PA-00-048: COLLABORATIONS FOR ADVANCED STRATEGIES IN COMPLICATIONS OF HIV INFECTION

Department of Health
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COLLABORATIONS FOR ADVANCED STRATEGIES IN COMPLICATIONS OF HIV INFECTION Release Date: January 28, 2000 PA NUMBER: PA-00-048 National Institute of Allergy and Infectious Diseases National Institute on Drug Abuse National Institute on Alcohol Abuse and Alcoholism National Institute of Diabetes and Digestive and Kidney Diseases National Institute of Mental Health Receipt Date: May 8, 2000 PURPOSE The National Institute of Allergy and Infectious Diseases (NIAID), the National Institute on Drug Abuse (NIDA), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Institute of Mental Health (NIMH) invite applicants to expand the clinical knowledge of the complications of HIV by expediting the translation of promising innovative preclinical findings into clinical research applications. NIAID, NIDA, NIAAA, NIDDK and NIMH are interested in supporting focused collaborative research between preclinical and clinical scientists to test, refine, and improve diagnostic, pathogenic, or therapeutic concepts. It anticipates such research will lead to innovative approaches for the prevention and management of complications causing significant morbidity or mortality in HIV infected persons, including the recently recognized metabolic complications, coincident pathogens such as hepatitis C virus, and the opportunistic pathogens. This type of collaborative research would be dedicated to the expedited development and use of advanced preclinical findings into clinical applications and would be designed to: elucidate pathogenic mechanisms involved in metabolic dysregulation or in the human host-pathogen relationship in HIV-associated complications, develop strategies to prevent or treat complications of HIV or HIV therapy, or develop approaches to measure treatment response. The NIDA will support research on metabolic disorders in drug users with HIV infection. The NIAAA is interested in supporting research as it relates to alcohol consumption as a cofactor in HIV infection. The NIMH will support research on the neurobiological/neuropsychiatric complications of HIV infection and associated therapies. The program encourages investigators to engage in interdisciplinary and collaborative research that focuses on clinical as well as basic studies and fosters collaborations among scientists with different expertise, abilities, and talents. Among the disciplines and expertise that may be appropriate for this research program are clinical investigation, immunology, microbiology, virology, endocrinology, pharmacology, molecular and cell biology, genetics, biostatistics, neuropathology/neuropsychiatry, and diagnostic radiology. The collaborations should focus on a common hypothesis with all component projects contributing scientifically to the central theme. The collaborative projects may include shared resources as long as the interdependence and multi disciplinary nature of the individual components is demonstrated. Applications that include collaborations with the private sector (e.g., pharmaceutical, chemical, or biotechnological companies) are strongly encouraged. Research projects that propose the development of new and advanced technologies for the development of targeted therapies, diagnostic tests, or tests for the monitoring of clinical response may also be within the areas of programmatic emphasis described in PAR-98-073, "Small Business Innovation Research Advanced Technology: NIAID (SBIR-AT-NIAID)" published in the NIH Guide May 22, 1998 and updated on August 16, 1999 or PAS-00-006, "Bioengineering Research Partnerships" Published in NIH Guide October 15, 1999. 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-99-124,"Innovative Drug Discovery Research in AIDS Opportunistic Infections," published in the NIH Guide, July 9, 1999. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS led national activity for setting priority areas. This Program Announcement (PA), Collaborations for Advanced Strategies in Complications of HIV Infection , is related to one or more of the priority areas including HIV Infection and Substance Abuse. Potential applicants may obtain a copy of "Healthy People 2010" at http://odphp.osophs.dhhs.gov/pubs/hp2000. 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 governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. Applicants must propose a multi disciplinary program, comprising basic and clinical science studies to be performed at one or more institutions. Investigators are encouraged to establish appropriate collaborations to meet the objectives of this PA. Collaborative groups may consist of either two or three research projects consisting of basic science and clinical studies, with a common theme. Interactions between basic and clinical scientists are expected to strengthen the research, enhance the transfer of fundamental research findings to the clinical setting, and identify new research directions. A coordinated multidisciplinary effort exploring focused questions can facilitate rapid advancements and lead to innovative approaches for identification and optimal treatment of high risk individuals. 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. Plans for the transfer of findings from basic to clinical studies should be described. Applications not proposing both basic and clinical research studies will not be considered responsive to this solicitation. MECHANISM OF SUPPORT This PA will use the National Institutes of Health (NIH) research project grant (R01) award mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this PA may not exceed 5 years. This PA has one annual receipt date. Future unsolicited competing continuation or revised applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. The anticipated award date is December 2000. The funding decision will be influenced by the scientific merit of the individual applications, the degree of collaboration among the investigators, the approaches taken to meet the objectives of the PA, and the programmatic balance and needs of National Institute of Allergy and Infectious Diseases (NIAID), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institute of Drug Abuse (NIDA) and National Institute of Mental Health (NIMH). Although applicants are required to submit collaborative applications, the NIAID, NIDDK, NIDA or NIMH may choose to fund individual R01s outside the collaborative arrangement owing to their special scientific merit and programmatic needs and balance. RESEARCH OBJECTIVES Background: The introduction of potent antiretroviral regimens has resulted in marked reductions in the incidence of opportunistic infections and dramatic declines in mortality for persons with HIV in the United States [Surveillance for AIDS-Defining Opportunistic Illnesses, 1992-1997. MMWR. April 16, 1999/ 48(SS-2), 1-22]. The beneficial effects of potent antiretroviral regimens are tempered by newly recognized metabolic complications. Patients treated with anti-retrovirals are presenting with a myriad of metabolic complications representing alterations in lipid and glucose metabolism. Clinicians are noting increasing cases of hyperlipemia, hyperglycemia, hyperinsulinemia and altered body habitus. The most commonly reported body habitus changes are loss of fat of the face and extremities, increase in abdominal fat, dorsocervical fat deposition and lipomas. Many of these metabolic complications are well known risk factors for cardiovascular disease in the general population. There have been reported cases of heart attack and angina among patients receiving highly active antiviral therapy treatment suggesting that premature atherosclerosis may be occurring. Clinical studies have been designed to estimate the prevalence and incidence of the complications, risk factors and to define the syndromes. The pathogenesis and long-term consequences of these complications are unknown. In addition, the neuropathological/neuropsychiatric complications associated with anti-retroviral therapy have not been extensively studied. The significant dysregulation of glucose and lipid metabolism that accompany HAART therapy could contribute to CNS vascular disease that results in serious neurologic functional deficits. Expectations of longer survival of HIV-infected persons raise concerns about the long-term sequelae of other chronic infections, such as hepatitis C virus (HCV). The natural history of HCV infection in persons co-infected with HIV is poorly understood, as are the mechanisms of pathogenesis and protective immunity. Ideal methods for detecting HCV infection, assessing HCV disease status and monitoring disease progression are not available. Of particular concern are the interactions between HIV and HCV, including the impact of HIV on HCV disease progression and the impact of HCV on HIV disease progression. HCV-induced liver disease, the complications of HIV and its therapies, and the overlapping toxicities of available HCV and HIV therapies impair the abilities to provide the best available treatments for HIV and HCV infections. While increasing attention needs to be focused on these newly recognized health threats, efforts must be maintained to enhance the prevention and management of the traditional opportunistic infections in persons with AIDS. Critical areas of research include better knowledge of the HIV-associated immune defects that render infected persons unable to prevent or overcome diseases caused by these organisms, the extent and duration of immune function restoration by highly effective antiretroviral regimens, immunomodulatory strategies to prevent and or treat infection, and the development of new OI therapies that can overcome drug resistance. Proposed Research Appropriate topics for investigation may include, but are not limited to, the following: METABOLIC COMPLICATIONS Elucidation of mechanisms and molecular sites of lipid and glucose dysregulation Determination of the significance of histological and biochemical changes in fat cells in body regions affected by abnormal fat distribution Development and testing of new methods for quantifying regional fat Determination of the extent and the significance of cellular metabolic changes caused by HIV-infection or specific antiretroviral therapy Determination of the interactions of alcohol-induced metabolic complications and the metabolic complications of HIV disease and its treatment including triglyceridemia, lipodystrophy, glucose dysregulation and cardiovascular disease Determination among drug users with HIV infection the clinical manifestations and underlying mechanisms of metabolic complications or the interactions between drugs of abuse and therapeutic agents used in the treatment of metabolic disorders. Evaluation of therapeutic strategies and preliminary clinical testing, with modifications as necessary based on clinical research findings Study of vascular complications in the CNS as a result of HAART therapy that contribute to neurologic and neuropsychiatric deficits HEPATITIS C COINFECTION Elucidation of viral and host factors contributing to HCV pathogenesis and disease progression in HIV-infected persons Elucidation of the contribution of alcohol and drug use to HCV pathogenesis and disease progression in HIV-infected persons Development of methods for improved detection of HCV infection and monitoring of disease progression and response to treatment in HIV-infected persons Evaluation of innovative therapeutic strategies for treatment of HCV in HIV- infected persons OPPORTUNISTIC INFECTIONS Elucidation of immune responses to the infection occurring in HIV-infected individuals, and identification of features of immune dysregulation 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) Evaluation of innovative therapeutic strategies (e.g., immune-based therapies, gene-based approaches, novel antimicrobials) and preliminary clinical testing, with modifications as necessary based on clinical research findings Determination of the role of chronic alcohol abuse -induced immune modulation (induction of Th2 cytokine responses) in progression of opportunistic infections, particularly tuberculosis Study of chronic opportunistic infections in the brain that impact on neuronal function. SPECIAL REQUIREMENTS Terms and Conditions of Award The NIH has responsibility to ensure the safety of participants in studies that it supports. Terms and conditions addressing NIH review of clinical protocols, reporting requirements, time-sensitive notifications to the Food and Drug Administration, and requirements for Data, Safety, and Monitoring Boards may 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. B. Federally Mandated Regulatory Requirements The research project 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 research project must be able to demonstrate that: (1) each institution conducting clinical 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 the 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. C. Patent Coverage Because the development and availability of innovative, effective strategies for the clinical management of complications of HIV 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 with Appendix materials. 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. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the "NIH Guidelines 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 in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994 available on the web at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not94-100.html INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects" that was published in the NIH Guide for Grants and Contracts, March 6, 1998. This document is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html For purposes of this PA, children are classified as individuals under the age of 18. Investigators may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff also may provide additional relevant information concerning the policy. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 4/98) and will be accepted at the stated deadline. Application kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: GrantsInfo@nih.gov, or at the following URL address: http://grants.nih.gov/grants/funding/phs398/phs398.html Applicants planning to submit an investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended/revised version of the preceding grant application types requesting $500,000 or more in direct costs for any year are advised that he or she must contact the Institute or Center (IC) program staff before submitting the application, i.e., as plans for the study are being developed. Furthermore, the application must obtain agreement from the IC staff that the IC will accept the application for consideration for award. Finally, the applicant must identify, in a cover letter sent with the application, the staff member and Institute or Center who agreed to accept assignment of the application. This policy requires an applicant to obtain agreement for acceptance of both any such application and any such subsequent amendment. Refer to the NIH Guide for Grants and Contracts, March 20, 1998 at http://grants.nih.gov/grants/guide/notice-files/not98-030.html 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 Vaccines Trials Network (VTN), Prevention Trials Network (PTN), and Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) programs, should describe how these programs are integrated with the proposed studies, if applicable, and should ensure that no scientific and budget overlap exists with the proposed project. The title and number of the program announcement must be typed on line 2 of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application, including the Checklist, and five signed photocopies and five copies of Appendix material in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) REVIEW CONSIDERATIONS Applications will be assigned on the basis of established NIH referral guidelines. Applications will be evaluated for scientific and technical merit by an appropriate scientific review group convened in accordance with the standard NIH peer review procedures. 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 applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council or board. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? (2) Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? (3) Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? (5) Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? In addition to the above criteria, in accordance with NIH policy, all applications also will be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects also will be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. AWARD CRITERIA Applications will compete for available funds with all other approved applications. The following will be considered in making funding decisions: Quality of the proposed project as determined by peer review, availability of funds, and program priority. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding NIAID programmatic issues to: Barbara Laughon, Ph.D. Division of Acquired Immunodeficiency Syndrome National Institute of Allergy and Infectious Diseases 6700 B Rockledge Drive, Room 5108, MSC 7624 Bethesda, MD 20892-7624 Telephone: (301) 402-2304 FAX: (301) 402-3171 Email: BL17U@nih.gov Direct inquiries regarding NIAID programmatic issues specific to hepatitis C virus to: Leslye D. Johnson, Ph.D. Chief, Enteric and Hepatic Diseases Branch Division of Microbiology and Infectious Diseases National Institute of Allergy and Infectious Diseases 6700-B Rockledge Drive, Room 3109, MSC 7630 Bethesda, MD 20892-7630 Telephone: (301) 496-7051 FAX: (301) 402-1456 Email: lj7m@nih.gov Direct inquiries regarding NIDA programmatic issues to: Jag H. Khalsa, Ph.D. Health Scientist Administrator Center on AIDS & Other Medical Consequences of Drug Abuse (CAMCODA) National Institute on Drug Abuse, NIH 6001 Executive Boulevard, Room 5198, MSC 9593 Bethesda, MD 20892-9593 Telephone: 301-443-1801 (443-2159 direct) Fax: 301-443-4100 Email: jk98p@nih.gov Direct inquiries regarding NIAAA programmatic issues to: Thomas F. Kresina, PhD Chief, Biomedical Research Branch Institute AIDS Coordinator National Institute on Alcohol Abuse & Alcoholism Room 402, 6000 Executive Blvd Bethesda, MD 20892-7003 Telephone: 301-443-6537 Fax: 301-594-0673 Email: tk13v@nih.gov Direct inquiries regarding NIDDK programmatic issues to: Philip F. Smith, Ph.D. Senior Advisor Neuroendocrinology and Endocrinology of Obesity Research Division of Diabetes, Endocrinology, and Metabolic Diseases NIDDK Natcher Building, Room 5AN-12C 45 CENTER DR MSC 6600 BETHESDA MD 20892-6600 Telephone: (301) 594-8816 Fax: (301) 480-3503 Email: ps56z@nih.gov Direct inquiries regarding NIMH programmatic issues to: Dianne Rausch, Ph.D Center for Mental Health Research on AIDS National Institute of Mental Health 6001 Executive Blvd, Room 6209, MSC 9619 Bethesda, MD 20892-9619 Telephone: (301) 443-7281 FAX: (301) 443-9719 Email: dr89b@nih.gov Direct inquiries regarding fiscal matters to: Laura Eisenman Division of Extramural Activities NIAID 6700-B Rockledge Drive, Room 2120, MSC 7614 Bethesda, MD 20892-7614 Telephone: (301) 402-5541 FAX: (301) 402-2638 Email: le55d@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.856 MID, 93.855 IA. Awards are made under authorization of the Public Health Service Act Sections 301 and 406 of (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The 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, and 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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