INTEGRATIVE CANCER BIOLOGY PROGRAMS RELEASE DATE: December 1, 2003 RFA Number: RFA-CA-04-013 Update: The following update relating to this announcement has been issued: March 6, 2009 - This RFA has been reissued as (RFA-CA-09-011). Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov) COMPONENT OF PARTICIPATING ORGANIZATION: National Cancer Institute (NCI) (http://www.nci.nih.gov/) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.396 LETTER OF INTENT RECEIPT DATE: February 13, 2004 APPLICATION RECEIPT DATE: April 13, 2004 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanisms of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Supplementary Instructions o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The goal of this initiative is to promote the analysis of cancer as a complex biological system, by supporting the development of reliably predictive in silico or computational models of cancer initiation and progression that can ultimately lead to the development of improved cancer interventions. The overall thrust of this program will be the integration of experimental and computational approaches towards the understanding of cancer biology. This initiative will encourage the emergence of integrative cancer biology as a distinct field. NCI recognizes that biomedical research is entering an era in which computational approaches will be increasingly used to deepen our understanding of biological behavior. Building upon mechanistic descriptions of individual biological constituents, there will be an increasing emphasis on concepts and methods that target systems and their integrated behavior and increasing dependence of cancer biologists on expertise from computational sciences as well as other fields of science that consider complex systems. This initiative is intended to facilitate the establishment of research programs in integrative cancer biology, which bring together cancer biologists and scientists from fields such as mathematics, physics, information technology, imaging sciences, and computer science to work on a common cancer biology problem. An ideal program in integrative cancer biology will be organized around an important problem in cancer that balances and seamlessly integrates experimental biology with computation and modeling. Standard and high-throughput experimental methods will generate large volumes of data, which will be used, in part, as input for computational/modeling approaches to the biological problem. These Integrative Cancer Biology Programs (ICBPs) will fund teams capable of addressing questions of cancer complexity with a wide scope of research activities. In order to further develop the field, the Programs will participate in active knowledge dissemination and have a role in educating future investigators in necessary approaches and skills. To accomplish this the individual Programs will also be responsible for establishing training and outreach programs. The Programs will operate independently but will be linked through a central focus on cancer, a common bioinformatics infrastructure, and a planned NCI-sponsored coordination committee consisting of the principal investigators (PIs) of the Programs, key program personnel and NCI staff. NCI interests related to this initiative include analysis of genome- scale data sets, understanding signal-transduction networks that maintain and promote the malignant process, and the performance of computationally-based modeling of critical cancer-related cell processes such as proliferation, migration, apoptosis, transcription and differentiation. The NCI is also interested in understanding the cellular and molecular interactions within the cancer microenvironment that facilitate tumor development and progression. Applications responsive to this initiative must concentrate on human cancer or on well-credentialed vertebrate models of human cancer. Since it is well recognized that cancer involves fundamental cellular processes that are often effectively studied in such model systems as yeast, worms, and flies, programs may incorporate these systems in comparative studies centered on human or higher-order vertebrate systems. While under appropriate circumstances NCI supports studies exclusively on lower model systems, such studies are generally referred to the National Institute of General Medical Sciences (NIGMS) for consideration. Groups interested in exploring complexity in such model organisms should refer to a series of NIGMS initiatives, including NIGMS Programs of Excellence in Complex Biomedical Systems Research (RFA GM-03-009). The NCI, through the NIH Biomedical Information Science and Technology Initiative or BISTI, also supports smaller specific applications primarily focused on bio-computing and bioinformatics. If the potential applicant has questions regarding the appropriateness of his/her proposed research project, he/she should contact program staff or address the issue in the letter of intent. Individual investigators will find an up-to-date list of relevant program announcements at http://www.bisti.nih.gov. RESEARCH OBJECTIVES Background The biomedical sciences have undergone a dramatic shift in both the conceptual and technical approaches that can be brought to bear on fundamental biological problems. These problems center on the understanding of the behavior of biological systems whose function is governed by the spatial and temporal ordering of multiple interacting components. This initiative is designed to foster the emergence of the new field of systems biology focused on the understanding of cancer as a complex disease. It will enable the formation of teams of researchers from a spectrum of fields, including biology, imaging, engineering, technology, bioinformatics, and computational modeling, who can focus on understanding and modeling some aspect of the complexity of cancer. Cancer is a complex system on at least two levels. First, malignant transformation leads to profound changes in the genetic and metabolic networks that control the functioning of the cell. We will never fully understand the development and progression of cancer without understanding the networks that support functioning in the normal human cell and the changes brought about by transformation. Second, it is now clear that the biology of a tumor depends not only on the characteristics of the malignant cell, but also on the tissue microenvironment, and other characteristics of the host in which the tumor exists. There are critical reciprocal influences among malignant cells, stromal cells, intercellular matrix components, and a host of soluble mediators, some produced locally and some systemically. There is also a complex interplay between the developing tumor and the immune system. All of these components are critical in the development of cancer; understanding them is critical to successful management of the disease. Complete understanding of living processes will certainly come first in systems much simpler than human cancer. Examples of first attempts to understand and model mathematically complex phenomena include the circuitry of bacteriophage lambda regulation, the yeast cell division cycle, and the quantitation of cellular processes such as metabolic flux and response to stress. However, the need to have an impact on human disease dictates that some effort be made as soon as possible to analyze and model immediately relevant systems such as cancer. Cancer is particularly suited to such analyses, given its complexity and the wealth of information about the underlying genetics, cell biology and cellular interactions. Cancer is largely a disease of genes, in which cumulative mutations in a spectrum of proto-oncogenes and tumor suppressor genes lead to the initiation and progression of cancer. The products of these mutant genes often include those associated with signal transduction pathways, with regulation of cell cycle and of apoptosis, each of which represents a complex cellular process. The cancer-associated mutations lead to perturbations in these processes, and thus could serve as models in the analysis of intracellular networks and in the development of in silico models. Part of the impetus for systems-scale approaches rests on recent advances in acquiring data of the necessary quality and quantity to permit systems-wide analysis, including computer-based modeling. Among the most striking recent examples is the availability of complete DNA sequences for a number of organisms, including humans. This advance has made it feasible to generate a truly comprehensive “parts list” for any organism. The enumeration of all the informational units of the genomes (protein coding regions, regulatory elements), their processed forms, and their positional significance, should be possible. The NCI has generated a large amount of data on gene expression in normal and cancer cells through such programs as Cancer Genome Anatomy Project (CGAP) and the Mammalian Gene Collection (MGC). These programs and other efforts have supplied considerable data on the “parts list” for human cancer cells. Thus, among the diseases, cancer is ideally suited for analysis by a systems, or integrative, biological approach. A comprehensive understanding of these genome-scale datasets depends on our ability to apply computational or mathematical modeling to them. The development of testable models is necessary as a framework for further experimentation, data analysis and validation. In turn, new data will help to refine model development. Multi-component, interactive processes at the sub-cellular, cellular, tissue, and organ levels should be amenable to modeling and simulation in ways previously limited by the lack of adequate data. Because this field is largely undeveloped, there is an opportunity to facilitate its development. Although these programs will be aimed at addressing and solving long term questions in cancer biology, they are expected to be focused on solving smaller and more specific problems in a 5-year to 10-year time frame. Addressing this opportunity requires a concerted effort at integrating the various disciplines into a collaborative systems biology program consisting of a cohesive group of dedicated researchers working on a common problem in cancer biology. Traditional molecular and genetic approaches, generally reductionist in nature, will continue to be needed and will be critical aspects of the ICBPs. However, they will need to be augmented with concepts and methods that will enable global data integration and systems analyses. This will require the involvement of scientists with new areas of expertise, particularly from the computational disciplines of mathematics, engineering, physics, and computer science. The need for quantitative data will drive the development of new instrumentation and methods, along with efforts in data validation and integration. The organization and representation of these data streams and their relation to preexisting knowledge will require bioinformatics advances, and the development of computer-based cancer biology hypotheses generated by testable models and intra- and inter-cellular simulations will require mathematical expertise, as will the development of new theoretical frameworks. It is expected that models and databases will be shared through an effort coordinated by the NCI. Objectives and Scope The NCI will support Integrative Cancer Biology Programs in research areas that have the potential to enhance understanding of human cancer. NCI mission areas for which these Programs would be particularly appropriate include, but are not limited to, the following: o Gene expression, including epigenetic, transcriptional and translational control systems o Metabolic networks and the control of the flux of substrates, intermediates, and products in cell physiology and cancer-related pathology o Signaling networks and the regulatory dynamics of cellular processes such as cell cycle and apoptosis, and response to environmental stress, as they relate to cancer o Supramolecular machines, such as the replisome, spliceosome, molecular motor assemblies in cell division and motility, and those related to DNA repair, as they are altered in cancer o Cell-cell and cell-matrix interactions that are critical to the functioning of the tumor microenvironment o Temporal processes such as cancer initiation and progression o Host systems such as tumor immunology NCI strongly encourages investigators who propose to develop applications to discuss their ideas with NCI program staff prior to submission, to ensure that applications will be responsive to the NCI mission and intent for this program. This RFA presents an opportunity for applicants to assemble teams of investigators from diverse disciplines that is not possible with other funding mechanisms. Projects must integrate multi-investigator, multi- disciplinary approaches with a high degree of interplay between cancer biological experimental approaches and computational and theoretical approaches. It is expected that individual programs will generate in silico models that will be testable and available to the larger cancer research community. Critical aspects that must be addressed in any application include cancer biology, mathematical/computational modeling, bioinformatics, and educational/outreach programs. Organizing projects that incorporate these approaches, and training and recruiting personnel, are complicated processes; these large Program grants (P50) are designed to facilitate these activities. A variety of approaches and organizational program structures are possible, and it is not the purpose of this announcement to prescribe any particular one. The program may be described as a single undertaking or broken out as specific interrelated projects with associated cores. It is expected that a program would contain both fully developed projects along with specific pilot projects that are still in the developmental phase. The training of professionals who are well-versed in bioinformatics and mathematical modeling and who have a deep understanding of the biology of cancer is critical for current and future progress of the field. Educational programs, both internal to the individual programs and external for the greater scientific community, that address the component disciplines of the integrative cancer biology approach need to be developed within the framework of a cancer biology research effort. It is expected that training and education activities will be established within the Programs and should include areas appropriate to the scope of research, including training in traditional cancer biology and in computational and information sciences. A full menu of educational efforts may be included, ranging from formal undergraduate, graduate, and post-graduate programs to courses and seminars for students and working researchers, visiting-scientist programs, one-to two-week intensive training programs, and other innovative programs to help spread the knowledge and resources generated. These educational programs will be directed towards and help integrate the various scientific disciplines of the individual program efforts. The Programs will be expected to help “seed” the greater scientific community by disseminating expertise and knowledge. To inform the biomedical research community at large, plans for workshops and symposia may be included. Because the Programs will be pioneering a new era in biological sciences, they are expected to provide outreach activities to traditional and non-traditional research institutions through supplement and partnership programs. Since each Program will have unique strengths and resources, the proportion of research and training should be determined individually by each applicant. Recognizing the difficulty of assembling such trans-disciplinary teams, planning grants (P20) will also be awarded to provide the time and resources needed to establish appropriate collaborations across the broad spectrum of scientific disciplines that need to be represented within the Program. The Exploratory Grant (P20) mechanism should be used when the applicant wishes to request a period of planning and preliminary investigation. The planning grant application must explicitly demonstrate how these specific grant activities will lead to collaborative efforts, and describe in substantial detail a vision of the research to be conducted by the Program. These preliminary efforts will be focused on the assemblage of teams and small pilot projects. It is expected that successful completion of a planning ICBP grant will enable the awarded group to fully develop an integrative cancer biology program using institutional and outside support. Upon future assessment of the overall program by NCI, these P20s may also compete for full Program status in any potential future issuance of the RFA or similar programs in either public or private settings. Awarding of a P20 does not imply a commitment from the NCI to future funding of a full Program. Generally, the full Program (P50) awards are reserved for those teams of investigators who can demonstrate an existing infrastructure supporting well-developed projects and integration of both scientific direction and management. If these components are not in place or need further development then applicants should apply for the planning grant (P20). Applicants should contact program staff if there is a question as to which mechanism is most appropriate. Both the P20 and P50 awardees will be considered full members of the ICBP and be expected to participate in Coordinating Committee and associated activities, and to comply with data deposition Guidelines, as established by the Coordinating Committee and the NCI. MECHANISMS OF SUPPORT This RFA will use NIH Specialized Center Grant P50 and Exploratory Grant P20 award mechanisms. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. The anticipated award date is September 30, 2004. This RFA uses just-in-time concepts. It also uses the non-modular budgeting format. (see http://grants.nih.gov/grants/funding/modular/modular.htm). Follow the instructions for non-modular budget research grants applications. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm. FUNDS AVAILABLE NCI intends to commit approximately $10 million in FY 2004 to fund 2-3 P50 Programs and 2-3 P20 Planning Grants in response to this RFA. An applicant for a P50 Program may request a project period of up to 5 years and a budget for total costs not to exceed $15 million for the duration of the award, or an average of $3 million/year. However, overall annual budgeting of the P50s will be flexible according to the needs and maturity of individual programs. Therefore, newly established programs may require less funding the first year, but greater funding in subsequent years, whereas more developed efforts may require larger “up-front” allocations for salaries, equipment, technology, etc. An applicant for a P20 planning grant may request a project period of up to three years and a budget for total costs of up to $500,000/year. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the NCI provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic institutions/organizations o Foreign institutions are not eligible to apply. INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS 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. SPECIAL REQUIREMENTS It is anticipated that awardees will be generating and analyzing large datasets dealing with cellular properties. To facilitate an interface with existing NCI datasets and interchange of data within the research and clinical communities, potential applicants will be invited to attend a pre-submission workshop to discuss the problems and potential of standard data formats and discuss possible guidelines for data sharing. This workshop will be co-sponsored by the NCI Center for Bioinformatics (NCICB). Participation in a pre-application ICBP bioinformatics meeting will be open to all parties interested in applying to the RFA. An announcement of the date and location of this workshop has been published concurrently with this RFA. The meeting is tentatively scheduled for the end of January in the Washington, D.C., area. Please consult NOT-CA-04-005 (http://grants.nih.gov/grants/guide/notice-files/NOT-CA-04-005.html) for details on the pre-application meeting. Information will also be available on the Division of Cancer Biology website (http://dcb.nci.nih.gov/). The workshop will be an opportunity to clarify questions about the overall program and to discuss specific concerns about data standards, infrastructure, and approaches to sharing of data and models as related to the ICBP and the community. The pre-submission workshop proceedings will be posted on a public NCI web site. Attendance at the pre-meeting is neither required nor is it necessary for a successful application. It is intended to be an opportunity for clarification and discussion on the larger question of data integration. To enhance interactions among the funded Programs, PIs, Co-PIs, key personnel from both P50 and P20 grants, and NCI scientific staff will constitute a “Coordinating Committee” that will meet twice a year to discuss current accomplishments, barriers encountered, and to identify areas of opportunity and unrepresented areas of expertise and individuals whose contributions should be brought to bear on addressing cancer complexity. The NCI would anticipate supporting these new opportunities through supplemental funds to the awards. PI’s and co- PI’s will be required to attend these Coordinating meetings and applicants will be expected to include funds for these semi-annual meetings in their travel budget. These meetings also will serve as a venue in which the bioinformatics platform and tools will be evaluated and discussed and suggestions for enhancements made to NCICB. After the awarding of grants, specific program guidelines for the bioinformatic data will be established by the ICBP Coordinating Committee. The coordinating committee will develop standards and guidelines for the exchange and dissemination of information and data for the benefit of the ICBP and the greater community. It will be required that the data exchange and dissemination guidelines be compatible with the overall NCI bioinformatics system that supports other NCI sponsored initiatives. As previously stated, awardees will be required to share data and models generated through this grant with each other and through an established centralized NCI or public resource, in a timely fashion and as stipulated in the guidelines that are ultimately adopted by the Coordinating Committee and the NCI. These guidelines will also be publicly available on the NCI website. In addition, awardees will be strongly encouraged to leverage or interact, whenever possible, with appropriate existing programs both within NIH as well as other public (e.g., NSF) and private efforts. This would include non-traditional biomedical researchers and programs. Programs will receive an administrative site visit during the third year of the first grant cycle. The fifth year of funding will depend on the outcome of that administrative review, and the Principal Investigator will receive advice about NCI interest in accepting a competing renewal application to extend the initial award. The Principal Investigator of a Program must commit a minimum effort of 30 percent. Programs will be expected to have a Board of Advisors, drawn from experts outside the project. These advisors will meet annually to review and provide guidance on Center activities. While a description of the Board's activities should be included in the application, potential members of the Board 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 Board of Advisors should be included in the budget. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA 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: o Direct your questions about scientific/research issues to: Dan Gallahan, Ph.D., Chief Structural Biology and Molecular Applications Branch Division of Cancer Biology National Cancer Institute 6130 Executive Boulevard, EPN Room 5000 Bethesda, MD 20892 Rockville, MD 20852 (for express/courier service) TEL: (301) 435-5226 FAX: (301) 480-2854 Email: firstname.lastname@example.org o Direct your questions about peer review issues to: Referral Officer National Cancer Institute Division of Extramural Activities 6116 Executive Boulevard, Room 8041, MSC 8329 Bethesda, MD 20892-8329 Telephone: (301) 496-3428 FAX: (301) 402-0275 Email: email@example.com o Direct your questions about financial or grants management matters to: Bill Wells Grants Administration Branch National Cancer Institute 6120 Executive Boulevard, EPS Room 243 Bethesda, MD 20892-7150 Telephone: (301) 496-8796 FAX: (301) 496-8601 Email: firstname.lastname@example.org LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NCI staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: Dan Gallahan, Ph.D., Chief Structural Biology and Molecular Applications Branch Division of Cancer Biology National Cancer Institute 6130 Executive Boulevard, EPN Room 5000 Bethesda, MD 20892 Rockville, MD 20852 (for express/courier service) TEL: (301) 435-5226 FAX: (301) 480-2854 Email: email@example.com SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). 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 DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone: (301) 435-0714, Email: GrantsInfo@nih.gov. SUPPLEMENTARY INSTRUCTIONS: The applicant should identify clearly in the abstract and more fully in the research plan the specific questions in current cancer biology that are to be explored and the new approaches and collaborations that will result from the establishment of the Program. The synergies to be achieved through the establishment of multi-disciplinary teams and novel collaborations should be fully described. It is anticipated that the proposed projects will be multi-disciplinary and will draw on a variety of resources. Thus, a well thought out and carefully described organization is required. The PI is responsible for ensuring that scientific goals are met, and for developing and managing a decision- making and administrative structure and process that will allow resources to be allocated (and reallocated, if necessary) to meet those goals. This will be particularly important for multi-institutional programs. A management plan should be included outlining the organization and administration of the proposed ICBP. P50 Application The P50 grant application should specify the administrative and organizational structure(s) that will be used to support the research. Projects with the complexity, both scientific and managerial, that NCI anticipates will characterize these Programs will require a substantial amount of the PI's effort to achieve success. Therefore, the PI will be required to devote at least 30 percent effort to the leadership and implementation of the Program. If core facilities or shared resources are required, these should be described, as should their management and service to the research projects. The applicant should explain how different components of the organization, including key personnel, will interact, why they are essential to accomplishing the research, and how the combined resources create capabilities that are more than the sum of the parts. "Centers-without-walls" or multi-institutional programs are welcome under this solicitation. If any of the components are physically separated from each other (i.e., located in different departments or institutions), the applicant should address how interactions will be facilitated. NCI is not specifying a specific organizational structure (e.g., specific numbers of projects and cores) in this RFA, preferring that applicants develop the structure that would best promote the research. However, applicants should note that the effectiveness of the proposed structure will be a criterion of the evaluation prior to an award and will be monitored after an award is made. All P50 applications must describe their plans for training and education. The range of activities that may be included is described under “Objectives and Scope” section of the RFA. Applicants are encouraged to contact program staff if they have specific questions. A timeline for the Program should be presented. This timeline should outline how the project's goals can be met within the time frame of an ICBP grant. The timeline also will assist the investigators, NCI, and its advisors in evaluating progress toward the project's goals. For those projects for which the investigator deems it appropriate to do so, NCI encourages applicants to present explicit, quantitative milestones. The Program may be presented with distinct but interrelated projects or as a comprehensive narrative of the objectives, scope, and specific aims. A well justified measure of budgetary flexibility is encouraged. For example, if individual projects are described, some may explicitly be pilot projects, and it is not necessary that any of the projects continue for the full term of the award. If such flexibility will be used, the process by which resources will be redirected should be described fully. Regardless of the structure of the application, the research plans (sections a-d of the PHS 398 form) for all projects, core(s) and training /outreach activities should not exceed 100 pages. Please note that there is no requirement to submit this maximum number of pages; instead, concise, articulate applications are desired. P20 Application The Exploratory Grant (P20) mechanism should be used when the applicant wishes to request a period of planning and preliminary investigation. The planning grant application must explicitly demonstrate how these specific grant activities will lead to collaborative efforts, and describe in substantial detail a vision of the research to be conducted by the Program. These preliminary efforts will be focused on the assemblage of teams and small pilot projects. Because of the complexity of the project and the development, the PI will be required to devote at least 30 percent effort to the leadership and implementation of the Program. Cost that would be allowable for the Planning grant (P20) include, but are not limited to, administrative cost for the planning effort, cost for meetings and retreats, cost for the development of specialized resources, cost of pilot projects and cost for the recruitment of critical personnel. The planning activities to be carried out, and the justification for their necessity, should be described. This should include the research plan for collection of preliminary data, and the scientific planning that will ensue to develop the Program. The application should also describe the activities proposed to strengthen the interdisciplinary team of researchers, to create a management structure for the team, and to develop the courses, curriculum, and other options that will be included in the training plan. The Program may be presented as distinct but interrelated projects or as a comprehensive narrative of the objectives and scope. In either case, the page limitation for the research plans (sections a-d of the PHS 398 form) for all planning and pilot project activities should not exceed 50 pages. Please note that there is no requirement to submit this maximum number of pages; instead, concise, articulate applications are desired. INTELLECTUAL PROPERTY MANAGEMENT PLAN Certain research plans will require collaboration and coordination between investigators at different institutions, some of whom may not be NIH funding recipients and who may have pre-existing intellectual property obligations to third parties. The technology transfer/IP management/licensing officer or equivalent of the principal investigator’s institution is to submit an intellectual property (IP) management plan. Intellectual property management plans are a just-in- time requirement; it is not necessary to include the plan in the grant application but plans must be in placed before the end of the first budget period. The applicant institution should provide a written assurance that it will protect the intellectual property rights of the ICBP investigators and their collaborators and under no circumstances engage in formal/legal agreements with commercial sources (e.g., pharmaceutical companies) that would compromise the ability of ICBP investigators to have unhampered access to institutional resources in ICBP related research or participate fully in collaborations with any other researchers. The statement of commitment should also include a written assurance that in its interactions with commercial entities under sponsored research agreements, the ICBP will comply with the requirements of the Bayh-Dole Act and NIH funding agreements while upholding basic principles of academic freedom. Sponsored research agreements with commercial entities should be entered into by the ICBP only upon due consideration of the points outlined in "Developing Sponsored Research Agreements: Considerations for Recipients of NIH Research Grants and Contracts (Federal Register, Vol. 59, No. 215, Tuesday, November 8, 1994, pp. 55674-55679)," a copy of which can be viewed at: http://ott.od.nih.gov/spons_research.html. The statement of commitment should also include a written assurance that the ICBP will manage its interactions with third parties so that they do not restrict the program’s ability to receive and disseminate biomedical research materials from and to the scientific community. Likewise, letters should be supplied by any relevant third parties confirming their adherence to these policies. Questions regarding intellectual property management plans should be directed to Technology Transfer Branch National Cancer Institute, NIH, DHHS (301) 496-0477 USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form 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. SENDING AN APPLICATION TO THE NIH: 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 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application and all copies of the appendix material must be sent to: Referral Officer 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) Appendices should be comprised of single-sided, unbound materials, with separators between documents. APPLICATIONS HAND-DELIVERED BY INDIVIDUALS TO THE NATIONAL CANCER INSTITUTE WILL NO LONGER BE ACCEPTED. This policy does not apply to courier deliveries (i.e., FEDEX, UPS, DHL, etc.) (http://grants.nih.gov/grants/guide/notice-files/NOT-CA-02-002.html) This policy is similar to and consistent with the policy for applications addressed to Centers for Scientific Review as published in the NIH Guide Notice http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-012.html. APPLICATION PROCESSING: Applications must be received on or before the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. 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. The Center for Scientific Review (CSR) will not accept any application in response to this RFA 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 an RFA, it is to be prepared as a NEW application. That is the application for the RFA 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. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NCI. Incomplete and/or nonresponsive applications will not be reviewed. 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 the Division of Extramural Activities of the NCI in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Receive a written critique o Receive a second level review by the National Cancer Advisory Board. REVIEW CRITERIA The goals of NCI-supported research are to advance our understanding of cancer biology, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to evaluate 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. o Significance o Approach o Innovation o Investigator o Environment 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 attack a highly significant research problem for which some of the details of approach have not been established through preliminary data. Review Criteria for P50 Applications: SIGNIFICANCE: o Does this Program address an important problem in cancer biology? o If the aims of the application are achieved, how will scientific knowledge in cancer biology be advanced? o What will be the effect of these studies on the concepts and methods that drive the field of cancer biology and those that drive the emerging field of integrative biology? APPROACH: o Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project, within the limits inherent in an emerging, complex approach to biological research? o Does the applicant acknowledge potential problem areas and consider alternative tactics? o Is the management plan appropriate for a large-scale, highly integrated Program of this type? Do the individual components exhibit a high degree of interrelatedness and synergy? Are the proposed core facilities, if any, essential to the success of the Program? o Is the training and outreach plan appropriate, i.e., is it likely to meet the needs of the Program and the scientific community in cancer and integrative biology? Does it integrate well with and leverage existing educational and training resources at the institution(s)? Will this Program serve as a model for cross-disciplinary activities? o Is there evidence of strong interaction and feed-back among the biology and computational components of the Program? o Are there appropriate plans to maximize Program flexibility by incorporating pilot projects and redirecting resources to maximize progress? Are the plans for oversight of such changes adequate? o Is there an adequate plan to organize external scientific and managerial oversight of the Program, including the selection of pilot studies for funding? INNOVATION: o Does the project employ novel concepts, approaches, or methods? Are the aims original and innovative? o Does the project challenge existing paradigms or develop new methodologies or technologies? INVESTIGATOR: o Is the Principal Investigator appropriately trained and well suited to lead and coordinate a Program of this size and complexity? o Does the overall research team have sufficient expertise in all of the critical aspects of this undertaking, i.e., cancer biology, mathematical modeling, bioinformatics, and training/outreach? ENVIRONMENT: o Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? o Is there strong evidence of institutional support? Is the Program that is being developed recognized as a major element within the organizational structure of the institution? Review Criteria for P20 Applications: SIGNIFICANCE: o Does this Program plan to address an important problem in cancer biology? APPROACH: o Is the scientific research plan of high quality? Are the exploratory research components well justified and do they contribute to the goals of the planning effort? Is it likely that the proposed planning grant will culminate in the ability to develop a competitive P50 grant application, or to obtain support through other means? o Is there an appropriate plan for acquisition, organization, and deployment of equipment and human resources needed to attain the goals of the exploratory research? Is there an adequate level of effort from key personnel? o Is the plan to develop an effective training/outreach component appropriate? o Is the plan to solicit and fund pilot studies adequate? INNOVATION: o Would the proposed Program be innovative in organization, scientific approach, or resources that could be mobilized, relative to more established efforts in integrative cancer biology? INVESTIGATOR: o Is the Principal Investigator appropriately trained and well suited to lead and coordinate a planning effort of this kind? o Is there an adequate pool of expertise at the applicant institution(s) in all of the critical aspects of integrative cancer biology, or are there plans to supplement available expertise through collaboration and/or recruitment? ENVIRONMENT: o Does the applicant institution(s) provide an environment conducive to the development of a high-quality research effort in integrative cancer biology? o Is the institution(s) committed to the Program in terms of space, administrative authority, and other necessary resources, e.g., donated faculty time, use of equipment, etc? Will the Program that is being developed be recognized as a major element within the organizational structure of the institution? 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 criteria included in the section on Federal Citations, below). 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. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below). 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 398 research grant application instructions (rev. 5/2001) will be assessed. ADDITIONAL REVIEW CONSIDERATIONS Sharing Research Data Applicants requesting more than $500,000 in direct costs in any year of the proposed research must include a data sharing plan in their application. The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or priority score. (See url in Federal Citations, below.) BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: February 13, 2004 Application Receipt Date: April 13, 2004 Peer Review Date: June 2004 Council Review: September 14, 2004 Earliest Anticipated Start Date: September 30, 2004 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities. REQUIRED FEDERAL CITATIONS HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm SHARING RESEARCH DATA: Starting with the October 1, 2003 receipt date, investigators submitting an NIH application seeking more than $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible. http://grants.nih.gov/grants/policy/data_sharing. Investigators should seek guidance from their institutions, on issues related to institutional policies, 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. 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 - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are 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 RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. 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 proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. A continuing education program in the protection of human participants in research is available online at: http://cme.nci.nih.gov/ 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. In addition to the mandated efforts for ICBP data sharing, applicants may wish to place data collected under this RFA in some other 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). Those who must comply with the Privacy Rule (classified under the Rule as “covered entities”) must do so by April 14, 2003 (with the exception of small health plans which have an extra year to comply). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on “Am I a covered entity?” Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. 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 RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm (also cite other relevant policies) 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.
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