groups is also proceeding. To date, approximately 34,600 epidemiology questionnaires have been completed and 21,564 blood samples have been provided by CFR participants. Tissue specimens were collected from 7,589 separate primary tumors (i.e., one per patient) for which 6,755 informative results for mismatch gene function or expression are available. Follow-up of all participants, now currently at 26,257 individuals, is ongoing. Registry-wide collection of tumor specimens and their characterizations for tumor microsatellite instability (MSI), as well as immunohistochemistry testing, have been completed on over 4,700 individuals. The results of tumor testing are utilized to assay for germline gene mutations in mutS homolog 2 (MSH2), mutL homolog 1 (MLH1), and mutS homolog 6 (MSH6) in selected participants. Testing for deleterious mutations in mismatch repair (MMR) genes has been completed for over 1,700 individuals and MLH1 methylation assays have also been performed on approximately 1700 individuals. As part of a pilot project, more than 270 fresh-frozen tissue specimens (i.e., one tumor per patient) have been collected to date.

A key objective of the C-CFR has been to collect, process, and store high quality biospecimens using standardized protocols and procedures, and to make these specimens available to outside researchers. The C-CFR biospecimen repository is comprised of samples derived from blood, archival tissues, and fresh tissues that are stored at all six collaborative sites. The C-CFR established a minimum standard for the collection, processing, storage, and distribution of these specimens. The C-CFR has to date collected, processed, and stored in excess of 1.5 million biospecimens and their products across its six participating sites. In addition, the C-CFR has developed a three-tier data-sharing plan that was approved by the NCI Executive Committee Subcommittee on C-CFR data sharing.

The C-CFR is a unique infrastructure, and there are no comparable initiatives to support interdisciplinary research in colon cancer currently funded by NCI. The world’s largest collection of CRC clinic- and population-based families, complete with epidemiologic data, biospecimens, and tumor tissues, has been assembled in an international collaborative environment. To clarify, the population-based families are contacted through the cancer registry, whereas the clinic-based families are recruited through the high-risk clinics. A thorough search for genetic, epigenetic, environmental, and other causes is being conducted for this disease. C-CFR investigators have participated in numerous projects with other researchers from around the world and have initiated C-CFR projects with new collaborators, including a number of young and promising investigators. However, the C-CFR infrastructure will be of even greater research potential, with follow-up data on the original C-CFR families, a sizable number of identified gene mutation carriers, new enrollments of members of minority populations, and easy access to quality biospecimens and data from all centers.

Specific Objectives

It is imperative that C-CFR remains as the unique resource available to continue support for more than 160 projects currently relying on it. As the C-CFR-based dynamic research agenda continues to advance, the current Core Activities will need to expand in order to respond to new opportunities, technologies, and innovative research questions. To do so, the applicants must implement the following recommended restructuring of the core activities:

Recruitment Core. This Core activity should focus on two distinct populations, high risk individuals and their families and type X families (which are defined below). The number of samples representing MMR carriers needs to be increased to enable informative analyses such as: (1) environmental/lifestyle cancer risk factors among MMR mutation carriers; (2) genetic modifiers of risk; (3) gender differences in penetrance; (4) heterogeneity of risk by specific MMR gene that is mutated; and (5) risk of other cancers, besides CRC (e.g., endometrial cancer). To date, the C-CFR has the largest number of MMR mutation carriers recruited into a single resource, identified through a standardized mutation testing protocol, with additional data derived from risk factor questionnaires and biospecimens all administered/collected according to standardized protocols. However, these are not enough for an informative cohort study. The C-CFR is in a very strong position to increase the number of carriers, using its well established laboratory and data collection protocols. In addition, the C-CFR investigators were the first to identify Type X families, who meet the Amsterdam criteria but who do not have evidence of an MMR defect. These Type X families have an increased risk of CRC but do not have an increased risk of other HNPCC-associated cancers. Research focusing on these families has important implications for their clinical management and also suggests that the underlying genetic cause(s) of CRC in Type X families are not the MMR gene defects (or at least not those identified to date). Therefore, the applicants should propose plans and approaches to increase the recruitment of Type X families in the C-CFR to allow researchers to better understand the cancer risk and to map the gene(s) responsible for CRC in these families.

Retention, Follow-up and Clinical Data Core. Theoretical models suggest that the average increase in CRC risk among first-degree relatives of CRC patients (approximately two-fold) is due to considerable variation in each individual’s personal cancer risk. Thus, it seems likely that there is a wide distribution in familial/genetic risk across this population. The C-CFR resources are extremely important for clarifying the complex interactions between genetic, epigenetic, and environmental factors that contribute to colorectal carcinogenesis among persons with increased familial/genetic risk. This group of individuals has been studied much less extensively in previous epidemiological research, which has focused on "representative" samples and hence studied the women and men who are mostly at inherently low risk. For example, the existence of gene-environment interactions implies that individuals with increased genetic predispositions are more sensitive to certain environmental exposures, defined broadly to include medical, demographic, behavioral, and other characteristics. If this paradigm is true, the C-CFR cohort, which is enriched for individuals at increased familial/genetic risk and for which there is extensive data on potential environmental factors, will be extremely informative for studies of environmental risk factors for CRC. The retention of current and newly enrolled participants and their prospective follow up for update of exposure data and re-bleeding (i.e., additional blood collections) are crucial to support such research. In addition, to facilitate more extensive translational research, additional clinical data need be systematically collected for all probands and affected relatives enrolled during Phase II and III of any associated clinical trials, including CRC stage, treatment (chemotherapy, radiation, surgery), surveillance, and outcomes. These data will afford novel clinicopathologic studies of genetic and epigenetic factors associated with CRC stage, treatment response, and prognosis, while also providing the framework for future investigations of CRC outcomes within minority populations, standardization of postoperative surveillance strategies, evaluation of predictive markers for recurrent disease, and resource utilization patterns across different healthcare systems.

Biospecimen Collection, Processing and Storage Core. A key objective of the C-CFR has been to collect process and store high quality biospecimens using standardized protocols and procedures, and to make these specimens available to outside researchers. Blood products, DNA, transformed lymphoblastoid cell lines, paraffin-embedded tissues, and a limited selection of fresh-frozen tissues all linked to the patients data is available for research projects. Opportunities to access large cohorts of carefully collected and well-characterized samples are rare. Investigators are responsive to the benefits of the C-CFR biorepository, with many new collaborative projects being undertaken that involve the use of the biospecimens. This success has presented the biospecimen repository with several new challenges, including protecting against the depletion of DNA reserves and meeting the considerable time and resource commitment involved in accessing, tracking, and distributing biospecimens. While the storage and processing of biospecimen for distribution will be centralized through a concomitant contract, the biospecimen core will support back-up repositories and biotracking at the local level (in cooperation with the C-CFR Informatics Center and the Centralized Repository), as well as collection and processing of new recruits biosamples, follow-up biospecimen collection, digitization of tissue slides for the Informatics Center Virtual Tissue Repository (VTR), and shipment of specimens to the centralized repository for processing and management.

Molecular Characterization Core. Microsatellite instability (MSI) testing of the enrolled African-American and Japanese participants will be needed to estimate the prevalence of MSI-high, MSI-low, and MS-stable tumors in those groups that are not well characterized in this regard. Some of these tests, which include immunohistochemical assays for the presence of MMR proteins and MSI (as reflected by mutations in the MMR gene MLH1), will be continued to completion. BRAF (v-raf murine sarcoma viral oncogene homolog B1) gene testing will also be implemented as a marker for CpG Island Methylator Phenotype (CIMP). These measures will constitute important covariates for the ongoing and future etiologic and clinical studies based on the C-CFR, and will provide the tool to disentangle colon cancer heterogeneity. The aims of the molecular characterization core are to provide baseline biodata on C-CFR specimens and participants, driven not by hypotheses, but by the growing understanding of the several distinct pathways leading to colorectal carcinogenesis.

Data Management and Informatics Core. The aim of this Core is to support the collection, management, and analysis of a tremendous number of data items including family history data, epidemiology data, follow-up data, pathology data, clinical outcomes data, diet data, biospecimen collection, storage, dispatching, and performing molecular characterization testing. Indeed, the total number exceeds tens of thousands of data items per case. Complex, robust, and intelligent data entities will be essential for the work of the C-CFR. This Core, which supports the local databases and interfaces with the C-CFR Informatics Center (to be separately funded), will continue to contribute to the success of all Cores and the implementation of all the C-CFR-based research. The core will also support harmonization and compliance with the NCI cancer Biomedical Informatics Grid (caBIG, http://cabig.cancer.gov/index.asp) specifications. Each C-CFR center will maintain their local database, collaborate on data-related protocols with the centralized Informatics Center, and transmit high quality data to it on a regular schedule. In addition, web-based interfaces with participants will be pilot-tested and implemented if demonstrated to represent a substantial improvement over existing subject interfaces. This core also supports the site-specific expenses related to public access to data through the Informatics Center.

Administration and Coordination Core. The C-CFR is the largest study of CRC-affected cases, relatives, and control subjects in the world. The work is conducted in multiple institutions in several states of the U.S. as well as in Australia and Canada. External collaborators can be from anywhere in the world. There are a variety of common C-CFR administrative tasks that are complicated by the sheer size, variety, and complexity of the organization. This core will support the internal coordination of the registry activities, the outreach effort to the scientific community and the travel for C-CFR-related purposes.

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

Section II. Award Information.

1. Mechanism(s) of Support

This FOA will use the NIH U24 cooperative agreement mechanism.

As an applicant, you will be solely responsible for planning, directing, and executing the proposed project.

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 PD/PI, as described under the Section VI. 2. Administrative Requirements, "Cooperative Agreement Terms and Conditions of Award."

This funding opportunity uses the just-in-time budget concepts. It also uses the non-modular budget format described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/phs398/phs398.html). A detailed categorical budget for the "Initial Budget Period" and the "Entire Proposed Period of Support" is to be submitted with the application.

2. Funds Available

The NCI intends to commit $32 million (total cost) over a project period of 4 years to fund up to six awards, depending on the merits of the submitted competing continuation applications.

An applicant may request a project period of up to 4 years.

Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size 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.

Facilities and administrative (F&A) costs requested by consortium participants are not included in the direct cost limitation, see NOT-OD-05-004.

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

Only those organizations funded under RFA-CA-02-501, are eligible to apply.

1.B. Eligible Individuals

Individuals with 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.

2. Cost Sharing or Matching

Cost sharing is not required.

The current Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/nihgps_2003/nihgps_Part2.htm#matching_or_cost_sharing.

3. Other-Special Eligibility Criteria

Applicants may only submit one application each.

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 on line 2 of the face page of the application form and the YES box must be checked.

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

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

Submission times: Not applicable.

3.A. Receipt, Review and Anticipated Start Dates
Letters of Intent Receipt Date: December 10, 2007
Application Receipt Date: January 10, 2008
Peer Review Date(s): February/March 2008
Council Review Date: October 2008
Earliest Anticipated Start Date: September 2008

3.A.1. Letter of Intent

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

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 members to estimate the potential review workload and plan the review.

The letter of intent is to be sent by the date listed at the beginning of this document.

The letter of intent should be sent to:

Dr. Daniela Seminara
Division of Cancer Control and Population Sciences
National Cancer Institute
National Institutes of Health
6130 Executive Boulevard, EPN Room 5142, MSC 7393
Bethesda, MD 20892-7393 (for U.S. Postal Service express or regular mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: (301) 594-7347
Email: seminard@mail.nih.gov

3.B. Sending an Application to the NIH.

Applications must be prepared using the research grant applications 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 (for 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 paper copies of the application and one copy of the appendix material in paper or pdf format must be sent to the address below (NCI encourages submission of Appendix materials in pdf format on a CD):

Referral Officer
Division of Extramural Activities
National Cancer Institute
6116 Executive Boulevard, Room 8062, MSC 8239
Bethesda MD 20892-8329 (for U.S. Postal Service express or regular mail)
Rockville, MD 20852 (for non-USPS delivery)
Bethesda MD 20892-8239
Telephone: (301) 496-3428
FAX: (301) 402-0275

Using the RFA Label: The RFA label available in the PHS 398 application instructions must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at http://grants.nih.gov/grants/funding/phs398/labels.pdf.

3.C. Application Processing

Applications must be received on or before the application receipt date(s) described above (Section IV.3.A.). If an application is received after that date, it will be returned to the applicant without review. Upon receipt, applications will be evaluated for completeness by the CSR and responsiveness by the NCI. Incomplete and 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 http://grants.nih.gov/grants/policy/policy.htm.

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 or competing continuation 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 or competing continuation 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.

The renewal application must include a section that addresses the progress made during the previous funding period as related to the goals mandated by the previous Colon CFR RFA (CA-02-501) under which the applicants are currently funded. In addition, the following materials, common to all the applicants, should be made available to the reviewers:

A Collaborative Report Component including:

a) An outline of the broad, interdisciplinary research agenda in the genetic and molecular epidemiology of cancer underpinning the C-CFR proposed core activities; and

b) A comprehensive report of the C-CFR collaborative activities to date, including a description of the development of the registry administrative and operational infrastructure, current, descriptive epidemiologic data on the overall registry, data on accrual of family history, epidemiologic and clinical data and biological specimens, status of data transmission to the central database, brief description of ancillary and collaborative projects (with internal and external investigators) currently using the C-CFR resources, publications, and any other pertinent information concerning the collaborative establishment of the C-CFR research infrastructure and its success in serving the scientific community.

This component should not exceed 30 pages.

Plan for Sharing Research Data

All applicants are expected to include a plan for sharing research data in their application. The data sharing policy is available at http://grants.nih.gov/grants/policy/data_sharing. All investigators responding to this funding opportunity are expected to agree to adhere to the following three-tier data sharing structure for the C-CFR, which incorporates the requirements of current NCI and NIH policies.

As the overall C-CFR database is composed of a gradually increasing number of relational modules, these different stages are made operational as soon as the data are ready for each level. Investigators should transmit high-quality anonymized data on a quarterly basis to the C-CFR Informatics Center, according to an agreed upon timely schedule. Data will be shared with the research community at large, according to their availability, through the three tier process described below. This policy has been adapted through the years to meet new NIH and NCI requirements and will continue to evolve to respond to new published NCI guidelines.

These guidelines and processes are subject to change to reflect future NIH/NCI policies concerning data and biospecimen sharing.

The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score.

Sharing Research Resources

NIH policy expects that grant recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (see the NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2003/index.htm and at http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.htm#_Toc54600131). Investigators responding to this funding opportunity should include a plan for sharing research resources addressing how unique research resources, such as biospecimen, will be shared or explain why sharing is not possible. The investigators will also agree to provide their biospecimen (blood, blood products, and immortalized cell lines) to a split centralized repository separately funded by NCI, retaining an aliquot locally for back up. The contractor for the centralized repository will provide biospecimen management, processing and tracking in cooperation with the C-CFR Informatics Center and participating site. Ownership of the biospecimens will reside with the individual awardees institutions. The local and centralized biorepositories should comply with the NIH and NCI guidelines for biospecimen repositories.

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, http://grants.nih.gov/grants/funding/2590/2590.htm). See Section VI.3. Reporting.

Section V. Application Review Information.

1. Criteria

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

The following will be considered in making funding decisions:

2. Review and Selection Process

Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by NCI in accordance with the review criteria stated below.

As part of the initial merit review, all applications will:

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, and/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?

Specific to this RFA: How will the selection of a patient population that is predisposed to a high risk for colon cancer, and the proposed core activities, contribute to the overall aims of the C-CFR? 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?

Is the conceptual framework for the resource well thought out and geared to the overall research agenda outlined in the application? What are the plans for specimen/data, acquisition, management, and storage? What are the plans to contribute to and interact with the planned centralized biospecimen laboratory? What procedures are in place for evaluating requests to use the resource? Are there adequate plans described to assure quality control and equitable access to the resource? Are there clear and sound plans for the following:

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, and/or technologies for this area?

Specific to this RFA: Does this application propose novel or improved ways and/or methods to enhance or better serve the goals of the C-CFR?

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 principal investigator and other researchers? Does the investigative team bring complementary and integrated expertise to the project?

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 the Research Plan, Section E on Human Subjects in the PHS Form 398).

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 the Research Plan, Section E on Human Subjects in the PHS Form 398).

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: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. The priority score should not be affected by the evaluation of the budget.

2.C. Sharing Research Data

Data Sharing Plan: The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score. The presence of a data sharing plan will be part of the terms and conditions of the award. Program Staff will be responsible for the administrative review of the plan for sharing research data. The funding organization will be responsible for monitoring the data sharing policy.

2.D. Sharing Research Resources

NIH policy expects that grant recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (see the NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps/part_ii_5.htm#availofrr and at http://www.ott.nih.gov/policy/rt_guide_final.html).

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 will be considered by Program staff of the funding organization when making recommendations about funding applications. Program staff may negotiate modifications of the data and resource sharing plans with the awardee before recommending funding of an application. The final version of the data and resource sharing plans negotiated by both will become a condition of the award of the grant. 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 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 (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part4.htm).

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 12 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 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 (U24), 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.

2.A.1 Awardee and Principal Investigator(s) Rights and Responsibilities

Responsibilities and rights of the awardees and Principal Investigators (PIs) will include the following:

1. Awardees and PDs/PIs will have primary rights and responsibilities to define projects and approaches and to plan and conduct project execution;

2. The awardee will retain custody of and 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);

3. The awardees designated PDs/PI(s), which may be either single or multiple per awardee, will participate as permanent members of the Steering Committee (SC);

4. The awardee will collaborate with the other awardees and the Informatics Center through the SC to follow the established C-CFR operating policies, collection and quality control protocols for biospecimens and data and to establish new ones as needed, as well as cooperate with the ongoing and proposed collaborative research efforts and with the establishment of the central database;

5. Each Awardee will implement and adhere to common study protocols and timelines, as established by the SC/Informatics Center/NCI.

6. The awardee will be required to accept and implement the common policies and procedures approved- by the C-CFR, SC, and NCI;

7. The awardee will abide by the final approval of the SC based on the scientific prioritization of such proposals made by the Advisory Committee (AC);

8. The awardee must agree to provide access to biospecimens (through the centralized and local biospecimen repositories) to the research community at large, to support unique collaborative research projects which could not be supported by a single institution or researcher;

9. The Awardee will be expected to actively participate in promoting the development of such collaborative projects with the scientific community (such projects may involve several awarded C-CFR sites as well as external collaborators and/or consortia);

10. The awardee investigators will be able to utilize data and biospecimens collected at their institution for non collaborative research projects (beyond the scope of this award) provided that such utilization will not: (a) lead to conflict of interest or overlap with already ongoing research; or (b) deplete an exhaustible resource beyond the point of recovery in the judgment of the AC/SC/NCI. A list of such projects will be compiled for the SC review to determine whether the two criteria above are met. Site-based research projects responding to these characteristics need not be reviewed by the AC, but accurate tracking will be maintained regarding all ongoing projects and pertinent biospecimens and data released;

11. The awardee will, in a timely manner, provide high quality, complete, core data and data sets to the Informatics Center for the Central Data Base, according to a schedule cooperatively established by the SC and the Informatics Center. Non-core data produced by the collaborative research projects will be transmitted in a timely manner to the central data base according to the policies and procedures commonly developed by the SC and the Informatics Center. Quarterly reports will be developed, in collaboration with the Informatics Center, to monitor progress toward the stated objectives;

12. The awardee must provide a semi-annual, detailed progress report to the Scientific Program Officer (SPO) of the Epidemiology and Genetics Research Program, (EGRP), National Cancer Institute (NCI), and a copy to the chairperson of the SC, according to the format required by the SPO. Information on the operation of the core maintenance module and on the progress of collaborative research projects is to be included;

13. Collaboration among awardees in the reporting of findings originated from this initiative is expected. Collaborative publications among awardees and NCI are anticipated; and

14. Immediately after the notification of award, the awardee should provide the name of one scientist not affiliated with his/her Institution as a potential member of the SC. In addition, each Awardee should provide the names and qualifications of two scientists not affiliated with the awardee institution as potential members of the AC, as needed. Letters of commitment and curriculum vitae from the potential members of the AC and SC should be attached.

2.A.2. NIH Responsibilities

An NIH Scientific Program Director (SPD), acting as a Project Scientist, will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below. The role of the SPD will be to assist and facilitate, but not to direct, the activities supported by the C-CFR.

The NCI Project Scientist will be designated by the Associate Division Director, EGRP, DCCPS, NCI.

Substantial scientific-programmatic involvement of the NCI Project Scientist during the conduct of this activity will include (but will not be limited to) the following aspects.

1. Participating as a voting member in SC activities, assisting in the continued development of operating guidelines, quality control procedures, and consistent policies for dealing with recurrent situations that require coordinated action;

2. Participating in AC activities as a non-voting member;

3. Serving as liaison between the SC and the AC, providing a degree of continuity, as the ad hoc AC composition may change depending on the expertise required to review the submitted collaborative research proposals;

4. Serving on subcommittees of the SC and the AC as required;

5. Assuring that the SC and the AC follow the NIH guidelines on conflict of interest issues; and play a critical role in promoting the availability and use of the registry for collaborative investigator-initiated research;

6. Providing technical assistance and advice to awardees;

7. Serving as liaison and helping to coordinate activities among the awardees and between the awardees and the NCI;

8. Sharing overall knowledge of the NCI- and NIH-sponsored colorectal cancer research to: a) facilitate the selection of scientists not affiliated with the awardees institutions, who are to serve in the AC and SC; and b) foster collaborative research with other NCI-funded programs;

9. Serving as information resource about extramural interdisciplinary cancer research activities in the area of genetics and molecular epidemiology of colorectal cancer;

10. Assisting in monitoring field data collection and helping to ensure standardization in methods across study centers;

11. Assisting in the interpretation and reporting of the collected information (which will be necessary because of the complexity of the multi-site structure and a high degree of coordination and program involvement required to achieve adequate standardization of procedures);

12. Assisting the promotion of the C-CFR resources to the scientific community at large, for use in translational, behavioral and prevention-oriented colorectal cancer research;

13. Functioning as liaison between the C-CFR and the Informatics Center and the centralized biospecimen repository; and,

14. Participating in C-CFR-related research and in the activities of related working groups as appropriate and justified by experience and expertise.

The NCI reserves the right to reduce the budget, to withhold support, and/or to suspend, terminate or curtail a study or an award in the event of substantial shortfall in specimen accrual, data reporting, inadequate quality control in specimens or clinical data collection, non-adherence to biohazard precautions, refusal to carry out the recommendations of the SC and AC, or substantial failure to comply with the terms of the award.

Additionally, an NCI Program Official (i.e., NCI Program Director) will be responsible for the normal scientific and programmatic stewardship of the award. The NCI Project Scientist and the NCI Program Official may be the same person. In that case, Program Official/Project Scientist will seek NCI waiver according to the NCI procedures for management of conflict of interest to enable her/him to attend peer review meetings of renewal (competing continuation) and/or supplemental applications when necessary.

2.A.3. Collaborative Responsibilities

Steering Committee (SC)

The SC will serve as the main governing board for the C-CFR. The SC membership will include the following voting members: the NCI Project Scientist; the PIs of the awarded institutions; the PI of the Informatics Center; one designated Co-PI from each awarded institution and the Informatics Center; and one research scientist with expertise in the field of interdisciplinary and translational colorectal cancer research, who will not be affiliated with any of the awardee institutions and will serve as the SC external member. The external member will be appointed by mutual agreement of the NCI Project Scientist and the PIs. Additional members can be added by action of the SC. Other appropriate NCI staff may need to attend the SC meetings if their expertise is required to participate in specific discussions (but these additional NIH representatives shall have no voting rights).

The SC will be responsible for establishing C-CFR operating policies, and collection and standardized protocols for the core activities. Working Groups may be appointed to complete these tasks. The SC will be responsible for reviewing the final establishment of the C-CFR research infrastructure proposed in the individual applications of the awardees. The SC also will serve as a coordinating body for all collaborative aspects of the proposed interdisciplinary research, including the coordination of efforts to develop additional collaborative protocols and policies as needed and required.

Awardees will be required to accept and implement the common guidelines and procedures approved by the SC and to work with the NCI Project Scientist to comply with NCI policies concerning data and biospecimen repositories.

The SC Chair shall be elected from the SC members by a majority vote. The Chair of the SC will be responsible for coordinating the Committees activities in cooperation with the coordinating unit of the Informatics Center, for preparing meeting agendas, and for scheduling and chairing meetings. The tenure of the SC Chair will be 2 years. The NCI Project Scientist will attend and participate in all meetings of the SC. The SC meetings will be held in Bethesda or Rockville, Maryland, or at another convenient location. Working groups and/or subcommittees may be established by the SC as it deems appropriate.

The SC will confirm the availability and accessibility of specimens and data for approved collaborative research project proposals that request the use of the C-CFR infrastructure. The SC will not overturn nor influence the recommendation of the AC, except when specimens and/or data are not available or there is a demonstrated conflict of interest. The SC will be responsible for reviewing the single site, noncollaborative, data only research applications for the use of the registry resource, to determine whether utilization of the site-specific resource will not lead to conflict of interest. All requests involving biospecimens or re-contact of participants will be reviewed by the AC.

The SC will select members for the AC, two for each awarded site. In the conduct of all business matters, the SC will pay particular attention to potential conflict of interest issues, and will bring such matters to the attention of the AC and the NCI SPD.

Advisory Committee (AC)

The AC will be responsible for reviewing, evaluating and approving all future collaborative research proposals submitted by investigators from the research community at large, in collaboration with the awardees for the use of the registry infrastructure, according to the evaluation and review criteria established by the SC and NCI.

The AC will be composed of eight to twelve senior scientists with expertise in interdisciplinary research relevant to colorectal cancer, which may include epidemiologists, laboratory researchers, bioinformaticians, clinicians, behavioral scientists, and other individuals with expertise that the SC deems needed. The membership of the AC may vary, depending on the scientific areas of the proposed research. Additional ad-hoc members may be elected if specific expertise is needed for certain applications, or to advice on specific issues. All permanent and ad hoc AC members will be selected by the SC. Each PI will select two permanent AC members; any such selections will be subject to confirmation by the SC according to a majority vote. Ad hoc members will be selected from candidates proposed by the SC members by majority vote. The tenure of the AC members will be 2 years. The AC Chairperson will be elected by the AC, through a majority vote. The NCI Project Scientist will function as a non-voting AC member to help coordinate AC activities with the activities of SC.

The members of the AC will evaluate research applications proposing collaborative projects among the awardees as well as from the research community at-large requesting access to the C-CFR resources, according to the evaluation and review criteria provided by the SC. The review can be conducted either in person, by conference call or by mail. All reviews will be conducted according to rules pertaining to the conduct of reviews for NIH grants, contracts, and cooperative agreements, paying special attention to issues of conflict of interest, whether real or apparent. The AC will provide a recommendation to the SC as to the priority of the proposed research.

The AC will meet with the SC at least once yearly, at one of the two scheduled SC meetings.

The AC also will also be responsible for periodically evaluating the conduct of the C-CFR research and infrastructure activities and for providing advice to both the C-CFR investigators and NCI on its performance, development, and any issue that may arise pertinent to the conduct of the C-CFR activities.

Changes in Administrative Structure

The administrative structure and processes described above can be modified by mutual agreement of the awardees and the NCI.

2.A.4. Arbitration Process

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. An Arbitration Panel composed of three members will be convened. It will have three members, including 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 arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

3. Reporting

Awardees will be required to submit the PHS Non-Competing Grant Progress Report, Form 2590, annually (http://grants.nih.gov/grants/funding/2590/2590.htm) and financial statements as required in the NIH Grants Policy Statement. In addition, awardees will be required to submit quarterly reports to the NCI Project Scientist. These quarterly reports should include: (1) a report on the progress of each of the supported Cores; and (2) an update on collaborative research projects and publications.

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:

Dr. Daniela Seminara
Division of Cancer Control and Population Sciences
National Cancer Institute
National Institutes of Health
6130 Executive Boulevard, EPN Room 5142, MSC 7393
Bethesda, MD 20892-7393 (for U.S. Postal Service express or regular mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: (301) 594-7347
Email: seminard@mail.nih.gov

2. Peer Review Contacts:

Referral Officer
Division of Extramural Activities
National Cancer Institute
6116 Executive Boulevard, Room 8042, MSC 8239
Bethesda, MD 20892-8329 (for U.S. Postal Service express or regular mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: (301) 496-3428
FAX: (301) 402-0275

3. Financial or Grants Management Contacts:

Crystal Wolfrey
Office of Grants Administration
National Cancer Institute
6120 Executive Boulevard, EPS Suite 243, MSC 7150
Bethesda, MD 20892-7150 (for U.S. Postal Service express or regular mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: (301) 496-8634
Fax: (301) 496-8601
Email: crystal.wolfrey@nih.gov

Section VIII. Other Information.

Required Federal Citations

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 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.

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/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.

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 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 RFA 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% of their time (at least 20 hours per week based on a 40 hour week) for 2 years to the research. For further information, please see http://www.lrp.nih.gov.

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