Department of Health and Human Services

Part 1. Overview Information
Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Cancer Institute (NCI)
National Center for Complementary and Alternative Medicine (NCCAM)

Funding Opportunity Title

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

Activity Code

U01 Research Project – Cooperative Agreements

Announcement Type

Reissue of PAR-10-208

Related Notices

Funding Opportunity Announcement (FOA) Number

PAR-11-152

Companion FOA

None

Number of Applications

See Section III. 3. Additional Information on Eligibility.

Catalog of Federal Domestic Assistance (CFDA) Number(s)

93.393, 93.396, 93.213

FOA 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. 

Key Dates
Posted Date

March 15, 2011

Open Date (Earliest Submission Date)

October 15, 2011

Letter of Intent Due Date

October 15, 2011; October 15, 2012 

Application Due Date(s)

November 15, 2011; November 15, 2012, by 5:00 PM local time of applicant organization.

AIDS Application Due Date(s)

Not Applicable

Scientific Merit Review

March 2012; March 2013

Advisory Council Review

May 2012; May 2013

Earliest Start Date(s)

July2012; July2013

Expiration Date

November 16, 2012

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the SF 424 (R&R) Application Guide except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Table of Contents

Part 1. Overview Information
Part 2. Full Text of the Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

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 ß with a greater affinity than the parent compound, daidzein. Furthermore, in studies that have assessed estrogen receptor-dependent transcription of ß-galactosidase in transfected yeast assays, equol induced transcription to a greater extent than daidzein in yeast carrying estrogen receptor "a or ß. 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:

Section II. Award Information
Funding Instrument

Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, scientific or program staff will assist, guide, coordinate, or participate in project activities.

Application Types Allowed

New
Resubmission

The OER Glossary and the SF 424 (R&R) Application Guide provide details on these application types.

Funds Available and Anticipated Number of Awards

The number of awards is contingent upon NIH appropriations, and the submission of a sufficient number of meritorious applications.

Award Budget

Application budgets are not limited, but need to reflect actual needs of the proposed project.

Award Project Period

The total project period for an application submitted in response to this funding opportunity may not exceed 5 years.

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
 
Eligible Organizations

Higher Education Institutions:

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

Nonprofits Other Than Institutions of Higher Education

For profit Organizations

Governments

Other

Foreign (non-U.S.) components on applications submitted by U.S. Organizations are allowed.

Required Registrations

Applicant organizations must complete the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. Applicants must have a valid Dun and Bradstreet Universal Numbering System (DUNS) number in order to begin each of the following registrations.

All Program Directors/Principal Investigators (PD/PIs) must also work with their institutional officials to register with the eRA Commons or ensure their existing eRA Commons account is affiliated with the eRA Commons account of the applicant organization.

All registrations must be completed by the application due date. Applicant organizations are strongly encouraged to start the registration process at least four (4) weeks prior to the application due date.

Eligible Individuals (Program Director/Principal Investigator)

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director/Principal Investigator (PD/PI) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF 424 (R&R) Application Guide.

Applicants are encouraged to consider designating multiple PD(s)/PI(s) with different areas of expertise such as, but not limited to, microbiology, nutrition, cancer biology, analytical chemistry, or genetics. Multiple PD(s)/PI(s) option may thus be used to address one of the goals of this initiative, which is 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

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

3. Additional Information on Eligibility

Number of Applications

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial peer review unless the applicant withdraws the pending application. NIH will not accept any application that is essentially the same as one already reviewed. Resubmission applications may be submitted, according to the NIH Policy on Resubmission Applications from the SF 424 (R&R) Application Guide.

Section IV. Application and Submission Information

1. Requesting an Application Package

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the “Apply for Grant Electronically” button in this FOA or following the directions provided at Grants.gov.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Letter of Intent

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.

By the date listed in Part 1. Overview Information, 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 PD(s)/PI(s)
Names of other key personnel
Participating institutions
Number and title of this funding opportunity

The letter of intent should be sent to:

Gabriela Riscuta, M.D., C.N.S.
Nutritional Science Research Group
Division of Cancer Prevention
National Cancer Institute
6130 Executive Boulevard, Room 3152, MSC 7328
Bethesda, MD 20892-7328 (for U.S. Postal Service regular or express mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: (301) 594-9692
Fax: (301) 480-3925
Email: gabriela.riscuta@nih.gov

Required and Optional Components

The forms package associated with this FOA includes all applicable components, mandatory and optional.  Please note that some components marked optional in the application package are required for application submission. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate “optional” components.

Page Limitations

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

R&R Budget Component

This FOA uses non-modular budget formats.

Costs of Travel to 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. Applicants should request travel funds in their budgets for senior/key personnel to attend one meeting per year.

PHS 398 Research Plan Component

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Resource Sharing Plan

Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide, with the following modifications:

Appendix

Do not use the appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

Foreign Organizations

Foreign (non-US) organizations must follow policies described in the NIH Grants Policy Statement, and procedures for foreign organizations described throughout the SF424 (R&R) Application Guide.

3. Submission Dates and Times

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit in advance of the deadline to ensure they have time to make any application corrections that might be necessary for successful submission.

Organizations must submit applications via Grants.gov, the online portal to find and apply for grants across all Federal agencies. Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration.

Applicants are responsible for viewing their application in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

4. Intergovernmental Review (E.O. 12372)

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 only as described in the NIH Grants Policy Statement.

6. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF 424 (R&R) Application Guide.  Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically.

Important reminders:
All PD/PIs must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF 424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the Central Contractor Registration (CCR). Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review, NIH. Applications that are incomplete will not be reviewed.

Requests of $500,000 or more for direct costs in any year

Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact NIH program staff at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF 424 (R&R) Application Guide.

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-10-115.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of 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 review criteria and additional review criteria (as applicable for the project proposed).

Scored Review Criteria

Reviewers will consider each of the review criteria below in the determination of scientific 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)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?   

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?      

Additional Review Criteria

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact/priority score, 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. For additional information on review of the Human Subjects section, please refer to the Human Subjects Protection and Inclusion Guidelines.

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. For additional information on review of the Inclusion section, please refer to the Human Subjects Protection and Inclusion Guidelines.

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 on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

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.

Resubmissions

For Resubmissions, 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.

Renewals

Not Applicable.

Revisions

Not Applicable.

Additional Review Considerations

As applicable for the project proposed, reviewers will consider 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 Agent Research

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

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genome Wide Association Studies (GWAS).

Budget and Period of Support

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

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), in accordance with NIH peer review policy and procedures, using the stated review criteria. Review assignments will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

Section VI. Award Administration Information

1. Award Notices

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. 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.      

Any application awarded in response to this FOA will be subject to the DUNS, CCR Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General  and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services 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.

The PD(s)/PI(s) will have the primary responsibility for:

Specific PD/PI rights and responsibilities will include the following: 

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. 

NIH staff will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

A designated NCI Program Director acting as a Project Scientist will have the following responsibilities will:

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

Areas of Joint Responsibility include:

The NCI Project Scientist and the PD(s)/PI(s) of the U01 awards funded under this FOA will be jointly responsible for the coordination of intra-program activities and the scientific integration of individual projects. These responsibilities include joint participation in the Steering Committee.

The Steering Committee will be composed of two representatives of each awardee (two PDs/PIs, or a PD/PI and a second key member) and the NCI Project Scientist. Each full member will have one vote. The members of the Steering Committee will select a chairperson (who cannot be an NCI Program staff member ).

The Steering Committee will be responsible for developing strategies to address issues common to all of the projects funded by this initiative. The Steering Committee will pay special attention to issues of data integration, management, analysis, and public release and may establish subcommittees as necessary.

Awardees under this FOA will be required to accept and implement policies approved by the Steering Committee to the extent consistent with the applicable grant regulations. 

The NCI Program staff members and the Steering Committee will organize and an annual meeting of the awardees of this initiative.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to 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 does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

3. Reporting

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

A final progress report, invention statement, and Financial Status Report are required when an award is relinquished when a recipient changes institutions or when an award is terminated.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later.  All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000.  See the NIH Grants Policy Statement for additional information on this reporting requirement. 

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.      

Application Submission Contacts

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading or navigating forms)
Contact Center Phone: 800-518-4726
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-435-0714
TTY 301-451-5936
Email: GrantsInfo@nih.gov

eRA Commons Help Desk(Questions regarding eRA Commons registration, tracking application status, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)
TTY: 301-451-5939
Email: commons@od.nih.gov

Scientific/Research Contact(s)

Gabriela Riscuta, M.D., C.N.S.
Nutritional Science Research Group
Division of Cancer Prevention
National Cancer Institute
6130 Executive Boulevard, Room 3152, MSC 7328
Bethesda, MD 20892-7328 (for U.S. Postal Service regular or express mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: (301) 594-9692
Fax: (301) 480-3925
Email: gabriela.riscuta@nih.gov

Phillip Daschner, Ph.D. 
Division of Cancer Biology
National Cancer Institute (NCI)
6130 Executive Boulevard, Suite 5014, MSC 7344 
Bethesda, MD 20892-7344 (for U.S. Postal Service regular or express mail) 
Rockville, MD 20852 (for non-USPS delivery)  
Telephone: (301) 496-1951
Email: daschnep@mail.nih.gov

Rina Das, Ph.D. 
Center to Reduce Cancer Health Disparities
National Cancer Institute (NCI)
6116 Executive Boulevard, Suite 602, MSC 8341 
Bethesda, MD 20892-8341 (for U.S. Postal Service regular or express mail) 
Rockville, MD 20852 (for non-USPS delivery)  
Telephone: (301) 496-8589
Email: dasr2@mail.nih.gov

Linda Duffy, Ph.D
Division of Extramural Research
National Center for Complementary and Alternative Medicine (NCCAM)
6707 Democracy Boulevard, Suite 401
Bethesda, MD 20892-5475
Office: 301 594-1285
Email: duffyl@mail.nih.gov

Peer Review Contact(s)

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

Financial/Grants Management Contact(s)

Heather Weiss
Office of Grants Administration 
National Cancer Institute 
6120 Executive Boulevard, Suite 243, MSC 6120 
Bethesda, MD 20892-6120 (for U.S. Postal Service regular or express mail) 
Rockville, MD 20852 (for non-USPS delivery)  
Telephone: (301) 496-7244
Fax:  (301) 496-8601
Email: weissh@mail.nih.gov

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: gt35v@nih.gov

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Authority and Regulations

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.


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