NATIONAL COOPERATIVE DRUG DISCOVERY GROUPS Release Date: April 14, 1999 RFA: CA-99-010 (see reissuance RFA-CA-05-001) P.T. National Cancer Institute Letter of Intent Receipt Date: June 16, 1999 Application Receipt Date: July 14, 1999 This RFA is a reissuance of CA-95-020, which was published in the NIH Guide on September 22, 1995. PURPOSE The Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, NCI, invites applications for the continuance of the National Cooperative Drug Discovery Group (NCDDG) and National Cooperative Natural Products Drug Discovery Group (NCNPDDG) Programs for the discovery of new and more effective anticancer treatments. 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 recompeting NCDDGs and NCNPDDGs as well as from new Groups. It will support broad, innovative, multidisciplinary, multi-project approaches to the discovery of new, rationally based or natural-source derived anticancer treatments or strategies. A multi-institutional, group approach involving academic, nonprofit, and/or commercial/industrial institutions 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. Both mechanism of action and disease-oriented approaches are being solicited. 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. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This RFA, National Cooperative Drug Discovery Groups, is related to the priority area of cancer. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800) or at http://www.crisny.org/health/us/health7.html. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and Local governments, and eligible agencies of the Federal Government. Although an NCDDG application may not be submitted by a foreign institution or an intramural laboratory from the National Institutes of Health, a foreign institution or an intramural laboratory may participate as a Laboratory Program or Scientific Core in an NCDDG submitted by a domestic institution. All incumbent NCDDG/NCNPDDGs are eligible to apply. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to participate. MECHANISM OF SUPPORT The administrative and funding instrument to be used for support of awards will be 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. Under the cooperative agreement, the NCI's role is to support and/or stimulate the recipient's activity by working jointly with the award recipient as a partner, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Details of the responsibilities, relationships and governance of the study to be funded under a cooperative agreement are discussed later in this document under the section "Terms and Conditions of Award." Assistance via cooperative agreement differs from the research project grant in that the Government component (NCI) awarding the cooperative agreement anticipates substantial programmatic involvement during performance of the award. This partnership relationship will facilitate technology transfer from Government-owned data bases and use of appropriate NCI-derived resources to enhance the efficiency and effectiveness of a Group's efforts. The nature of NCI staff participation is described below under "Terms and Conditions of Award." There is no intent, real or implied, for NCI staff to direct Group activities or to limit the freedom of investigators. An award will be made only to the Principal Investigator's (grantee) institution. All Group activities will be coordinated through an administrative core located at the grantee institution. Individual projects, called Programs, are funded as consortium projects to the grantee institution if not located at the institution. The total project period requested for applications submitted in response to the present RFA may not exceed five years. The earliest anticipated award date is April 1, 2000. Because the nature and scope of the research proposed in response to this RFA may vary, it is anticipated that the size of awards will vary. The number of awards and the level of support depend on receipt of a sufficient number of applications of high scientific merit. Although this program is provided for in the financial plans of the NCI, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. At this time, the NCI anticipates that there will be periodic recompetition of this program. However, if not, awardees may submit renewal grant applications through the usual investigator-initiated grants program which will be reviewed according to customary peer review procedures. FUNDS AVAILABLE The NCI has budgeted $12 million total costs (direct plus facilities and administrative costs) for the first year of funding, subject to the availability of funds. It is expected that 12 - 14 awards will be made for periods up to five years. The number of awards and individual level of support is dependent on the receipt of a sufficient number and diversity of applications with high scientific merit. Program balance and diversity of topics will be factors in selecting applications for award. Budget requests should be justified and commensurate with the needs of the project. Those in excess of $1.1 million total costs for the first year must be carefully justified, and the projects must be highly meritorious. Annual budgets for years two to five should not exceed the first year budget plus a 3% yearly increase. Equipment needs, especially in future years, must be well justified. RESEARCH OBJECTIVES Background Important new findings in molecular biology, cell biology 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 utilize facilitating resources of NCI's drug development program within these teams, the NCI acted on advice of a special subcommittee of the Division of Cancer Treatment's Board of Scientific Counselors and established the NCDDG program in 1982. Since that time, Requests for Applications (RFAs) were issued in July 1983, August 1984, October 1986, August 1987, August 1991, March 1994, and September 1995. National Cooperative Natural Products Drug Discovery Groups were established through an RFA issued in September 1988 and continued with issuances in October 1989, March 1994 and September 1995, in order to enhance discovery of novel chemotypes from natural sources for subsequent development as anticancer agents. For additional information on the NCDDG program, visit the web site: http://dtp.nci.nih.gov (under DTP Grants and Contracts). NCDDGs are peer-reviewed, multi-component, multidisciplinary 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 which is 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 advanced development including scale-up synthesis, pharmacology, toxicology, Investigational New Drug Applications (INDAs) to the Food and Drug Administration (FDA), and clinical trials support can be made available through the NCI (Sausville, E.A, Working with the National Cancer Institute, from: Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval, edited by: B. Teicher, Humana Press Inc., Totowa, NJ). Additional information can be obtained at the DTP web site: http://dtp.nci.nih.gov or the Cancer Therapy Evaluation Program (CTEP) web site: http://ctep.info.nih.gov. Extended preclinical developmental support may be obtained though the Rapid Access to Intervention Development (RAID) mechanism (http://dtp.nci.nih.gov) or through private venture capital. Objectives and Scope The purpose of this RFA is to encourage the discovery of novel treatments or strategies to improve the survival of cancer patients. Groups should utilize innovative approaches to drug discovery based on recent advances in tumor biology and the molecular understanding of cancer. Projects directed at targets and regulatory pathways specifically altered in tumor cells are encouraged, whereas approaches based solely on inhibition of cellular proliferation 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, 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 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. NCDDGs focused on the discovery and evaluation of new entities from natural sources should emphasize novelty of the natural product sources and utilize molecular target-based screening assays. Biosynthetic approaches are considered within the scope of the RFA. The development or use of preclinical 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 products 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. Lead optimization utilizing modern combinatorial chemistry technology is encouraged. If appropriate, Programs could include analysis of new and relevant procedures to evaluate in vivo efficacy which 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 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 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) which 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 to encompass any naturally occurring chemical or biological entity of non-human origin selected and evaluated preclinically against cancer. NCI COORDINATOR. A scientist from the NCI extramural program staff, appointed after award by the NCI Program Official, 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 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 may serve as a Program Leader. 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 interrelated Laboratory Programs. While no maximum number of programs is stipulated, when an award exceeds five programs the overall Group may become difficult to manage. Groups may also have Scientific Cores which 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 when appropriate. F. Pharmaceutical 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. 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 applicants provide plans to assure such coverage. The situation could be complicated since multiple institutions are likely to be involved. Each 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 institution. Procedures must be described for resolution of legal problems should they arise. Your attention is drawn to P.L. 96-517 as amended by P.L. 98-620 and 37 CFR Part 401. Instructions were also published in the NIH GUIDE FOR GRANTS AND CONTRACTS, Vol.19, No. 23, June 22, 1990. 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 prior to award to Dr. George S. Johnson at the address provided under INQUIRIES. For applications involving natural products, a formal statement of agreement must be provided signed by authorized representatives of all institutions in the Group, assuring that an equitable portion of royalties or profits arising from drugs discovered, 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 drug was derived. The signed document must be submitted prior to award to Dr. George S. Johnson at the address provided under INQUIRIES. A plan must be developed for disposition of natural products samples, combinatorial libraries, etc., in conformance with TERMS AND CONDITIONS OF AWARD, Item 1.C, listed below. The signed document must be submitted prior to award to Dr. George S. Johnson at the address provided under INQUIRIES. The three documents listed above will be considered confidential and will not be included with review material. Awards will not be made until they are received and approved by NCI. H. 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 which include NIH intramural components, the intramural resource level will be accounted for in the total cost of the overall application. 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. Prior to award the Group must formulate a policy for final disposition of the samples and ownership rights in the event that the samples are transferred to other parties who make discoveries using them. 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 a Coordinator. The NCI Coordinator will be selected after award by the NCI Program Official for the NCDDG Program from the extramural but not intramural staff. During performance of the award, NCI may provide appropriate assistance by participating in the design of activities; advising in the selection of sources for resources, staff, etc.; and advising in management and technical performance. 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 of materials, chemical structures and biological activity, 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 Program Official 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 (appointed from the NCI extramural staff after the award) 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. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided 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 research involving human subjects should read the "NIH Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research," which was published in the Federal Register of March 28, 1994 (59 FR 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994, available on the web at: https://grants.nih.gov/grants/guide/notice-files/not94-100.html. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH 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 clear and compelling 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 was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: https://grants.nih.gov/grants/guide/notice-files/not98-024.html. Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by June 16, 1999, a letter of intent that includes a descriptive title of the overall proposed research; the name, address, telephone number, and institution of the Principal Investigator; names of prospective Program Leaders, other key investigators, and their respective participating institutions; title and Program Leader for each Group Program; and the number and title of the RFA in response to which the application may be submitted. Although the letter of intent is not required, is not binding, and is not a factor in the peer review of the application, the information it contains is helpful in planning for the review of applications. It allows NCI staff to estimate the potential review workload and to avoid conflict of interest in the review process. The letter of intent is to be sent to Dr. George S. Johnson at the address listed under INQUIRIES. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these awards. These forms are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda MD 20892-7910, Telephone: (301) 710-0267, Email: GrantsInfo@nih.gov. Application kits are also available on the internet at: https://grants.nih.gov/grants/forms.htm This RFA requires the submission of a single application. Because of the multi- disciplinary and likely multi-institutional nature of an NCDDG and the special requirements in this RFA, additional written instructions regarding format, which are incorporated by reference as if fully set forth herein, are available at http://dtp.nci.nih.gov (under DTP Grants and Contracts) or from Dr. George S. Johnson (see INQUIRIES below). Potential applicants are urged to obtain the "Special Instructions to Applicants for Preparation of NCDDG Applications" to avoid omitting essential information and to expedite review. If required information is not contained within the application, the application will be returned without review. On line 2 of the face page of the application form, the YES box must be marked, the Number should be listed as RFA CA-99-010 and the Title must be given as "National Cooperative Drug Discovery Groups"; personalized titles more fitting for the application should be listed on line 1. The RFA label available in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application with the result that it may not reach the review committee in time for review. The following special instructions must be followed when NIH intramural laboratories serve as a Laboratory Program or Scientific Core. Application procedures specified in the PHS 398 form must be followed. The Principal Investigator of the NCDDG must incorporate into the application, in the usual grant format, a full description of the project, including technical details and methodology. The budget pages should supply the time and effort for each intramural program participant, but no other budget information should be provided. A letter of approval from the Scientific Director must be provided which specifies that not 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 Principal Investigator must submit a signed, typewritten original application, including NIH intramural laboratory component, if applicable, 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 must also be sent to: Ms.Toby Friedberg Division of Extramural Activities National Cancer Institute 6130 Executive Boulevard, Room 636 - MSC 7407 Bethesda, MD 20892-7407 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-3428 Applications must be received by July 14, 1999. If an application is received after that date, it will be returned to the applicant without review. 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. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of a substantial revision of an application already reviewed, but such an application must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS General Considerations 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. Review Method Upon receipt, applications will be reviewed for completeness by CSR and responsiveness by NCI. Incomplete applications will be returned to the applicant without further consideration. If NCI staff finds that the application is not responsive to the RFA, it will be returned without further consideration. 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 NCI in accordance with the review criteria stated below. As part of the initial merit review, all applicants will receive a written critique and may undergo a process in which only those applications deemed to have the highest scientific merit generally the top half of the applications will be discussed, assigned a priority score, and receive a second level review by the National Cancer Advisory Board (NCAB). Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. 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. Review Criteria for NCDDG as a Whole Significance. Does the study address an important problem? 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 conceptual framework, design, methods, and analyses adequately developed, 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 study address an important problem? If the aims 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? Investigators: Is the Program Leader appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the project 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? 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. The qualifications, experience, and commitment of the personnel involved in the Core. Additional Considerations. Each application will be evaluated for the extent of progress on prior award (RECOMPETING GROUPS) or preliminary results (NEW APPLICANTS). 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). The review group will critically examine: the budget requested for each program, core and overall NCDDG and will recommend an appropriate budget and period of support for each approved application; adequacy of plans to include both genders, children, and minorities and their subgroups as appropriate for the scientific goals of the research and plans for recruitment and retention of subjects; provisions for protection of human and animal subjects; and the safety of the research environment. AWARD CRITERIA Applications recommended by the NCAB will be considered for award based on scientific merit as reflected in the priority score; on programmatic priorities and relevance; on program balance; and on funds available. The following schedule will be followed: Schedule Letter of Intent Receipt Date: June 16,1999 Application Receipt Date: July 14, 1999 NCAB Meeting Date: January/February 2000 Earliest Award Date: April 1, 2000 INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues and for a copy of the "Special Instructions to Applicants" on application format to: George S. Johnson, Ph.D. Division of Cancer Treatment and Diagnosis National Cancer Institute 6130 Executive Boulevard, Suite 841, MSC 7456 Bethesda, MD 20892-7456 Rockville, MD 20852-7456 (for express/courier service) Telephone: (301) 496-8783 FAX: (301) 402-5200 Email: johnsong@exchange.nih gov For specific information related to chemistry or structural biology contact Dr. John Biesler, or related to natural products research contact Dr. Yali Hallock, at the same address and telephone number. Direct inquiries regarding fiscal matters to: Ms. Priscilla Grant Grants Administration Branch National Cancer Institute 6120 Executive Boulevard, Room 243, MSC-7150 Bethesda, MD 20892-7150 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-7800, Ext. 245 FAX: (301) 496-8601 Email: pg38h@nih.gov Direct inquiries regarding review issues to: Ms. Toby Friedberg Division of Extramural Activities National Cancer Institute 6130 Executive Boulevard, Room 636, MSC 7407 Bethesda, MD 20892-7407 Rockville, MD 20852-7407 (for express/courier service) Telephone: (301) 496-3428 FAX: (301) 402-0275 Email: tf12w@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.395, Cancer Treatment Research. Awards are made under authorization of the Sections 301 and 405 of the Public Health Service Act, as amended ( 42 USC 241 and 284) and administered under PHS grants policies and Federal Regulations 42 CFR Parts 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The Public Health Service strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-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 case, 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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