STRATEGIC PARTNERING TO EVALUATE CANCER SIGNATURES RELEASE DATE: January 29, 2004 RFA Number: RFA-CA-04-015 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): 93.394, and 93.395 LETTER OF INTENT RECEIPT DATE: June 22, 2004 APPLICATION RECEIPT DATE: July 22, 2004 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism(s) of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Pre-Application Meeting o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The purpose of this initiative is to build on recent demonstrations that molecular signatures correlate with important clinical parameters in cancer. NCI invites investigators to form strategic partnerships that will bring together the multi-disciplinary expertise and resources needed to determine how the information derived from comprehensive molecular analyses can be used to improve patient care and ultimately, patient outcomes. Applicants are asked to propose evaluation of potential clinical usefulness of molecular signatures already developed using a variety of molecular analysis technologies including DNA, RNA or protein-based technologies. Molecular signatures have been able, in retrospective studies, to identify subgroups of patients whose tumors are histopathologically the same but who have different clinical outcomes. The challenge is to translate the information in these molecular signatures into tools that can be used in clinical decision-making. To meet this challenge, signatures must be confirmed in independent studies. Critical elements of signatures that correlate most strongly with the clinical endpoint of interest must be identified and confirmed. Robust assays feasible for use in the clinical setting must be developed and validated. This iterative process of signature refinement and confirmation and assay refinement requires diverse scientific expertise and access to significant patient and tissue resources. This initiative is an open competition that will provide the cancer research community the opportunity to establish collaborations focused on the translation of promising molecular profiles toward clinical application. NCI will continue the policy of requiring public release in a timely fashion of the rich data sets generated during these projects. Access to these data sets will benefit the entire cancer research community. This initiative will help ensure that the NCI goal of eliminating the suffering and death from cancer by 2015 is met. RESEARCH OBJECTIVES Background: The projects funded by this RFA are intended to exploit the successes of the many research projects applying comprehensive molecular analysis in cancer. Comprehensive molecular technologies have been demonstrated to provide a snapshot of the biological state of a tumor. The ability of molecular profiles to provide useful clinical information is now being demonstrated in many projects throughout the cancer research community and needs to be evaluated further. Projects are discovering molecular signatures by analysis of gene expression at the RNA level, gene expression following protein translation, gene mutations, DNA deletions, DNA amplifications, epigenetic changes of DNA and post-translational modification of proteins. The challenge is to move beyond the initial discovery of potentially useful profiles, to decide what subset of the elements in the profiles needs to be measured, to confirm that the profiles are robust and can be reproducibly measured and to evaluate the clinical utility of the profiles. Objectives and Scope: This RFA is open to all interested, qualified investigators. The initiative is intended to support projects carrying out the extensive research needed to bridge the gap between discovery of molecular profiles and their integration into clinical decision- making. Applicants should propose projects that address clinical issues or needs in a specific cancer or a closely related set of cancers or in a group of patients whose cancers have related molecular alterations. Collaborations must be established to provide all of the expertise and clinical resources required to achieve proposed project goals. It is anticipated that these will be multi-institutional projects involving investigators with expertise in technology development and application, cancer biology, oncology, pathology, clinical cancer research, biostatistics, bioinformatics and, possibly, biomedical imaging. Applicants must propose projects that build on previously identified molecular profiles. Applications proposing only profile discovery or technology development projects will not be considered responsive to this RFA. The proposed studies should be designed to confirm and refine signatures that have been demonstrated to provide information that is potentially useful clinically and that may be used to aid in making clinical decisions. Applicants may propose to define critical components in the signature, to confirm that the selected components continue to provide the desired clinical information and to develop robust assays for measuring those components. They may continue to develop and/or modify analytical technologies and algorithms for data analysis required to meet the goals of the proposed projects. Applicants must establish the collaborations necessary to bring together the expertise needed for the project. Successful completion of the project will require expertise in analytical technologies, cancer biology, oncology, pathology, clinical cancer research, biostatistics, bioinformatics and possibly biomedical imaging. Applicants must describe the clinical question(s) or need(s) they plan to address. The clinical questions posed should address a well-defined clinical need in one or a closely related set of tumors or in a group of patients whose cancers have related molecular alterations. Examples of questions of interest may include, but are not limited to: risk of progression in early stage disease; prognosis at the time of diagnosis; identification of subsets within a tumor stage or grade where there is known heterogeneity in clinical behavior including differential response to standard therapies and/or radiation response; and selection of appropriate patients for or prediction of response to selected or targeted therapies. Applicants to this initiative should not propose projects addressing early detection of cancer in asymptomatic or high-risk populations or risk of progression of pre-malignant lesions. Applicants may propose the use of a variety of analytical platforms(s). Applicants may propose to evaluate signatures the have previously been identified using analytical technologies such as, but not limited to, gene expression microarrays, SAGE, multiplex PCR or any of a large number of protein analysis technologies. Genomic analysis technologies such as array CGH, comprehensive mutational analysis technologies, SNP analysis and analysis of epigenetic events are also appropriate. Applicants must demonstrate that they have experience with the analytical technologies that will be used in the project and demonstrate that the technologies can be used for analysis of standard pathological specimens. Applicants are encouraged, but not required, to propose the use of multiple analytical strategies. For example, projects may be proposed to analyze gene expression in both frozen tissue and paraffin-embedded tissue, to analyze gene expression at both the RNA and protein level or to analyze both epigenetic alterations and gene expression. The integration of data to build clinically useful profiles that can be measured reproducibly in a clinical setting must be the focus of the project, no matter which technologies or analytic platforms are proposed. Applicants must justify the numbers of specimens to be analyzed based on appropriate statistical designs for the proposed studies. Applicants must have established collaborations to ensure availability of the clinical materials required. The availability of tissue resources with appropriate clinical annotation is critical to the successful completion of the projects. Experience has demonstrated that the dimensionality of the molecular profiling data requires the analysis of hundreds, not tens, of specimens to get statistically significant results. Applicants may propose to obtain tissues from a previous collection or prospectively, as long as the specific aims proposed can be accomplished within the period of the grant award. Demonstrated access to the requisite tissues will be critical to the successful review of the application. It is recognized that tissue needs may change as the projects are carried out. NCI staff will work with investigators to help identify additional tissue resources needed to meet project goals. Applicants should request sufficient resources to ensure that they will be able to collect, manage and analyze the data generated. Applicants must address issues related to obtaining, managing and controlling the quality of the clinical data needed for specimen annotation. Continued development of strategies to more effectively address issues of data management and analysis will be an inter-project cooperative activity of the funded projects. Applicants should request sufficient resources for their bioinformatics staff to be able to provide an appropriate interface with the NCI Center for Bioinformatics (NCICB). Sharing of the data between projects where appropriate and public release of data after publication will be a requirement for this initiative. Gene expression data will be shared through the NCICB Gene Expression Database using the Gene Expression Data Portal and database. Proteomics data and other types of data can be shared through the NCICB site as the capabilities of the site are expanded. They may also be shared through investigators websites or on other publicly available websites. The confirmation, refinement and evaluation of clinically useful molecular profiles and the development of robust clinical assays are the primary goals of this initiative. Clinical utility of the signatures and performance of the clinical assays in the context of their intended clinical use must be validated before they can be integrated into clinical practice. Final validation of the profiles in a clinical trial setting is beyond the scope of this initiative. However, it is anticipated that some of the projects may be ready to move profiles into clinical trials as early as the midpoint of the project period. NCI staff will facilitate collaborations between the projects funded on this initiative and other clinical resources and clinical trials activities supported by NCI including: the clinical cooperative groups; the Program for the Assessment of Clinical Cancer Tests (PACCT); the SPORE programs and the NCI Cancer Centers. MECHANISM OF SUPPORT This RFA will use the NIH cooperative agreement (U01) award mechanism. 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 April 1, 2005. Applications that are not funded in the competition described in this RFA may be resubmitted as NEW investigator-initiated applications using the standard receipt dates for NEW applications described in the instructions to the PHS 398 application. This RFA uses just-in-time concepts. It also uses the non-modular budgeting formats. Follow the instructions for non-modular budget research grant 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. The NIH (U01) 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 "Cooperative Agreement Terms and Conditions of Award." At this time, it is not known if this RFA will be reissued. FUNDS AVAILABLE NCI intends to commit approximately $10,000,000 in FY04 to fund three to four new grants in response to this RFA. An applicant may request a project period of up to five years and a budget for total direct costs of up to $2,500,000 per 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 or foreign institutions/organizations 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 In order to ensure maximum progress in the projects funded by this initiative and to maximize progress toward the NCI 2015 goals, several special activities will be required of the funded investigators. An annual meeting of all funded investigators will be held to share progress and research insights that may benefit all of the projects. The annual scientific meeting will be initiated after the first year of funding. One or more other focused meetings will be held each year to address arising issues or to take advantage of special scientific opportunities. Applicants should request travel funds in their budgets for key personnel to attend two meetings per year. The funded investigators will be asked to work together on issues common to all funded projects. Although each applicant will propose an independent project, all applicants are expected to face many of the same challenges and will benefit from the experiences of and interactions with the other funded investigators. The interactions of the funded groups will be overseen by a Steering Committee made up of two investigators, the PI and one additional investigator, from each funded project and appropriate NCI staff members. A Steering Committee organizing meeting will be held shortly after funding is initiated. The Steering Committee will focus on common problems and issues, especially issues of data management and analysis. Applicants should state in their applications their commitment to participating on the Steering Committee and in interactions among the funded groups. When proposed studies involve collection of human samples, specimens and/or clinical data, investigators should consider the issues raised and guidance provided in the NIH Brochure entitled "Research on Human Specimens: Are You Conducting Research Using Human Subjects?" (http://www-cdp.ims.nci.nih.gov/policy.html) and in the OHRP Guidance on Repositories, Tissue Storage Activities and Data Banks (http://www.hhs.gov/ohrp/humansubjects/guidance/reposit.htm) to ensure appropriate protection of human subjects in research. Applicants must describe how they intend to meet the NIH policies for sharing of data or why data sharing is not possible. In this regard, attention is drawn to the NIH Final Statement on Sharing Research Data (http://grants.nih.gov/grants/policy/data_sharing/index.htm and http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html), which was published in the NIH Guide on February 26, 2003 ("Data Sharing Guidelines"). This is an extension of NIH policy on sharing research resources, and reaffirms NIH support for the concept of data sharing. The new policy becomes effective with the October 1, 2003 receipt date for applications or proposals to NIH. Investigators submitting an NIH application will be required to include a plan for data sharing or to state why data sharing is not possible. The statement required by this section should be prepared with reference to the provision below for Awardee Rights and Responsibilities within Terms and Conditions of Award, Intellectual property (IP) issues continue to provide challenges to the establishment of complex, collaborative projects. This issue is being addressed and managed in different ways by many different projects supported by NCI. The policy of the NIH is to make available to the public the results and accomplishments of the activities that it funds. NIH recognizes that certain research activities may result in inventions and that grantees are entitled to protect such inventions through patenting and licensing activities in accordance with the Bayh- Dole Act, 35 USC 200 et seq. and the implementing regulations, 37 CFR Part 401 ( Bayh-Dole Act ). To address the interest in assuring that research resources are accessible, NCI requires applicants who respond to this RFA to submit a plan (1) for sharing the unique research resources generated through the grant; and (2) addressing how they will exercise IP rights, should any be generated through this grant, while making such research resources available to the broader scientific community. The sharing of research resources and IP plans must 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/nihgps_2001/) 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://www.ott.nih.gov/policy/rt_guide_final.html and http://ott.od.nih.gov/NewPages/64FR72090.pdf) ( NIH Research Tools Guidelines ). These documents also define terms, parties, responsibilities, prescribe the order of disposition of rights, prescribe a chronology of reporting requirements, and 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). If applicant investigators plan to collaborate with third parties, the research tools sharing plan must explain how such collaborations will not restrict their ability to share research materials produced with NIH funding. All applicants will be expected to have addressed IP issues with their proposed collaborators before submitting their applications and to have documented the status of their arrangements by providing a copy of a signed agreement, a signed Memorandum of Understanding between collaborating institutions or a letter of collaboration countersigned by all relevant parties that describes the IP issues and provides applicants with all rights necessary to perform activities required by the research plans . Successful applicants are expected to have resolved any outstanding IP issues before funding is awarded. It is anticipated that successful applicants may subcontract with third party for profit institutions to perform certain aspects of the research plans described in their applications. Successful applicants will be expected to ensure that they obtain sufficient rights in such subcontracts to enable them to meet their obligations under the NIH Research Tools Guidelines and the Data Sharing Guidelines, both of which are extensions of the distribution of unique research resources policy contained in the NIH Grants Policy Statement (page II-62). In drafting these subcontracts, grantees will want to give some thought to the relative rights and responsibilities of the parties, particularly with respect to the dissemination and use of raw data, results and analyses. The NCI Technology Transfer Branch staff works with NCI funded investigators on IP issues and has developed strategies for sharing IP. Staff of the NCI Technology Transfer Branch will provide their expertise as needed to the investigators funded under this initiative and their technology transfer and grants and contracts administration offices. Addressing IP issues will be a component of the review of the projects As discussed earlier, grantees will be required to publicly release data to the cancer research community through the NCI Center for Bioinformatics web site or through other appropriate public websites. Applicants should commit to the public release of data and request funds in their budgets to support bioinformatics staff interactions with the NCICB staff. Cooperative Agreement Terms and Conditions of Award These special Terms of Award are in addition to and not in lieu of otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR Parts 74 and 92, and other HHS, PHS, and NIH Grant Administration policy statements. [Part 92 applies when state and local governments are eligible to apply as a "domestic organization."] The administrative and funding instrument used for this program is a cooperative agreement (U01), an "assistance" mechanism (rather than an "acquisition" mechanism) in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the activity resides with the awardee(s) for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees, NCI Project Scientist and other NCI staff with required expertise. 1. Awardee Rights and Responsibilities Awardees will have primary responsibility for the project as a whole, including research design and conduct, data collection, data quality control, data analysis and interpretation and preparation of publications, as well as collaborations with other awardees. The NCI Project Scientist will coordinate and facilitate interactions and collaborations among the awardees. The funded investigators will form a Network with a Steering Committee to coordinate Network activities. While each of the projects will propose independent projects and work independently, each will also work with the other investigators to address issues common to all of the projects. Awardees will retain primary rights to the data developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. However, awardees will release the data to the cancer research community through collaboration with the NCI Center for Bioinformatics (NCICB) or through another appropriate publicly accessible website. The release of data will occur after the individual investigators have had a reasonable period of time to evaluate their results and realize the appropriate benefits of their own research efforts. Awardees will also share research results during meetings of the funded investigators. 2. NCI Staff Responsibilities This program will be administered by the NCI Project Scientist who will have significant programmatic involvement in the project, above and beyond the normal programmatic stewardship responsibilities in the administration of grants, as described below. Additional NCI staff who are subject matter experts will assist the Project Scientist, e.g., a Biostatistician, NCI Center for Bioinformatics (NCICB) staff, NCI Technology Transfer Branch staff. The NCI Project Scientist will: - be voting members of the Steering Committee (SC). Other designated NCI staff may attend SC meetings as non-voting members. - coordinate interactions with other NCI staff in assisting the projects, especially in public release of data generated in the individual projects. - work with investigators to access tumor specimens to meet unanticipated research needs. - coordinate annual meetings to share progress and research insights that may benefit all of the projects - facilitate collaborations with other NCI-funded research groups involved in clinical trials to help initiate clinical validation of promising profiles, if necessary. - assist the project PIs to identify members of an Expert Consultant Panel for the program, if necessary. - assist the project PIs and the Expert Consultant Panel in developing strategies to meet the Network goals. NCI staff from the NCI Technology Transfer Branch (TTB) will act as advisors to the Network on issues of Intellectual Property (IP). The NCI reserves the right to terminate or curtail the project (or an individual award) if there is inadequate progress or data reporting, or insufficient use of this resource. An NCI Program Director will be responsible for normal stewardship of the award. The Program Director may also serve as an NCI Project Scientist. 3. Collaborative Responsibilities The Steering Committee, composed of the PI, a second member of each funded project and the NCI Project Scientist, will be responsible for developing strategies to address issues common to all of the projects funded by this initiative. Investigators agree to follow common policies and procedures developed by the Steering Committee. The Steering Committee will pay special attention to issues of data management, analysis and public release and may establish subcommittees as necessary. The participants will select a chairperson for the Steering Committee. NCI Program Staff cannot serve as chair. An Expert Consultant Panel will be appointed by NCI with concurrence of the Steering Committee. The Panel will consist of no more than six members with expertise in comprehensive molecular technologies, oncology, statistics and data analysis and bioinformatics. The Panel will advise the NCI staff and the Steering Committee and assist in the development of strategies to meet Network goals. Members of the Expert Consultant Panel will attend Network meetings and will advise the Steering Committee on an ad hoc basis as needed. 4. Arbitration Any disagreement that may arise on scientific/programmatic matters (within the scope of the award) between award recipients and the NCI may be brought to arbitration. An arbitration panel will be composed of three members -- one selected by the Steering Committee or by the individual awardee in the event of an individual disagreement, a second member selected by NCI, and the third member selected by the two prior selected members. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 16. 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: James W. Jacobson, Ph.D. Division of Cancer Treatment and Diagnosis National Cancer Institute 6130 Executive Boulevard, EPN Room 6035A Bethesda, MD 20892 Telephone: (301) 402-4185 FAX: (301) 402-7819 Email: jacobsoj@mail.nih.gov or Tracy Lugo, Ph.D. Division of Cancer Treatment and Diagnosis National Cancer Institute 6130 Executive Boulevard, EPN Room 6035A Bethesda, MD 20892 Telephone: (301) 496-1591 FAX: (301) 402-7819 Email: lugot@mail.nih.gov 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: ncirefof@dea.nci.nih.gov o Direct your questions about financial or grants management matters to: Ms. Kelli Oster Grants Administration Branch National Cancer Institute 6120 Executive Boulevard, Room 243 Bethesda, MD 20892-7150 Telephone: (301) 496-8627 FAX: (301) 496-8601 Email: osterk@gab.nci.nih.gov PRE-APPLICATION MEETING A meeting of interested investigators will be held on May 14, 2004 at 9:00 AM in the Natcher Conference Center, NIH, Bethesda, MD. The meeting is intended to answer questions potential applicants may have about the intent of the initiative. 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: James W. Jacobson, Ph.D. Division of Cancer Treatment and Diagnosis National Cancer Institute 6130 Executive Boulevard, EPN Room 6035A Bethesda, MD 20892 Telephone: (301) 402-4185 FAX: (301) 402-7819 Email: jacobsoj@mail.nih.gov 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) 710-0267, Email: GrantsInfo@nih.gov. 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) Appendix materials 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 non-responsive 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; and o Receive a second level review by the National Cancer Advisory Board. 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 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 the following 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 carry out important work that by its nature is not innovative but is essential to move a field forward. SIGNIFICANCE: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? Do the proposed projects build on previously identified molecular profiles? Does the proposed project address a well-defined clinical question or need? 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? Has the investigator documented access to the patients and/or specimens with appropriate annotation in sufficient quantities to satisfy the statistical design and other goals of the proposed studies? INNOVATION: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? INVESTIGATOR: Is the investigator appropriately trained and well suited to carry out this work? Has the investigator established appropriate collaborations to bring together the required expertise? Is the work proposed appropriate to the experience level of the principal investigator and other researchers? ENVIRONMENT: 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? Is there evidence of institutional support? 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: INTELLECTUAL PROPERTY: Have the collaborating institutions provided evidence of or documented their commitment to an appropriate agreement on handling of IP arising from the proposed projects? It is recognized that final IP agreements may not yet be executed because of the short time available for application preparation. However, a memo of understanding or other documentation indicating an agreement in principle that IP issues will not hinder research progress should be presented. 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. (http://grants.nih.gov/grants/policy/data_sharing) 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: June 22, 2004 Application Receipt Date: July 22, 2004 Peer Review Date: October 2004 Council Review: February 16, 2005 Earliest Anticipated Start Date: April 1, 2005 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 DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required for all types of clinical trials, including physiologic, toxicity, and dose-finding studies (phase I); efficacy studies (phase II); efficacy, effectiveness and comparative trials (phase III). The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risk to the participants. (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). Clinical trials supported or performed by NCI require special considerations. The method and degree of monitoring should be commensurate with the degree of risk involved in participation and the size and complexity of the clinical trial. Monitoring exists on a continuum from monitoring by the principal investigator/project manager or NCI program staff or a Data and Safety Monitoring Board (DSMB). These monitoring activities are distinct from the requirement for study review and approval by an Institutional review Board (IRB). For details about the Policy for the NCI for Data and Safety Monitoring of Clinical trials see: http://deainfo.nci.nih.gov/grantspolicies/datasafety.htm. For Phase I and II clinical trials, investigators must submit a general description of the data and safety monitoring plan as part of the research application. See NIH Guide Notice on Further Guidance on a Data and Safety Monitoring for Phase I and II Trials for additional information: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html. Information concerning essential elements of data safety monitoring plans for clinical trials funded by the NCI is available: http://www.cancer.gov/clinical_trials/ SHARING RESEARCH DATA: Starting with the October 1, 2003 receipt date, investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible. http://grants.nih.gov/grants/policy/data_sharing. Investigators should seek guidance from their institutions, on issues related to institutional policies, 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/ 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 RFA 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). 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 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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