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)
National Center for Complementary and Alternative Medicine (NCCAM), (http://nccam.nih.gov)

Title: The Role of Microbial Metabolites in Cancer Prevention and Etiology (U01)

Announcement Type
New

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

• March 15, 2011 - This PAR has been expired and reissued as PAR-11-152.
• February 23, 2011 The Expiration Date for this announcement has been changed to May 8, 2011 per NOT-OD-11-048, which redefines the U01 activity code and announces the transition of U01 applications to electronic submission through Grants.gov using the SF424 (R&R) forms for due dates on or after May 25, 2011.

Looking ahead: As part of the Department of Health and Human Services' implementation of e-Government the NIH will gradually transition each research grant mechanism to electronic submission through Grants.gov and the use of the SF 424 Research and Related (R&R) forms. For more information and an initial timeline, see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-06-035.html. NIH will announce each grant mechanism change in the NIH Guide to Grants and Contracts (http://grants.nih.gov/grants/guide/index.html).

Program Announcement (PA) Number: PAR-10-208

Catalog of Federal Domestic Assistance Number(s)
93.393, 93.396, 93.213

Key Dates
Release Date: May 27, 2010
Letters of Intent Receipt Dates: October 15, 2010; October 15, 2011; October 15, 2012
Application Receipt Dates: November 15, 2010; November 15, 2011; November 15, 2012
Peer Review Dates: March 2011; March 2012; March 2013
Council Review Dates: May 2011; May 2012; May 2013
Earliest Anticipated Start Dates: July 2011; July2012; July2013
Additional Information To Be Available Date (Url Activation Date): Not Applicable
Expiration Date: (Now Expired March 15, 2011 per issuance of PAR-11-152); Previously Changed to May 8, 2011 (Per NOT-OD-11-048) ; Original Date November 16, 2012

Due Dates for E.O. 12372

Not Applicable

Additional Overview Content

Executive Summary

• Purpose. This Funding Opportunity Announcement (FOA) issued by the National Cancer Institute (NCI), and the National Center for Complementary and Alternative Medicine, (NCCAM), at the National Institutes of Health, encourages the submission of grant applications that characterize the effects of microbially generated metabolites of dietary components on host cell biology. Specifically, this FOA seeks to characterize microbially generated metabolites and better understand their molecular mechanisms of action that affect host cell proliferative/apoptotic responses, cytokine production, inflammatory and immunomodulatory effects. This FOA will also encourage the conduct of human intervention studies that identify inter-individual variability among various racial and ethnic groups in the production of bacterial metabolites and determine their efficacy in cancer prevention. This research is necessary to better understand the role of dietary components in cancer etiology, prevention, and cancer health disparities to identify who might benefit from specific dietary recommendations and who might be placed at risk. One of the goals of this program will be to facilitate interdisciplinary collaborations among scientists engaged in nutrition, cancer prevention, cancer cell biology research, and cancer disparities research with those conducting studies with gut microorganisms. All applications must include multiple principle investigators with different areas of expertise such as microbiology, nutrition, cancer biology, analytical chemistry, or genetics. In addition, all investigators will be required to attend annual meetings with NIH personnel. Investigators may use either clinical or preclinical approaches.
• Mechanism of Support. This FOA will utilize the NIH U01 cooperative agreement mechanism.
• Funds Available and Anticipated Number of Awards. Awards issued under this FOA are contingent upon the availability of funds and the submission of a sufficient number of meritorious applications.
• Budget and Project Period. The total project period for an application submitted in response to this FOA may not exceed 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.
• Application Research Strategy Length: The U01 Research Strategy section may not exceed 12 pages, including tables, graphs, figures, diagrams, and charts. See Table of Page Limits.
• 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) will be required on the application.
• Number of Applications. Applicants may submit more than one application, provided that each application is scientifically distinct.
• Resubmissions. Applicants may submit a resubmission application, but such application must include an Introduction addressing the previous peer review critique (Summary Statement). See new NIH policy on resubmission (amended) applications (NOT-OD-09-003, NOT-OD-09-016).
• Renewals. Applicants may not submit a renewal application.
• 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.
• General Information. For general information on SF424 (R&R) Application and Electronic Submission, see these Web sites:
  • SF424 (R&R) Application and Electronic Submission Information: http://grants.nih.gov/grants/funding/424/index.htm
  • General information on Electronic Submission of Grant Applications: http://era.nih.gov/ElectronicReceipt/
• 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 of Support
2. Funds Available

Section III. Eligibility Information
1. Eligible Applicants
A. Eligible Institutions
B. Eligible Individuals
2. Cost Sharing or Matching
3. Other-Special Eligibility Criteria

Section IV. Application and Submission Information
1. Request Application Information
2. Content and Form of Application Submission
3. Submission Dates and Times
A. Submission, Review, and Anticipated Start Dates
1. Letter of Intent
B. Submitting an Application Electronically 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
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. Dispute Resolution Process
3. Reporting

Section VII. Agency Contacts
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

This Funding Opportunity Announcement (FOA) issued by the National Cancer Institute (NCI), and the National Center for Complementary and Alternative Medicine, (NCCAM), at the National Institutes of Health, encourages the submission of grant applications that characterize the effects of microbially generated metabolites on host cell biology. Specifically, this FOA seeks to leverage recent advances through the Human Microbiome Project Roadmap Initiative to characterize microbially generated metabolites and better understand their molecular mechanisms of action that affect host cell proliferative/apoptotic responses, cytokine production, inflammatory and immunomodulatory effects. This FOA will also encourage the conduct of human intervention studies that identify inter-individual variability among various racial and ethnic groups in the production of bacterial metabolites and determine their efficacy in cancer prevention. This research is necessary to better understand the role of dietary components in cancer etiology, prevention, and cancer health disparities to identify who might benefit from specific dietary recommendations and who might be placed at risk. One of the goals of this program will be to facilitate interdisciplinary collaborations among scientists engaged in nutrition, cancer prevention, cancer cell biology research, and cancer disparities research with those conducting studies with gut microorganisms. All applications must include multiple principle investigators with different areas of expertise such as microbiology, nutrition, cancer biology, analytical chemistry, or genetics. In addition, all investigators will be required to attend annual meetings with NIH personnel. Investigators may use either clinical or preclinical approaches.

Background

The adult human gut contains up to 100 trillion organisms, known as the microbiota. Microbially generated metabolites from certain food components may be important mediators of both cancer protective effects and of cancer initiation and progression. Major advances in defining the quality, quantity, and physiological activity of the intestinal microbiota were precipitated by the conversion from culture-based techniques to metagenomics and through the NIH Microbiome Roadmap Initiative. The colonic microflora plays a critical role in human health and disease and has been suggested to influence cancer risk among various populations. Specific strains of bacteria have been implicated in the pathogenesis of cancer, including Streptococcus bovis, Bacteriodes, Clostridia, and Helicobacter pylori. Conversely, some strains of bacteria, including Lactobacillus acidophilus and Bifidobacterium longum, have been shown to be protective against colon cancer. Thus, this balance between detrimental and beneficial bacteria may have implications for cancer risk. It is increasingly clear that dietary components can significantly modify this balance via either the selective growth of specific bacteria or the effect of specific metabolic products. However, the production and biological effects of microbially generated metabolites from food components and their role in cancer prevention, etiology, and cancer health disparities have not been adequately investigated. This concept focuses on characterizing these microbially generated metabolites, determining their molecular targets, the inter-individual variation among various racial and ethnic groups in their production, their role in the maintenance or disruption of host intestinal epithelial cell homeostasis, their contribution to initiation of neoplasia, and/or their potential efficacy in cancer prevention.

Equol as Proof of Principle . One of the most abundant isoflavones in soy, daidzein, is differentially metabolized to equol and O-desmethylangolensin (DMA) by gut microflora in humans. In several studies, equol and O-desmethylangolensin have been shown to bind to human estrogen receptors ?a and with a greater affinity than the parent compound, daidzein. Furthermore, in studies that have assessed estrogen receptor-dependent transcription of -galactosidase in transfected yeast assays, equol induced transcription to a greater extent than daidzein in yeast carrying estrogen receptor ?a or . Therefore, because equol mediates many of its biological effects by binding to the estrogen receptors, in vitro studies suggest that equol is more biologically active than daidzein.

Equol has been found to inhibit the growth of benign and malignant prostate epithelial cells in vitro at concentrations that can be obtained naturally through dietary soy consumption. Furthermore, Asians are significantly more likely to produce the metabolite equol than Caucasians and this has been associated with the lower prostate cancer incidence among Asians. Mammographic density was 39% lower in equol producers compared with non-producers. Furthermore, soy consumption increased the ratio of urinary 2-hydroxyestrogens to 16?-hydroxyestrone, another possible biomarker of decreased breast cancer risk, only in women who are equol producers. Therefore, soy consumption may lower the risk of prostate and breast cancers to a greater extent in individuals who are equol producers than in those who are not.

Dietary isoflavones have also been shown to differentially induce gene expression changes in lymphocytes from postmenopausal women who form equol compared to those who do not. In general, isoflavones had a stronger effect on some putative estrogen-responsive genes in equol producers than in non-producers. Because equol appears to mediate its cancer protective effects via binding to the estrogen receptor, these results further suggest that the capacity to form equol may be an important determinant of the responsiveness to isoflavone treatment. Additional studies are needed to clarify if a similar change in gene expression occurs in organs such as the mammary or prostate gland where soy intake tends to be associated with protection against cancer. Finally, it will be important to determine if non-equol producers will respond to dietary equol physiologically similar to what is observed in equol producers.

Bacterial Metabolism of Other Dietary Components. In addition to daidzein, several other dietary components can be metabolized by intestinal bacteria to cancer protective compounds. For example, plant lignans can be converted by the intestinal microbiota to the mammalian lignans, enterodiol, and enterolactone. Elevated plasma concentrations of enterolignans, in particular, enterodiol, were associated with a significant reduction in colorectal adenoma risk in a case control study. Enterolactone has been reported to induce apoptosis and inhibit growth of Colo201 human colon cancer cells in culture and following transplantation into athymic mice. Similarly, SW480 cell growth is inhibited in a dose- and time-dependent manner by enterolactone and enterodiol. When the lignans matairesinol and secoisolariciresinol were fed to Min mice, there were increased plasma concentrations of enterolactone and enterodiol but no inhibition of intestinal tumorigenesis. In contrast, secoisolariciresinol diglycoside concentrations in wheat bran from four selected wheat cultivars correlated with the cancer protective effects in Min mice, suggesting that secoisolariciresinol diglycoside may contribute to the cancer preventive effects of wheat bran. The reasons for these inconsistencies warrant future examination. Nevertheless, these studies suggest that bacterial metabolism of plant lignans can lead to compounds that are protective against colorectal cancer.

Similarly, preclinical studies have shown that enterolactone can reduce human breast cancer cell adhesion, invasion, migration and estrogen synthesis. While high serum concentrations of enterolactone in humans have been associated with a decrease in breast and prostate cancer risk, the data is not overly compelling. These inconsistencies may relate to genetic differences and should be better evaluated.

An individual’s genotype may influence their response to lignans. Women homozygous for the A2 allele of cytochrome P450c17? appear to benefit more from higher plasma enterolactone concentrations and a high consumption of dietary precursors than women without this allele. This also suggests that an individual’s genetic background, their dietary patterns, and their microbiota interact and must be considered simultaneously for cancer prevention. A better understanding about how genetic polymorphisms influence the biological response to bacterial metabolites of bioactive food components is warranted.

Ellagic acid is a polyphenol that has been reported to possess a plethora of biological properties including antioxidant and cancer protective activities. Ellagic acid is present in many foods including strawberries, raspberries, walnuts, and pomegranates. Ellagic acid is metabolized by human colonic microflora to yield urolithins A and B. These urolthins have been shown to antagonize the growth promoting effect of estradiol in MCF7 human breast cancer cells in a dose-dependent manner. Furthermore, similar to equol, the production of urolithins, has been hypothesized to depend on the composition of the microflora of each individual because there is large interindividual variability in production. This variability was demonstrated in a human supplementation study: when 10 volunteers consumed 25 g fresh strawberries, excretion of urolithin B derivatives ranged from <1 to 6%; when they consumed 35 g of walnuts, excretion ranged from 1 to 81%; and when they consumed 300 ml of oak-aged red wine, excretion ranged from 2-7%. Thus, the potential biological effects for this cancer protective dietary compound may also be different among individuals depending on their microflora. It has not been determined whether ellagic acid or urolithins are more biologically active for cancer prevention. It is also not known whether genetic polymorphisms in ellagic acid metabolizing enzymes (i.e. catechol-O-methyltransferase and glucuronyl transferases) might be associated with differences in ellagic acid metabolism, urolithin production and the resulting impact on cancer risk.

Metabolism by gut microflora may also influence tissue exposure to other polyphenols. This is particularly true for higher-molecular-weight polyphenols including proanthocyanidins or oxidized polymeric polyphenols, which are poorly absorbed in the proximal part of the gastrointestinal tract. These polyphenols are abundant in wine, tea, chocolate and many fruits. Ferulic acid, which is present in considerable quantities in most fruits, vegetables, and cereals, forms three major metabolites when incubated with human microbiota. These metabolites have also been found in human fecal samples and are more potent inhibitors of prostaglandin metabolism than the parent compound in vitro. The physiological significance of these microbial metabolites and whether this inhibition of inflammatory pathways contributes to a decreased cancer risk when consuming a polyphenol rich diet remains to be determined.

Gut Microbes and Obesity. Obesity has been linked with both cancer incidence and mortality. Recent work also suggests that obesity may have a microbial component. Investigators have used genetic sequencing to determine that 12 obese individuals had more Firmicutes and nearly 90% less Bacteroidetes than 5 lean individuals. Furthermore, when the obese volunteers spent one year on a low-fat or low-carbohydrate diet and lost as much as 25% of their body weight, the proportion of Firmicutes in their colon dropped and that of the Bacteroidetes rose. Similar to humans, mice that are genetically obese (ob/ob) have a higher proportion of intestinal Firmicutes and 50% fewer Bacteroidetes than their lean siblings. When germ-free mice were colonized with either the microbiota from obese (ob/ob) or lean (+/+) littermates, the mice given the microbiota from obese mice extracted more calories from their food and had a significantly greater increase in total body fat than in mice colonized with the microbiota from lean mice. These data suggest that differences in the efficiency of caloric extraction from food may be determined by the composition of the microbiota, which in turn, may contribute to differences in body weight. Future work is needed to determine whether manipulation of the gut microbial community could be an approach for the treatment and/or prevention of obesity in humans and whether this modifies cancer risk.

Transplanting the gut microbiota from normal mice into germ-free recipients increased their body fat without a change in food consumption by increasing caloric release from the diet and by modulating host genes that affect energy deposition in adipocytes including fasting-induced adipocyte factor (Fiaf). Fiaf is a circulating lipoprotein lipase inhibitor and its suppression is essential for the microbiota-induced deposition of triglycerides in adipocytes. These findings suggest that the composition of the gut microbial community may affect the amount of energy that is extracted from the diet. In contrast to mice with a gut microbiota, germ-free animals are protected against the obesity that develops after consumption of a Western-style, high fat, sugar-rich diet. Their continuously lean phenotype is associated with increased skeletal muscle levels of AMP-activated protein kinase and its downstream targets involved in fatty acid metabolism such as acetyl CoA carboxylase and carnitine-palmitoyl transferase. Moreover, germ-free knockout animals lacking Fiaf are not protected from diet-induced obesity because of reduced expression of genes involved in fatty acid oxidation. Therefore, the gut microbiota can influence both sides of the energy balance equation; namely, as a factor that influences energy utilization from the diet and as a factor that affects host genes that regulate how energy is expended and stored. Future studies are needed to better understand whether the microbiota has a similar effect on energy utilization and gene expression in humans.

Specific Objectives and Scope of this FOA

Specific research areas of interest include, but are not limited to, the following areas:

• Examine metabolites of polyphenols generated by gut bacteria and determine their role in inflammation and colorectal cancer.
• Utilize mouse models of human cancer with either a human flora or germ free for evaluating the role of soy constituents/metabolites on key cancer related processes.
• Examine urolithin production in humans as a function of ellagic acid intake on activities and expression of cytochrome P450 and phase II enzymes in human buccal cells and esophageal tissue.
• Evaluate the role of dietary animal fat on the population of sulfur-reducing bacteria and their production of genotoxic metabolic products such as hydrogen sulfide.
• Define functional changes and mechanisms that demonstrate microbial product’s carcinogenic effects on host cell biology.
• Examine the ability of oral probiotic or prebiotic supplementation to modulate colon cancer initiation or progression through their effects on microbial metabolites.
• Identify microbially generated metabolites of ginseng (Panax ginseng or quinquefolius) with documented cancer preventive activity, and sources of individual variation in generation or utilization of these metabolites.
• Identify differences in the biological effects of microbially generated metabolites among various racial and ethnic populations that may contribute to cancer health disparities

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 announcement (FOA) will use the NIH Cooperative Agreement U01 award mechanism. The applicant will be solely responsible for planning, directing, and executing the proposed project.

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).

This is a cooperative agreement award 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".

2. Funds Available

Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the IC(s) provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds.

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

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;
• Regional Organizations;
• Non-domestic (non-U.S.) Entities (Foreign Organizations); and
• Eligible Agencies of the Federal Government.

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research 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 programs.

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://grants.nih.gov/grants/ElectronicReceipt/preparing.htm for instructions).

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.

Applications may include multiple principal investigators (Or PD(s)/PI(s) with different areas of expertise such as, but not limited to, microbiology, nutrition, cancer biology, analytical chemistry, or genetics.

One of the goals of this program will be to facilitate interdisciplinary collaborations among scientists engaged in nutrition, cancer prevention, cancer cell biology research, and cancer disparities research with those conducting studies with gut microorganisms.

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

Number of Applications. Applicants may submit more than one application, provided that each application is scientifically distinct.

Resubmissions. Applicants may submit a resubmission application, but such application must include an Introduction addressing the previous peer review critique (Summary Statement). Beginning with applications intended for the January 25, 2009 official submission due date, all original new applications (i.e., never submitted) and competing renewal applications are permitted only a single amendment (A1). See new NIH policy on resubmission (amended) applications (NOT-OD-09-003, NOT-OD-09-016). Original new and competing renewal applications that were submitted prior to January 25, 2009 are permitted two amendments (A1 and A2). For these grandfathered applications, NIH expects that any A2 will be submitted no later than January 7, 2011, and NIH will not accept A2 applications after that date.

Renewals. Renewal applications may not be submitted.

Section IV. Application and Submission Information

1. Address to Request Application Information

The current 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: [email protected].

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

2. Content and Form of Application Submission

Prepare all applications using the PHS 398 application forms in accordance with the PHS 398 Application Guide (http://grants.nih.gov/grants/funding/phs398/phs398.html).

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.

Foreign Organizations [Non-domestic (non-U.S.) Entity]

NIH policies concerning grants to foreign (non-U.S.) organizations can be found in the NIH Grants Policy Statement at: http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part12.htm#_Toc54600260.

Applications from foreign organizations must:

• Request budgets in U.S. dollars.
• Contain detailed budgets. See NOT-OD-06-096.

In addition, for applications from foreign organizations:

Charge back of customs and import fees is not allowed.

• Every effort should be made to comply with the format specifications, which are based upon a standard U.S. paper size of 8.5 x 11 within each PDF.
• Funds for up to 8% Facilities and administrative (F&A) costs (excluding equipment) may be requested. See NOT-OD-01-028, March 29, 2001.
• Organizations must comply with Federal/NIH policies on human subjects, animals, and biohazards.
• Organizations must comply with Federal/NIH biosafety and biosecurity regulations. See Section VI.2., Administrative and National Policy Requirements.

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.

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 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.

Multiple PD/PI Leadership Plan: For applications designating multiple PDs/PIs, the 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.

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

3. Submission Dates and Times

See Section IV.3.A. for details.

3.A. Submission, Review and Anticipated Start Dates
Letter of Intent Receipt Dates: October 15, 2010; October 15, 2011; October 15, 2012
Application Receipt Dates: November 15, 2010; November 15, 2011; November 15, 2012
Peer Review Dates: March 2011; March 2012; March 2012
Council Review Dates: May 2011; May 2012; May 2013
Earliest Anticipated Start Dates: July 2011; July2012; July2013

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, address, and telephone number of the Principal Investigator
• Names of other senior/key personnel
• Participating institutions
• 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 IC 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.

Cindy Davis, Ph.D.
Division of Cancer Prevention
National Cancer Institute
6130 Executive Boulevard, Suite 3160, MSC 7328
Rockville, MD 20892
Telephone: (301) 594-9692
Fax: (301) 480-3925
Email: [email protected]

3.B. Sending an Application to the NIH

Applications must be prepared using the research grant application 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 express/courier service; non-USPS service)

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 materials 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 20892 (for non-USPS delivery)
Telephone: (301) 496-3428
Fax: (301) 402-0275
Email: [email protected]

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 CSR. Incomplete 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 merit review unless the applicant withdraws the pending application. The NIH will not accept any application that is essentially the same as one already reviewed. However, the NIH will accept a resubmission application, but such application must include an Introduction addressing the critique from the previous review.

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.

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 NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part6.htm.)

6. Other Submission Requirements

Annual Meeting: An annual meeting of all funded investigators will be held to facilitate the standardization of protocols for preclinical or clinical studies and to share progress and research insights that may benefit all of the projects. The Program Directors will be responsible for organizing this annual meeting. Applicants should request travel funds in their budgets for senior/key personnel to attend one meeting per year.

Cooperative Agreement

Awardees must agree to the Cooperative Agreement Terms and Conditions of Award in Section VI. 2.A Award Administration Information .

PHS398 Research Plan Sections

All application instructions outlined in the PHS 398 Application Instructions are to be followed, with the following additional requirements:

• Introduction (required for a resubmission or revision application) is limited to 1 page.
• Specific Aims is limited to 1 page.
• Research Strategy, including tables, graphs, figures, diagrams, and charts, is limited to 12 pages. See Table of Page Limits.

Budget

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

All foreign applicants must complete and submit budget requests using the Research & Related Budget component found in the application package for this FOA. See NOT-OD-06-096.

Specific Instructions for Applications Requesting $500,000 (direct costs) or More per Year

Applicants requesting $500,000 or more in direct costs for any year (excluding consortium F&A costs) must carry out the following steps:

1) Contact the IC program staff at least 6 weeks before submitting the application, i.e., as plans are being developed for the study;

2) Obtain agreement from the IC staff that the IC will accept the application for consideration for award; and,

3) Include a cover letter with the application that identifies the staff member and IC who agreed to accept assignment of the application.

This policy applies to all new, renewal, revision, or resubmission applications. See NOT-OD-02-004.

Appendix Materials

All paper PHS 398 applications submitted must provide appendix material on CDs only. 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. 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: Regardless of the amount requested, investigators 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/.

Specific Instructions for Foreign Applications

All foreign applicants must complete and submit budget requests using the Research & Related Budget component found in the application package for this FOA. See NOT-OD-06-096,

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

Review Process

Applications that are complete 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.

Receive a second level of review by the National Cancer Advisory Board.

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.

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 scored review criteria, and additional review criteria (as applicable for the project proposed).

Scored 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?

Investigator(s). Are the PD/PIs, collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? Do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project? Does the research team have a track record of prior successful collaborative research and if not is evidence provided that they could develop meaningful collaborations? If collaborating institutions involve industry or small business entities, how will this inclusion enhance the applicants research and their plans for technology translation/dissemination? Are the designated roles and responsibilities of the PDs/PIs well defined, adequate and appropriate for achieving the goals?

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?

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, or collaborative arrangements? Are consortium/contractual arrangements, if any, appropriate?

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. For additional information, see http://grants.nih.gov/grants/olaw/VASchecklist.pdf.

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.

Resubmission Applications. When reviewing a Resubmission application (formerly called an amended application), the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Renewal Applications. Renewals are not allowed in this FOA.

Revision Applications. When reviewing a Revision application (formerly called a competing supplement application), the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

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.

Applications from Foreign Organizations. Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Select Agents 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).

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

Selection Process

Applications submitted in response to this funding opportunity will compete for available funds with all other recommended applications. The following will be considered in making funding decisions:

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

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.

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.

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.

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, 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. Project Director/Principal Investigator (PD/PI) Rights and Responsibilities

The Principal Investigator will have the primary responsibility for defining objectives and approaches, and to plan, conduct, analyze and publish results, interpretations, and conclusions of studies conducted under this program. The PD(s)/PI(s) assumes(s) 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 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;
• A PD/PI of each U01 project and at least one additional PD/PI or senior/key personnel member 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 will 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.

Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

2.A.2. NIH Responsibilities

A designated NCI Program Director 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 main NCI responsibilities include the following activities. Specifically, the NCI Project Scientists 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 NIH-supported projects, programs, and centers;
• Participate in program meetings;
• Review all major transitional changes that the awardees might propose (e.g., a change in partnering institution) and advise 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 research awardees and investigators at other institutions, as appropriate for the program;
• Assist in avoiding unwarranted duplication of effort with other NIH efforts;
• Monitor institutional commitments and resources 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; and
• Organize and conduct regular meetings to share progress either by teleconference, videoconference, or face-to-face, as needed between the awardees.

Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. A Program Official may also have substantial programmatic involvement (as Project Scientist) and may be the same person as the Project Scientist. In that case, the individual involved will seek NCI waiver prior to attending peer review meetings.

2.A.3. Collaborative Responsibilities

The NCI Project Scientist and the PD(s)/PI(s) of the U01 awards funded under the research initiative will be jointly responsible for the coordination of intra-program activities and the scientific integration of individual projects.

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

The Steering Committee, composed of the PIs/PDs, a second key member of each funded project, and the NCI Project Scientist, will be responsible for developing strategies to address issues common to all of the projects funded by this initiative. Investigators agree to follow common policies and procedures developed by the Steering Committee. The Steering Committee will pay special attention to issues of data integration, management, analysis, and public release and may establish subcommittees as necessary. The participants will select a chairperson for the Steering Committee. An NCI Program staff member cannot serve as chairperson.

Each full member will have one vote. Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee.

2.A.4. Dispute Resolution 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 dispute resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure 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

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.

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:

Cindy Davis, Ph.D.
Division of Cancer Prevention
National Cancer Institute (NCI)
6130 Executive Boulevard, Suite 3166, MSC 7328
Rockville, MD 20852
Telephone: (301) 594-9692
Email: [email protected]

Phillip Daschner, Ph.D.
Division of Cancer Biology
National Cancer Institute (NCI)
6130 Executive Boulevard, Suite 5014, MSC 7344
Rockville, MD 20852
Telephone: (301) 496-1951
Email: [email protected]

Rina Das, Ph.D.
Center to Reduce Cancer Health Disparities
National Cancer Institute (NCI)
6116 Executive Boulevard, Suite 602, MSC 8341
Rockville, MD 20852
Telephone: (301) 496-8589
Email: [email protected]

Anil Wali, Ph.D.
Center to Reduce Cancer Health Disparities
National Cancer Institute (NCI)
6116 Executive Boulevard, Suite 602, MSC 8341
Rockville, MD 20852
Telephone: (301) 496-7344
Email: [email protected]

Barbara C. Sorkin, Ph.D
Coordinator, Centers of Excellence for Research on CAM Program
Division of Extramural Research
National Center for Complementary and Alternative Medicine (NCCAM)
6707 Democracy Boulevard, Suite 401
Bethesda, MD 20892-5475
Office: (301) 594-8018
Email: [email protected]

2. Peer Review Contacts:

Not Applicable

3. Financial or Grants Management Contacts:

Heather Weiss
Office of Grants Administration
National Cancer Institute
6120 Executive Boulevard, Suite 243, MSC 6120
Bethesda, MD 20892
Telephone: (301) 496-7244
Fax: (301) 496-8601
Email: [email protected]

George Tucker, M.B.A.
Chief Grants Management Officer
National Center for Complementary and Alternative Medicine
National Institutes of Health
6707 Democracy Blvd., Suite 401, MSC 5475
Bethesda, MD 20892-5475
Phone: 301-594-9102
Fax: 301-480-1552
Email: [email protected]

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); 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.

Policy for Genome-Wide Association Studies (GWAS):
NIH is interested in advancing genome-wide association studies (GWAS) to identify common genetic factors that influence health and disease through a centralized GWAS data repository. For the purposes of this policy, a genome-wide association study is defined as any study of genetic variation across the entire human 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. All applications, regardless of the amount requested, proposing 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. Data repository management (submission and access) is governed by the Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088. For additional information, see http://grants.nih.gov/grants/gwas/.

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.

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 public 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.

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-09-116.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 for them 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/.