NATIONAL COOPERATIVE DRUG DISCOVERY GROUPS FOR CANCER RELEASE DATE: January 16, 2004 RFA Number: RFA-CA-05-001 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): 93.395 LETTER OF INTENT RECEIPT DATE: April 19, 2004 APPLICATION RECEIPT DATE: May 19, 2004 This RFA is a reissue of RFA-CA-99-010, which was published in the NIH Guide on April 14, 1999. THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism 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 Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI) invites applications to continue the National Cooperative Drug Discovery Group (NCDDG) Program for the discovery of new and more effective anticancer treatments. This program will further the NIH Roadmap Initiatives (http://nihroadmap.nih.gov) and the NCI goal of eliminating the suffering and death due to cancer by the year 2015. For this Request for Applications (RFA), the term NCDDG will apply, whether the products are from natural sources or of synthetic or biological origin. Applications are sought from both new and re-competing NCDDGs (also called Groups). This RFA will support broad, innovative, interdisciplinary, multi- project approaches to the discovery of new, rationally based or natural-source derived anticancer treatments or strategies. The initiative provides a framework for interactions that will reduce the time from concept to product. A multi-institutional, public-private partnership approach involving academic, nonprofit, and/or commercial/industrial institutions with Government staff participation is envisioned because the creative talents in the required scientific disciplines are rarely available in a single institution. Although not required, the active participation of industry is encouraged because it will allow this segment of the scientific community to contribute its considerable intellectual and material resources. Further, the interaction of academic and non-profit research institutions with industry and Government will facilitate subsequent development and marketing of new therapies, although these latter activities are not within the scope of this RFA. Biological or molecular targets for drug discovery and the sources and types of natural products to be investigated will be selected by the applying Group. Subsequent studies required for development of new treatments (e.g., formulation development, large-scale production for clinical trials, or toxicology in support of Investigational New Drug Applications, etc.) as well as the clinical trial itself, are beyond the scope of this RFA. However, a timely evaluation of products is encouraged. The development of analogs of established or well-studied anticancer agents is not responsive to this RFA. RESEARCH OBJECTIVES Background Important discoveries in molecular biology, cell biology, chemistry and related fields, together with major technological advances, permit the design of highly selective and specific approaches to discovery of new cancer therapies. Harnessing these exciting advances for development of more effective cancer therapy requires the organization of outstanding scientists from diverse scientific disciplines within the biological, chemical, and pharmacological sciences into highly synergistic research teams without regard to institutional affiliation. To realize this objective as well as to make use of facilitating resources of NCI's Developmental Therapeutics Program within these teams, the NCI acted on the advice of the former Division of Cancer Treatment's Board of Scientific Counselors and established the NCDDG program in 1982. Since then the NCDDG program has been recompeted several times. For additional information on history and past accomplishments of NCDDGs, visit the web site: http://dtp.nci.nih.gov/ (under Grants and Contracts). NCDDGs are peer-reviewed, multi-component, interdisciplinary projects focused on discovery of new approaches for treatment of cancer. An NIH intramural laboratory or a foreign institution may participate as a Laboratory Program or a Scientific Core in an NCDDG submitted by a domestic institution. NCDDGs are funded as cooperative agreements, a mechanism in which the NCI, through its extramural staff, is an active partner in the Group. NCI staff, represented by a Project Coordinator appointed after award, provides advice and guidance in the area of drug discovery and development and facilitates access to NCI resources including repositories, chemical searches, and screens. Resources for development include, but are not limited to, scale-up synthesis, formulation, pharmacology, toxicology, and Investigational New Drug Applications (INDAs) to the Food and Drug Administration (FDA). Information can be found at the DTP web site: http://dtp.nci.nih.gov/. Clinical trials support may be made available through the Cancer Therapy Evaluation Program (CTEP): http://ctep.info.nih.gov/. Additional pre- clinical developmental support may be obtained though the Rapid Access to Intervention Development (RAID) or Drug Discovery Group (DDG) mechanisms (http://dtp.nci.nih.gov/). Objectives and Scope The purpose of this RFA is to encourage the discovery of novel treatments or strategies to eliminate suffering and death due to cancer. Groups should use innovative approaches to drug discovery based on recent advances in tumor biology and the molecular understanding of cancer. Projects directed at molecular targets and regulatory pathways specifically altered in tumor cells are encouraged, whereas approaches based solely on inhibition of cellular proliferation without regard to exploitation of alterations in cancer cells are discouraged. Specific approaches may encompass a wide range of topics such as gene therapies, monoclonal antibodies, and vaccines; biological response modifiers; design of agents to interfere with transcription factors, signal transduction, cell adhesion factors, angiogenesis, hormone or other receptors; and other novel targets involved in the initiation and/or maintenance of the transformed state and for which a strong rationale can be provided. Development and use of new chemical libraries, structural biology, proteomics or computer modeling of receptor targets should be considered. Non-mammalian models may be used if appropriate to the goals of the project. Applications related to treatment of childhood cancers as well as AIDS-related malignancies are encouraged. It should be emphasized that approaches to realization of the goals of this RFA are broad and limited only by the creativity and scientific abilities of the applicants. For more information on the research priorities of NCI in cancer prevention and treatment, visit http://cancer.gov/pdf/nci_2005_plan. NCDDGs focused on the discovery and evaluation of new entities from natural sources should emphasize the novelty of the natural product sources and use molecular target-based screening assays. Biosynthetic approaches are considered within the scope of the RFA. The development or use of pre-clinical models based on their ability to discriminate for antitumor activity and to test the rationale for natural product selection and isolation is encouraged. Programs for collection and screening of natural product extracts or existing combinatorial libraries without strong rationales for material selection or testing models, and projects designed to produce analogs of extensively studied natural products or their derivatives are not responsive to this RFA. To be considered responsive to this RFA, natural product discovery Groups must include lead optimization strategies, such as modern combinatorial chemistry technology. If appropriate, Group projects could include analysis of new and relevant procedures to evaluate in vivo efficacy that will facilitate decisions regarding potential clinical utility. Approaches could include development of molecular end points or non-invasive agent imaging for tumor and organ distribution analysis. Development and use of assays that can be applied to clinical evaluation following completion of NCDDG-supported research are especially encouraged. Funds for projects or cores which depend on the successful completion of other activities, such as the availability of certain reagents or scale-up synthesis, may be included, but use of such phase-in funds will be restricted and released only on specific written approval by the NCI. Definitions: AWARDEE. The institution to which the NCDDG U19 is awarded. BIOLOGICAL RESPONSE MODIFIER. Agent that alters the relationship between the tumor and its host by altering the host's response to the tumor cells. CORE, ADMINISTRATIVE. An administrative unit located at the Principal Investigator's institution that coordinates all Group activities. It is separately budgeted from the PI's Laboratory Program (if any) and budgets for activities pertinent to the Group as a whole, such as travel for intra-Group meetings. CORE, SCIENTIFIC. A separately budgeted scientific service component which provides essential facilities or services to two or more of the proposed Laboratory Programs. Core components typically use established procedures or protocols rather than generating new research. An NIH intramural laboratory or foreign institution may participate as a Scientific Core. CORE LEADER. The director of a scientific core component who is responsible for the conduct of that core. DRUG. In the context of this RFA, a term used broadly to encompass synthetic agents, natural products and biological products, as well as novel therapeutic strategies and inventions designed to treat and cure cancer. Strategies also encompass creative methods to maximize antitumor selectivity. GROUP. See NCDDG below. LABORATORY PROGRAM. A research component headed by a Program Leader within an NCDDG with a separate, detailed research plan and budget. An NIH intramural laboratory or foreign institution may participate as a Laboratory Program. NATIONAL COOPERATIVE DRUG DISCOVERY GROUP (NCDDG). A unit consisting of a Principal Investigator, Program Leaders, Core Leaders (if any), their respective programs (at least three laboratory programs), and an NCI Coordinator (from the NCI extramural staff, appointed after award) that functions as a unit with a common goal: the conceptualization, invention, and evaluation of new entities and strategies or rational selection, isolation, and evaluation of new entities from natural sources for treatment and cure of cancer. In this RFA, the terms NCDDG and Group are used synonymously. NATURAL PRODUCT. In the context of the NCDDG program, a term used broadly for any naturally occurring chemical or biological entity of non-human origin selected and evaluated pre-clinically against cancer. NCI COORDINATOR. A scientist from the NCI extramural program staff who is appointed by the NCI Program Official just before award, who participates as a member of the Group, interacts scientifically with the Group and facilitates the role of NCI as partner in the Group. The Program Official also may serve as the NCI Coordinator for a Group. NCI PROGRAM OFFICIAL. The senior staff member of the Grants and Contracts Operations Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis who provides leadership and guidance for the overall NCDDG Program within the NCI, maintains overall scientific balance for the NCDDG Program, and ensures that the NCDDG Program is consistent with the NCI mission for treatment research. PRINCIPAL INVESTIGATOR. The scientist who is designated by the applicant institution to direct the NCDDG. The PI will assume responsibility and accountability to the applicant institution and to the NCI for the performance and proper conduct of the NCDDG in accordance with the terms and conditions specified in this RFA. An NIH intramural scientist or a scientist from a foreign institution may not serve as a Principal Investigator. PROGRAM LEADER. A senior scientist with proven independent research capabilities who serves as director of one of the scientific Laboratory Programs of the Group and is responsible for the scientific conduct of that program. The Principal Investigator of the Group may be a Program Leader. An NIH intramural scientist or a scientist from a foreign institution may serve as a Program Leader. MECHANISM OF SUPPORT This RFA will use the NIH cooperative agreement (U19) award mechanism. As an applicant you will be primarily responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing-continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The earliest anticipated award date is May 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 uses the non-modular budgeting formats. Applicants should 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 U19 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. Plans for future competitions of this RFA are currently indefinite. FUNDS AVAILABLE NCI intends to commit approximately $12 million in FY 2005 to fund 10 to12 new and/or competitive continuation grants in response to this RFA. An applicant may request a project period of up to 5 years and a budget for total costs of up to $1.2 million 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 institutions/organizations o Foreign institutions are not eligible to apply. Foreign collaborators are allowed as Leaders of Programs or Cores. 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 A. The Group's objectives and goals should be relevant to and compatible with the NCI's mission in cancer treatment as stated in this RFA. Applicants should describe their plans to accommodate the stated NCDDG requirements, criteria, and NCI involvement. B. All proposed Groups must consist of at least three interdisciplinary Laboratory Programs with each complementing the others expertise. While no maximum number of programs is stipulated, when a consortium exceeds five programs the overall Group may become difficult to manage. Groups may also have Scientific and/or Administrative Cores that provide essential services to two or more Laboratory Programs, but a Core cannot serve as one of the three required Laboratory Programs. C. The Principal Investigator and each Program Leader must provide a signed statement of acceptance of the participation of NCI staff during performance of the award as outlined under "NCI Staff Responsibilities" below. D. A plan should be described for decision-making regarding identification and evaluation of promising agents for development. A plan should be provided for developmental activities not supported by this RFA but required for introduction of an agent into clinical trial. E. For projects involving natural products, a plan for lead optimization should be included. F. Participation by pharmaceutical companies and biotechnology firms is strongly encouraged. Industrial partners should include key personnel who have authority within the company to allocate resources to ensure successful completion of the proposed discovery and development efforts. G. INTELLECTUAL PROPERTY AND PATENT COVERAGE: Since the discovery of new and improved anticancer treatments is the objective of this effort and active involvement by industrial laboratories is facilitated by the existence of adequate patent coverage, it is essential that successful applicants (those likely to receive awards) provide plans to assure such coverage. The situation could be complicated since multiple institutions are likely to be involved. Following peer review of the application, each successful applicant Group must therefore provide a detailed description of the approach to be used for obtaining patent coverage and for licensing where appropriate, in particular where the invention may involve investigators from more than one country and institution. Procedures must be described for resolution of legal problems should they arise. Your attention is drawn to the NIH Extramural Technology Transfer Policies and Documents at http://ott.od.nih.gov/NewPages/602-rev2.htm. A formal statement of Patent Agreement among all Group members and their institutions as well as a detailed description of procedures to be followed for resolution of legal problems which may develop, signed and dated by the organizational official authorized to enter into patent arrangements for each Group member and member institution, must be developed. The signed agreement must be submitted after review and prior to award to the assigned NCI Coordinator. For applications involving natural products, a formal statement of agreement must be provided and signed by authorized representatives of all institutions in the Group, assuring that an equitable sharing of royalties or profits arising from the discovery, if any, will be returned to indigenous peoples, research collaborators, research institutions or Governmental entities as appropriate, in the country of origin of the natural product sample from which the lead or drug was derived. The signed document must be submitted prior to award to the assigned NCI Coordinator. A plan must be developed for disposition of natural product samples, compound libraries, etc., that are generated over the course of the award in conformance with TERMS AND CONDITIONS OF AWARD, Item 1., listed below. The signed document must be submitted prior to award to the assigned NCI Coordinator. The three documents listed above will be considered confidential and should not be included with the application. These documents must be provided after the peer review of applications but before award to the assigned NCI Coordinator. However, awards will not be made until these documents are received and approved by NCI. H. Funds from this RFA can be used for sample acquisition only from locations, domestic or foreign, where the Investigators have secured signed documents of Memorandum of Understandings and have obtained collection permits. I. An NIH intramural scientist (IMS) may not serve as the Principal Investigator of an NCDDG but may participate in a Group as a Program Leader, Scientific Core Leader, collaborator, or consultant. However, an IMS may not receive salary, equipment, supplies, or other remuneration from this RFA. The IMS must obtain approval of his/her NIH Institute Scientific Director to allocate resources to the project. This letter must specify that no more than $500,000 direct costs of intramural resources will be allocated to the project and provide assurance that the conduct of the project will comply with the DHHS regulations for research involving human subjects (if applicable) and with the PHS policy of vertebrate animal research. The participation of an intramural scientist is independent of and unrelated to the role of the NCI Program Official and Coordinator as described below in TERMS AND CONDITIONS OF AWARD. For NCDDG applications that include NIH intramural components, the intramural resource level will be accounted for in the total cost of the overall application. COOPERATIVE AGREEMENT TERMS AND CONDITIONS OF AWARD The following terms and conditions will be incorporated into the award statement and provided to the Principal Investigator as well as the institutional official at the time of award. Failure to abide by any of the Terms and Conditions of Award pertaining to awardee responsibilities stipulated in this Section may result in a reduction of funding, withholding of support, suspension or termination of the award. These special Terms and Conditions of Award are in addition to and not in lieu of otherwise applicable OMB administrative guidelines, DHHS Grant Administration Regulations at 45 CFR parts 74 and 92, and other DHHS, PHS, and NIH Grant Administration policy statements. The administrative and funding instrument used for this program is a cooperative agreement (U19), 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. To qualify as an NCDDG, the overall program must include a minimum of three laboratory programs. 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 for the project as a whole, although specific tasks and activities in carrying out the studies will be shared between the awardee and the NCI Coordinator. 1. Awardee Rights and Responsibilities a. The Principal Investigator will have primary authority and responsibility to define objectives and approaches and to plan and conduct the proposed research. She/he will assume responsibility and accountability to the applicant organization and to the NCI for performance and proper conduct of the research supported in the NCDDG, including the NIH intramural component, if applicable, in accordance with the TERMS AND CONDITIONS OF AWARD. b. The Principal Investigator, Program Leaders, and NCI Coordinator will meet periodically to review progress, plan and design research activities, and establish priorities. The frequency of meetings, not fewer than two per year, will be determined by the Principal Investigator who will be responsible for scheduling the time and place (generally at one of the performance sites) and for preparing concise proceedings or minutes (two or three pages) which will be delivered to the members of the Group within 60 days of the meeting. NCI Coordinator or Program Official may not chair Group meetings. c. The Government, via the NCI Coordinator, will have access to data generated under this cooperative agreement and may periodically review the data consistent with current DHHS, PHS, and NIH policies. However, the awardee will retain primary custody of and have primary rights to data, and timely publication of major findings by the Group members is encouraged. Publication or oral presentation of work done under this agreement will require appropriate acknowledgment of NCI support, including the assigned cooperative agreement award number. Dissemination of information on synthetic or natural substances supplied to the Group by NCI (e.g., for comparative testing purposes, as reference material, etc.) will require clearance by NCI to assure conformity with existing confidentiality agreements with suppliers. d. Ownership of natural product samples and combinatorial libraries acquired during the course of the research rests with the Group. The Group must follow its policy, approved by NCI, for final disposition of the samples and ownership rights in the event that the samples are transferred to other parties who use them to make discoveries. e. In order that samples be fully evaluated for anticancer potential after the Group has concluded its evaluation, but before the samples are transferred to other parties for evaluation in other therapeutic areas, it is requested that the Group provide lists of completed samples to the NCI Coordinator, who may facilitate additional biological evaluation in NCI's contract-based screening facilities or at an additional testing resource of mutual agreement to NCI and the Group. f. The NCI recognizes that most countries retain interest in samples collected within their domains. All applicants who propose foreign collections of natural products must provide a formal statement of agreement to NCI prior to award, signed by authorized representatives of all Group member institutions, for equitable return of a portion of any profits or royalties derived from NCDDG discoveries to indigenous peoples, research collaborators, cooperating institutions or Governmental entities in the countries of origin, as appropriate to their contributions. g. Foreign trips for collection purposes must be itemized separately. These funds will be restricted by NCI and require prior approval for release. Written approval for release of funds will be granted only after appropriate clearance documentation from the source country is provided. 2. NCI Staff Responsibilities NCI will participate as a member of the Group and will be represented by an NCI Coordinator, who will have substantial scientific programmatic involvement during the conduct of this activity that is above and beyond the normal stewardship for grant awards. In all cases, the role of NCI will be to assist and facilitate and not to direct activities. The NCI Coordinator, as well as any other Group member, may assist in research planning; may suggest studies within the scope of the Group's objectives and research activities; may present to the Group experimental findings from published sources or from contract projects in support of these suggestions; may participate in the design of experiments agreed to by the Group; and may participate in the analysis of results. However, the NCI Coordinator will not conduct laboratory studies. Upon recommendation of the NCI Coordinator, NCI may utilize its drug development resources (http://www.dtp.nci.nih.gov/) in support of Group research activities when such resources may be required on an occasional basis. The following is a list of resources that may be supplied if they become desirable during performance, are not anticipated as a continuing need, and are readily available: a. Reference compounds for standardization of test systems, as analytical standards, and for related purposes. b. Needed resources such as test materials and information that may not otherwise be available to the Group. c. Data from testing conducted in resource contract laboratories. d. Laboratory testing capacity, whenever appropriate and possible, in the current contract- based preclinical therapy-related laboratory testing program. The Group is expected to provide sufficient test material for such testing. e. Searches of computer files for information about materials, chemical structures and biological activities, if requests for such searches are sufficiently focused to avoid excessive costs. Information given to a Group will be restricted by any standard confidentiality agreements between the Government and suppliers of test materials to the Government. f. Experimental animals and cultured cells, if available, to Groups whose main research activities do not require these materials on a regular basis. Groups whose experimental approach involves studies that require animals on a regular basis must budget for these costs in their application. These "Terms and Conditions of Award" require that the NCI Coordinator approve the following: changes in the Principal Investigator or Program Leaders; reports intended for inclusion in Investigational New Drug Applications (INDAs) and Clinical Brochures; redistribution, outside the NCDDG, of biological and chemical materials received from the Government; and dissemination of research findings resulting from the use of such materials. 3. Collaborative Responsibilities The following Collaborative Responsibilities are based on the premise that the NCDDG is a unit consisting of a Principal Investigator, Program Leaders, Core Leaders, and their respective programs, and an NCI Coordinator which functions as a unit as specified in this RFA. Foreign institutions and NIH intramural laboratories may be participants as Programs or Scientific Cores but not as the awardee institution, and their scientists may not serve as the Principal Investigator. a. The principal end product of NCDDG activities will be the discovery of new entities and strategies for development to clinical trial. Subsequent developmental work through private resources is encouraged. Alternatively, the Group may recommend that development be sponsored by NCI. In the latter case, it will be necessary for the Principal Investigator and NCI Coordinator to cooperate in the analysis, summarization, preparation, and presentation of data to the appropriate NCI staff. b. NCI will retain the option to cross-file or independently file an application for investigational clinical trial (e.g., an Investigational New Drug Application [INDA] to the United States Food and Drug Administration) of any invention resulting from these NCI supported cooperative agreements. Reports of data generated by the Group or any of its members required for inclusion in INDAs and Clinical Brochures and for cross-filing purposes shall be submitted promptly by the Principal Investigator to the NCI Coordinator upon request. Such reports shall include background information, methods, results, and conclusions. They will be subject to approval and revision by NCI and may be augmented with test results from other Government-sponsored projects prior to submission to the appropriate regulatory agency. 4. Arbitration Any disagreement that may arise on scientific/programmatic matters (within the scope of the award, including the NIH intramural component) between the awardee and the NCI may be brought to arbitration. An arbitration panel will be composed of three members: one Group designee, one NCI designee, and a third designee with expertise in the relevant area chosen by the other two. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations at 42 CFR Part 50, Subpart D, and DHHS regulations 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 Mary K. Wolpert, Ph.D. Division of Cancer Treatment and Diagnosis National Cancer Institute 6130 Executive Boulevard, EPN Room 8153, MSC 7456 Bethesda, MD 20892-7456 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-8783 FAX: (301) 402-5200 Email: wolpertm@exchange.nih.gov For specific information related to chemistry or structural biology contact: Dr. Ronald Dubois Division of Cancer Treatment and Diagnosis National Cancer Institute 6130 Executive Boulevard, EPN Room 8153, MSC 7456 Bethesda, MD 20892-7456 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-8783 FAX: (301) 402-5200 Email: duboisro@mail.nih.gov For specific information related to natural products research, contact: Dr. Yali Hallock Division of Cancer Treatment and Diagnosis National Cancer Institute 6130 Executive Boulevard, EPN Room 8153, MSC 7456 Bethesda, MD 20892-7456 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-8783 FAX: (301) 402-5200 Email: hallocky@mail.nih.gov o Direct your questions about peer review issues to: Referral Officer Division of Extramural Activities National Cancer Institute 6116 Executive Boulevard, Room 8041, MSC 8329 Bethesda, MD 20892-8329 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-3428 FAX: (301) 402-0275 Email: ncirefof@dea.nci.nih.gov o Direct your questions about financial or grants management matters to: Ms. Jill Rogers Grants Administration Branch National Cancer Institute 6120 Executive Boulevard, EPS Room 243 Bethesda, MD 20892-7150 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-8796 FAX: (301) 496-8601 Email: jr261m@nih.gov 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 to by the date listed at the beginning of this document. The letter of intent should be sent to: Mary K. Wolpert, Ph.D. Division of Cancer Treatment and Diagnosis National Cancer Institute 6130 Executive Boulevard, EPS Room 8153, MSC 7456 Bethesda, MD 20892-7456 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-8783 FAX: (301) 402-5200 Email: wolpertm@exchange.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 Grants Info, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. SUPPLEMENTARY INSTRUCTIONS: The submission of a single application for a proposed NCDDG is required (that is, all parts of the application must be packaged together and submitted by the applying organization). Because of the interdisciplinary and usually multi-institutional nature of an NCDDG, the special requirements of the RFA, and the special provisions which must be followed when NIH intramural laboratories are participants, the following guidance is provided to help the applicant include all necessary information and still provide a document that can be readily reviewed. Applications that are incomplete will be returned without review. Information about the NCDDG program can be found at http://dtp.nci.nih.gov. FORMAT OF APPLICATION General instructions for the preparation of applications are contained in the Grant Application Form PHS 398 (revised 5/2001) and can be found at http://grants.nih.gov/grants/funding/phs398/phs398.html. These instructions are designed primarily for traditional research project (R01) applications. NCDDG applications require additional information as outlined below. Page limitations are presented in the PHS 398 instructions and these should be followed for each individual Laboratory Program and Core unless otherwise noted. Please note that an NCDDG is headed by a Principal Investigator and includes research components called Laboratory Programs headed by Program Leaders and may include Cores headed by Core Leaders. Programs are equivalent to R01 projects as far as the PHS 398 Instructions are concerned and the instructions are the same except as noted below. Description, Performance Sites, and Key Personnel (PHS 398 Form Page 2 and Continuation Pages: This section should concisely state the overall goals of the NCDDG and clearly state the contribution of each component to the overall goals. Key personnel for the entire Group including consultants and consortium collaborators should be listed alphabetically. Use the terms "Program Leader" and "Core Leader" as appropriate to identify personnel performing these roles. Research Grant Table of Contents (PHS 398 Form Page 3 and Continuation Pages: The application is reviewed as a whole as well as Program by Program; therefore, prepare a detailed Table of Contents that enables reviewers to find specific information readily. Identify Laboratory Programs by number, title, and responsible investigator. Identify Cores by letter, title and responsible investigator. A sample table of contents is included at the end of these special instructions to show the order and format in which the application should be organized. Agreement to Accept NCI Participation (PHS 398 Continuation Pages): The agreement to accept NCI participation in the NCDDG as described in the RFA text, and signed by all parties, must be inserted in the application after the Table of Contents. Budget Instructions for Initial Budget Period: Follow the Detailed (not modular) Budget Instructions for Initial Budget Period (PHS 398 Form Page 4. Items in this section of the PHS 398 Instructions must be followed carefully in preparing the total NCDDG budget. Budgetary information is also required for each grant component as part of the write up for that component (Laboratory Program or Core). Specify and justify personnel effort even if no salary support is requested. Present a detailed composite budget for all requested support for the first year, using page 4 of the PHS 398 application form. If collaborative efforts or "purchased services" involving other institutions or organizations are anticipated, itemize all costs associated with such third party participation, including any applicable Facilities and Administrative (F&A) costs on a separate budget page and enter the total under the "Consortium/Contracted Costs" direct costs budget category. For details on consortium budgets, see the NIH Grants Policy Statement (03/01) at http://grants.nih.gov/grants/policy/nihgps_2001/index.htm. Under NIHGPS (03/01) in the left hand corner of the screen, scroll down to Part II: Other Terms then click Consortiums. Travel costs for Group meetings should be included in the budget for the Administrative Core. All other scientific travel should be included in the budget for each individual Program or Scientific Core. Budget Instructions for Entire Proposed Period of Support (PHS 398 Form Page 5 and Continuation Pages: Present a composite summary budget for all years of requested support for the overall Group by category, i.e., personnel, equipment supplies, etc. All increases for future years, whether standard cost of living or projected special requirements, should be stated explicitly and clearly justified. Often the various research tasks necessary to reach the Group's goals may need to be phased in, at least in part, in sequential fashion. In such cases, the budgets for the individual Laboratory Programs should, logically, reflect an appropriate change in relative emphasis among tasks until an operational steady state situation is attained. Detailed justification for phase-in budgets must be provided. Costs for Group meetings and intra-Group communications should be budgeted in the Administrative Core taking care not to duplicate these costs in the budgets for individual Programs. Budgetary provision should be made for items such as scale-up synthesis; actual use of funds for these purposes will be restricted by the NCI to the purposes stated and funds will be released if and as needed only on specific recommendation of the NCI Program Official. Foreign trips for collection purposes must be itemized separately. These funds will be restricted by NCI and require prior approval. Approval for release of funds will be granted only after appropriate clearance documentation from the source country is provided. Biographical Sketches (PHS 398 Format page "BIOGRAPHICAL SKETCH" and Continuation Page; PHS 398 Instructions): Biographical sketches as described in this section of the instruction sheet must not exceed four pages. Therefore, cite only the most relevant publications. Place the biographical sketches in alphabetical order by last name immediately after the budget sections. Do not repeat biographical sketches in each Program component. Biosketches are required for all professional personnel participating in individual Laboratory Programs and cores and for all consultants. Include all biosketches in the application and not in an appendix. Overall NCDDG Description (PHS 398 Continuation Pages): The overall NCDDG description should explicitly provide the required information in the order noted below. This description should not exceed 25 pages, excluding publications. o Goals: Present the general problem area to be studied, the overall long-term objectives of the research described in this application and the hypotheses to be tested. Discuss the relationship of your goals to the discovery of new treatments for cancer. o Interrelationships: The NCDDG is a confederation of interrelated and interdependent Laboratory Programs. It is important to address the integration of the components, demonstrating how each individual program and core benefits from and contributes to the overall Group as well as how the Group intends to interact with the NCI. A diagram illustrating the effective interactions between components may be helpful to reviewers. Details should be provided about Group meetings which are expected to be held at least twice per year and how frequent communication between Group meetings will be maintained. The agreement to accept NCI participation should be discussed in this section. o Research Plan: This section delineates the research addressed by the Group as a whole and explains the strategic approach to the problem, briefly mentioning each component (Laboratory Program or Scientific Core) as it relates to the overall NCDDG. Descriptions of prior collaborative efforts among investigators in the Group, as well as the sequence of events leading to the current application may also be included in this section. It is important to discuss the advantages expected from a group effort, and how they will further the goals of the research. o Lead Optimization: Discuss how the Group plans to optimize lead structures discovered in Group research. o Development Plan: As required in the RFA, discuss how the Group intends to pursue leads discovered in the research towards advanced pre-clinical and clinical development. o Preliminary Studies (for new applications): This section should focus on research already underway and current accomplishments of the investigators. More detailed preliminary results are to be included separately under each individual Laboratory Program or Core. Items to be included are a summary of major accomplishments attributed to the participating investigators that relate to the overall theme of the Group and a list of all publications and manuscripts accepted for publication already produced by the interactions of the participating investigators. o Progress Report (for competing renewal applications): This section should describe the achievements of the Group since the last competitive review with emphasis on the discovery of new anticancer treatments and new leads. Separate progress reports are included in the individual Laboratory Programs, so this section should focus on the overall Group rather than reiterating information provided in each component. Include the following: Summarize the major accomplishments that can be attributed to the Group. Identify which components were involved in these accomplishments. Discuss the role of the NCI in your accomplishments. Discuss any changes in the composition of the Group and the reasons for the changes. Provide a list of all publications and completed manuscripts that have resulted from the award. Indicate those which involved participation of more than one Group component. o Institutional Environment and Resources: Discuss the overall resources that are available to the Group, particularly those which relate to the overall Group and provide special opportunities. These could include resources of industrial collaborators, consultants, etc. The resources and environments specific to the laboratory components and cores are to be detailed in their individual parts of the application. o Organization and Administrative Structure: Describe in detail and by diagram the chain of authority for decision making and administration, beginning at the level of the Principal Investigator. Include all investigators responsible for individual Laboratory Programs and cores and detail how the tasks are planned, coordinated, and evaluated. If internal or external advisory groups are to be used, list the membership (actual but not proposed members) and describe the role of each. List in a separate table all consultants, both paid and unpaid. o Literature Cited: While this section is not included in the page limitation, it is important to be concise and to select only those literature references pertinent to the overall description. List complete literature citations as directed in the PHS 398 Instructions. o Appendix: Again, this section is not included in the page limitations. Organize appendix materials in the following sequence: Appendix material for the overall NCDDG, followed by appendix material for numbered Laboratory Programs, if needed, followed by appendix material for lettered Cores, if needed. Limit the appendix to those few most essential publications necessary to document your application o Laboratory Programs: Describe each Laboratory Program (term used to describe an individual research project in a Group) in sufficient detail to enable reviewers to judge the scientific merit from the written application. Use the outline below. In each Laboratory Program, sections A-D of the Research Plan should not exceed 25 pages. Cover Page (Use a PHS 398 Continuation Page and NOT form page 1, FACE PAGE from PHS 398). Clearly denote the Laboratory Program number, the title of the Laboratory Program, the name of the Program Leader, and the Program Leader's Institution. Key Personnel (PHS 398 Form page 2). The title of Principal Investigator is reserved for the director of the overall Group. The directors of the individual Laboratory Programs should be referred to as "Program Leaders". Omit Table of Contents (already included in OVERALL section). Budget. Use detailed budget formats even if no more than $250,000 direct costs per year are requested for an individual program. Use PHS 398 Form Pages 4 and 5 and PHS 398 Instructions, Pages 10-14. A detailed budget is required for the first year and the budget summary for each additional year. The budget justifications are to be explicit, including those for changes for future years. Omit Biographical Sketches as these are included elsewhere in the application. Resources and Environment: List only those specific to the Laboratory Program. Clearly explain the position of Program Leaders from pharmaceutical companies. The Program Leader should be responsible for allocation of resources required for the research. No page limitation. Research Plan: Laboratory Program aspects - Include Sections A, B, C and D. Limited to 25 pages. Relation of Laboratory Program to overall NCDDG: (This item is not included in PHS 398 Instructions.) Describe in this section the relevance of the Laboratory Program to the primary theme of the Group and the collaborations with other investigators within the Group. Limited to one page. Human Subjects: If any organizational component within an NCDDG uses human subjects, this information must be noted on the face page for the overall application. If human subjects are involved in the application, be sure to address all aspects including Gender and Minority Inclusion for Research Involving Human Subjects and Inclusion of Children as Participants in Research Involving Human Subjects. HS 398 Instructions, Pages 17-2. There are no page limitations here but be succinct and address the four points for each laboratory program that uses human subjects. Vertebrate Animals: If any organization within a NCDDG uses vertebrate animals, this information must be noted on the face page for the overall application. Again, there are no page limitations but be succinct, and address the five points for each laboratory program that uses vertebrate animals. Consultants/Collaborators: (PHS 398 Continuation Pages). List only those consultants or collaborators who are specific to this Laboratory Program. No page limitation. Literature Cited: (PHS 398 Continuation Pages; PHS 398 Instructions, Page 28). List complete literature citations at the end of each Laboratory Program. Each citation must include the names of all authors, full title, name of book or journal, volume, pages and year of publication. No page limitation but select only pertinent references. Do NOT include a checklist for each Laboratory Program. There should be only one checklist at the very end of the entire application, and that should come from the organization submitting the overall NCDDG. Cores: (PHS 398 Continuation Pages). The Cores within a Group may include laboratory facilities, equipment, and services which will be shared by two or more Laboratory Programs. A core may also include support of administration, such as the costs of business management, consultants, and secretarial services associated with the Group where these items are not included in the institution's indirect cost rate. Using a Form PHS 398 Continuation Page, denote "Core Component" (followed by a letter if there is more than one core), the title of the core, and the name and institution of the Core Leader. The Administrative Core at the Principal Investigator's institution must be designated as "Core A", followed by Scientific Cores, if any. An Administrative Core may be omitted in special circumstances, such as an application from a single institution. For each Scientific Core component, follow the specific instructions and page limitations for the Laboratory Program, above, except that in place of the item "Research Plan", describe the role of the core component as a resource to the NCDDG as a whole. Clearly present the facilities, resources, services, and professional skills that the core component provides. Checklist for overall application (Use PHS 398, CHECKLIST FORM PAGE: Self-explanatory. Additional documentation of a legal and proprietary nature, described in the RFA under SPECIAL REQUIREMENTS, will need to be sent to the NCI Coordinator assigned to the application before an award can be made. This information will be considered confidential and will not be provided to reviewers as part of the application material. This documentation must be signed by authorized representatives of all Group participants. The three documents include a Patent Agreement (required by all Groups), a formal statement providing assurance that an equitable portion of profits will be returned to indigenous people from the country of origin (required by Groups discovering drugs from natural products obtained from foreign sources), and a plan for ownership and use of natural product extracts or chemical libraries after the Group has decided that they are no further value to the Group Programs (required by Groups generating these products). Although this documentation is to be sent when requested by NCI staff after the peer review of applications but before award, applicant organizations would be well advised to have this information ready to be supplied. Incumbent applicants can state on an appropriate continuation page that there are no changes from previously submitted information, if this is the case. SAMPLE TABLE OF CONTENTS: IN ORDER TO AID THE REVIEW OF APPLICATIONS, PLEASE ORGANIZE YOUR MATERIALS IN THE ORDER SHOWN IN THIS SAMPLE TABLE. SECTION I Face Page Table of Contents Agreement to Accept NCI Participation Detailed Group budget for First 12-Month Period Budget Estimate for Each Year of Funding Biographical Sketches (alphabetical order by last name) SECTION II Overall NCDDG Description: Goals Interrelationships Research Plan Development Plan Preliminary Studies/Progress Report Institutional Environment and Resources Organization and Administrative Structure Literature Cited with complete titles and authors Laboratory Program 1 (Title): Cover Page Description of Research Plan/ List of Key Personnel Detailed budget for First 12-Month Period Budget Estimate for Each Year of NCDDG Resources and Environment Research Plan (Human Subjects) (Vertebrate animals) Consultants/Collaborators Literature Cited with complete titles and authors Laboratory Program 2 (Title): Cover Page Description of Research Plan/ List of Key Personnel, etc. Core Component A (Title) (Administrative Core, if present): Cover Page Description of Core/List of Key Personnel Detailed budget for First 12-Month Period Budget Estimate for Each Year of NCDDG Resources and Environment Role and Justification for the Core Component Core Component B (Title) (Scientific Core, if Present): Cover Page Description of Core/List of Key Personnel Detailed budget for First 12-Month Period Budget Estimate for Each Year of NCDDG Resources and Environment Role and Justification for the Core Component (Human Subjects) (Vertebrate animals) Literature Cited with complete titles and authors Check List Appendix (if appendix is needed, put documents in following sequence): Overall Group Description Numbered Laboratory Programs Lettered Cores 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 us 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) Telephone: (301) 435-0715 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) Telephone: (301) 496-3428 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 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 CSR and responsiveness by 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 applicants 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 NCI National Cancer Advisory Board (NCAB). REVIEW CRITERIA Review Criteria for NCDDG as a Whole 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. All applications will be judged on the basis of the scientific merit of the proposed project and documented ability of the investigators to meet the RESEARCH OBJECTIVES of the RFA. Although the technical merit of the proposed studies is important, the likelihood of identifying a clinical trial candidate and the plan for pre-clinical development activities beyond the scope of the RFA will be part of the evaluation. Within this framework the specific goal of this RFA is the discovery and pre-clinical analysis of new agents to treat cancer. The reviewers will address the following criteria in assigning priority scores, weighting them as appropriate for each application. Individual Programs and Cores within the NCDDG, as well as the NCDDG as a whole, will be evaluated. Note that each Program within the NCDDG does not need to be strong in all categories as long as it contributes a necessary function to the goals of the Group. Each application will be evaluated for the extent of progress on prior award (RECOMPETING GROUPS) or preliminary results (NEWAPPLICANTS). Groups will be evaluated for extent of effectiveness of cooperation with the NCI (RECOMPETING GROUPS) and adequacy of plans for cooperation with the NCI (ALL APPLICANTS). SIGNIFICANCE: Does the applicant address an important problem in anticancer drug discovery and/or development? If the aims of the application are achieved, what is the likelihood of a new cancer therapy or strategy for clinical evaluation? Is the development plan adequate to bring the agent to clinical trial? APPROACH: Are the overall conceptual frameworks, designs, methods, and analyses adequatelydeveloped, well-integrated, and appropriate? Are the scientific disciplines represented in Programs and Scientific Cores adequate to achieve Group objectives? Does the applicant acknowledge potential problem areas and consider alternate tactics? Are targets and screens relevant to the neoplastic process? Are plans adequate for ensuring effective intra-Group communication and for assuring Group cohesiveness? Is the plan to optimize lead structures, from both synthetic and natural sources, adequate to ensure that the most efficacious drug will result? Are plans for decision-making regarding identification and pursuit of lead candidates reasonable and appropriate? INNOVATION: Does the NCDDG employ novel concepts, approaches, or methods? Are the aims original and innovative? Does the NCDDG challenge existing paradigms or develop new methodologies or technologies? Is the target under investigation for drug discovery novel? Will new paradigms for drug discovery emerge? INVESTIGATORS: Are the Principal Investigator and Program/Core Leaders appropriately trained and well suited to carry out this work? Is the time commitment for each sufficient to achieve goals? Has the Principal Investigator demonstrated leadership in development, implementation and management of comprehensive research programs? ENVIRONMENT: Does the scientific environment in which the Programs will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific expertise and foster effective collaborations? Is there evidence of institutional support and competence of the applying Institution to serve as the Administrative Core for the Group? Review Criteria for Programs SIGNIFICANCE: Does this program address an important problem in anticancer drug discovery and/or development? If the aims of the program are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the program? Does the applicant acknowledge potential problem areas and consider alternative tactics? INNOVATION: Does the program employ novel concepts, approaches or methods? Are the aims original and innovative? Does the program challenge existing paradigms or develop new methodologies or technologies? INVESTIGATOR: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the Program Leader and other researchers (if any)? 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? Review Criteria for Cores The utility of the Core to the NCDDG. Each Core must provide essential facilities or services for two or more programs judged to have substantial merit. The quality of the facilities or services provided by the Core (including procedures, techniques, and criteria for prioritizing activities). The qualifications, experience, and commitment of the personnel involved in the Core. For an Administrative Core: Resources and plans provided for Group communication and coordination of Group activities. 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). The four items described in PHS 398 must be included in each program or core that uses human subjects. 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 any program or core, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. The five items must be included in each program or core that uses animals. 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. Instructions concerning this policy are listed below under REQUIRED FEDERAL CITATIONS. 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: April 19, 2004 Application Receipt Date: May 19, 2004 Peer Review Date: October 2004 NCAB Review: February 2005 Earliest Anticipated Start Date: May 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 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/ HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide, in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s) to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this 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. VERTEBRATE ANIMALS: The PHS Policy on Humane Care and Use of Laboratory Animals requires that applicant organizations proposing to use vertebrate animals file a written Animal Welfare Assurance with the Office for Protection from Research Risks, establishing appropriate policies and procedures to ensure the humane care and use of live vertebrate animals involved in research activities supported by the PHS. The PHS policy stipulates that an applicant organization, whether domestic or foreign, bears responsibility for the humane care and use of animals in PHS-supported research activities. Additional information in outlined in the PHS 398 instructions and available at: http://grants.nih.gov/grants/olaw/references/phspol.htm. 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 that 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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