Full Text PA-96-069 COLLABORATIONS FOR ADVANCED STRATEGIES IN OPPORTUNISTIC INFECTIONS NIH GUIDE, Volume 25, Number 27, August 9, 1996 PA NUMBER: PA-96-069 P.T. 34 Keywords: AIDS Infectious Diseases/Agents Clinical Medicine, General Diagnosis, Medical Disease Prevention+ National Institute of Allergy and Infectious Diseases Letter of Intent Receipt Dates: September 16, 1996; August 1, 1997; August 2, 1998 Application Receipt Dates: October 25, 1996; September 1, 1997; September 1, 1998 PURPOSE The National Institute of Allergy and Infectious Diseases (NIAID) gives special consideration for funding to scientifically meritorious applications that propose research that would meet the objectives and program priorities that have been described in a Program Announcement. Program Announcements identify areas of ongoing research emphasis for the NIAID. The Opportunistic Infection Research Branch (OIRB) of the Therapeutics Research Program in the Division of AIDS (DAIDS), NIAID, invites applications for Collaborations for Advanced Strategies in Opportunistic Infections (CASOI). The purpose of this Program Announcement (PA) is to expand the clinical knowledge of opportunistic infections in people with AIDS by expediting the translation of promising innovative preclinical findings into clinical research applications. This PA announces the interest of the NIAID in supporting focused collaborative research between preclinical and clinical scientists to test, refine, and improve diagnostic, pathogenic, or therapeutic concepts leading to innovative approaches for the prevention and management of opportunistic infections (OIs) in individuals infected with HIV. This type of collaborative research would be dedicated to the expedited development and use of advanced preclinical findings into clinical applications. The opportunistic pathogens emphasized in this PA are Mycobacterium avium, Cryptosporidium parvum, and cytomegalovirus. Because the NIAID would like to fund more research in this area, the NIAID announces the intent to give special funding consideration to applications for integrated, multidisciplinary, translational research activities that use molecular or cellular approaches to: o develop and clinically validate innovative methods for detection of opportunistic infection; o elucidate the mechanisms of the human host-pathogen relationship in opportunistic infections; o develop innovative approaches to measure response to treatment in HIV-infected individuals; and/or o develop innovative strategies for the prevention or treatment of opportunistic infection. Research projects that principally encompass preclinical laboratory research are not within the area of interest of this PA, but may be within the areas of programmatic emphasis described in PA-96-068, "Innovative Drug Discovery Research in AIDS Opportunistic Infections," published in the NIH Guide, Vol 25, No. 26, August 2, 1996. Applications that include collaborations with 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 PA, Collaborations for Advanced Strategies in Opportunistic Infections (CASOI), 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 Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-0325 (telephone 202/512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local government, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT A request for up to five years of support in an application for a ~traditional~ research project grant (R01) will be considered if the proposed research would help meet the objectives of this PA. At this time, the NIAID has not determined whether or how this solicitation will be continued beyond the three annual receipt dates of this PA. Prior approval by NIAID program staff must be obtained before submitting an application that requests direct costs of $500,000 or more for any budgetary year (see APPLICATION PROCEDURES). RESEARCH OBJECTIVES Background HIV-infected persons experience progressive immunological deterioration and are subject to life-threatening disease caused by a variety of viruses, fungi, bacteria, and protozoa that, in the normal human host, are either nonpathogenic or cause only minor, limited infection. Such opportunistic infections (OIs) are a clinical hallmark of advanced HIV disease and are the primary cause of the morbidity and mortality associated with AIDS. Progress in the prevention, detection, and management of OIs is essential to improve the health status and quality of life of HIV- infected persons. Advances in this area, though, are limited by incomplete knowledge of the pathogenesis and clinical course during HIV infection, as well as inadequate knowledge about the HIV-induced immune defects that render infected persons unable to prevent or overcome diseases caused by these organisms. Therapeutic interventions are limited by inadequate information about the molecular or antigenic targets upon which the rational design of new therapies could be based. Finally, methods for diagnosis and treatment assessment are limited, complex, and expensive, which hinders the assessment and measurement of treatment responses in patients with several OIs. Advancing this knowledge base requires the collaboration of several disciplines such as clinical investigation, microbiology, immunology, molecular biology, pharmacology, and others. A coordinated multidisciplinary effort involving laboratory-based scientists and clinical investigators exploring focused questions should facilitate rapid advancement and lead to the development of innovative approaches to the diagnosis and treatment of these OIs. Such approaches may have a more than average risk-to-benefit ratio, but are likely to have greater potential for effective, long-term therapeutic returns. The Division of AIDS/NIAID supports a range of preclinical and clinical research in opportunistic infections: the National Cooperative Drug Discovery Group for the Treatment of Opportunistic Infections In AIDS, research project grants, screening contracts, animal model contracts, the AIDS Clinical Trials Group, and the Terry Beirn Community Program for Clinical Research in AIDS. While scientific exchange occurs among these disciplines and groups, funding opportunities for prospective multidisciplinary research are infrequent. The intent of this PA is to encourage research that bridges the gap between preclinical and clinical scientists, encouraging clinically focused collaborative research and allowing refinement and proof-of-concept of innovative strategies leading to effective clinical applications. Research Objectives and Scope This PA announces the interest of the NIAID in encouraging and supporting the advanced preclinical research and clinical proof-of- concept strategies needed to more effectively combat the opportunistic infections caused by human cytomegalovirus, Mycobacterium avium, or Cryptosporidium parvum. This PA encourages laboratory-based scientists and clinical investigators collaboratively to design and propose multi-component research that has a common thematic goal for which advanced preclinical data exist. This will entail iterative research and information exchange between preclinical and clinical studies in order to refine and improve matters such as the following: o molecular approaches to readily detect critical opportunistic infections in humans, o identification of human host factors contributing to infection (e.g., defects in immune response), and o methods of assessing response to treatment. If appropriate to the research aims of the applicant group, projects may include the implementation of proof-of-concept clinical trials of innovative therapeutic strategies. It is envisioned that feedback from the patient care setting will validate hypotheses of pathogen- host relationships, direct refinement of quantitative assessment methodologies needed for advancement of care, or foster design of improved therapeutic strategies. Areas of special interest include, but are not limited to: A. Elucidation of immune responses to the infection occurring in HIV-infected individuals, such as specific humoral and cellular responses, and identification of features of immune dysregulation, such as cytokine abnormalities, humoral factors, and effector cell defects that promote infection. B. Elucidation of pathogenic mechanisms of the organism in HIV- infected individuals, and identification of molecular targets that can be exploited in innovative therapeutic approaches. C. Clinical evaluation of methods for early detection of infection and quantitative assessment of response to therapy in inaccessible infections (e.g., quantitative PCR, surrogate markers). D. Evaluation of innovative therapeutic strategies (e.g., immune- based therapies, gene-based approaches) and preliminary clinical testing, with modifications as necessary based on clinical research findings. Applicants are encouraged to focus on one infectious organism and to link several research objectives from basic research laboratories, clinical centers, and the private sector. All proposed studies should carefully consider the ultimate potential for clinical application. Examples of the types of projects to study the pathogens emphasized by this PA include, but are not limited to, the following: o Characterization of organism/infected cell interactions at various stages of HIV immunodeficiency for one of the targeted infections. o Evaluation of the role of cytokines and immune effector cells in the pathogenesis of infection caused by Cryptosporidium parvum in AIDS. o Advanced testing of convenient methods to quantify total parasite burden of Cryptosporidium parvum (in contrast to methods relying on cyst quantitation in stool samples). o Evaluation of drug delivery and distribution to intestinal and extra-intestinal sites for the treatment of Cryptosporidium parvum disease in HIV-infected persons. o Identification of immunological correlates of human CMV viral proliferation; development and testing of diagnostic or immunologic markers to facilitate identification of patients at high risk of CMV disease or to provide improved quantitative indicators of response to treatment. o Characterization of M. avium pathogenic mechanisms and associated control of gene expression in individuals with HIV-infection; identification of potential targets for innovative therapeutic approaches (e.g., gene-based therapies); evaluation of novel delivery systems to intracellular sites. o Identification of M. avium-specific defects in the response of HIV-infected hosts (e.g. T-cell and macrophage function, T cell- macrophage interaction); and identification of M. avium antigens associated with protective immune responses. SPECIAL REQUIREMENTS A. Terms and Conditions of Award The following terms and conditions will be incorporated into the Notice of Grant Award and provided to the Principal Investigator as well as the institutional official at the time of award. These terms and conditions are a reiteration of and in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Parts 74 and 92 [Part 92 is applicable when State and local Governments are eligible to apply], and other HHS, PHS, and NIH grant administration policies. All clinical trials involving human subjects must be reviewed and approved by the Clinical Science Review Committee, DAIDS, NIAID prior to implementation. Clinical and laboratory leadership will be expected to attend an annual meeting with NIAID program staff in Bethesda, MD to review progress and share information among awardees. B. Patent Coverage Because the development and availability of innovative, effective strategies for the clinical management of OIs is the principal goal of this PA, and because active involvement by the private sector is facilitated by the existence of adequate patent coverage, it is essential that applicants provide plans to ensure such coverage. Since several institutions may be involved in this collaborative research, complex patent situations may arise. Each applicant must therefore provide a detailed description of (1) 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; and (2) the procedures to be followed for the resolution of legal problems that potentially may develop. Attention is drawn to the reporting requirements of 35 U.S.C. Parts 200-212 and 37 CFR Part 401 or FAR 55.227-11. Instructions were also published in the NIH Guide for Grants and Contracts, Vol. 19, No. 23, June 22, 1990. Note that non-profit organizations (including universities) and small business firms retain the rights to any patent resulting from Government contracts, grants or Cooperative Agreements. It is also noted that a Presidential memorandum of February 18, 1983 extended to all business concerns, regardless of size, the first option to the ownership of rights to inventions as provided in P.L. 96-517. As a result of this memorandum, the relationships among industrial organizations and other participants are simplified, since all members can now 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, exclusive licensing arrangements, etc. Applicants are encouraged to develop an arrangement that is most suitable for their own particular circumstances. The patent agreement among the collaborating institutions, signed and dated by the organizational officials authorized to enter into patent arrangements for each investigator and institution, must be delivered to Dr. Barbara Laughon prior to an award at the address listed under INQUIRIES. A copy of the proposed patent agreement may be submitted with the application. If the collaborators wish to place all inventions and discoveries resulting from these studies within the public domain, a letter to that effect must be submitted to Dr. Laughon in lieu of the patent agreement prior to award. The letter must be co-signed by the Principal Investigator, each investigator, and each of the business officials representing the respective institutions. 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 Division of Extramural Invention and Technology Resources, Office of Extramural Research, NIH, 6701 Rockledge Drive, Room 3188, Bethesda, MD 20892. C. Federally Mandated Regulatory Requirements The CASOI must be in compliance with all Federal regulations and NIH policies that apply to the conduct of research involving human subjects. These include, but are not limited to, Title 21 CFR 50, 56, 312, and Title 45 CFR 46. The CASOI must be able to demonstrate that: (1) each institution conducting CASOI trials has a current, approved Assurance Number on file with the NIH Office for Protection from Research Risks (OPRR); (2) each protocol and informed consent is approved by the responsible Institutional Review Board (IRB) prior to subject entry; (3) each investigator has supplied a completed (including curriculum vitae) FDA 1572 to Division of AIDS for each protocol conducted at each site; and (4) each subject (or legal representative) gives written informed consent prior to entry on study. The CASOI must assure timely reporting of all serious and unexpected toxicities and adverse experiences to the IND sponsor with concurrent notification to the NIAID Scientific Coordinator if the IND sponsor is other than Division of AIDS. 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 sub-populations 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 new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations), which have been in effect since 1990. The new policy contains some provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and printed in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators also may obtain copies of the policy 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 a letter of intent that includes a descriptive title of the overall proposed research, the name, address and telephone number of the Principal Investigator, and the number and title of this PA. The annual receipt dates for the letter of intent are shown at the top of this PA. Although the letter of intent is not required, is not binding, does not commit the sender to submit an application, and does not enter into the review of subsequent applications, the information that it contains allows DRG and NIAID staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be sent to Dr. Dianne Tingley at the address listed under INQUIRIES. APPLICATION PROCEDURES Applicants are strongly encouraged to call NIAID program staff with any questions regarding whether or not their proposed project is within the scope of the programmatic area of emphasis described in this PA. Applications are to be submitted on the grant application form PHS 398 (rev. 5/95). Applications kits are available at most institutional offices of sponsored research and through the NIH web site (http://www.nih.gov). If the application kit cannot be obtained from either of those sources, contact ASKNIH, Office of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714, email: ASKNIH@odrockm1.od.nih.gov. Because of the relatively broad and potentially complex nature of research encouraged, applications that include consortium/contractual arrangements should fully explain the programmatic research, fiscal, and administrative arrangements in section (h) of the research plan. The description of consortium arrangements should follow the outline in "Guidelines for Establishing and Operating Consortium Grants, January 1989," available from the individuals listed under INQUIRIES. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director or Principal Investigator could be included with the application. Applicants from an institution receiving government funds under Center for AIDS Research (CFAR), AIDS Clinical Trial Unit (ACTU), AIDS Vaccine Evaluation Unit (AVEU), DATRI, and CPCRA programs, should describe how these programs are integrated with the proposed studies, if applicable, and ensure that no scientific and budget overlap exists with the proposed project. The National Institute of Dental Research (NIDR) also has an interest in the basic biology, biochemistry, pathophysiology, diagnosis, prevention and treatment of opportunistic pathogens; in particular, how these organisms interact with host tissues and defense mechanisms in the oral cavity. Applications that are of mutual interest to NIAID and NIDR are likely to be given a secondary assignment to NIDR in accordance with the NIH referral guidelines. The NIH Policy Update on Acceptance for Review of Unsolicited Applications that Request More Than $500,000 Direct Cost for Any One Year applies to applications in response to this Program Announcement. The Policy update was published in the NIH Guide, Vol. 25, No. 14, May 3, 1996, and is effective June 1, 1996. An application that proposes research within the programmatic areas described by this PA must be identified by "YES" and the number and title of this program announcement in section 2 of the face page of the application. This will facilitate the assignment of the application by the Referral Office. However, the fundamental factor upon which the assignment will be based is the content of the proposed research. The completed original and four legible, single-sided copies of the application and four sets of the appendices must be sent or delivered to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817-7710 (for express/courier service) At the same time, one complete copy of the application and appendices must be sent or delivered to: Dianne Tingley, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 4C07 6003 Executive Boulevard Bethesda, MD 20892-7610 Rockville, MD 20852 (for express/courier service) REVIEW CONSIDERATIONS Review Procedures Upon receipt, applications will be reviewed for completeness by the NIH Division of Research Grants (DRG). Incomplete applications will be returned to the applicant without further consideration. Applications that are complete will be assigned, based on the content of the proposed research, the PHS Referral Guidelines, and the elaboration of those guidelines set forth by this PA. Applications for research topics that are not within the areas described by this PA will be assigned and reviewed according to standard procedures. Applications that propose research that is within the scope described by this PA will be assigned to a peer review group convened by DRG and NIAID. Each application will be evaluated for scientific and technical merit by in accordance with the review criteria for research project grant applications. These criteria and an elaboration of the meaning thereof in the context if this area of interest are stated below. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council. The assignment for funding consideration and the second level of review for applications that propose research within the areas of emphasis described by this PA will be the National Institute of Allergy and Infectious Diseases. Review Criteria o scientific, technical, or medical significance and originality of the proposed research, specifically including relevance of study objectives to advancing the prevention, diagnosis, or treatment of opportunistic infections in HIV infected persons and the likelihood that innovative and potentially practical strategies will be identified during the course of the proposed project; o appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research, specifically including assessment of the clinical and basic components in terms of the incorporation of state-of-the-art approaches and methodologies of the proposed project towards the attainment of the stated programmatic goals; cohesiveness, multi-disciplinary and multifaceted scope of the application and the coordination and interdependence of all proposed components to the common theme; o qualifications and research experience of the Principal Investigator and collaborators, particularly, but not exclusively, in the area of the proposed research, as well as the leadership, and administrative competence of the Principal Investigator for the development, implementation, and management of the research program, and the Principal Investigator's commitment to devote sufficient time and effort to the project; and the qualifications, experience, and commitment of all other investigators, including their ability to devote adequate time and effort to the project; o availability of the resources necessary to perform the research, particularly the soundness of the administrative and organizational structure that facilitates attainment of the project objectives, including the administrative planning and leadership capability to provide for internal quality control of on-going research, allocation of funds, day-to-day management, internal communications and cooperation among the investigators involved in the project. o appropriateness of the proposed budget and duration in relation to the proposed research; o adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. The initial review group will also examine the provisions for the protection of human and animal subjects and the safety of the research environment. Concerns expressed by the initial review group about any of these factors may influence the recommendation of the National Advisory Allergy and Infectious Diseases Council. AWARD CRITERIA Applications will compete for available funds with all other favorably recommended applications. The following will be considered when making funding decisions: quality of the proposed project as determined by peer review, program balance among research areas of the announcement, and availability of funds. The National Institute of Allergy and Infectious Diseases gives special consideration for funding to scientifically meritorious applications that propose research in the areas of programatic emphasis described in PAs issued by the NIAID. INQUIRIES Written and telephone inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Barbara Laughon, Ph.D. Division of AIDS National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 2C26 - MSC 7620 Bethesda, MD 20892-7620 Rockville, MD 20852 (for express/courier service) Telephone: (301) 402-2304 FAX: (301) 402-3171 Email: barbara_laughon@nih.gov Direct inquiries regarding fiscal and administrative matters to: Ms. Jane Unsworth Division of Extramural Activities National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 4B22 - MSC 7610 Bethesda, MD 20892-7610 Rockville, MD 20852 (for express/courier service) Telephone: (301) 402-6824 FAX: (301) 480-3780 Email: jane_unsworth@nih.gov Direct inquiries regarding application preparation and review, the letter of intent and ONE copy of the completed application to: Dianne Tingley, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 4C07 - MSC 7610 Bethesda, MD 20892-7610 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-2550 FAX: (301) 402-2638 Email: dt15g@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.855, Immunology, Allergic and Immunological Diseases Research, and 93.856, Microbiology and Infectious Diseases Research. Grants are awarded under the authority of the Public Health Service Act, Section 301 (42 USC 241) and administered under 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. The PHS strongly encourages all grant and contract 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 cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. .
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