Centers of Cancer Nanotechnology Excellence

RFA Number: RFA-CA-05-024

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.nci.nih.gov/)

Announcement Type
New

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

• May 29, 2009 - This RFA has been reissued as (RFA-CA-09-012) .
• December 2, 2004 (NOT-CA-05-006) - NCI will hold a pre-application meeting for investigators planning to submit applications in response to RFA-CA-05-024.

Catalog of Federal Domestic Assistance Numbers
93.393, 93.399

Key Dates

Release Date: December 2, 2004
Pre-application Meeting Date: December 14, 2004
Letters-Of-Intent Receipt Date: February 25, 2005
Application Receipt Date: March 25, 2005
Peer Review Date: June/July 2005
Council Review Date: September 2005
Earliest Anticipated Start Date: September 2005
Additional Information To Be Available Date (URL Activation Date): Not Applicable
Expiration Date: March 26, 2005

Due Dates for E.O. 12372
Not Applicable

Executive Summary

The NCI invites applications from investigators interested in participating in an initiative to establish up to five Centers for Cancer Nanotechnology Excellence (CCNEs). The CCNEs will be a national resource that will integrate the basic and clinical sciences with engineering to develop and apply nanotechnology to cancer research to accelerate the application of this science to the clinic. Using the NIH U54 cooperative agreement mechanism, the NCI intends to commit approximately $90.8 M in FY 2005-2009 (approximately $20 M in FY 2005) to fund up to five CCNEs. Eligible organizations include for-profit or non-profit organizations; public or private institutions, such as universities, colleges, hospitals, and laboratories; units of State and local governments; eligible agencies of the Federal government; and domestic institutions and organizations. Foreign institutions may participate as subcontractors within a Center. Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with his or her institution to develop an application for support. An individual can be the PI on only one application submitted under this announcement. However, an individual may be listed as a participant in multiple CCNE applications provided that his/her research proposals are discrete. Application materials are available from the NIH Office of Extramural Research (OER); http://grants.nih.gov/grants/oer.htm. Telecommunications for the hearing impaired is available at: TTY 301-451-5936.

Table of Contents

Part I Overview Information

Part II Full Text of Announcement

Section I. Funding Opportunity Description
1. Research Objectives

Section II. Award Information
1. Mechanism(s) of Support
2. Funds Available

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

Section IV. Application and Submission Information
1. Address to Request Application Information
2. Content and Form of Application Submission
3. Submission Dates
A. Receipt and Review and Anticipated Start Dates
1. Letter of Intent
B. Sending an Application to the NIH
C. Application Processing
4. Intergovernmental Review
5. Funding Restrictions
6. Other Submission Requirements

Section V. Application Review Information
1. Criteria
2. Review and Selection Process
3. Merit Review Criteria
A. Additional Review Criteria
B. Additional Review Considerations
C. Sharing Research Data
D. Sharing Research Resources

Section VI. Award Administration Information
1. Award Notices
2. Administrative Requirements
A. Cooperative Agreement Terms and Conditions of Award
1. Principal Investigator Rights and Responsibilities
2. NIH Responsibilities
3. Collaborative Responsibilities
4. Arbitration Process
3. Award Criteria
4. Reporting

Section VII. Agency Contact(s)
1. Scientific/Research Contact(s)
2. Peer Review Contact(s)
3. Financial/ Grants Management Contact(s)

Section VIII. Other Information - Required Federal Citations

1. Research Objectives

Purpose

The NCI invites applications from investigators interested in participating in an initiative to establish up to five Centers for Cancer Nanotechnology Excellence (CCNEs). The CCNEs will be a national resource that will integrate nanotechnology development into basic and applied cancer research to facilitate the rapid application of this science in the clinic. Nanotechnology has potentially widespread application in cancer research and treatment, and this initiative will support the development of nanomaterials and nanoscale devices for molecular imaging and early detection, in vivo imaging, reporters of efficacy, multifunctional therapeutics, prevention and control, and research enablers. The intent of this RFA is to establish interdisciplinary research teams that collectively have the breadth of expertise to not only identify approaches, but to validate and translate nanotechnology for a variety of cancer applications, up to and including pre-clinical testing.

The over-arching goals of the CCNE initiative are to design and test nanomaterials and nanodevices and to translate their use into clinical research, resulting ultimately in the introduction of novel diagnostic tools and techniques to modulate and overcome cancer processes. The NCI's primary objective for this effort is to develop products and devices that constitute a new set of research tools for use by scientists in both the public and private sectors. In addition, it is anticipated that many of these developments will be made available to both public and private sector scientists as new diagnostic and therapeutic platforms. Outcomes objectives (performance measures) represent technologies that are developed and effectively utilized to overcome cancer processes.

On the basis of discussions with a wide range of clinicians, cancer researchers, and technologists, it is clear that virtually unlimited possibilities exist for using nanotechnology to solve mission-critical problems in cancer research. This initiative will increase the visibility and availability of nanomaterials and nanoscale device technology within the cancer research and development communities. This initiative will catalyze targeted discovery and development efforts that offer the greatest opportunity for advances in the near and medium terms and will lower the barriers for those advances to be translated to the private sector for commercial development. The CCNEs will be the hub of a network of translational research and development, addressing challenges in those areas where nanotechnology can have the biggest and fastest impact.

In this regard, the NCI recognizes that significant issues exist concerning intellectual property rights with respect to patentable inventions developed within the CCNE program. This subject is discussed more fully below. Within this context, however, it is the NCI's intent that inventors will exercise any intellectual property rights retained on inventions developed as part of the CCNE program in a way that will promote wide accessibility to and further development of the resources that are generated.

Background

Nanotechnology offers an unprecedented and paradigm-changing opportunity to study and interact with normal and cancer cells in real time, at the molecular and cellular scales, and during the earliest stages of the cancer process. As a result, nanotechnology will be a mission-critical tool to meet the NCI's Challenge Goal of eliminating death and suffering from cancer. Through the focused development of nanoscale devices or devices with nanoscale components, the following areas of cancer research will be advanced:

• Early imaging agents and diagnostics that will allow clinicians to detect cancer in its earliest, most easily treatable, presymptomatic stage;
• Systems that will provide real-time assessments of therapeutic and surgical efficacy for accelerating clinical translation;
• Multifunctional, targeted devices capable of bypassing biological barriers to deliver multiple therapeutic agents at high local concentrations, with physiologically appropriate timing, directly to cancer cells and those tissues in the microenvironment that play a critical role in the growth and metastasis of cancer;
• Agents capable of monitoring predictive molecular changes and preventing precancerous cells from becoming malignant;
• Novel methods for managing the symptoms of cancer that adversely impact quality of life; and
• Research tools that will enable investigators to quickly identify new targets for clinical development and predict drug resistance.

To enable nanotechnology to become a fundamental driver of advances in clinical oncology and cancer research, the NCI has developed a series of directed programmatic mechanisms known collectively as the NCI Alliance for Nanotechnology in Cancer (http://nano.cancer.gov). The Alliance is an integrated 5-year initiative to develop and apply nanotechnology to cancer prevention, detection, diagnosis, and treatment. The Alliance will support the creation and maintenance of the CCNEs, provide support necessary to train members of a cross-disciplinary workforce, and support directed research programs that employ nanotechnology for the detection and treatment of cancer. Specifically, the NCI seeks to address the following significant obstacles:

• The need for cross-disciplinary collaborations to enable the integration of the fundamental biological knowledge base with physical sciences and engineering approaches to address cancer processes
• The widening gap between discovery and early development of diagnostics and therapeutics;
• The requirement for cross-cutting technology platforms;
• The critical lack of available standards or publicly available datasets of characterized (e.g., physically, chemically, and physiochemically) nanoscale devices and their interactions with living systems; and
• The application and adaptation of extant technology to mission-oriented tasks.

The NCI recognizes that these translational initiatives will benefit greatly from a concerted and coordinated effort to characterize and standardize the wide range of nanoscale devices that are now available for use by the research community. A primary objective is to develop data on how nanomaterials and nanodevices interact with biological systems. These research endeavors will chart the common baseline and scientific data that would inform research and development (R&D) and define clinical and commercial pathways for integration of nanoscale diagnostics, imaging agents, and therapeutics. Moreover, this information will be linked to the Comprehensive Cancer Centers and related programs through public databases available through the Cancer Biomedical Informatics Grid [caBIG] http://cabig.nci.nih.gov/.

Through the creation of the CCNEs, the NCI aims to overcome biological barriers in cancer research by supporting the development and assessment of nanotechnology platforms. In the future, nanotechnology may become a core component in the training and translational programs at all leading cancer research institutions and a significant part of comprehensive cancer care.

Achieving this vision will also require training a cadre of researchers who are skilled in applying the tools of nanotechnology to critical problems in cancer research and clinical oncology. Given the complex nature of this endeavor, multidisciplinary teams will be essential to realize this vision, and the NCI supports the creation and development of multidisciplinary research teams for this initiative. Solicitation for career development of interested applicants who wish to participate in these teams will be provided by the NCI in a separate RFA (http://grants.nih.gov/grants/guide/rfa-files/RFA-CA-05-025.html).

Organizational Structure of the CCNEs

The CCNEs represent the core units of the NCI Alliance for Nanotechnology in Cancer (http://nano.cancer.gov). Each CCNE will be a virtual center, headed by a Principal Investigator (PI), and comprised of a network of laboratories and research facilities (academic and/or private sector) that represents various sites throughout the country or the world. The CCNEs will be established as collaborative research networks of investigators with complementary abilities organized to address one or more specific cancer nanotechnology platform needs. Applicants must provide a signed, binding agreement between all institutions comprising the CCNE to share knowledge, research materials, and any other resources necessary and relevant to the Center's particular focus.

Each CCNE must demonstrate the following critical components explicitly (provide examples and plans) and all components must be adequately addressed for an application to be eligible for peer review:

• A focus on cancer applications, as demonstrated through integration with an NCI-designated Cancer Center and/or Specialized Program of Research Excellence (SPORE) which are involved in each Center project, with established, formal arrangements for team interactions;
• Explicit affiliation(s) with academic or research centers of engineering or physical sciences (e.g., mathematics, chemistry, physics, computational and/or materials science) that are directly involved with and actively contribute to the Center projects (such a relationship is required for each proposed project but does not need to be unique for each);
• Nanomaterials fabrication/synthesis facilities and/or collaborative capabilities;
• Facilities and capabilities for animal models/small animal imaging;
• Biocomputing capabilities to support proposed projects and the capacity to link with the NCI's Cancer Biomedical Informatics Grid (caBIG); http://cabig.nci.nih.gov;
• Modules for integrative training (i.e., programs that provide and develop a knowledge base relevant to cancer biology that includes biophysics, materials engineering, and physical sciences e.g., graduate programs, courses, seminars, and workshops);
• Education and outreach programs to disseminate information to the clinical oncology community (e.g., CDs, pamphlets, web sites, seminars);
• Technology assessment capabilities to identify new nanomaterials for development;
• Existing private/not-for-profit technology development partnerships that are specific to the technologies proposed;
• Mechanisms to share students and postdoctoral fellows among participating labs; and
• A framework to disseminate the products (e.g., research tools, nanomaterials, or diagnostic devices).

NCI does not specify how these functions are to be organized. The applicant may choose to organize the proposed Centers in terms of separate Cores or in any other manner deemed appropriate for the implementation of an effective pipeline. However, the applicant must clearly address how the proposed organization of the Center will ensure that each of these functions is effectively accommodated. Because of the complexity of each CCNE, NCI program staff expect to visit each CCNE periodically to conduct an administrative site visit. U54 centers must be prepared for annual site visits and must budget appropriately (including travel for collaborators to participate on site and other necessary costs).

One overarching goal of the CCNEs is to provide an environment that will foster integration among the physical, biological, and clinical sciences with respect to nanoscience for cancer. As a whole, t he CCNEs will span the range from exploratory research to technology innovation and will involve a broad spectrum of disciplines such as engineering, mathematics, computer science, and the physical, biological, environmental, and materials sciences. Applicants must therefore demonstrate a commitment to, and a strategy for, engaging physical science, materials science, and engineering programs. Centers will bring together researchers with diverse expertise to address complex, interdisciplinary challenges involved with designing and testing nanomaterials and nanodevices in biological systems. CCNEs will integrate research with education both internally and through a variety of partnership activities, and each CCNE must have an overarching research and education theme, well-integrated programs, and a coherent and effective management plan.

CCNE applicants are strongly encouraged to take advantage of the range of existing opportunities in nanotechnology research and development through partnerships with other Federal agencies, such as the National Science Foundation (NSF); http://www.nsf.gov and the Department of Energy (DOE); http://www.energy.gov. Crosscutting national nanotechnology initiatives such as the NSF Nanoscale Science and Engineering (NSE); http://www.nsf.gov/home/crssprgm/nano/start.htm; http://www.nsf.gov/pubs/2004/nsf04043/nsf04043.htm and the DOE Nanoscale Science Research Centers (NSRCs); http://foundry.lbl.gov/nsrc/nsrc_prog.html offer opportunities for partnerships commensurate with those expected from the CCNEs. The NSE and DOE programs are components of the National Nanotechnology Initiative (http://www.nano.gov/), a multi-agency framework of nanotechnology research that may serve as a resource for applicants to this RFA.

In addition to the functions described above, there are a number of other issues important to the successful operation of the CCNEs that should be addressed separately in the application. Details of the governance structure for the CCNEs, which includes Center-specific Steering Committees and CCNE Coordinating and Governance Committee to oversee all Centers, are provided in Section VI.2.A., Cooperative Agreement Terms and Conditions of Award. To assist with these activities, the NCI will appoint program staff scientists consisting of a Program Director who will have responsibility for normal program oversight and stewardship of the CCNEs and one or more NCI Project Scientists to have substantial scientific involvement during the conduct of this activity above and beyond normal program stewardship for grants.

Applicants will be required to submit an intellectual property management plan and a plan to disseminate research results as a condition of award (just-in-time requirements). Details of these requirements are found in Section IV.6, Other Submission Requirements.

Objectives

The NCI will facilitate the use of nanotechnology to accelerate the discovery and development of research tools, diagnostic tools, and therapeutic agents (e.g., ligands, imaging probes, and nanoscale devices) that will reduce the suffering and death due to cancer. It is anticipated that the CCNEs will catalyze scientific breakthroughs that will contribute to the creation of materials or devices that have potential benefit for the development of therapeutics or diagnostics by the private sector. In accordance with the principles of the Alliance, the NCI has identified six thematic/programmatic areas of focus for directed nanotechnology-based research platforms (detailed below) where nanotechnology can have pronounced short- and long-term impacts.

The examples listed below in each of thematic/programmatic area represent a subset of the potential applications in which NCI's goals could be pursued. The specific cancer nanotechnology applications described under each thematic/programmatic area illustrate the diverse tools and strategies of cancer nanotechnology research supported by this RFA and are not meant to be comprehensive.

Thematic/programmatic areas of focus for nanotechnology in cancer include:

1) Molecular imaging and the early detection of cancer - Novel nanotechnologies can complement and augment existing genomic and proteomic techniques to analyze variations across different tumor types, thus offering the potential to distinguish between normal and malignant cells. Sensitive biosensors constructed of nanoscale components (e.g., nanocantilevers, nanowires, and nanochannels) can recognize genetic and molecular events and have reporting capabilities, thereby offering the potential to detect rare molecular signals associated with malignancy. Such signals may then be collected for analysis by nanoscale harvesters that selectively isolate cancer-related molecules from tissues. Another area with near-term potential for early detection is the identification of mutations and genomic instability in situ .

2) In vivo imaging - A pressing need in clinical oncology is for imaging methods (e.g., optical, magnetic resonance-based, ultrasound) that can identify tumors that are orders of magnitude smaller than those detected with current technology. When utilized in conjunction with powerful contrast agents, and coupled with nanoparticles such as dendrimers, these methods can improve targeting capability and increase signal intensity. In the future, implantable nanoscale biomolecular sensors may enable clinicians to more carefully monitor the disease-free status of patients who have undergone treatment or individuals susceptible to cancer because of various risk factors. Furthermore, imaging agents that target changes in the environment surrounding a tumor, such as angiogenesis, will further augment methodologies and will be invaluable to obtain optimal benefit from therapeutics that target such specific cancer-related processes.

3) Reporters of therapeutic efficacy - Nanotechnology offers the potential to develop highly sensitive imaging-based devices and ex vivo diagnostics that can determine whether a therapeutic agent is reaching its intended target and whether that agent is killing malignant or support cells. Optical imaging devices that use nanoscale agents may also enable surgeons to more readily detect the margins of a tumor prior to resection or to detect micrometastases in lymph nodes or tissues distant from the primary tumor. Nanoparticle-based systems to detect apoptosis or reactivation of the critical tumor suppressor systems and targeted nanoparticles that can bind to a tumor and be re-released into the bloodstream as tumor cells undergo apoptosis following therapy represent another potential application of nanotechnologies as reporters of efficacy.

4) Multifunctional therapeutics . Because of their multifunctional capabilities, nanoscale devices can contain both targeting agents and therapeutic payloads, particularly in areas of the body that are difficult to access because of a variety of biological barriers, including those developed by tumors. Multifunctional nanoscale devices also offer the opportunity to utilize new approaches to therapy, such as localized heating or reactive oxygen generation, and to combine a diagnostic or imaging agent with a therapeutic and/or a reporter of therapeutic efficacy. Smart nanotherapeutics may provide clinicians with the ability to time the release of an anticancer drug or deliver multiple drugs sequentially in a timed manner or at several locations in the body, potentially ushering in an era of sustained therapy for cancers that must be treated chronically. Such nanotherapeutics could also house engineered cellular factories that make and secrete proteins and other antigrowth factors that impact a tumor and/or its immediate environment. Many nanotherapeutics (e.g., nanoparticulate hydrogels, nanoparticles, and quantum dots) can also double as imaging agents.

5) Prevention and control of cancer - Many of the advances that nanotechnology will enable in each of the four preceding areas will also find widespread applicability in efforts to prevent and control cancer. Once specific biomarkers of cancer susceptibility and precancerous lesions have been identified, nanotechnology can enable devices that signal their presence and deliver targeted therapy. Nanoscale devices may also prove valuable for delivering or mimicking polyepitope cancer vaccines that engage the immune system or cancer-preventing nutraceuticals or other chemopreventive agents in a sustained, timed-release, and targeted manner.

6) Research enablers - Nanotechnology offers a wide range of tools, from chip-based nanolabs capable of monitoring and manipulating individual cells to nanoscale probes that can track the movements of cells, and even individual molecules, as they move about in their environments. Using such tools will enable cancer biologists to study, monitor, and alter the multiple systems that are implicated in cancer processes and to identify key biochemical and genetic targets for future molecular therapies. As such, nanotechnology can complement other technology platforms, such as proteomics and bioinformatics. Another near-term application of nanotechnology to accelerate basic research is to use molecular-size nanoparticles with wide ranges of optical properties (e.g., quantum dots) to track individual molecules or cells as they move through local environments, thereby monitoring multiplexed cellular and molecular events in real time. When combined with mouse models that reproduce the genetic, biochemical, and physiological properties of human cancers, these nanolabels will be useful for integrative, systems biology research. Finally, nanoscale devices that enable simultaneous biochemical measurements (e.g., time, size, dynamic events) on multiple cells, particularly those grown in such a way as to mimic tissue development in vivo , will open new dimensions to basic cancer research.

Project Design

Successfully applying nanotechnology to cancer research requires an understanding of how synthetic materials interface with biological systems. Thus, each CCNE will be required to demonstrate expertise with both the biological and non-biological aspects of this work. Applicants must clearly describe how their proposals will address fundamental principles of cancer biology (e.g., protein synthesis and assembly, apoptosis, DNA repair, angiogenesis, cell cycle regulation) at the molecular and sub-cellular levels. Emphasis should be placed on why the approach is revolutionary within the context of related research and how it will overcome biological barriers and interfere with the biological processes involved in carcinogenesis.

In a general sense, applications must include:

• A pre-formed group of named investigators that will interact as a multidisciplinary team;
• A nanotechnology* or nanomaterials synthesis/fabrication component;
• An application to cancer research, with an emphasis on translational research;
• A focus toward ultimate application in clinical care (e.g., preparation of nanomaterials for future use in clinical trials); and
• A framework to disseminate the products developed at the CCNEs (e.g., research tools, nanomaterials, or diagnostic devices), defined explicitly in letters of commitment and/or signed consortia agreement from each participating institution.

* To be characterized as nanotechnology under this solicitation, the following criteria must be met: 1) Applicants must propose devices or base materials that are less than 1000 nm in size although the assembly, synthesis, and/or fabrication of components at dimensions less than 300 nm should be demonstrated and 2) Projects must incorporate synthetic materials or biomaterials engineered to provide novel properties or modified functions based on nanoscale size, i.e., nanomaterials. Projects that propose only the use of naturally-occurring materials (e.g., carbohydrates, proteins, viruses) that are not specifically engineered or modified for a biomedical application will not be considered. Furthermore, projects focused primarily on genetic engineering or gene therapy (e.g., DNA sequencing or gene vector methods) are not appropriate for these Centers. For the purposes of this application, applicants are encouraged to use the National Nanotechnology Initiative (NNI); http://nano.gov/html/facts/whatIsNano.html definition as a guideline.

More specifically, applicants must select one or more of the six thematic/programmatic areas of focus for directed nanotechnology-based research programs as described previously: molecular imaging/early detection, in vivo imaging, reporters of efficacy, multifunctional therapeutics, prevention and control, and research enablers. Within the context of the area(s) identified, the homeostatic changes in the cancer cell that Center research will address (e.g., apoptosis, protein folding and assembly, DNA repair, recognition of mutational deletions in lymphocytes, loss of heterozygosity) must be defined clearly. Applicants must describe how the proposed research will modulate or measure these changes at the sub-cellular and molecular levels in terms of the biology and chemistry involved (e.g., energy transfer and cellular thermodynamics, surface properties and phenomena, molecular self-assembly). In addition, applicants must demonstrate how the proposed approach is a revolutionary way to address these issues.

Applicants must then propose a multidisciplinary team of researchers that will comprise a CCNE, with a single PI, that meets the Center critical components listed in the following section, Organizational Structure of the CCNEs. This team must include representatives of fields necessary to complete the proposed basic research and translational projects, and it should include expertise from these areas: molecular biology, chemistry, physics, materials science, biomedical engineering, computational science, clinical oncology, and mathematics. Involvement of basic and clinical scientists and engineers who may not have a specific record in cancer research, but who possess the potential to provide experience crucial to the success of the CCNE, is encouraged.

For each CCNE, a minimum of five (and as many as eight) projects focused on multiple nanotechnology platforms should be proposed for the first year, each with discrete, quantitative milestones and a dedicated research team. The individual Center Steering Committee will review and select projects to support on a rolling basis, such that the Center will always maintain five to eight active projects. Applications must include explicit discussions of both the specific aims of the research projects and the applicant's efforts to forge creative new links between disciplines. Applicants must also provide a set of quantitative milestones for the CCNE as a whole and a plan to assess overall Center progress.

Within the context of the specific directed research program(s) identified, each CCNE will offer the full range of support necessary to develop products suitable for clinical trial testing, including:

• Creating or supplying the appropriate starting materials, such as relevant nanomaterials (e.g., contrast agents for imaging or nanoshells for targeted delivery) or prototype research tools (e.g., simulated biological systems that can be used to model drug disposition, trafficking, or systems biology);
• Establishing proof-of-concept through in vitro studies;
• Conducting in vivo studies in animal models, including safety profiles and toxicology studies;
• Conducting pharmacologic studies (e.g., pharmacodynamic and pharmacokinetics) studies necessary for pre-clinical trials;
• Conducting in situ studies using animal models; and
• Providing quality assurance and control and proof of reproducibility.

Note: This initiative will not support clinical trials or in vivo studies in human subjects. However, in vitro investigations that employ clinical biospecimens or the theoretical modeling of human systems are within the scope of activities that will be considered for support by this initiative.

Partnerships

The CCNEs will increase the ability of investigators in the public and private sectors to deploy nanotechnology in basic biological research and to translate the resultant findings into discovery and therapeutics development for cancer. While the CCNEs are expected to provide a comprehensive array of pre-clinical technology evaluation services, the Centers will be integrated with NCI-supported resources that includes Comprehensive Cancer Centers (http://www3.cancer.gov/cancercenters/), Specialized Programs of Research Excellence (http://spores.nci.nih.gov/), and the Early Detection Research Network (http://www3.cancer.gov/prevention/cbrg/edrn/). CCNEs will also engage with relevant NCI initiatives such as the Developmental Therapeutics program (http://dtp.nci.nih.gov/docs/raid/raid_index.html), the Academic Public Private Partnership Program (http://grants2.nih.gov/grants/guide/rfa-files/RFA-CA-04-005.html), the Development of Clinical Imaging Drug Enhancers program (http://www3.cancer.gov/bip/dcide.htm), the Integrative Cancer Biology Program (http://dcb.nci.nih.gov/branchdetail.cfm?branch=1), In vivo Cancer Molecular Imaging Centers (http://imaging.cancer.gov/programsandresources/specializedinitiatives/icmics), the Innovative Molecular Analysis Technologies program (http://otir.nci.nih.gov/tech/imat.html), Unconventional Innovations Program (http://otir.nci.nih.gov/tech/uip.html), the Fundamental Technologies for Biomolecular Sensors program (http://otir.nci.nih.gov/tech/ftbs.html), and the Mouse Models of Human Cancer Consortium (http://emice.nci.nih.gov/), that will increase the visibility of availability of nanomaterials and nanoscale device technology within the cancer research and development communities. The CCNEs will therefore serve as hubs to integrate and assimilate nanotechnologies for cancer application, conducting the testing necessary to support investigational new drug (IND) applications and becoming the pivot points to usher new materials and technologies into clinical development. As such, collaboration with these and other programs is strongly encouraged, and applicants should identify mechanisms and approaches that will be used to promote and enable collaboration.

The CCNEs are also encouraged to interface with the Nanotechnology Characterization Laboratory for Cancer Research (NCL), a resource developed by the NCI in partnership with the National Institute for Standards and Technology (NIST) to perform preclinical characterization of nanoscale devices in a way that will accelerate regulatory review and translation of these devices into the clinical realm. The NCL will develop an assay cascade that can serve as the universal protocol for preclinical toxicology, pharmacology, and efficacy testing of nanoscale devices. This assay cascade will characterize a nanoscale device's physical attributes, in vitro biological properties, and in vivo compatibility. In carrying out these functions, the NCL will provide a comprehensive set of baseline characterization parameters that will enable researchers to apply these tools to clinical oncology, while establishing a scientific foundation that will help provide a pathway for clinical development and commercialization concerning the testing and approval of nanoscale cancer diagnostics, imaging agents, and therapeutics. When appropriate, CCNEs are encouraged to use the NCL characterization resources for nanoscale technologies developed and tested at the CCNEs.

The CCNEs will describe existing as well as planned partnerships with private/not-for-profit technology development partners that are specific to the technologies proposed. The applicant must describe the role of commercial partners in the development of the proposed technology platforms. Applicants may also consider SBIR program partners as a means of leveraging resources for cancer technology development and commercialization.

Progress Reviews Milestones and Evaluations

The progress of the CCNEs will be reviewed annually by the NCI Program Director and Project Scientists to assure that satisfactory progress is being made in achieving the project objectives. During the first year of funding, and during subsequent years if deemed necessary by the Program Officer(s) as described above, reviews may be more frequent. The adherence of the CCNEs to the approved data sharing plan and intellectual property plans, which will be part of the Terms and Conditions of award (see Section VI.3. Award Criteria) , will also be reviewed annually. Should problems arise in the conduct of the study, the NCI Program Director may require that the Center awardee submit quarterly reports on progress and fiscal matters.

Quantitative Milestones. All applications must include a specific section labeled Milestones for each proposed project in the Center. Milestones should be annual, well-described, quantitative, and scientifically justified and not simply a restatement of the specific aims. Rather, the milestones should offer a timeline and a pathway for the development of the proposed technology. These milestones will be used to judge the success of the proposed research on an individual-project basis and evaluate the criteria for the program. Applications that lack this information as determined by the NCI program staff will be returned to the applicant without review.

As evaluation of progress is an increasing priority for NCI, CCNEs will be required to participate in global Center evaluation activities that will be established and conducted by the CCNE Coordinating and Governance Committee in conjunction with NCI Program Officers and staff. Outcomes include: peer-reviewed publications, applied model development, new intervention formats, new research tools, and opportunities for effective dissemination. The purpose of the evaluation component is to monitor and assess the performance of the CCNEs in achieving the goals of this RFA. This component includes evaluating the quality and innovation of the science conducted at the CCNEs, as well as assessing critical intermediate indicators of success, such as infrastructure development and capacity building, career development, linkages and resource and data sharing arrangements within and among Centers, and the interdisciplinary and multilevel nature of the research. Criteria for the evaluation component will be developed in partnership between the CCNE Coordinating and Governance Committee and NCI program staff.

Objective criteria for the evaluation component will include the extent to which: 1) the overall capacity to employ nanotechnology to understand and intervene in the mechanisms of carcinogenesis in the CCNEs has increased as a result of the new funding; 2) collaborative relationships within and among Centers have been established and institutionalized; 3) training and career development opportunities exist for new and established investigators; 4) a transdisciplinary research culture has been engendered that takes into account multiple levels of analysis; and 5) CCNE investigators' ability to compete for future research project grants and participate in other research mechanisms has been enhanced.

The evaluation will also examine intermediate markers of the importance and potential impact of the science conducted by CCNE investigators in deploying nanotechnologies to prevent, detect, diagnose, and treat cancer. Possible metrics include: 1) the design of new cancer diagnostic tools; 2) the fabrication and testing of novel nanomaterials for cancer research; 3) new treatments or interventions; and 4) novel and/or improved models of human cancers.

The progress report will have two components. The first will be the standard NIH progress report (Form 2590). The second will be a more specialized report that will be developed by the CCNE Coordinating and Governance Committee. This specialized report should be included as an attachment to the standard progress report and will go to the NCI Program Director.

The contents or the report may be changed according to programmatic needs based on discussion among NCI Program Officers, the Center PI, and the CCNE Coordinating and Governance Committee.

The Center awardees' yearly milestones will be provided to the NCI Program Director and the CCNE Coordinating and Governance Committee. It is expected that the milestones will be adjusted annually at the award anniversary dates to incorporate the group's scientific accomplishments and progress and to reflect any recommendations of the Coordinating and Governance Committee. Following the review of milestones, the NCI may recommend reducing or withholding funds for any Center or specific Center project that substantially fails to meet its milestones or, if the situation warrants, augmenting any Center or specific Center project. However, simply meeting milestones may not be considered sufficient accomplishment for maintaining funding at the initially committed level. Failure to remain at state-of-the-art will also be considered grounds for reduction or cessation of funding.

1. Mechanism of Support

This funding opportunity will use the NIH U54 award mechanism. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project.

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

The NIH U54 is a cooperative agreement award mechanism. In the cooperative agreement mechanism, the Principal Investigator 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

The NCI intends to commit approximately $90.8 M in FYs 2005-2009 (approximately $20M in FY 2005) to fund up to five Centers of Cancer Nanotechnology Excellence. An applicant should request a project period of 5 years. The budget may not exceed $5 million in total costs per year. Costs for equipment may be included in year 1, up to $500,000; these costs will not count against the $5,000,000 total cost limit but should be well justified. Applicants should include travel funds in the budget for the annual site visit, annual CCNE meetings, and CCNE Coordinating and Governance Committee meetings.

This RFA is a one-time solicitation, and plans for this initiative beyond the current funding opportunity are indefinite. The NCI may expand or reduce the scope and direction of the CCNEs by amendment during the course of the 5-year period of set-aside funding, terminate it upon expiration, or extend or expand it prior to expiration by reissuing the RFA soliciting competitive applications for translational research for nanotechnology in oncology. It is anticipated that individual projects of a CCNE will mature, complete aims, add new aims, end, and/or be replaced by other projects. Developments that successfully translate to clinically feasible or research-oriented instruments and methods are expected to stimulate investigator-initiated applications for clinical and basic research grants under other support mechanisms, such as the R01, R21, R21/R33, R33, R41, R42, R43, and R44.

Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size of each award will also vary. Although the financial plans of the NCI provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications.

1. Eligible Applicants

1.A. Eligible Institutions

You may submit (an) application(s) if your organization has any of the following characteristics:

• For-profit organizations
• Non-profit organizations
• Public or private institutions, such as universities, colleges, hospitals, and laboratories
• Units of State government
• Units of local government
• Eligible agencies of the Federal government
• Domestic Institutions only
• Faith-based or community-based organizations

Foreign institutions may participate only as subcontractors within Centers.

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their 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.

An individual can be the PI on only one proposal submitted under this announcement. However, an individual may be listed as a participant in multiple CCNE applications provided that his/her research project activities within those centers are entirely discrete. An individual may not propose overlapping research projects on multiple applications.

2. Cost Sharing

This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part2.htm.

3. Other-Special Eligibility Criteria

Applications must demonstrate a Center composition that meets the criteria and possesses sufficient capabilities as explicitly defined in this RFA to be eligible for merit review of proposed Center projects and activities (see Organizational Structure of the CCNE, above).

Programs will be expected to have a Center-specific Steering Committee, including experts outside the project. While a description of the Steering Committee's activities should be included in the application, potential members of the Steering Committee should not be named, contacted, or selected until an award has been made. This stipulation will allow a wider pool of potential reviewers of the application. Costs for activities of the Steering Committee should be included in the budget.

1. Address to Request Application Information

The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance, contact GrantsInfo, Telephone: (301) 710-0267, Email: [email protected]. Applicants are strongly encouraged to reference http://grants.nih.gov/grants/guide/notice-files/NOT-OD-05-006.html which describes the revisions in the PHS 398 form as of 09/2004.

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

2. Content and Form of Application Submission

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

The title and number of this funding opportunity must be typed on line 2 of the face page of the application form and the YES box must be checked.

Given the multicomponent nature of this RFA, applicants should structure the application as follows:

Part A Overall CCNE Organizational Framework : Describe composition, leadership, integration, focus, and core structural requirements (see Organizational Structure of the CCNEs ). Applications should include a face page listing all key personnel (p.2 and continuation page) and level of effort by each team member by project and explicitly identify one or more of the thematic/programmatic areas in the Objectives section of this RFA; abstract page; overall budget (including all proposed projects, core support functions, and travel), listing direct and indirect costs separately; and Center-specific milestones. Part A is limited to a maximum of 40 pages.

Part B CCNE Projects : Number each proposed project (minimum of five) sequentially and include its own face page, abstract page (Form p.2), budget, and project-specific milestones. Each project is limited to a maximum of 25 pages for sections a-d.

Part C CCNE Core Support Functions : Include capability examples and development plans for education, training, dissemination, technology assessment, and partnership development, with budget details and specific milestones for each. Identify budget and resources set aside for Alliance activities, including CCNE Coordinating and Governance Committee meetings and activities, annual CCNE meeting, and annual CCNE site visits (all participating institutions must be present). Each Core is limited to 10 pages for the description of each Core Support function, with a maximum of 50 pages for Part C.

Appendices should be comprised of unbound materials with separators between documents, collated by project.

3. Submission Dates
Applications must be received on or before the receipt date described below in Section IV.3.A.

3.A. Receipt, Review and Anticipated Start Dates

Release Date: December 2, 2004
Pre-Application Meeting Date: December 14, 2004
Letters Of Intent Receipt Date: February 25 2005
Application Receipt Date: March 25, 2005
Peer Review Dates: June/July 2005
Council Review Date: September 2005
Earliest Anticipated Start Date: September 2005

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 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 at the beginning of this document.

The letter of intent should be sent to:

Gregory J. Downing, D.O., Ph.D.
Director, Office of Technology and Industrial Relations
Office of the Director
National Cancer Institute, NIH, DHHS
Building 31, Room 10A-52, MSC 2580
31 Center Drive
Bethesda, MD 20892-2580
Telephone: (301) 496-1550
FAX: (301) 496-7807
E-mail: [email protected]

Pre-Application Meeting

A pre-application meeting will be held on December 14, 2004, at the Natcher Conference Center on the NIH campus in Bethesda, MD, to help communicate the goals of this RFA and answer questions for potential applicants. Attendance at the pre-application meeting is not required to submit an application in response to this RFA. The meeting will be open to the public and webcast. The specific time and agenda will be posted on the NCI Alliance for Nanotechnology in Cancer web site, http://nano.cancer.gov.

3.B. Sending an Application to the NIH

Applications must be prepared using the PHS 398 research grant application instructions and forms as described above. 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)

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

Referral Office
National Cancer Institute
Division of Extramural Activities
6116 Executive Boulevard, Room 8041, MSC 8329
Bethesda, MD 20892-8329
Rockville, MD 20852 (for express/courier service)
Telephone: (301) 496-3428
FAX: (301) 402-0275
Email: [email protected]

Appendices should be comprised of unbound materials with separators between documents.

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

3.C. Application Processing

Applications must be received on or before the application receipt date listed in the heading of this funding opportunity. If an application is received after that date, it will be returned to the applicant without review.

Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NCI. Incomplete and/or non-responsive applications will not be reviewed.

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

Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks.

4. Intergovernmental Review
This initiative is not subject to intergovernmental review.

5. Funding Restrictions

All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm (see also Section VI.3. Award Criteria).

6. Other Submission Requirements

It is recognized that the applications in response to this RFA will be longer and more complex than those of many other NIH applications. To ensure effective review, the application should be well organized as described in Section IV.2. In particular, each of the functions identified earlier in the RFA in the section Organizational Structure of the CCNEs must be clearly addressed.

For cooperative agreements, awardees must agree to the "Cooperative Agreement Terms and Conditions of Award" in Section VI.3 Award Criteria. Other submission requirements are described in detail below.

Plan for Sharing Research Data

The precise content of the data-sharing plan will vary, depending on the data being collected and how the investigator is planning to share the data. Applicants who are planning to share data may wish to describe briefly the expected schedule for data sharing, the format of the final dataset, the documentation to be provided, whether or not any analytic tools also will be provided, whether or not a data-sharing agreement will be required and, if so, a brief description of such an agreement (including the criteria for deciding who can receive the data and whether or not any conditions will be placed on their use), and the mode of data sharing (e.g., under their own auspices by mailing a disk or posting data on their institutional or personal web site, through a data archive). Investigators choosing to share under their own auspices may wish to enter into a data-sharing agreement. References to data sharing may also be appropriate in other sections of the application.

All applicants are expected to include a plan for sharing research data in their application. The data sharing policy is available at http://grants.nih.gov/grants/policy/data_sharing. All investigators responding to this funding opportunity should include a description of how final research data will be shared, or explain why data sharing is not possible.

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

Sharing Research Resources

NIH policy requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication. See the NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2003/index.htm and at http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.htm#_Toc54600131. Investigators responding to this funding opportunity are expected to include a plan for sharing research resources addressing how unique research resources will be shared or explain why sharing is not possible.

The adequacy of the resources sharing will be considered by Program staff of the NCI when making recommendations about funding applications. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590, http://grants.nih.gov/grants/funding/2590/2590.htm). See Section VI.3. Award Criteria.

Dissemination of Research Results

This initiative encourages investigators to facilitate translating effective interventions and tools into practice. As part of the NCI's commitment to the rapid translation of research evidence into practice, applicants should include explicit plans to disseminate research results into practice.

Guidance for Preparation of Research Tools Sharing Plan and Intellectual Property Plan.

Restricted availability of unique research resources, upon which further studies are dependent, can impede the advancement of research. The NIH is interested in ensuring that the research resources developed through this grant also become readily available to the broader research community in a timely manner for further research, development, and application, in the expectation that this will lead to products and knowledge of benefit to the public health.

Investigators conducting biomedical research frequently develop unique research resources. The policy of the NIH is to make available to the public the results and accomplishments of the activities that it funds. To address this interest in ensuring research resources are accessible, NIH expects applicants who respond to this RFA to submit a plan: (1) for sharing the research resources generated through the grant (e.g., human biospecimens and novel cancer biomarkers); and (2) addressing how they will exercise intellectual property rights, should any be generated through this grant, while making such research resources available to the broader scientific community consistent with this initiative. Therefore, such research resources tools sharing plan and intellectual property management plans would make unique research resources readily available for research purposes to qualified individuals within the scientific community in accordance with the NIH Grants Policy Statement (http://grants.nih.gov/grants/policy/ and the Principles and Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining and Disseminating Biomedical Research Resources: Final Notice, December 1999 http://ott.od.nih.gov/NewPages/64FR72090.pdf) ( NIH Research Tools Guidelines Policy ). These documents also: (1) define terms, parties, and responsibilities; (2) prescribe the order of disposition of rights and a chronology of reporting requirements: and (3) delineate the basis for and extent of government actions to retain rights. Patent rights clauses may be found at 37 CFR Part 401.14 and are accessible from the Interagency Edison web page (http://www.iedison.gov); see also, 35 USC 210(c); Executive Order 12591, 52 FR 13414 (Apr. 10, 1987); and Memorandum on Government Patent Policy (Feb. 18, 1983). If applicant investigators plan to collaborate with third parties, the research tools sharing plan would need to address how such collaborations would not restrict their ability to share research materials produced with NIH funding. The applicant's institution should avoid exclusively licensing those inventions that are research tools, unless either: (1) the field of use of the exclusive license is restricted to commercial use, or (2) the exclusive licensee will make the research tool available on reasonable terms.

Intellectual property management plans are a just-in-time requirement; it is not necessary to include the final plan approved by all parties in the grant application, but final, approved plans will be expected before a U54 grant can be awarded.NIH program staff will consider the adequacy of the plans in determining whether to recommend an application for award. The approved plans would become a condition of the grant award and Progress Reports must contain information on activities for the sharing of research resources and intellectual property.

In the development of any research resource sharing and intellectual property management plans, applicants should confer with their institutions' office(s) responsible for handling technology transfer related matters and/or sponsored research. If applicants or their representatives require additional guidance in preparing such plans, they are encouraged to make further inquiries to the appropriate contacts listed above for such matters. Further, applicants may wish to independently research and review examples of approaches considered by other institutions such as those described on the NCI Technology Transfer Branch web site (http://ttc.nci.nih.gov/intellectualproperty/). The foregoing guidance is provided by way of example to assist applicants in preparing the expected research resources sharing and intellectual property management plans in a manner that encourages partnerships with industry. While these approaches will likely suit most situations, these approaches are not exclusive and applicants should feel free to submit alternative versions for consideration.

The majority of transfers to not-for-profit entities should be implemented under terms no more restrictive than the Uniform Biological Material Transfer Agreement (UBMTA). In particular, recipients are expected to use the Simple Letter Agreement (SLA) provided at http://ott.od.nih.gov/NewPages/SimplLtrAgr.pdf, or another document with no more restrictive terms, to readily transfer unpatented tools developed with NIH funds to other recipients for use in NIH-funded projects. If the materials are patented or licensed to an exclusive provider, other arrangements may be used, but commercialization option rights, royalty reach-through rights, or product reach-through rights back to the provider are inappropriate. Similarly, when for-profit entities are seeking access to NCI-funded tools for internal use purposes, recipients should ensure that the tools are transferred with the fewest encumbrances possible. The Simple Letter Agreement (SLA) may be expanded for use in transferring tools to for-profit entities, or simple internal use license agreements with execution or annual use fees may be appropriate.

1. Criteria

Only the review criteria described below will be considered in the review process. Only those applications demonstrating a Center composition that meets the criteria and possesses sufficient capabilities as explicitly defined in this RFA will continue through review (see Organizational Structure of the CCNE , above).

2. Review and Selection Process

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

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

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

3. Merit Review Criteria

The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. The scientific review group will address and consider each of these criteria in assigning the application's overall score, weighting them as appropriate for each application.

• Significance
• Approach
• Innovation
• Investigator
• Environment
• Additional Review Criteria

The application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward.

The scientific review group will address and consider each of the above criteria with respect to the proposed CCNE framework , projects , and core support functions in assigning the application's overall score, weighting them as appropriate for each application.

CCNE Framework

Significance: Does the CCNE address an important cancer problem with development and application of nanotechnology to cancer? If the milestones of the CCNE are achieved of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive the use of nanotechnology approaches in cancer research?

Approach: Are the conceptual framework, design, methods, and capabilities adequately defined and developed, well integrated, and appropriate to the aims of the overall application, within the limits inherent in an emerging, complex approach to cancer research? Does the applicant acknowledge potential problem areas and consider alternative tactics? Is the governance plan appropriate for a large-scale, highly integrated CCNE of this type? Do the individual components exhibit a high degree of interrelatedness and synergy? Are the proposed core facilities and collaborative capabilities adequate and essential to the proposed focus of the CCNE?

Will the CCNE serve as a model for cross-disciplinary activities? Is there evidence of strong interaction and feedback among the CCNE's collaborating academic or research centers in bioengineering or the physical sciences? Is there an adequate plan to disseminate the nanotechnology products that will be produced by the CCNE?

Innovation: Does the proposed CCNE employ novel concepts, approaches or methods? Are the aims original and innovative? Does the CCNE challenge existing collaborative paradigms and effectively integrate across scientific and clinical disciplines? Does the CCNE demonstrate an adequate plan to identify and attract new nanotechnologies for development?

Investigators: Is the Principal Investigator appropriately trained and well-suited to lead and coordinate a Center program of this size and complexity? Does the overall research team have sufficient expertise in all the critical aspects of this undertaking?

Environment: Does the scientific environment of the proposed CCNE contribute to the probability of success? Is there strong evidence of institutional support and interdisciplinary interactions? Is the CCNE that is being developed recognized as a major element within the organizational structure of the institution?

CCNE Projects

Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field?

Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics?

Innovation: Do the proposed projects employ novel concepts, approaches or methods? Are the aims original and innovative? Do the projects challenge existing paradigms or develop new methodologies or technologies? Do projects include clear plans for translation to clinical application?

Investigators: Are the investigators appropriately trained and well suited to carry out this work? Are the projects proposed apposite to the experience and expertise of the principal investigator and other researchers and team members?

Environment: Does the scientific environments of the proposed CCNE in which the project work will be done contribute to the probability of success? Do the proposed projects take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support?

CCNE Core Support Functions

Significance: Are there examples of and plans identified for translating research advances and knowledge of key technologies across disciplines and particular to clinicians? Will the CCNE establish adequate portals for education, training, and potential input?

Approach: Are the conceptual framework, design, methods, and core support capabilities adequately defined and developed, well integrated, and appropriate to the aims of the overall application, within the limits inherent in an emerging, complex approach to cancer research? Is the training and outreach plan appropriate (i.e., is it likely to meet the needs of the CCNE and the scientific community in cancer and the application of nanotechnologies? Does it integrate well with and leverage existing educational and training resources at the CCNE?

Innovation: Do the proposed education, training and dissemination efforts employ novel concepts, approaches or methods? Are the aims truly cross-disciplinary, original and innovative? Do the projects challenge existing paradigms or develop new methodologies or technologies?

Investigators: Are the investigators directly involved in planning and executing cross-disciplinary training, education, and dissemination of technology development and research results?

Environment : Are there mechanisms in place for the sharing of researchers, students and post doctoral fellows among participating labs and/or institutions in the CCNE?

3.A. Additional Review Criteria:

In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score:

Protection of Human Subjects from Research Risk: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. See also (see the Research Plan, Section VIII - Other Information on Human Subjects in the PHS Form 398).

Inclusion of Women, Minorities and Children in Research: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated. See also (see the Research Plan, Section VIII-Other Information on Human Subjects in the PHS Form 398).

Care and Use of Vertebrate Animals in Research: If vertebrate animals are to be used in the project, the five items described under Section F of the PHS Form 398 research grant application instructions will be assessed.

3.B. Additional Review Considerations

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

3.C. Sharing Research Data

Data Sharing Plan: The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. Reviewers will factor the proposed data sharing plan into the determination of scientific merit or the priority score. A final data sharing plan will be part of the terms and conditions of the award. The funding organization will be responsible for monitoring the data sharing policy (http://grants.nih.gov/grants/policy/data_sharing).

3.D. Sharing Research Resources

NIH policy requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication. See the NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2003/index.htm and at http://www.ott.nih.gov/policy/rt_guide_final.html. Investigators responding to this funding opportunity are expected to include a sharing research resources plan addressing how unique research resources will be shared or explain why sharing is not possible

The adequacy of the both the data and resources sharing plans will be considered by Program staff of the funding organization when making recommendations about funding applications. Program staff may negotiate modifications of the data and resource sharing plans with the awardee before recommending funding of an application. The final version of the data and resource sharing plans negotiated by both will become a condition of the award of the grant. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report. (PHS 2590). See Section VI.3. Award Criteria.

1. Award Notices

After the peer review of the application is completed, the Principal Investigator will also receive a written critique called a Summary Statement.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part4.htm).

A formal notification in the form of a Notice of Grant Award (NGA) will be provided to the applicant organization. The NGA signed by the grants management officer is the authorizing document.

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NGA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

The NGA will be sent via email or postal system to the administrative official whose name is listed in Block 12 on the Face Page of the Form PHS 398.

2. Administrative Requirements

All NIH Grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the notice of grant award. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General at 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 at 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, DHHS 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 DHHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement (NIH U54), 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 reside 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. Principal Investigator Rights and Responsibilities

The PI will coordinate project activities scientifically and administratively at the awardee institution, including research design and protocol development, data collection, quality control, interim data and safety monitoring, final data analysis and interpretation, and preparation of publications . The PI will have primary responsibility for defining the details for the projects within the guidelines of this RFA and for performing all scientific activities. The PI will be responsible for collaborations between his/her Center and NCI Comprehensive Cancer Centers and/or SPOREs as appropriate. The PI will agree to accept the close coordination, cooperation, and participation of the NCI Program Director, NCI Project Scientists, and the CCNE Coordinating and Governance Committee in those aspects of scientific and technical management of the project as described below.

Specifically, the PI will:

• Determine experimental approaches, design protocols, set project milestones, and conduct experiments;
• Propose protocol modifications as required;
• Analyze and interpret research data;
• Provide goals for assay optimization, screening throughput, quality, and cost to the NCI Program Director as requested, usually at the outset of the award and in six-month progress reports, but also at other times if requested;
• Release data according to the approved plans for timely sharing of research resources and data generated through the award, and publish results, as agreed upon by the CCNE Coordinating and Governance Committee;
• Ensure that primary and secondary screening data and assay protocols are deposited in a centralized database, caBIG, according to the timeline implemented by the NCI;
• Establish a Center Steering Committee (CSC) consisting of key Center personnel, external scientific advisors, and the NCI Project Scientist (a public advocate/representative is also recommended), and prepare a concise summary of their meeting within 30 days;
• Serve on the CCNE Coordinating and Governance Committee or appoint an appropriate designee to do so;
• Provide information to the NCI Program Director and Project Scientists concerning progress by submitting periodic progress reports in a standard format, as agreed upon by the CCNE Coordinating and Governance Committee;
• Accept and implement all scientific, practical, and policy decisions approved by the CCNE Coordinating and Governance Committee;
• Share with other CCNE facilities research resources, tools, and data of interest to those facilities, as directed by the CCNE Coordinating and Governance Committee; and
• Be prepared for annual administrative site visits by NCI staff.

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 DHHS, PHS, and NIH policies.

2.A.2. NIH Responsibilities

The NCI Project Scientist will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below. The Project Scientist will:

• Attend CSC meetings and serve as a CSC participant;
• Assist in avoiding unwarranted duplication of effort across Centers;
• Help coordinate collaborative research efforts that involve multiple Centers;
• Review and comment on critical stages in the research program before subsequent stages are implemented;
• Assist in the interaction between the awardee and investigators at other institutions; and

NCI Project Scientist(s) will also assist the NCI Program Director in stimulating broader NCI program interaction to accelerate the translational research efforts of the CCNE towards clinical trial applications of nanotechnologies developed under this initiative.

In order to carry out these duties, the NCI Project Scientist(s) may consult with other NCI and NIH staff as well as non-NIH experts in the field.

One NCI Project Scientist will be designated as the as the NCI voting participant on the CCNE Coordinating and Governance Committee and attend meetings;

The dominant role and prime responsibility for the activity resides with the awardees for the project as a whole, although specific tasks and activities in carrying out the projects/programs will be shared among the awardees and the NCI Project Scientists.

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. The NCI Program Director may recommend the termination or curtailment of an investigator or project/program (or an individual award) in the event the partnerships fail to evolve within the intent and purpose of this initiative. The NCI Program Director may also serve as a NCI Project Scientist.

A given individual may be the Program Director for more than one Center.

The NCI Program Director will:

• Exercise the normal stewardship responsibilities of an NIH Program Officer;
• Carry out continuous review of all activities to ensure objectives are being met;
• Have the option to recommend, with the advice of the CCNE Coordinating and Governance Committee, the withholding or reduction of support from any center that substantially fails to achieve its goals according to the milestones agreed to at the time of the award, fails to maintain state-of-the-art capabilities, or fails to comply with the Terms and Conditions of the award;
• Retain the option to recommend additional research endeavors within the constraints of the approved research and negotiated budget.

2.A.3. Collaborative Responsibilities

CCNE Coordinating and Governance Committee:

A CCNE Coordinating and Governance Committee will be established to optimize the flow of information between the Centers, as well as provide statistical, logistics and informatics support for the CCNE network. The CCNE Coordinating and Governance Committee will play a key role in standardizing data collection and reporting with respect to nanotechnology use in clinical oncology. Through its central position as a conduit for the CCNE network, the Coordinating and Governance Committee will be instrumental in disseminating research results and accelerating the translation of research discoveries enabled by the CCNEs into clinically-relevant diagnostics and therapeutics. Specific services provided by the CCNE Coordinating and Governance Committee include: 1) prioritizing materials for further characterization and standardization via an evaluation team; 2) monitoring contemporary developments at external nanotechnology programs; 3) matching appropriate technologies to individual Centers; 4) assessing appropriate destinations/areas for export of technologies developed at the CCNEs; 5) integrating programs across CCNEs; 6) coordinating with the NCL to characterize nanodevices and nanomaterials developed at the CCNEs; 7) interfacing with NCI clinical trials programs; 8) maintaining a set of common data elements that coordinate with caBIG to allow pooling and/or comparisons across and among the CCNEs; 9) establishing an interactive web site partitioned for public access and password-protected study access; 10) developing manuals of policies and procedures for the CCNEs; 11) organizing conference calls and investigator meetings; and 12) providing senior biostatistical and bioinformatics expertise.

The CCNE Coordinating and Governance Committee is the operational governing board responsible for overall coordination of the CCNE program and the committee through which the NCI interacts and collaborates with individual Centers. The CCNE Coordinating and Governance Committee membership will include at least one member from each CCNE (the PI or his/her designee, who must be an investigator from the CCNE research team as identified in the application), one NCI Project Scientist and representatives from public advocacy groups and other Federal agencies. The CCNE Coordinating and Governance Committee will oversee the coordination of the activities of the Centers and disseminate data, protocols, and other materials to the wider scientific community. Before the end of year 1, the Coordinating and Governance Committee will initiate a review process for proposals for developmental projects, either for pilot projects that have the potential to become new primary projects, or to expand the scale and scope of primary projects towards translational research.

Each CCNE representative will have one vote in the CCNE Coordinating and Governance Committee. The NCI (i.e., the CCNE CGC Project Scientist, or, in his/her place, his/her designated NCI Project Scientist.) and the public advocacy representative will also have one vote each. Center membership on the Coordinating and Governance Committee becomes effective upon issuance of the Notice of Grant Award. The Coordinating and Governance Committee may establish additional by-laws, subcommittees, or workgroups for specific tasks. The NCI Project Scientist(s) may not chair any committee or subcommittee and has (have) no voting rights unless a single Project Scientist is designated by the CCNE CGC Project Scientist to vote in his/her place.

The CCNE Coordinating and Governance Committee meetings will be convened at least twice yearly to assess scientific progress, identify new research opportunities, establish priorities, consider policy recommendations, and discuss strategy. CCNE Coordinating and Governance Committee decisions will be made by a majority vote of a quorum, with an attempt for consensus when possible. A quorum is the presence of a majority of the Center representatives and the CCNE CGC Project Scientist. The CCNE Coordinating and Governance Committee can convene through telephone conference or in person. Outside consultants/experts may be asked to participate in these discussions as nonvoting advisors. The CCNE Coordinating and Governance Committee may also be used to endorse methods, standard operating procedures for quality control, validation methods, data analysis, and data deposition formats that will be used across multiple centers.

The CCNE Coordinating and Governance Committee will:

• Recommend the assignment and scheduling of tasks;
• Develop guidelines to standardize the validation of procedures and data storage across Centers;
• Develop uniform procedures and policies for validation and data quality measures, assessment procedures, and annotation conventions for data depositions in conjunction with the NCI caBIG designee;
• Serve as a venue to coordinate improving the state-of-the-art use of nanotechnology in the academic sector by reporting progress, disseminating best practices, and collectively evaluating new procedures, resources, and technologies;
• Monitor, develop, and implement quality control procedures that assure consistency across Centers;
• Develop a plan for terminating projects that become unpromising or unproductive;
• Schedule meetings (at least twice yearly) and telephone conference calls as necessary for conducting business;
• Schedule one annual meeting at which all CCNE investigators will present their scientific progress and future plans;
• Facilitate the timely release of data in the format and on the schedule recommended by the CCNE Coordinating and Governance Committee; and
• Develop and recommend progress report formats for both individual centers and for the CCNE Program as a whole.

2.A.4. Arbitration Process

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NCI may be brought to arbitration. An Arbitration Panel composed of three members will be convened. It will have three members: a designee of the Coordinating and Governance Committee chosen without NCI staff voting, one NCI designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual awardee disagreement, the first member may be chosen by the individual awardee. This special arbitration panel will establish a procedure to arbitrate the dispute and deliver a recommendation. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

3. Award Criteria

The following criteria will be considered in making funding decisions:

• Scientific merit of the proposed projects as determined by peer review
• Availability of funds
• Relevance of program priorities
• Programmatic balance--The purpose of the CCNEs is to develop a network of pilot Centers with complementary capabilities that will allow the network to address a wide range of biological opportunities for nanotechnology in cancer-- therefore, decisions about awards will consider the mix of capabilities offered by the proposed Centers; and
• Adequacy of proposed data and research resource sharing plans (required in application) and intellectual property management plan (just-in-time requirement).

Adequacy of proposed data and research resource sharing plans and intellectual property management plan. The goals of the CCNE program are to create nanotechnology-based tools and products for the prevention, detection, diagnosis, and treatment of cancer that are suitable for testing in clinical trials, to make data publicly available through caBIG, and to identify/generate a diverse set of research tools to explore mechanisms of cancer.

Applicants selected for funding in response to this RFA are expected to include a plan addressing how they will exercise their intellectual property rights, should any intellectual property be generated under a Center award, while making such research resources available to the broader scientific community for research purposes consistent with the goals of the NCI Alliance for Nanotechnology in Cancer. A reasonable time frame for release of materials should be specified in the data sharing plan and will be considered by NCI Program staff. Furthermore, transfers of research resources must be made consistent with the NIH Research Tools Policy (http://www.ott.nih.gov/policy/rt_guide_final.html) and other NIH sharing policies. In the development of any sharing and intellectual property plans, applicants should confer with their own institution's office(s) responsible for handling technology transfer related matters and/or their sponsored research office. If applicants or their representatives require additional guidance in preparing these plans, they are encouraged to make further inquiries to the appropriate contacts listed below for such matters.

NCI program staff, in determining whether the application shall be awarded, will consider the adequacy of the proposed plans. The plans as approved after negotiation with the applicant when necessary will be part of the terms and conditions of the award. Evaluation of non-competing continuation applications will include assessment of the Center awardee's adherence to the proposed plans, and will be a criterion for continued funding of the award.

Applicants also are reminded that the grantee institution is required to disclose each subject invention to NCI within 2 months after the inventor discloses it in writing to grantee institutional personnel responsible for patent matters. The NCI reserves the right to monitor awardee activity in this area to ascertain if patents or patent applications are adversely affecting the goals of this RFA.

Public Domain of Data

All awards made under this RFA are subject to the Final NIH Statement on Sharing Research Data (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html) and the Principles and Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining and Disseminating Biomedical Research Resources (http://www.ott.nih.gov/policy/rt_guide_final.html). This document also defines terms, parties, responsibilities, prescribes the order of disposition of rights, prescribes a chronology of reporting requirements, and delineates the basis for and extent of government actions to retain rights. Patent rights clauses may be found at 37 CFR Part 401.14 and are accessible from the Interagency Edison web page, http://www.iedison.gov. It is expected that research resources generated through the award will be shared by awardees according to these guidelines. The plans for the development of resources for use by the biomedical community will have the appropriate timelines and milestones. NCI program staff will evaluate the compliance with the sharing plan and scientific progress in the non-competing progress report (Form 2590); such compliance will be a criterion for continued funding of the award.

Awardees are expected to comply with the intellectual property guidelines adopted by NCI for the CCNE RFA. In the interim, awardees will comply with their approved plan for addressing if, or how, they will exercise their intellectual property rights, should any intellectual property be generated under a center award, while making such research resources available to the broader scientific community consistent with the goals of the NCI Alliance for Nanotechnology in Cancer. The plan would include a reasonable time frame for release of materials. This plan would also include disclosure of any pre-existing agreements involving intellectual property rights, including options to for-profit research sponsors that are associated with biomaterials and data that may be generated.

NCI program staff will evaluate the compliance with the sharing plan and scientific progress in the non-competing progress report (Form 2590); such compliance will be a criterion for continued funding of the award.

4. Reporting

Awardees will be required to submit the PHS Non-Competing Grant Progress Report, Form 2590 annually (http://grants.nih.gov/grants/funding/2590/2590.htm) and financial statements as required in the NIH Grants Policy Statement. The annual progress report for the U54 award will use the standard 2590 form as well as supplementary information that will be more extensive. Additional information in the progress report will include both the progress made in the Center as well as the relationship between the Center and collaborators. Details of the U54 progress report are spelled out in the notice of grant award and in the Terms and Conditions section of this RFA. Applications for U54 centers should contain appropriate personnel to collect the needed information and to prepare this progress report.

Because of the complexity of the CCNEs, NCI program staff will conduct annual administrative site visits. U54 centers should be prepared for annual site visits and should budget appropriately (including travel for collaborators and other necessary costs).

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:

Gregory J. Downing, D.O., Ph.D.
Director, Office of Technology and Industrial Relations
Office of the Director
National Cancer Institute, NIH, DHHS
Building 31, Room 10A-52, MSC 2580
31 Center Drive
Bethesda, MD 20892-2580
Telephone: (301) 496-1550
FAX: (301) 496-7807
Email: [email protected]

2. Peer Review Contacts:

Referral Officer
National Cancer Institute
Division of Extramural Activities
6116 Executive Boulevard, Room 8041, MSC 8329
Bethesda, MD 20892-8329
Rockvile, MD 20852 (for express/courier service)
Telephone: (301) 496-3428
FAX: (301) 402-0275
E-mail: [email protected]

3. Financial or Grants Management Contacts:

Kathy Dunn
Grants Management Specialist
Grants Administration Branch
National Cancer Institute
6120 Executive Boulevard, EPS Room 243
Bethesda, MD 20892
Rockville, MD 20852 (for express/courier service)
Telephone: ( 301) 846-6829
FAX: (301) 846-5720
E-mail: [email protected]

Required Federal Citations

Use of Animals in Research:
Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf), as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm), as applicable.

Human Subjects Protection:
Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Data and Safety Monitoring Plan:
Data and safety monitoring is required for all types of clinical trials, including physiologic toxicity, and dose-finding studies (Phase I); efficacy studies (Phase II); and efficacy, effectiveness, and comparative trials (Phase III). Monitoring should be commensurate with risk. The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risks to the participants. (See the NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts at 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 (http://grants.nih.gov/grants/policy/data_sharing) or state why this is not possible.

Investigators should seek guidance from their institutions, on issues related to institutional policies, local IRB rules, as well as local, State, and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score.

Sharing of Model Organisms:
NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time, the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh-Dole Act (see the NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm). All investigators submitting an NIH application or contract proposal beginning with the October 1, 2004, receipt date, are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.

Inclusion of Women And Minorities in Clinical Research:
It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/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 that is available at http://grants.nih.gov/grants/funding/children/children.htm.

Required Education on The Protection of Human Subject Participants:
NIH policy requires education on the protection of human subject participants for all investigators submitting NIH applications for research involving human subjects and individuals designated as key personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

Human Embryonic Stem Cells (hESC):
Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov/). It is the responsibility of the applicant to provide in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s) to be used in the proposed research. Applications that do not provide this information will be returned without review.

Public 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 PA 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.

Standards for Privacy of Individually Identifiable Health Information:

The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information," the "Privacy Rule," on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR web site (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to 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 PA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

Authority and Regulations:
This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Kirschstein-NRSA Awards are made under the authorization of Section 487 of the Public Health Service Act as amended (42 USC 288) and Title 42 of the Code of Federal Regulations, Part 66. 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/.

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