Full Text AI-92-16 NATIONAL COOPERATIVE DRUG DISCOVERY GROUPS FOR THE TREATMENT OF HUMAN IMMUNODEFICIENCY VIRUS INFECTION NIH GUIDE, Volume 21, Number 38, October 23, 1992 RFA: AI-92-16 P.T. 34 Keywords: AIDS Drug Design Pharmaceuticals Pharmacology National Institute of Allergy and Infectious Diseases Letter of Intent Receipt Date: January 15, 1993 Application Receipt Date: March 17, 1993 PURPOSE The National Institute of Allergy and Infectious Diseases (NIAID) invites applications for the establishment of National Cooperative Drug Discovery Groups for the Treatment of Human Immunodeficiency Virus Infection (NCDDG-HIV). The NIAID announces availability of an RFA for funding of the National Cooperative Drug Discovery Groups for the Treatment of HIV Infection (NCDDG-HIV). The prime objective of this RFA is to support innovative research of sound scientific rationale, which requires intra-Group interactions and that is likely to result in the discovery of more effective therapeutic strategies against HIV. This RFA will support original and/or under-exploited studies that are at the cutting edge of biomedical research. Such studies may have a greater risk-to-benefit quotient than is currently considered under the more traditional investigator initiated (R01) mechanism, but may also have a greater potential for effective, long-term therapeutic returns. Applications that include research projects or core components from the private sector (e.g., pharmaceutical, chemical, or biotechnological companies) are strongly encouraged. 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 for the Treatment of HIV Infection (NCDDG-HIV), is related to the priority area of HIV infection. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign for-profit and non-profit organization, private and public, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Applications from minority individuals and women are encouraged. MECHANISM OF SUPPORT Awards will be made as Cooperative Agreements (U01s). The NIAID, in awarding a Cooperative Agreement, anticipates substantial programmatic staff involvement during performance of the award. The nature of NIAID staff participation is described in SPECIAL REQUIREMENTS - Terms of Award. There is no intent, real or implied, for NIAID to direct Group activities or to limit the freedom of investigators. It is the Principal Investigator who defines his/her objectives in accord with his/her interests and perceptions of novel, promising strategies for the treatment of HIV infection. The applicant institution and the Principal Investigator will be responsible for the Group's application. Awards will be made to the applicant institution on behalf of the group as a whole and not to individual research projects within the Group. The applicant institution will provide a Central Operations Office for the Group, will be responsible for the performance of the entire Group, and will be accountable for the funds awarded. The participation of the Government through the NIAID extramural staff is intended to facilitate a concerted effort by members of the Group by (1) providing appropriate scientific input; (2) making available biological materials for testing; (3) accessing appropriate data bases; and (4) providing ancillary testing and other resources available under existing contracts. The interaction of academic, non-profit research institutions, commercial (including industrial) organizations, and Government under this Cooperative Agreement is expected to promote and expedite discoveries of new entities and strategies for the treatment of HIV infections and facilitate their subsequent development to clinical trial. Under the Cooperative Agreement, a partner relationship between the recipient of the award and NIAID exists in which the Group is responsive to the requirements and conditions set forth in this RFA. Specifically, the Principal Investigator defines the details for the project within the guidelines of the RFA, retains primary responsibility for the performance of the scientific activity, and agrees to accept close assistance in coordination, cooperation, and participation of NIAID staff in all aspects of scientific and technical management of the project in accordance with the terms formally and mutually agreed upon prior to the award. It is presently envisioned that the NIAID will be actively engaged in assisting the awardee in the coordination of scientific-programmatic components consisting of: o Cooperative participation in data analysis and reporting. o Prior approval of changes of key personnel including the Principal Investigator or Project Leaders o Retention of the option to withhold support if the Principal Investigator or a Project Leader withdraws from the Group and a suitable replacement of key personnel is not obtained. All policies and requirements that govern the grant program of the U.S. Public Health Service and the National Institutes of Health (NIH) apply. FUNDS AVAILABLE The NIAID has set aside $3.0 million for the initial year's funding of this RFA. The amount spent is dependent on the continuing availability of funds for this purpose and the quality and diversity of approved applications. Funding of three to four awards is anticipated. New awards are subject to a first year limit of $800,000 in total costs (direct plus indirect costs), unless a written request for waiver is submitted, and a written approval of the request is obtained from the NIAID prior to submission of the application. The Principal Investigator is urged to contact Dr. Nava Sarver (301-496-8197) prior to submitting a written request for waiver to discuss the extenuating circumstances or needs that may justify waiving the $800,000 total budget limit. Applications in excess of $800,000 total (direct and indirect) costs, and without a written waiver from the NIAID, will be returned without review. Funding in subsequent years will be at a level no greater than year one plus four percent. Funding duration will be four years for competitive renewals and three years for new awards. The anticipated starting dates for the initial annual period are December 1993. When the applicant institution is outside the United States, awards will be limited to three years. When the applicant institution is within the United States and the application contains laboratory projects in a foreign country, the request for funding may be up to four years. Previously funded NCDDG-HIVs may compete for renewal or for supplemental support under this RFA. The NIAID plans to continue its support of the National Cooperative Drug Discovery Group program through RFA-initiated new awards and competitive renewals. Reissuance of this initiative in future years is anticipated but not certain. RESEARCH OBJECTIVES Research Goals and Objectives of the NCDDG-HIV Program The goals of the NCDDG-HIV program are: o The conceptualization, discovery and preclinical development of drugs and strategies designed to effectively treat individuals infected with HIV. o The recommendation of therapies, entities or strategies for development to clinical trial. o The conduct of biological, biochemical, and pharmacological studies that will permit design of predictive clinical evaluation supported by sophisticated technology, and which may provide information leading to the future discovery of more effective treatments. Applications for an NCDDG-HIV should stress creative approaches to the discovery of effective anti-HIV therapies and should emphasize the following: o Specific objectives of the proposed NCDDG-HIV. o Research approaches to the realization of objectives and the provision of comprehensive information (including citations) in support of the rationale(s) for the proposed approaches. o The scientific and technical areas of expertise (Principal Investigators and Project Leaders) required to attain Group objectives and the leadership ability of the Principal Investigator. The Group's objectives and goals should be relevant and compatible with NIAID Program's missions and directions as stated in this RFA. Background and Summary Acquired Immune Deficiency Syndrome (AIDS) is a disease that destroys the body's capacity to overcome a variety of infections. As of June 30, 1992, 230,179 cases of AIDS had been reported in the United States by the Centers for Disease Control (CDC) and more than 152,153 of these patients (66.1 percent) had died. Recent projections indicate that between 1,000,000 to 1,200,000 persons in the United States may already be infected with HIV, the infectious virus associated with AIDS. Three drugs, zidovudine (AZT, 3'- azidothymidine), dideoxyinosine (ddI), and dideoxycytidine (ddC) are currently licensed for the treatment of HIV-1 infection. Of these, ddC has only recently been conditionally approved by the FDA for combination treatment with AZT. All three drugs are nucleoside analogues and all interfere with HIV reverse transcriptase (RT) functions. A serious shortcoming with these nucleoside analogues, however, are toxic side effects which preclude their use, or require discontinuation of treatment in certain patients. Another serious deficiency with these inhibitors is the emergence of HIV drug resistant variants, generally within six to twelve months of treatment. Rapid emergence of HIV drug resistant variants also occurs with most non-nucleoside RT (NNRT) inhibitors (see below), at times as early as four weeks after initiation of treatment. Defined sequence mutations associated with resistance to AZT, ddI, ddC, other nucleoside analogues, or NNRT inhibitors have now been mapped to the RT coding region. Given the precedence of resistance to both nucleoside analogue and NNRT inhibitors in clinical isolates, it is expected that resistance to inhibitors directed against other viral targets is likely to occur. Indeed, at the recent VIII International Conference on AIDS (July 19-24, Amsterdam, The Netherlands), resistance (6-8 fold) to two protease inhibitors was shown to develop in vitro. The search for improved and diverse therapies to treat HIV-1 infection and AIDS is thus among the highest priorities of the Department of Health and Human Services. The NIAID and the PHS Centers for Disease Control are currently supporting comprehensive extramural and intramural projects for (1) the study of the etiology, natural history, and demographics of AIDS; (2) determining means of diminishing the risk of infection; (3) screening of high risk individuals; (4) developing prophylactic vaccines; (5) developing of therapies to treat those with AIDS-related complex developing (ARC); and (6) developing of therapies that may be useful chemopreventive or prophylactic agents. Notwithstanding these efforts, the rapidity of the increase in diagnosed cases of AIDS and the morbidity of the disease require mobilization of the most creative scientific talents, regardless of their scientific discipline or organizational affiliations, into groups whose objective is to pursue aggressively a concerted research effort to discover entities and strategies for treating this disease. The NIAID realized that many single institutions may not have either the critical mass or all the talents and ancillary resources needed to translate discoveries of potential therapeutics from basic studies into new entities and strategies for HIV/AIDS treatment. A cooperative arrangement that permits close interactions of the highest quality research experts from diverse institutions with the facilitating resources of the NIAID was, therefore, established. Units in which these research talents and resources are combined are referred to as "National Cooperative Drug Discovery Groups" (NCDDG). NCDDG-HIVs are envisioned as having the capacity to generate new approaches and strategies for the treatment of HIV infection and to rapidly translate their concepts into anticipated effective treatments. Results from the research proposed under this RFA should be used to identify and develop information for long-term planning of potential therapeutic approaches or to recommend new potential treatments worthy of further consideration in a clinical trial setting. The recognition of HIV as the etiological agent associated with AIDS, the isolation and characterization of the virus, the ability to grow HIV on a large scale, and the amassed knowledge of the molecular biology of HIV have made it possible to screen for potentially effective antiviral compounds, and to target specific antivirals to unique steps in HIV infectious cycle. The possibility of discovering an effective treatment for HIV infection based on compounds targeted against selected steps in the viral replication cycle has been demonstrate in vitro with several analogues of natural substrates (3'-azidothymidine, dideoxyinosine, dideoxycytidine), or non-nucleoside allosteric compounds (e.g., nevirapine) as reverse transcriptase inhibitors; peptide isosteres (e.g., A77003, A80987, other C2 symmetric analogues) as HIV-1 protease inhibitors; a benzodiazipine (Ro24-7429) as a Tat inhibitor; and fatty acid analogues as inhibitors of N-myristoyltransferase and thus of HIV assembly. Most of the effort to date has been made with nucleoside analogues designed to interfere with HIV-1 reverse transcriptase. Considerable effort has also been directed toward development of soluble CD4 and its congeners to block attachment of HIV to uninfected cells, or CD4-toxin conjugates to kill cells expressing HIV gp120 on their surface. Despite the encouraging data with sCD4 obtained in cell culture studies, results from clinical trials to date have been disappointing. X-ray crystallography studies have yielded the structure of HIV-1 encoded enzymes (protease and RNaseH), both critical in the viral life cycle. In the case of HIV protease, the crystal structure has already proven valuable in the design of potent inhibitors of HIV replication. Several groups are also working toward establishing the crystal structures of reverse transcriptase and of HIV capsid protein (p24), and the crystal structure at 3.5 Angstrom resolution of RT complexed with nevirapine has recently been reported (LA Kohlstaedt et. al., Science 256:1783, 1992). But protease, RNaseH, and RT represent only three of the more than 15 HIV processed proteins identified to date, and additional structural work for other structural and regulatory proteins is imperative for structure-driven computational drug design. Current efforts to block other viral specific targets, or the use of substrate analogues to interfere with a cellular pathway obligatory for virus maturation (e.g., myristoylation) are insufficient. In part, this is due to the fact that the function(s) and role(s) of each HIV encoded protein in the infectious cycle, and their effect - direct or indirect - on host immune system, are yet to be charted. The involvement of cellular factors and biochemical processes in the induction of HIV gene from a non-replicative state, or the enhancement of HIV gene expression, must be addressed. Conversely, HIV-induced impairment(s) in cellular biochemical pathways need be explored as another approach to counteract the consequences of infection. Complicating many of the proposed antiviral modalities to date is the emergence of drug resistant HIV strains which imposes a constant and relentless demand for alternative and combination therapies. As of August 1, 1992, 18 Groups will be funded under the NCDDG-HIV program. Eight of these Groups are eligible for competitive renewals in 1993 in response to this RFA. Current research pursuits within the NCDDG-HIV program include: Chemistry, delineation of HIV functions, and inhibition assays: o Synthesis, inhibition, and functional studies of RT o Pharmacology of nucleoside analogues and non-nucleoside RT inhibitors o Structure-function studies of RNaseH o Design and synthesis of HIV protease inhibitors o Assays and inhibitors of Tat activity o Inhibitors of N-myristoyltransferase for blocking HIV assembly o Interference with RNA/Gag interaction o Integration process and assays for integrase inhibitors o Ribosomal frame shifting and potential interference o Natural products from plant and marine sources, metabolism, pharmacology and toxicology Regulation, intracellular suppression, and gene delivery: o Tat and Rev and their cognate cis-acting elements, TAR and RRE o Cellular transcription factors associated with HIV-LTR o Dominant repressors of viral functions (Tat, Rev, Gag, integrase) o Catalytic RNA (ribozyme)-mediated inhibition of HIV gene expression o Mouse, mouse/human chimera, and simian models for gene therapy in HIV/AIDS o Retroviral mediated transduction of antiviral genes into hematopoietic CD34 progenitor cells and pluripotent stem cells Structure-based drug design: o Structure-based drug design of HIV protease, RNaseH, Rev, p24/FAb complex and gp120/CD4 complex o Non-peptide blockers of HIV binding to CD4 o RNA specific organic repressors Immunology, immune therapy, and animal models of AIDS: o CTL and monoclonal antibodies as potential therapeutics in HIV infection o Universal CTLs for adoptive immunotherapy o CD4/gp120 interaction and mapping of functional gp120 and CD4 domains o Dendritic cells and their contribution to HIV spread o HIV interaction with neural cells o Molecular mechanisms of drug resistance, cross resistance, and correlation with HIV sequence variation o FIV as a potential model of AIDS, and for evaluation antiviral therapies o SIV/rhesus model for evaluating post exposure chemoprophylaxis, and single/multiple agent therapies The NCDDG-HIV program provides assistance to talented scientists to interact as a unit to carry out the preclinical research essential for the realization of project objectives. An NCDDG-HIV could be composed of scientists from any combination of academic, non-profit research, and commercial organizations. Scientific Scope, Restrictions and Exclusion The prime objective of this RFA is to stimulate original and innovative research of sound scientific rationale that requires intra-Group interactions and is likely to result in the discovery of new agents and modalities effective against HIV. In line with this objective, the NCDDG-HIV program supports projects for innovative and under-exploited studies that are at the cutting edge of biomedical research. Such studies may have a greater risk-to-benefit quotient than is currently considered under the more traditional investigator initiated (R01) mechanism, but may also have a greater potential for effective, long-term therapeutic returns. In addition to the scientific criteria, these efforts are to be implemented through a collaborative, concerted effort by components of the Group. Applications where collaborations among components of the Group are not required for the success of Group activities will not be funded under the NCDDG mechanism. In these instances, investigators are encouraged to submit independent R01 (or equivalent) grant applications. Applications that include a research project(s) or a core component(s) from the private sector (e.g., pharmaceutical, chemical, or biotechnological companies) are strongly encouraged. The private sector generally has the infrastructure to continue development of a promising antiviral lead and can mobilize additional resources rapidly as needed. Research directed toward drug discovery in the following major areas will be considered responsive to this RFA: o Discovery, elucidation and application of modalities that inhibit HIV gene expression via interference with HIV regulatory elements. o Inhibition of critical steps in HIV replication via intracellular delivery and expression of antagonists using viral vectors or other delivery strategies (gene therapy). o Intervention with cellular biochemical pathways required for induction of HIV from a 'latent' or non-replicative state and/or for enhancement of HIV replication. o Structure-based drug design encompassing novel chemistry, synthesis and development of stable, small molecules that block HIV infection or impair virus replication. o Innovative exploitation of the humoral and cellular arms of the immune system for a targeted anti-HIV affront and immune system reconstitution. o Studies of non-T cells compartment(s) that may serve in the initial infection by HIV, and which may play an essential role in free virus transport, cell-cell transmission, and general dissemination of HIV in the body. o New and sound conceptual strategies which are not or minimally pursued for the discovery of new entities (or combinations) with potential for the treatment of HIV infection. Examples include triplex-forming oligonucleotides, agents which disrupt virus structure, newly identified enzymatic activities as targets, catalytic RNAs, transdominant suppressors, gene therapy for the treatment of HIV, new inroads into deciphering and treating HIV-induced immune dysfunction(s), and others. Examples of proposed research in these major areas are: structure-function of HIV encoded target proteins; early events in viral replication suitable for drug targeting; biochemical pathways and host interactions critical to virus replication and/or drug action; drug metabolism; innovative drug delivery strategies; emergence of resistance to drugs targeted to specific HIV enzymatic, structural or regulatory function; and innovative ways to control, counteract and/or prevent drug resistance. Projects or cores with proposed animal model development and/or efficacy testing in animal models must be integrated into and required to attain the Group's objectives. Animal model component(s) may be requested by the NIAID to evaluate in vivo compounds other than those generated by the Group. Funds awarded for the evaluation of new agents in animal models will be withheld until compounds generated by the Group or provided by the NIAID are available for animal efficacy studies. Due to budgetary limitations, primate animal models should not be requested in the original application. Should the need for such models become evident during the course of studies under this cooperative agreement, the Principal Investigator may submit a competitive supplement request for the support of primate animal models. Funding of competitive supplement will be from set aside funds allocated to future RFAs for this initiative, and is not guaranteed. Consideration for funding will also depend on the competitive merit and justification of the competitive supplement relative to all other competing applications submitted in response to the RFA. Projects utilizing non-random cell-based assays for screening natural products, biologics and/or synthetic compounds must not exceed 25 percent of the total level of effort of the Group. The following research areas currently under intense investigation or that have already been included in other NIH initiatives are specifically excluded from this RFA: (1) synthesis or development of analogues or prodrugs of known anti-HIV nucleosides and non-nucleoside inhibitors of RT; (2) reverse transcriptase screens; (3) evaluation of recombinant human cytokines; (4) development of exogenous, soluble CD4 or its conjugated peptidyl congeners; (5) anti-protease screens and peptide-based protease inhibitors; (6) mechanism of action studies unlinked to inhibitor identification; (7) large scale random screening of compounds with potential activity against HIV in cell culture-based systems; such a program is operated by the National Cancer Institute (see below); (8) research on opportunistic infections associated with AIDS. A separate Request for Applications (RFA) for the National Cooperative Drug Discovery Groups for the Treatment of Opportunistic Infections Associated with AIDS (NCDDG-OI) is re-issued in 1992 for the fourth consecutive year. Scientists whose research does not lie within the areas defined as responsive to this RFA are encouraged to apply for investigator- initiated (R01) grants. To permit rapid and thorough analysis of agents developed by the NCDDG-HIV, applicants are strongly encouraged, but not required, to include in their application a core for testing such agents in screening systems. When and where appropriate, cooperation among funded Groups or with the National Cancer Institute may be arranged through the Scientific Coordinator (see Terms of Award: Awardee Rights and Responsibilities: Nature of Participation of NIAID Staff), these cooperations would serve to broaden the base of screening efforts beyond those used by the NCDDG-HIV or to confirm the biological findings of the NCDDG-HIV. While it is recognized that testing of drugs against HIV in a cell-based assay is an essential element in evaluating potential anti-HIV agents, a random screening program is beyond the scope of this RFA and will not be supported under this RFA. A random screening program is operated by the National Cancer Institute. For information contact: Dr. Robert Schultz Drug Synthesis and Chemistry Branch National Cancer Institute Executive Plaza North, Room 831 Bethesda, MD 20892 Telephone: (301) 496-8795 Studies required for the IND-directed preclinical development (formulation, toxicology) of identified potential treatments are beyond the scope of this RFA, but development through private venture capital is encouraged. Alternatively, an NCDDG-HIV may request that the NIH assist in these developmental tasks using contracts now in place. The NIH has a contract program for the preclinical development of compounds for the treatment of HIV/AIDS. The NIAID has contracts for the evaluation of relevant therapies in appropriate animal models. In addition, the NIAID has awarded AIDS Clinical Treatment Units (ACTUs) for Phase I, Phase II and Phase III clinical trials at different geographical sites. It is envisioned that these ACTU cooperative agreements will be available for clinical studies of treatments discovered under this initiative, upon the recommendation of the NCDDG-HIV and concurrence of the AIDS Clinical Drug Development Committee, ACTU investigators and the Division of AIDS. DEFINITIONS ADMINISTRATION CORE - An administrative facility that provides support for the management of the grant and services shared by the Group as a whole. The Administrative Core will have in its budget travel costs for (i) one required Group meeting; (ii) NCDDG-HIV program meetings; (iii) travel expenses for the Scientific Advisor Panel (see below). The Administrative Core will be responsible for allocating required travel expenses to appropriate members of the Group. These travel expenses will be restricted to travel listed above. (For additional details of required travel see Special Requirements - Terms of Award, PART A.1,2,3). ARBITRATION PANEL - A group composed of one Group designee, one NIAID designee not from the Developmental Therapeutics Branch, and a third designee with expertise in the relevant research area and chosen by the other two. The interaction of this panel is detailed in Terms of Award. COOPERATIVE AGREEMENT - An assistance mechanism in which substantial NIAID programmatic involvement is anticipated with the recipient organization during the performance of the planned activity. CORE COMPONENT - Laboratory facilities for equipment and services which are shared by two or more projects of the NCDDG-HIV. Examples of core components are: screening studies, biochemical assays, cell-based assays, animal model evaluation, toxicology studies, pharmacology studies, scale- up synthesis of drugs (10 grams or less). The core can be defined as any project with established techniques and assays which performs a service function resulting in an economy of effort and savings in the overall costs of the NCDDG. The core unit must be described with the same detail as the research projects to enable evaluation of its scientific merit. DISCOVERY - The term 'discovery' is used explicitly to limit activities of the NCDDG-HIV to preclinical identification, design and development of new entities. The NIAID encourages the investigator to determine if the drug or biologic proposed can be used in the treatment of HIV-infected individuals. INVENTION - A new drug or innovative treatment that is or may be patentable under Title 35 of the United States Code. NATIONAL COOPERATIVE DRUG DISCOVERY GROUP for the Treatment of HIV Infection (NCDDG-HIV) - In this RFA the terms National Cooperative Drug Discovery Group, NCDDG-HIV, and "Group" are synonymous. A Group comprises a number of laboratory research projects representing diverse scientific disciplines and organizations which join together under a single Principal Investigator and which function as a unit with a common goal, namely the conceptualization, invention, and evaluation of new entities and strategies for the treatment of HIV infection. All applications must consist of at least two independent projects conducted by at least two independent laboratories. More than one Project Leader may be enlisted from a single institution but at least two Projects Leaders must be from independent laboratories. For the purpose of this RFA, two (or more) projects within a single company or academic department will not be considered independent. A CORE COMPONENT can not be used toward fulfillment of the two research projects requirement. NEW DRUG - In the context of the NCDDG-HIV program, the term "drug" is used broadly to encompass new synthetic agents, natural and biological products, or novel therapeutic strategies designed to effectively treat HIV infection. NIAID NCDDG-HIV PROGRAM DIRECTOR - A Senior Scientist of the NIAID extramural staff who coordinates NIAID's participation in the NCDDG-HIV program. This responsibility includes (1) overseeing the entire NCDDG-HIV program; (2) assuring that Groups' objectives are consistent with the Division of AIDS preclinical program and NIAID mission and goals; (3) assigning Scientific Coordinators to appropriate Groups based on scientific expertise and compatibility with the Group research interests; (4) assuring overall scientific balance among Groups in the NCDDG-HIV program; (5) networking and facilitating collaboration among Groups and industry to expedite development of promising anti-HIV agents; (6) keeping the NCDDG-HIV program current with regard to scientific developments and breakthroughs; and (7) identifying research gaps not adequately pursued. NIAID SCIENTIFIC COORDINATOR - A Senior or Associate Scientist of NIAID extramural staff who functions as a peer with the Principal Investigator and Project Leaders and facilitates the partnership relationship between NIAID and the Group. The Scientific Coordinator, based on his/hers scientific expertise, interests and compatibility with the Group's areas of research, is assigned to the Group by the NCDDG-HIV program director, and is the immediate contact person for the Group. PRINCIPAL INVESTIGATOR - The person who assembles the NCDDG-HIV, assembles a single application with the information provided by the Project Leaders and submits the application in response to this RFA, and who is responsible for the performance of the Group as a whole and each of the Project Leaders. The Principal Investigator is strongly encouraged to lead one of the research projects of the Group and is expected to coordinate Group activities scientifically and administratively. The Principal Investigator's (awardee) institution establishes and operates the Central Operations Office that funds Group members and is legally and fiscally accountable for the disposition of funds awarded. PROJECT LEADER - The leader of one of the scientific research projects of the NCDDG-HIV. SCIENTIFIC ADVISORS PANEL - A panel, comprised of two to three peers from the scientific community, whose mission is to provide the Principal Investigator with a comprehensive review of the Group's activities and progress, consult on future goals and strategies, and recommend alternative directions, as appropriate. Selection and appointment of the Panel is the responsibility of the Principal Investigator. The Scientific Coordinator will participate in all meetings of the Panel, which may be combined with Group meetings. Members of the Panel will not be affiliated with any of the institutions comprising the Group. A Scientific Advisors Panel is required of all Groups. The composition of the designated Panel will be provided to the NIAID within six months of funding. The Panel will provide the Principal Investigator and the NIAID Scientific Coordinator with a comprehensive written review of the Group's activity in years one, two, three (and four, if applicable) of funding. These reviews will encompass timeliness of progress in individual projects relative to original projections; progress relative to Group's objectives and needs; continued relevance of a given project to Group's goals; continued coordination of Group's objectives with the objectives of the NCDDG-HIV program; and recommendations for new directions, as appropriate. SPECIAL REQUIREMENTS Composition of an NCDDG-HIV The NCDDG-HIV will consist of the following: o Principal Investigator. o Project Leaders, each heading an independent research project (see also item "E" below, this section). The research projects will utilize diverse scientific disciplines or alternative disciplines that are appropriate to the realization of Group objectives (e.g., virology, humoral immunology, cellular immunology, structural biology, biophysics, biochemistry, medicinal chemistry, organic chemistry, pharmacology, toxicology, drug delivery, etc.). Interdisciplinary projects are encouraged. o A Scientific Coordinator designated from the NIAID extramural staff by the NIAID NCDDG-HIV program director. o A Scientific Advisors Panel to be designated within six months of funding (see Section VII: DEFINITIONS: SCIENTIFIC ADVISORS PANEL). The Panel will meet with the Group, evaluate and advise on Group's progress, future goals, strategies and new directions, as appropriate. Panel members will not be affiliated with any of the institutions comprising the Group. o Administrative core that disburses travel expenses to required meetings specified in the RFA (see Terms of Award: Awardee Rights and Responsibilities, Part A.1, 2, 3, for details of required meetings). The travel budget in the Administrative Core will be restricted for the sole purpose of attending required meetings. The Administrative Core may also include support for the costs of administration, purchasing and secretarial services. Items described above that are included in the institution's indirect cost rate are subject to negotiations, based on their applicability as direct or indirect charges. OPTIONAL - core components which provide laboratory facilities, equipment and services to be shared by two or more projects. The Principal Investigator, in addition to providing scientific and administrative leadership, is strongly encouraged to have a research project. Project Leaders will be directly responsible to the Principal Investigator. The formation of the Group, the application in response to this RFA, the overall management of the Group, and the allocation of funds to the various laboratory projects will be the responsibility of the Principal Investigator and the Principal Investigator's institution in accordance with PHS policies. The composition of the Group and its research projects should depend on the talents required to accomplish its scientific and technical objectives as perceived by the Principal Investigator and Project Leaders. The major consideration in structuring an NCDDG-HIV should be the mobilization of maximum intellectual talent and the ability to carry out the proposed research in an integrated and synergistic manner. An individual scientist may be proposed as a Project Leader by more than NCDDG-HIV as part of a CORE COMPONENT. Project Leaders who do not have a core function will not be supported by more than one Cooperative Agreement awarded under this RFA unless the research is clearly delineated in separate NCDDG-HIV applications. Individuals currently supported under an existing NCDDG-HIV or other NCDDG (e.g., NCDDG-OI) may be funded under this RFA provided there is no scientific or budgetary overlap in funded activities. More than one Project Leader of an NCDDG-HIV may be enlisted from a single institution but at least two Projects Leaders must be from independent laboratories. However, the varied talents and commitment required for effective drug discovery are not usually present in most single institutions and it is anticipated that the Project Leaders within a Group will be "enlisted" from, or associated with several institutions. For the purpose of this RFA, two (or more) projects within a single company or academic department will not be considered independent. A minimum of two but no maximum number of research projects per Group is stipulated. However, the Principal Investigator could experience difficulty in providing the desirable level of guidance, and Project Leaders might communicate and collaborate less efficiently if the Group were to contain more than five or six research projects. A CORE COMPONENT can not be considered as a research project in fulfilling the requirement of two research projects per Group. In forming an NCDDG-HIV, the Principal Investigator should remain cognizant of the need for communication, including regular meetings of the members. Although it is not a requirement of this RFA, the formation on a geographically regional basis may be advantageous. This is a particularly important factor to be considered by applicants from outside the United States or if the applicant proposes laboratory projects in foreign countries. An NCDDG-HIV is encouraged to consist of scientists from academia, non-profit institutions, and/or commercial organizations. The active participation of industry is encouraged because it allows this sector of the scientific community to contribute its intellectual and material resources. The private sector is also efficient in mobilizing additional manpower and other resources as needed for the expeditious development of promising anti-HIV lead therapies. Patent Coverage Since the discovery of active anti-HIV entities and strategies is the objective of this effort, and since active involvement by private sector laboratories is facilitated by the existence of adequate patent coverage, it is essential that applicants provide plans to assure such coverage. With multiple institutions involved, complex patent situation may arise. 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. In addition each Group must provide a detailed description of the procedures to be followed for the resolution of legal problems which potentially may develop. All Group members can be full partners in the research and in any inventions resulting therefrom. The specific patenting arrangements among the institutions may vary, and could include joint patent ownership and exclusive licensing arrangements. Applicants should implement an arrangement that is most suitable for their own particular circumstances. The NIAID will not be a partner in any patents or royalties ensuing from the Group's research. The patent agreement, signed and dated by the organizational officials authorized to enter into patent arrangements for each Group member and member institution, must be sent before the application deadline to Dr. Nava Sarver, Targeted Drug Discovery Section, Developmental Therapeutics Branch, Basic Research and Development Program, Division of AIDS, 6003 Executive Boulevard, National Institutes of Health, Bethesda, MD 20892. Federal regulation clause 37 CFR 401 and HHS Inventions regulations at 45 CFR Parts 6 and 8 require that NIH be informed of inventions and licensing occurring under NIH funded research. Invention and licensing reports must be submitted to the Extramural Invention Reports Office, Office of Extramural Research, Building 31, Room 5B41, NIH, with a copy to Dr. Nava Sarver, Chief, Targeted Drug Discovery Section, Developmental Therapeutics Branch, Basic Research and Development Program, Division of AIDS, 6003 Executive Boulevard, NIH, Bethesda, MD 20892. Terms of Award: Awardee Rights and Responsibilities and Nature of NIAID Participation Assistance via Cooperative Agreement differs from the traditional research grant in that in addition to the normal programmatic and administrative stewardship responsibilities, the component awarding the Cooperative Agreement anticipates substantial programmatic involvement during performance of the project. However, the applying Group must define its objectives and approaches in accord with its own interests and perceptions of novel and exploitable approaches to the discovery of effective anti- HIV treatment and must develop the details of the research design following the guidance given in this RFA. It is the primary responsibility of the Principal Investigator to clearly state the objectives and approaches of the Group, to plan and conduct the research stipulated in the proposal, and to ensure that the results obtained are analyzed and published in a timely manner. The data obtained will be the property of the awardee. The NIAID will participate as a member of the Group and will be represented by a Scientific Coordinator or the NCDDG-HIV program director. The Scientific Coordinator will be selected by the NIAID NCDDG-HIV program director from the Developmental Therapeutics Branch of the Division of AIDS, which is an extramural program of the NIAID. The specific Terms of Award are detailed below. The Terms of Award will be presented in the Notice of Award. Failure to abide by these Terms of Award may result in withholding of funds by the NIAID. Awardee Rights and Responsibilities o The Principal Investigator, Project Leaders, and the NIAID Scientific Coordinator will meet periodically to review progress, plan and design research activities, and establish priorities. The frequency of meetings (not less 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), notifying the Scientific Coordinator at least thirty days prior to the meeting date. The NIAID Scientific Coordinator will participate but not chair Group meetings. The Principal Investigator will prepare concise (2-3 pages) minutes or summary of Group meetings which will be delivered to Group members, including the Scientific Coordinator, within thirty days following the meeting. Travel funds for attending one of the required Group meetings should be included in the Administrative Core budget for Project and Core Leaders, and will be restricted solely for this purpose. The application should also include plans for scheduling Group meetings, notifying Group members including the NIAID Scientific Coordinator, and documenting and disseminating Group meeting proceedings. o In addition to these meetings, one meeting every 12-18 months will be held at a site designated by NIAID during which all Principal Investigators and Project Leaders will present significant findings in symposium format. The NCDDG-HIV program meeting is one of the central points for information flow among the Principal Investigators, Project Leaders, NCDDG-HIV program director NIAID Scientific Coordinator, the private sector, other drug development concerns, and NIAID. The NIAID NCDDG-HIV program director consults with the Groups' key personnel in formulating the overall agenda, selecting session Chairs and in identifying key topics for discussion. Session Chairs select the workshop participants who constitute the bulk of invited speakers. This forum is central for cross fertilization of ideas, inter-Group collaborations, integration of unique anti-HIV strategies, and a critical source for updating NIAID and keeping it abreast of scientific and technological innovation toward the discovery of new anti-HIV modalities. Data presented at this meeting are selected by the individual presenters in consultation with their Principal Investigator thus affording appropriate protection of proprietary or commercially sensitive information. It is expected that selected NIH staff, members of established committees and advisory boards, and others active in the process of discovery and development of therapies for HIV/AIDS will be invited to this meeting. The Principal Investigator will have control over the data and results presented by his/her Group. In addition to the Group meetings discussed above, funds for attending the NCDDG-HIV program meeting should be included in the Administrative Core budget for the Principal Investigator, and Project and Core Leaders. Historically, the NCDDG-HIV program meeting has been held every 18 months. For budgetary purposes, anticipated dates for future NCDDG-HIV program meetings are November 1994 and May 1996. Travel budget to the NCDDG-HIV program meetings should, therefore, allow for two program meetings during the duration of the grant. These travel funds will be solely restricted for this purpose. Invited NCDDG-HIV speakers will be expected to utilize budgeted travel funds to cover expenses incurred while attending the program meeting. Funds to cover operating costs of the NCDDG-HIV meeting will be contributed by one or more Groups. The NIAID will provide administrative supplements for this purpose, as needed. o Groups will designate a Scientific Advisors Panel within six months of funding. The Principal Investigator will convene a meeting, or meetings, of the Group with the Panel in years 01, 02, 03, and 04 (if applicable) of funding. Meeting with the Panel may be in conjunction with the Group's own meeting (see item 1, above). The Panel will meet with the Group, and advise the Principal Investigator on Group's progress, future goals, strategies and new directions, as appropriate. The Panel will provide the Principal Investigator and the NIAID Scientific Coordinator a comprehensive written review of the Group's activity in years one, two, three and four (if applicable) of funding, as specified under Definitions: NIAID Advirors Panel. Members of the Panel will not be affiliated with any of the institutions comprising the Group. Funds to cover expenses incurred by the Panel should be included in the Administrative Core component of the application and will be restricted solely for this purpose. o A critical determinant of Group's success will be the degree of communication among its members. Therefore, additional informal meetings among all participants as well as regular telephone and written communication will be important. o The Principal Investigator will be responsible for the timely submission of all abstracts, manuscripts and reviews (co)authored by members of the Group and supported in part or in total under this Cooperative Agreement. The Principal Investigator and Project Leaders are requested to submit manuscripts to the Scientific Coordinator within three weeks of acceptance for publication so that up-to-date summary of program accomplishments is maintained. o Each Progress Report should include a complete and cumulative list of all publications (abstracts, manuscripts, reviews) (co)authored by Groups members and supported in part or in total under this Cooperative Agreement. Each progress report should also include a brief section outlining intra-Group interactions which have augmented activities, citing specific occurrences (e.g., compound 'X' was synthesized under Project 1 and transferred to Project 2 for bioassays). Inter-Group collaboration with other NCDDG- HIV should be specified, where applicable. Interaction with and facilitation of the Group effort by the Scientific Coordinator and the NIAID during the reporting period should be described. o Publications or oral presentations of work done under this Cooperative Agreement is the responsibility of the Principal Investigator and appropriate Project Leaders. o All published (abstracts, peer reviewed manuscripts, reviews) and oral presentations of work supported in part or in total by the NCDDG-HIV cooperative agreement must be acknowledged as part of the presentation and must include the grant mechanism, grant number and Institute; for example, "This work was supported in part by the NIAID NCDDG-HIV program, grant number U01-AI-12345. NIAID Assistance in Implementation and Management of Research Activities o The NIAID Scientific Coordinator, like other Group members, 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 and execution of experiments as agreed to by the Group; and may participate in the analysis and publication of results. o The NIAID Scientific Coordinator may assist the Group or other individual members in research planning, particularly with respect to (1) reduction of duplication of efforts conducted in other extramural projects; (2) provision of needed resources and information that otherwise may not be available to the Group; and (3) provision of data from testing conducted in resource contract laboratories. o The NIAID Scientific Coordinator may serve as a resource for information, laboratory testing, animal model testing and biological supplies when such resources are not a normal requirement of the Group's day-to-day research activities but may be required on an occasional basis. The following are examples of resources available from the NIAID; these resources are intended for initial studies and will not be available on a continual basis: (1) Reference compounds for standardization of test systems, as analytical standards, and for related purposes. (2) Materials for biological testing. (3) Biochemical and cell based laboratory testing capacity. Whenever appropriate and possible, current contract-based preclinical/therapy-related testing will be used. On occasion, and under mutual agreements, NIAID will arrange for limited preclinical testing at other NCDDG-HIV sites. The Groups are expected to provide sufficient test material for requested testing. (4) Testing in appropriate animal model(s) when the occasional need arises in Groups whose main research activities do not require these resources on a regular basis. Groups whose experimental approach involves studies that require testing in animals on a regular basis must budget for costs to be paid from award funding. Requests for testing in NIAID's animal model program are contingent upon NIAID's recommendation and prioritization. (5) Searches of NIAID's computer files of chemical structures and biological activity, if requests for such searches are sufficiently focused to avoid excessive costs and time. Information given to an NCDDG-HIV will be restricted by standard confidentiality agreements between the Government and suppliers of test materials to the Government. (6) Computer processing and statistical evaluations if costs and time are not excessive. (7) Networking with other NIH Staff, NCDDG-HIVs, collaborators and other Government and non-Government investigators who may provide guidance, expertise or resources to facilitate development of therapies identified by the Group. NOTE: It is understood that the Government provides its testing services in the interest of promoting experimental anti-HIV agents through preclinical and clinical testing and development in the most expeditious fashion, and that newly marketed agents that have utilized these services will be offered to the public at reasonable costs. o The NIAID Scientific Coordinator may assist the Groups by providing them with compounds for voluntary initial or confirmatory testing. In testing compounds supplied by the NIAID, the Groups agree to abide by any confidentiality agreement between the NIAID and a third party who has supplied the compounds for testing through NIAID. o The role of NIAID is to facilitate and not direct the Group's activities. It is expected that decisions in all activities outlined below will be reached by consensus of the Group, and that the NIAID Scientific Coordinator will be given the asked to offer input to this process. The manner of reaching this consensus and the final decision-making authority will rest with the Principal Investigator. Collection and Analysis of Data, Procedures for Submission of Results to NIAID, and Preparation of Group Findings for Presentation and Publication In addition to the special reports and stipulations described below, reporting requirements will be identical to those currently in existence for awardee of traditional NIH research project grants. o The principal end product of NCDDG-HIV activities will be the discovery of new entities and strategies for development to clinical trials against HIV infection. Subsequent preclinical and clinical development through private resources is encouraged. Alternatively, the Group may recommend that preclinical and/or clinical development be sponsored by NIAID. In this case, it will be necessary for the Principal Investigator, appropriate Project Leaders and the NIAID Scientific Coordinator to collaborate in the analysis, summary preparation, and presentation of data to appropriate Division of AIDS staff and its advisory committees, such as the Animal Model Operating Committee or the AIDS Clinical Drug Development Committee. o The NIAID will retain the option to cross-file or independently file an application for investigational clinical trial; e.g., an Investigational New Drug (IND) application to the United States Food and Drug Administration of any invention resulting from these NIAID-supported Cooperative Agreements. Reports of data generated by the Group or any of its members required for inclusion in INDs and Clinical Brochures and for cross-filing purposes will be submitted by the Principal Investigator to the Scientific Coordinator upon request. Such reports will be in final draft form and include background information, methods, results, and conclusions. They will be subject to approval and revision by NIAID and may be augmented with test results from other Government sponsored projects prior to submission to the appropriate regulatory agency. o The NIAID will have access to data generated under this Cooperative Agreement and will review the data and progress reports. Information obtained from the data may be used by the Scientific Coordinator for the preparation of internal reports on the Group's activities. However, the applicant will retain custody of and rights to the data, and timely publication of major findings is encouraged. Inasmuch as certain activities under "Terms of Award: NIAID Assistance in Implementation and Management of Research Activities" require approval by NIAID staff during performance of this Cooperative Agreement (specifically, reports intended for inclusion in INDs and Clinical Brochures, change in Principal Investigator or Project Leader(s), redistribution of biological materials received through the Scientific Coordinator and dissemination of research findings resulting from the use of these materials), NIAID will establish an arbitration process to resolve any differences of opinion with regard to these scientific programmatic matters. An arbitration panel, composed of one Group designee, one NIAID designee not from the Developmental Therapeutics Branch, and a third designee with expertise in the relevant area and chosen by the other two, will be formed to review any disagreements regarding scientific-programmatic issues that are restricting progress. This arbitration process in no way affects the right of an award recipient to appeal selected post-award administrative decisions in accordance with HHS, PHS, and NIH regulations and policies. These special arbitration procedures for scientific-programmatic matters in no way affect the awardee's right to appeal an adverse action in accordance with PHS regulations at 42 CFR Part 50, Subpart D, and HHS regulations at 45 CFR, Part 16. The special "Terms of Award: NIAID Assistance in Implementation and Management of Research Activities" described in this section are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR Part 74, and other HHS, PHS, and NIH grant administration policy statements. NOTE: Failure to abide by any of the "Terms of Award" stipulated in this Section may result in withholding of funds by the NIAID until compliance with the Terms is restored. Minimum Requirements for Application Applicants seeking funding as a NATIONAL COOPERATIVE DRUG DISCOVERY GROUP FOR THE TREATMENT OF HIV Infection must meet the following requirements: The application must be from a Group and must: o Name a single Principal Investigator who is an employee of the applicant institution and who will be responsible for the application, for Group research activities, and for the support of Group activities through a Central Operations Office. o Identify the single applicant organization (awardee institution) that will provide the Central Operations Office and be legally and financially responsible and be accountable for the use and disposition of funds awarded on the basis of this RFA; show availability of personnel and facilities capable of performing and supporting the administrative functions of the NCDDG-HIV. o Provide a description of the Group's plan for assuring adequate patent coverage of new inventions that may issue as a result of Government funding of the proposed work. NOTE: 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 the resolution of legal problems which potentially may develop, signed and dated by the organizational official authorized to enter into patent arrangements for each Group member and member institution is to be submitted before the application deadline to Dr. Nava Sarver, Chief, Targeted Drug Discovery Section, Developmental Therapeutics Branch, Basic Research and Development Program, Division of AIDS, 6003 Executive Boulevard, Bethesda Maryland, 20892, in advance of the application receipt date (see 'Patent coverage', above). o Provide a clear, concise plan in narrative and diagrammatic form that depicts the interrelationships among the members of the Group and the contribution of each to fulfillment of Group objectives; provide an organizational chart of the Group showing the name, organization, and scientific discipline of the Principal Investigator and Project Leaders; provide an organizational chart for each laboratory project within the Group showing relationships among the key personnel. o Provide a plan to assure the maintenance of close collaboration and effective communication among members of the Group which will include letters of commitment to this plan and a letter accepting the assistance of the Scientific Coordinator, defined under the TERMS OF AWARD, this section. o Provide an introductory section that states the rationale of the research proposed in each project describing how it relates to drug discovery and the anticipated therapeutic approach which may result (see APPLICATION PROCEDURES). o Demonstrate that each component laboratory project contributes to the attainment of the Group's objectives and that each has available the professional and technical personnel to permit efficient and successful conduct of the proposed research; show that total personnel of the Group are sufficient in quality and quantity to assure successful conduct of the proposed research. Other activities which are essential to maintaining or achieving the objectives of the stated research projects (e.g., large scale production of reagents, animal maintenance) should be included as subcontracts under the budget for core resources. o Demonstrate that each component laboratory project and the Group as a whole have available facilities required for conduct of the proposed research; demonstrate that appropriate biohazard facilities and safety procedures are in place for activities involving HIV, related viruses and virus-producing cell lines as outlined in The Federal Register, Volume 49, Number 201, Part II, Tuesday, October 16, 1984, p. 40556; include a description of the Institutional Safety Guidelines and administrative approval procedures for each proposed laboratory project. NOTE: The Principal Investigator will provide a narrative, supported by diagrammatic presentation(s) as needed, addressing the points raised above. This description should clearly demonstrate the interactive, cooperative, integrated and interdependent nature of each proposed project and core to the Group activities as a whole. The narrative is to be included under the Administrative Core; it will serve as one of the criteria used by the peer review study section to evaluate and rate the ability of the Principal Investigator to assemble a comprehensive, interactive Group. STUDY POPULATIONS SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDY POPULATIONS NIH policy is that applicants for NIH clinical research grants and cooperative agreements will be required to include minorities and women in study populations so that research findings can be of benefit to all persons at risk of the disease, disorder or condition under study; special emphasis should be placed on the need for inclusion of minorities and women in studies of diseases, disorders and conditions which apply to males and females of all ages. If women or minorities are excluded or inadequately represented in clinical research, particularly in proposed population-based studies, a clear compelling rationale should be provided. The composition of the proposed study population must be described in terms of gender and racial/ethnic group. In addition, gender and racial/ethnic issues should be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. This information should be included in the form PHS 398 in Sections 1-4 of the Research Plan AND summarized in Section 5, Human Subjects. Applicants are urged to assess carefully the feasibility of including the broadest possible representation of minority groups. However, NIH recognizes that it may not be feasible or appropriate in all research projects to include representation of the full array of United States racial/ethnic minority population (i.e., Native Americans (including American Indians or Alaskan Natives), Asian/Pacific Islanders, Blacks, Hispanics). The rationale for studies on single minority population groups should be provided. For the purpose of this policy, clinical research includes human biomedical and behavioral studies of etiology, epidemiology, prevention (and preventive strategies), diagnosis, or treatment of disease, disorders or conditions, including but not limited to clinical trials. The usual NIH policies concerning research on human subjects also apply. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are excluded from the clinical research requirements. However, every effort should be made to include human tissues from women and racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. For foreign awards, the policy on inclusion of women applies fully; since the definition of minority differs in other countries, the applicant must discuss the relevance of research involving foreign population groups to the United States' populations, including minorities. If the required information is not contained within the application, the application will be returned. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women or minorities in a study design is inadequate to answer the scientific questions(s) addressed and the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and will be reflected in assigning the priority score to the application. All applications for clinical research submitted to NIH are required to address these policies. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. LETTER OF INTENT Prospective applicants are asked to submit by January 15, 1993, a letter of intent (maximum of two pages) that includes: o A descriptive title of the overall proposed research. o The name, address, telephone number, and institution of the Principal Investigator. o Names of prospective Project Leaders, other key investigators, and their respective institutions. o The number and title of this RFA in response to which the application is 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 NIAID 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: Nava Sarver, Ph.D., Chief, Targeted Drug Discovery Section Developmental Therapeutics Branch Basic Research and Developmental Program Division of AIDS National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 2C11 Bethesda, MD 20892 Telephone: (301) 496-8197 FAX: (301) 402-3211 Applicants who use express mail or courier services should use the city and zip code of Rockville, MD 20852. APPLICATION PROCEDURES It is important to follow the instructions in this RFA for preparing the application. Failure to do so may result in an application with insufficient information for appropriate scientific review. The prospective applicant is also urged to carefully read the sample application which accompanies this RFA. If additional information on how to prepare a multi-project application is required, the applicant may request the NIAID Information Brochure on Program Project and Center Grants, available from: Scientific Review Branch Division of Extramural Affiars National Institute of Allergy and Infectious Diseases Solar Building, Room 4C19 6003 Executive Boulevard Bethesda, MD 20892 Telephone: (301) 496-0123 Questions concerning review requirements of a complete application may be directed to Dr. Dianne Tingley, (301) 496-0818. Questions regarding responsiveness to the RFA may be directed to Dr. Nava Sarver, (301) 496-8197. Receipt Date The deadline for receipt of applications is March 17, 1993. Applications received after this date will be considered not responsive to this RFA and will be returned without review. General o The research grant application forms PHS-398 (rev. 9/91) is to be used in applying for cooperative agreements. These forms are available at most institution sponsored research offices and from the Office of Grants Inquiry, Division of Research Grants, National Institutes of Health, ,Westwood Building Room 449, 5333 Westbard Avenue, Bethesda, Maryland 20892, telephone (301) 496-7441. o Submit a signed, typewritten original of the application, including the Checklist, and three signed, exact, single-sided photocopies, in one package to: Division of Research Grants National Institutes of Health Westwood Building Room 240 Bethesda, MD 20892** The RFA label available in form PHS 398 (rev. 9/91) must be affixed to the bottom of the face page of the original signed application. Failure to use this label could result in delayed processing of the application such that it may not reach the committee in time for review. o To assure the identification of your application with this RFA -the application form must have "NATIONAL COOPERATIVE DRUG DISCOVERY GROUP FOR TREATMENT OF HUMAN IMMUNODEFICIENCY VIRUS INFECTION (NCDDG-HIV)" (RFA AI-92-16) typed on item 2a of the face page of the application form. o Submit two exact copies of your application directly to: Dianne Tingley, Ph.D. Chief, AIDS Scientific Review Section Scientific Review Branch National Institutes Allergy and Infectious Diseases Solar Building, Room 4C16 6003 Executive Boulevard Bethesda, MD 20892 Telephone: (301) 496-0818 Applicants who use express mail or a courier service should use the city and zip code of Rockville, MD 20852. Organization of Application and Suggested Modifications of Form PHS-398 (rev. 9/91) This RFA requires the submission of a single application for the proposed NATIONAL COOPERATIVE DRUG DISCOVERY GROUP HIV. Because of the multi-institutional nature of a NCDDG-HIV and the special requirements in this RFA, additional instructions regarding format are contained in the NIAID Information Brochure on Program Project and Center Grants. The special requirements of this RFA will also necessitate the following modification. The Introductory Section should apply to the proposed NCDDG-HIV as a whole with respect to goals, objectives, and overall research plan. The Introductory Section, not to exceed two pages, should contain any additional information about the proposed Principal Investigator or his/her institution as evidence of capability to carry out the scientific and administrative duties required in this RFA and the functions of the Central Operations Office. In addition, the Introductory Section must include the following elements to be considered responsive to minimum requirements (See SECTION VIII of this RFA): o The name of a single Principal Investigator in accordance with the section on Minimum Requirements for Application. o The name of the single applicant organization that will provide and operate the Central Operations Office in accordance with the Section on Minimum Requirements for Applications. o A statement assuring adequate patent coverage of new inventions that may issue as a result of Government funding in accordance with Patent Coverage. o A statement of acceptance of the provisions of Terms of Awards: Awardee Rights and Responsibilities and Nature of Participation of NIAID Staff. o A description of the interrelationships among members of the Group and organizational charts in accordance with Composition of an NCDDG-HIV. o A plan to assure maintenance of close collaboration and effective communication among members of the Group in accordance with Minimum Requirements for Application. o A rationale for the drug discovery approach(es) proposed and discussion of therapeutic approaches that may derive from the research projects. REVIEW CONSIDERATIONS applications that are not received as a single package from the Principal Investigator and that do not conform to the instructions contained in the PHS 398 (rev. 9/91) application kit will be judged non-responsive and will be returned to the applicant. Applications will be reviewed by the Division of Research Grants for completeness and by NIAID staff to determine administrative and programmatic responsiveness to this RFA; those judged to be non-responsive will be returned to the applicant without review. Applications with first year total costs (direct and indirect) in excess of $800,000 will be returned without review unless the applicant has received a written waiver from the NIAID to exceed this amount. Those applications that are complete and responsive may be subjected to a triage by an NIAID peer review group to determine their competitiveness relative to the other applications received in response to this RFA. The NIAID will remove from further competition those applications judged to be noncompetitive for award and will notify the applicant (Principal Investigator) and responsible institutional official. Those applications judged to be competitive for award will be further reviewed for scientific and technical merit by a Review Committee convened by the Division of Extramural Activities, NIAID during June 1993. Second level of review will be provided by the National Advisory Allergy and Infectious Diseases Council. Review Procedures and Criteria: Applications will be reviewed in the AIDS Review Section, NIAID, by an appropriate committee. The application must be directed towards the attainment of the stated programmatic goals (see Research Goals and Objectives of the NCDDG-HIV. The following factors will be considered in the scientific and technical review of the application: o Relevance of applicant's (Group) objectives to the discovery of new entities and strategies for the treatment of HIV infection. o Scientific and technical significance, originality and uniqueness of proposed research. o Scientific merit of approaches to realization of objectives. o Likelihood that new potential therapy will be identified during the course of the proposed study. o Specific competencies of the Principal Investigator and Project Leaders to conduct the proposed work: research experience, commitment, and time availability of the Principal Investigator, Project Leaders, and other key personnel. Although there is no maximum percent effort set, it is anticipated that due to the complexity and time required to maintain a well coordinated and productive research effort a minimum 20 percent (time) effort by the Principal Investigator and each Project Leader should be devoted to the study, unless there is compelling evidence to the contrary. o Accomplishments of the Group to date (for renewal and supplemental grant applications). o Technical merit of proposed methods for producing or obtaining test materials and for their evaluation. o Technical sufficiency of methods for evaluation of new discoveries, laboratory test systems, models, etc. o Administrative experience and competence of Principal Investigator in the development, implementation, and management of comprehensive research programs. o Plans for effective intra-Group communication and for assuring Group cohesiveness. o Adequacy of existing physical facilities and resources available to the Principal Investigator and Project Leaders including biohazard containment facilities as stipulated in Section VIII - Minimum Requirements for Application. o Documented commitment of institutions represented by Group members; documented capability of Principal Investigator's institution to serve as Central Operations Office for the Group. o Commitment to accept the assistance of NIAID staff in accordance with the guidelines outlined under "Terms of Award: Awardee Rights and Responsibilities and Nature of NIAID Participation." o Mechanism for selecting and replacing key professional or technical personnel using the framework of the RFA. o Conformance to "Minimum Requirements for Application." o Reasonableness of cost. INQUIRIES Inquiries concerning the programmatic and scientific aspects of this RFA may be addressed to: Nava Sarver, Ph.D., Chief, Targeted Drug Discovery Section Developmental Therapeutics Branch Basic Research and Developmental Program Division of AIDS National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 2C11 Bethesda, MD 20892 Telephone: (301) 496-8197 FAX: (301) 402-3211 Inquiries regarding matters pertaining to the review of this application may be addressed to: Diane Tingley, Ph.D. Chief, AIDS Scientific Review Section Scientific Review Branch National Institute of Allergy and Infectious Diseases Solar Building, Room 4C16 6003 Executive Boulevard Bethesda, MD 20892 Telephone: (301) 496-0818 Inquiries regarding fiscal matters may be addressed to: Ms. Jane Unsworth Chief, AIDS Grants Management Section Grants Management Branch National Institute of Allergy and Infectious Diseases Solar Building, Room 4B22 Bethesda, MD 20892 Telephone: (301) 496-7075 FAX: (301) 480-3780 A separate request for Applications for the National Cooperative Drug Discovery Groups for the Treatment of Opportunistic Infections Associated with AIDS (RFA AI-92-15) has been issued. To receive a copy, please contact Dr. Barbara Laughon, Developmental Therapeutics Branch, Basic Research and Development Program, Division of AIDS, NIAID, 6003 Executive Boulevard, Bethesda, MD 20892, telephone: (301) 402-2304. AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Nos. 93.856, Microbiology and Infectious Diseases Research and 93.855 - Immunology, Allergic and Immunological Diseases Research. Grants are awarded under the authority of the Public Health Service Act, Section 301 (42 USC 241) and administered under the PHS grants policies and Federal Regulations, most specifically at 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of the Executive Order 12372 or Health Systems Agency Review. .
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