PA-01-113: THERAPEUTICS RESEARCH ON AIDS-ASSOCIATED OPPORTUNISTIC INFECTIONS AND MALIGNANCIES

Department of Health
and Human Services (HHS)

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This Program Announcement expires on May 2, 2004, unless reissued. THERAPEUTICS RESEARCH ON AIDS-ASSOCIATED OPPORTUNISTIC INFECTIONS AND MALIGNANCIES Release Date: June 28, 2001 PA NUMBER: PA-01-113 (see replacement PA-04-157) (see NOT-AI-04-014 and NOT-AI-04-010) National Institute of Allergy and Infectious Diseases (http://www.niaid.nih.gov) National Cancer Institute (http://www.nci.nih.gov) National Institute of Dental and Craniofacial Research (http://www.nidcr.nih.gov) Application Receipt Dates: January 2, May 1, September 1 THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA/PA. The purpose of this Program Announcement (PA) is to encourage research grant applications aimed at novel approaches to discovery and preclinical development of therapeutic agents against opportunistic infections (OIs) and malignancies in people with AIDS. The intent of this PA is to seek investigator-initiated grant applications that involve creative and original preclinical research utilizing state-of-the-art technologies necessary to propel advances in new or improved therapies. No clinical trials will be supported under this PA. This PA is being issued by NIAID, and co-sponsored by the National Cancer Institute (NCI) and the National Institute of Dental and Craniofacial Research (NIDCR). The National Heart, Lung, and Blood Institute (NHLBI), and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) also have an interest in and support research on opportunistic infections associated with AIDS. Applicants may wish to contact these NIH components listed under INQUIRIES to find out about other funding opportunities. Applicants for Small Business Innovation Research (SBIR) projects on investigational areas included in this PA should consider applying through NIAID PAR 00-126, published in the NIH Guide for Grants and Contracts on July 26, 2000, which is available on the World Wide Web at: http://grants.nih.gov/grants/guide/pa-files/PAR-00-126.html 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), Therapeutics Research on AIDS-Associated Opportunistic Infections, is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. 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. MECHANISM OF SUPPORT This PA will use the National Institutes of Health (NIH) individual research project grant (R01) and the exploratory/developmental grant (R21) mechanism. A sound rationale and a well-designed research plan with limited preliminary data are required for a R21. The R01 supports more advanced projects. Responsibility for the planning, direction, and execution of the proposed research for all applicable mechanisms of support will be solely that of the applicant. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. Complete and detailed instructions and information on Modular Grant applications can be found at http://grants.nih.gov/grants/funding/modular/modular.htm. A notice of modification and update (OD-00-046) regarding modular grants was released on 7/24/00 and can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-046.html. SBIR applicants should refer to NIAID PAR-00-126 cited above. Applicants for R01 grants will request direct costs in $25,000 modules, up to a total direct cost request of $250,000 per year. This applies only up to $250,000. Applications that request more than $250,000 direct costs in any year must follow the traditional PHS 398 application instructions. A typical modular grant application will request the same number of modules in each year. Applications for R01 grants may request a maximum five years of support. Applicants for the R21 grant mechanism may request up to $150,000 (6- $25,000 modules) direct costs per year and support may not exceed two years. This mechanism provides short-duration support for preliminary studies of a highly speculative nature, which are expected to yield sufficient information upon which to base a well-planned and rigorous series of further investigations. The R21 grants are non-renewable and competitive continuation of projects developed under this grant mechanism will be through the R01 research grant mechanism. Funds and time requested should be appropriate for the research proposed. RESEARCH OBJECTIVES AIDS-Associated Opportunistic Infections The most notable advance in AIDS-associated opportunistic infections (OIs) has been the decline in their incidence, which is a result of the effect of potent antiretroviral therapy. Recent findings also suggest that although the natural history of OIs in patients with HIV infection is changing, OIs are still an important clinical and pathophysiological manifestation of HIV disease. For example, HIV-infected patients have an elevated risk of primary or reactivated tuberculosis, and such active infectious processes may enhance HIV replication and increase risk of death. The long-term effectiveness of antiretroviral therapy in developed countries remains unknown, and it is unclear whether the reduced rates of OIs are temporary or permanent. HIV/AIDS continues at an epidemic rate in developing countries where antiretroviral therapy remains unavailable. Significant pathological consequences associated with OIs in AIDS include tuberculosis (Mycobacterium tuberculosis), pneumonia (Pneumocystis carinii), protracted diarrhea (Cryptosporidium parvum, Enterocytozoon bieneusi) and painful oral ulcerative lesions. Limitations of currently available drugs for treatment and prevention of OIs include the static nature of most agents, toxicity, and emergence of resistance. The discovery of more potent and less toxic compounds would provide improved medical management of these AIDS-associated complications. Furthermore, no standard treatments exist for opportunistic pathogens such as C. parvum, and E. bieneusi. AIDS-Associated Malignancies As HIV-infected individuals survive longer, the number of cases of AIDS- associated malignancies (AAMs) continues to increase. While the incidence of Kaposi’s sarcoma and primary CNS lymphomas in HIV-infected individuals has been reduced since the widespread use of potent antiretroviral therapy, there has been no substantial change in the incidence of non-Hodgkin’s lymphomas, cervical cancer and anogenital cancers. Many of these malignancies are associated with viral infections such as Kaposi’s sarcoma herpesvirus (KSHV) with Kaposi’s sarcoma, Epstein-Barr virus (EBV) with certain lymphomas, and human papillomavirus (HPV) with cervical and anogenital cancers. Therapies developed for cancers in the non-immunocompromised setting have not always proven to be effective in patients with HIV/AIDS. Oral cancers may in fact remain the same or increase following potent antiretroviral treatment. The discovery of new therapies for AAMs remains an unmet need. Research Objectives and Experimental Approaches The goal of this PA is the development of agents for treatment of AIDS- associated OIs and malignancies. Given present advances in molecular biology, the principal objectives of the PA are to stimulate original and innovative preclinical research to (1) identify and characterize new, pathogen-specific or malignancy-specific molecular targets and (2) develop promising therapeutic approaches. Applications directly linking disease pathogenesis to molecular target identification are encouraged. AIDS-associated opportunistic pathogens emphasized by this PA are: Mycobacterium tuberculosis, Pneumocystis carinii, Cryptosporidium parvum, and the microsporidia. AIDS-associated malignancies emphasized by this PA are: Kaposi’s sarcoma, lymphomas, cervical cancer, oral warts and cancers, and anogenital cancers. Areas of study may include but are not restricted to the following examples: o discovery and development of efficacious new therapeutic agents for treatment of AIDS-associated OIs and malignancies, o validation of molecular targets for therapeutic agents utilizing state-of- the-art molecular genetic technology, o discovery and evaluation of novel, selective chemical entities generated by combinatorial chemistry or combinatorial genomics methodologies, o development of improved delivery systems for therapeutic agents (improved bioavailability, pharmacokinetics), and o development of improved assays, in vitro (cell culture) and in vivo (animal model) systems for drug evaluations. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the "NIH Guidelines 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 (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects" that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at: http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. Applications are to be submitted on the grant application form PHS 398 (rev. 4/98) at http://grants.nih.gov/grants/forms.htm and will be accepted at the standard application deadlines (http://grants.nih.gov/grants/dates.htm) as indicated in the application kit. Application kits are also 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. 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 SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $250,000 per year. (Applications that request more than $250,000 direct costs in any year must follow the traditional PHS 398 application instructions.) The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: PHS 398 o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period. Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the total direct costs requested for each year. This is not a Form page. o Under Personnel, List all project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of all personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by reviewers in the assessment of each individual"s qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm - Complete the educational block at the top of the form page, - List position(s) and any honors, - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years. - List selected peer-reviewed publications, with full citations, o CHECKLIST - This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. o The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. 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 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 Review Procedures 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. The reviewers will comment on the following aspects of the application in their written critiques 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 by the reviewers 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 a 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 will also 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 will also 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 recommended applications. The following will be considered in making funding decisions: o scientific merit (as determined by peer review) o availability of funds o programmatic priorities. INQUIRIES Written and telephone inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. The National Institute of Allergy and Infectious Diseases has an interest in the validation of novel molecular targets for drug development programs and the evaluation of new and novel therapies against AIDS-associated opportunistic infections. Inquiries regarding programmatic issues may be directed to: Chris Lambros, Ph.D. Division of AIDS National Institute of Allergy and Infectious Diseases 6700B Rockledge Drive, Room 5227, MSC 7624 Bethesda, MD 20892-7624 Telephone: 301-435-3769 FAX: 301-402-3171 Email: clambros@niaid.nih.gov The National Cancer Institute (NCI) has an interest in the discovery and validation of novel molecular targets for drug discovery programs and the evaluation of new and novel therapies against AIDS-associated malignancies. Therefore, applications of interest on AIDS-associated malignancies are likely to be given primary assignment to NCI in accordance with the NIH referral guidelines. Inquiries regarding NCI programmatic issues may be directed to: Kenneth Cremer, PhD Division of Cancer Biology National Cancer Institute Room 5016 6130 Executive Boulevard, MSC 7398 Bethesda, MD 20892-7398 Telephone: 301-496-6085 FAX: 301-496-2025 Email: kc47i@nih.gov The National Institute of Dental and Craniofacial Research (NIDCR) has an interest in opportunistic infections in the oral cavity. Therefore, applications of interest will be assigned to NIDCR in accordance with the NIH referral guidelines. Inquiries regarding NIDCR programmatic issues may be directed to: Dennis F. Mangan, Ph.D. Division of Extramural Research National Institute of Dental and Craniofacial Research Building 45, Room 4AN-32F, MSC 6402 Bethesda, MD 20892-6402 Telephone: 301-594-2421 FAX: 301-480-8318 Email: dennis.mangan@nih.gov The National Heart, Lung, and Blood Institute (NHLBI) has an interest in supporting research on the pulmonary, cardiovascular and hematologic aspects of opportunistic infections associated with HIV infection. Therefore, applications of interest are likely to be given a may be primary or secondary assignment to NHLBI in accordance with the NIH referral guidelines. Inquiries regarding NHLBI programmatic issues may be directed to: Hannah H. Peavy, M.D. Division of Lung Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 10018, MSC 7952 Bethesda, MD 20892-7952 Telephone: 301-435-0222 FAX: 301-480-3557 Email: hannah_peavy@nih.gov The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) has an interest in supporting research on the influence of opportunistic pathogens on the enterocytes in the gastrointestinal tract as well as the hepatocytes in the liver in liver disease expression. Therefore, applications of interest are likely to be given a may be primary or secondary assignment to NIDDK in accordance with the NIH referral guidelines. Inquiries regarding NIDDK programmatic issues may be directed to: Frank A. Hamilton, M.D., Ph.D. Chief, Digestive Diseases Program Branch Room 6AN12B DDDN/NIDDK Natcher Building 45 45 Center Drive, MSC 6600 Bethesda, MD 20892-6600 Telephone: 301-594-8877 FAX: 301-480-8300 Email: hamiltonf@extra.niddk.nih.gov Direct inquiries regarding fiscal matters to: Ms. Linda Shaw Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 2125 6700B Rockledge Drive, MSC 7614 Bethesda, MD 20892-7614 Telephone: 301-402-6611 FAX: 301-480-3780 Email: lshaw@niaid.nih.gov Mr. Bill Wells Grants Administration Branch National Cancer Institute Executive Plaza South, Room 243 6120 Executive Boulevard, MSC 7150 Bethesda, MD 20892-7150 Telephone: 301-496-8796 FAX: 301-496-8601 Email: wellsw@mail.nih.gov Mr. Martin R. Rubinstein Grants Management Branch Division of Extramural Research National Institute of Dental Research Natcher Building, Room 4AN-44A Bethesda, MD 20892-6402 Telephone: 301-594-4800 FAX: 301-480-8301 Email: martin.rubinstein@nih.gov AUTHORITY AND REGULATIONS This program is supported under authorization of the Public Health Service Act, Sec. 301 (c), Public Law 78-410, as amended. The Catalogue of Federal Domestic Assistance Citations are Sec. 93.856, Microbiology and Infectious Diseases Research, No. 93.855 - Immunology, Allergy, and Transplantation Research, and 93.121, Oral Diseases and Disorders Research Awards. Awards will be administered under PHS grants policies and Federal Regulations 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems 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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