RFA-AI-04-047: PARTNERSHIPS FOR TOPICAL MICROBICIDES

Department of Health
and Human Services (HHS)

NIH... Turning Discovery Into Health^®

PARTNERSHIPS FOR TOPICAL MICROBICIDES RELEASE DATE: August 13, 2004 (see addendum NOT-AI-05-003) RFA Number: RFA-AI-04-047 EXPIRATION DATE: December 21, 2004 Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov/) COMPONENT OF PARTICIPATING ORGANIZATION: National Institute of Allergy and Infectious Diseases (NIAID) (http://www.niaid.nih.gov) CATALOGUE OF FEDERAL DOMESTIC ASSISTANCE NUMBERS: No. 93.855, Immunology, Allergy, and Transplantation Research No. 93.856, Microbiology and Infectious Diseases Research LETTER OF INTENT RECEIPT DATE: November 19, 2004 APPLICATION RECEIPT DATE: December 20, 2004 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Cooperative Agreement Terms and Conditions of Award o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA Research of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, strives to understand, treat and ultimately prevent the myriad infectious, immunologic, and allergic diseases that threaten millions of human lives. The NIAID supports extramural research to control and prevent diseases caused by virtually all infectious organisms. Studies to evaluate these organisms involve basic biomedical research in areas of microbial physiology and antigenic structure; applied research, including the development of diagnostic tests; and clinical trials to evaluate experimental drugs and vaccines. This Partnership Program will support the development and testing of topical microbicides that target multiple organisms for the control and prevention of Sexually Transmitted Infections (STIs), including co-infections of the Human Immunodeficiency Virus (HIV) and other STIs. PARTNERSHIPS A key component of this initiative is the development of appropriate partnerships between the government and industry. For the purpose of this RFA, "industry" is defined as large and small, domestic or foreign, pharmaceutical, biotechnology, bioengineering, and chemical companies. Since academic organizations are often the source of new candidate products, this RFA can also support a partnership between industry and a collaborator(s) as necessary from academic and/or non-profit research organizations. The involvement of an academic and/or non-profit research organization is NOT a requirement; therefore, industry does not need a collaborator to submit an application to this program. All projects must demonstrate substantive involvement by the industry partner. For the purpose of this RFA, "substantive involvement" is defined as the commitment of one or more of the following resources: funds; personnel; or in-kind contributions of materials and/or reagents, including, but not limited to, chemical libraries, GMP chemical synthesis or recombinant or other high capacity method of protein production, provision of animal or other laboratory models, and assays, subcontracts, data management resources and regulatory support. The Principal Investigator of the project may be affiliated with either industry or academic organizations (if academia is part of a partnership with industry). See information under Eligible Institutions below. The Partnership Program is intended to support a variety of phases of development of a candidate product. For this RFA, the Partnership Program will support the develop of a candidate product that has moved from early discovery to preclinical evaluation including, but not limited to, pre- clinical evaluation studies, formulation optimization, IND enabling studies, and pilot lot production. Clinical evaluation of products will not be supported under this RFA. NIAID recognizes that the inherent nature and demands of the product development process may require funding large, complex grants with interdependent specific aims. Furthermore, some aspects of the product development process (e.g., production of GLP and cGMP product) are inherently not innovative. Recognizing that product development is often an iterative and sequential process, and that steps early in the process may not be successful and may need to be modified or reworked, NIAID staff, through the cooperative agreement grant mechanism, will be actively involved in evaluating the milestones of awardees and determining whether additional investment in the development is warranted. RESEARCH OBJECTIVES Background for Partnerships In late 2000, the NIAID convened a panel of experts to discuss the role and nature of NIAID/industry collaborations in antimicrobial drug development for public health needs and to learn how NIAID could better facilitate and engage industry and academia in these endeavors ("Summit on Drug Development for Infectious Diseases."). One of the recommendations from this meeting was a continued pursuit of innovative opportunities to form partnerships with the private sector for the control of a number of infectious diseases with public health importance. A report of this meeting is available at http://www.niaid.nih.gov/dmid/drug/. Since 2002, NIAID has identified a diverse set of priority areas for partnership solicitations that have included Partnerships for Novel Therapeutic, Diagnostic and Vector Control Strategies in Infectious Diseases (PAR-02-026, http://grants.nih.gov/grants/guide/pa-files/PAR-02-026.html), Partnerships for Hepatitis B and Vector Borne Diseases Control (RFA-AI-03-003, http://grants.nih.gov/grants/guide/rfa-files/RFA-AI-03-003.html) and Partnerships for Vaccine and Diagnostic Development (RFA-AI-03-028), http://grants.nih.gov/grants/guide/rfa-files/RFA-AI-03-028.html). NIAID is also using this mechanism to solicit applications related to biodefense. The importance of supporting the research specified by the current RFA has been emphasized by the need to address the increasing global problem of STIs and HIV transmission and infection. Development of safe, efficacious and acceptable topical microbicides for STIs and/or HIV, as a complement to vaccine development efforts, will provide an additional component to existing control and prevention strategies. Investment by industry in the commercialization of products for the control of a number of infectious diseases of public health importance remains limited. This initiative is designed to stimulate industry participation in transitioning potential compounds identified by basic research programs into available products. Background for Topical Microbicides STIs are critical global and national health priorities because of the devastating impact on women and infants, and the inter-relationships with HIV/AIDS. Each year an estimated 15 million Americans suffer the effects of STIs at a cost exceeding $16 billion. STIs and HIV are linked both by biological interactions and by infections occurring in the same populations. Certain STIs can increase the risk of HIV acquisition and transmission, as well as alter the course of disease progression. Recent studies indicate that the more prevalent STIs (Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, and organisms associated with bacterial vaginosis) that cause non-ulcerative diseases, as well as the STIs that cause ulcerative diseases (herpes simplex virus type 2, Treponema pallidum and Haemophilus ducreyi) increase the risk of HIV transmission by at least two-to five-fold. While all sexually active persons are susceptible, women and their children bear a disproportionate burden of the harm caused by STIs. Biologically, STIs are more easily passed from men to women than from women to men. Because some STIs can ascend to the upper female genital tract, the long-term consequences of infection are also more severe for women and may result in infertility, ectopic pregnancy or premature birth. In addition, many infections are often asymptomatic in women, resulting in a delay or lack of treatment. A lack of female controlled protective strategies may make it more difficult for women to avoid exposure to STIs and HIV. STIs are an area of significant health disparity. African Americans are hardest hit with rates more than thirty times greater than white Americans for some STIs. Poverty, inadequate health care and partner mixing patterns contribute to the excess disease observed in this and other affected communities. In addition, STIs contribute to the spread of HIV, which is also increasingly concentrated among women and minorities in the United States. Internationally, current estimates indicate that 35 to 45 million people are infected with HIV and that the majority of these infections were acquired through sexual intercourse. Therefore, there is an intensified need for the development of prevention strategies for controlling this global threat. One approach to prevention in women is the development of topical microbicides, products a woman can use intravaginally to protect herself against infection. Results from Phase III efficacy trials of vaginal products containing the spermicidal detergent, nonoxynol-9 (N-9), have indicated that N-9 does not provide protections against the sexual transmission of HIV and when used frequently may increase the risk of HIV transmission. Until recently, no other microbicide candidates have advanced sufficiently to be considered for Phase III testing. Those candidates now poised for efficacy trials are predominantly representatives of a class of compounds that block HIV attachment with the exception of a direct virucidal agent that acts via acidification of the mucosal environment and a surfactant-based agent that preferentially attacks several STIs, including HIV. Candidates with other modes of action, or candidates that target multiple organisms, have been slower to progress in the product development pipeline. The goal of this RFA is to support the development of products that target multiple organisms. Research Goals and Objectives The proposed research should focus on development of a topical microbicide for the prevention of the vaginal transmission of STIs, targeting more than one of the following infections: gonorrhea, chlamydial infection, syphilis, chancroid, genital herpes, human papillomavirus, and HIV. Research targeting solely HIV, or any one organism, will not be supported under this RFA; however, research targeting HIV and another STI is responsive. The applicant should provide a rationale for the choice of multiple targets, e.g., a mechanism that would target both herpes simplex virus and HIV or a mechanism that would target both gonorrhea and chlamydial infection. While the development of contraceptive products is not within the scope of this RFA, products in the development pipeline for contraception that also can target STIs and HIV are responsive. Whether or not a contraceptive indication will be sought for the product, the level of contraceptive activity must be defined for all microbicides. In addition, while the intended use of these products is for the intravaginal prevention of STIs and HIV, safety evaluations must encompass all potential routes of administration. The research supported through this RFA is not required to result in a final marketable product, but must advance an identified candidate product through a preclinical development plan to obtain an initial product that may be suitable for clinical evaluation. In developing the proposed preclinical evaluation plan, applicants may want to refer to the International Working Group on Topical Microbicides Nonclinical Guidelines, JAIDS 2004, 36:541-552. It is anticipated that the clinical evaluation of the products developed through this Partnership Program will subsequently be supported through other mechanisms. A major objective of this RFA is to stimulate scientifically sound, original, and innovative research requiring a comprehensive, multidisciplinary team effort that is likely to advance promising candidate products through the product development pathway. All applications should define the proposed project goal(s), interim objectives (development milestones), a general description of the potential ultimate product (a specific product profile that is defined by licensing indication is not requested), and provide a schedule or timeline for milestone and goal attainment. When appropriate, research plans should include an awareness of and incorporate measures that address the guidelines that govern GLP (as defined by 21 CFR(58)) and GMP (as defined by 21 CFR(211). Manufacturing and/or IND enabling studies carried out under this award should be performed to provide evidence applicable to eventual product licensure in the U.S. MECHANISM OF SUPPORT This RFA will use the NIH cooperative agreement (U01). The applicant will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing- continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is August, 2005. Applications that are not funded in the competition described in this RFA may be resubmitted as NEW investigator-initiated applications using the standard receipt dates for NEW applications described in the instructions to the PHS 398 application. The NIH U01 is a cooperative agreement award mechanism in which the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the section "Cooperative Agreement Terms and Conditions of Award. The total project period for applications submitted in response to this RFA may not exceed five years. At this time, the NIAID has not determined whether and how this solicitation will be continued beyond the present RFA. This RFA uses just-in-time concepts. It also uses the modular budgeting as well as the non-modular budgeting formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if the investigator is submitting an application with direct costs in each year of $250,000 or less, use the modular budget format. Otherwise follow the instructions for non-modular budget research grant applications. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part2.htm. FUNDS AVAILABLE The NIAID intends to commit approximately $2.3 million in FY 2005 to fund approximately two to four new grants in response to this RFA. An applicant may request a project period of up to 5 years and a budget of not more than $750,000 in total costs per year. Applications requesting greater than $750,000 in total costs per year will be returned to the applicant without review. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the NIAID provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. At this time, it is not known if this RFA will be reissued. ELIGIBLE INSTITUTIONS The applicant may submit (an) application(s) if the institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign institutions/organizations. FOREIGN ORGANIZATIONS Several special provisions apply to applications submitted by foreign organizations. o Funds for alterations or renovations cannot be requested. o Charge back of customs and import fees is not allowed. o Format: every effort should be made to comply with the format specifications, which are based upon a standard US paper size of 8.5" x 11." o Funds for up to 8% administrative costs can now be requested, (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-028.html) o Organizations must comply with federal/NIH policies on human subjects, animals, and biohazards. o Organizations must comply with federal/NIH biosafety and biosecurity regulations o Proposed research should provide a unique research opportunity, not available in the U.S. INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. SPECIAL REQUIREMENTS All applications must propose a research and development plan whose ultimate goal is to develop a topical microbicide targeted to the designated STIs, either alone or in combination with an HIV indication. The application must document substantive involvement by the industry partner. In addition, all applications should include the following: 1. Preliminary Data and Target Organisms o Preliminary data to support the development of the particular compound as a topical microbicide, including but not limited to, in vitro and in vivo toxicity/safety and activity/efficacy profiles. o A description of the proposed target organisms and the rationale for the proposed use, such as supporting in vitro activity against the organism or a discussion of the rationale for a non-specific mechanism. o Preliminary data for more advanced concepts or development plans should include assessment against a range of clinical isolates for the target organisms, if clinically significant; 2. Product Development Plan o A description of the proposed development plan for the eventual product, including product manufacturing, formulation optimization, and GLP and GMP mandated product characterization and identification, such as stability testing, etc. o A discussion of the strategies and approaches that will be used to provide appropriate placebos for animal testing and the role of the placebo in the development plan. 3. Preclinical Testing o A description of the preclinical evaluation plan, including a discussion of the currently utilized animal models and any proposed comparison with other frequently used animal models. o The preclinical development plan should describe and provide milestones for mandated preclinical pharmacology and toxicology assessments and should include plans for specifically assessing reproductive tract safety. 4. Use in Resource Constrained Settings A discussion of the applicability of the proposed product for use in developing or resource constrained settings. 5. Milestones and Goals Applications must propose clear project goal(s), including a description of the final product that will be proposed for subsequent clinical evaluation. The applicant must clearly state the interim objectives (developmental milestones) to be achieved during the project, identify impediments or critical decision points that could require a revision in the work plan or milestones, and provide a detailed schedule or timeline for the attainment of each milestone and/or goal. For each critical decision point, the applicant must define criteria that clearly describe how decisions will be made to advance a product through the proposed development pathway. In other words, provide criteria by which go/no go decisions will be made for each milestone. Intellectual Property: The successful development of high priority products for STI and HIV prevention will require substantial involvement and support of private sector industries and may also involve collaborations with multiple organizations, including academic and/or non-profit research institutions. It is the intent of this initiative to support the formation of the appropriate public-private partnerships that are essential to meet these urgent public health needs. NIAID recognizes that intellectual property rights are likely to play an important role in achieving the goals of this program. To this end, the NIAID requires that at the time of application, all applicants provide a letter ("Proprietary Rights Assurance Letter") containing the following assurances, which is signed by a representative who is duly authorized to provide such assurances on behalf of the applicant organization: o Applicant is solely responsible for the timely acquisition of all proprietary rights, including intellectual property rights, and all materials needed for applicant to perform the project; o Applicant acknowledges that prior to, during, and subsequent to the award, the U.S. Government is not required to obtain for applicant any proprietary rights, including intellectual property rights, or any materials needed by applicant to perform the project; o Applicant acknowledges the requirement to report to the U.S. Government all inventions made in the performance of the project, as specified at 35 U.S.C. Sect. 202 (Bayh-Dole Act). Apart from the Proprietary Rights Assurance Letter, applicants are encouraged to reach early consensus with their proposed partners regarding intellectual property and other legal matters that may arise during the project. In addition, applicants are expected to exercise their Bayh-Dole rights in a manner that does not conflict with the goals of this award or the intent of the Bayh-Dole Act to promote the utilization, commercialization and availability of U.S. Government-funded inventions for public benefit. Finally, applicants are expected to make new information and materials known to the research community in a timely manner through publications, web announcements, and reports to the NIAID or other mechanisms. Mandatory Meetings The Principal Investigators, one or two key personnel designated by the Principal Investigators, and NIAID program staff will meet once a year to review progress and aid program development, and to foster collaborations among the awardees. This meeting will be held at the NIH in Bethesda, MD and budget requests should include travel funds for these annual meetings. COOPERATIVE AGREEMENT TERMS AND CONDITIONS OF AWARD The following terms and conditions will be incorporated into the award statement and provided to the Principal Investigator as well as the institutional official at the time of award. These special Terms of Award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR part 74 and 92, and other HHS, PHS, and NIH Grant Administration policy statements. The administrative and funding instrument used for this program is the cooperative agreement (U01), an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during the performance of the activity. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the activity resides with the awardees for the project as a whole, although specific tasks and activities in carrying out the research will be shared among the awardees and the NIAID Scientific Coordinator. 1. Monitoring Clinical Studies When clinical studies or trials are a component of the research proposed, NIAID policy requires that studies be monitored commensurate with the degree of potential risk to study subjects and the complexity of the study. AN UPDATED NIAID policy was published in the NIH Guide on July 8, 2002 and is available at: http://grants.nih.gov/grants/guide/notice-files/NOT-AI-02-032.html. The full policy, including terms and conditions of award, is available at: http://www.niaid.nih.gov/ncn/pdf/clinterm.pdf. 2. Awardee Rights and Responsibilities Awardees will have primary responsibility for defining the research objectives, approaches and details of the projects within the guidelines of the RFA and for performing the scientific activity. Specifically, awardees have primary responsibility as described below. Awardees will attend annual meetings at the NIH in Bethesda, to be coordinated by NIAID program staff. The Principal Investigator 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 scientific and technical management of the project in accordance with the terms formally and mutually agreed upon prior to the award. The responsibility for the planning, direction, and execution of the proposed project will be solely that of the Principal Investigator. o Publications: The Principal Investigator will be responsible for the timely submission of all abstracts, manuscripts, and reviews (co)authored by members of the grant and supported in part or in total under this Agreement. The Principal Investigator and Project Leaders are requested to submit manuscripts to NIAID program staff within 2 weeks of acceptance for publication so that an up-to-date summary of program accomplishments can be maintained and joint press conferences prepared. Publications or oral presentation of work done under this Agreement is the responsibility of the Principal Investigator and appropriate Project Leaders and will require appropriate acknowledgement of NIAID support. Timely publication of major findings is encouraged. o Data: While the NIAID Scientific Coordinator and program staff have a right of access to the data (see NIAID staff responsibilities below,) the applicant will retain custody of and right to the data. The awardee must have an approved data-sharing plan in place (see http://grants.nih.gov/grants/policy/data_sharing/index.htm). 3. NIAID Staff Responsibilities NIAID staff assistance will be provided by the NIAID's Scientific Coordinator. The NIAID Scientific Coordinator will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice and coordination above and beyond normal program stewardship for grants, as described below. The Scientific Coordinator will coordinate other appropriate NIAID program staff assistance. During performance of the award, the NIAID Scientific Coordinator may provide appropriate assistance, advice, and guidance by: participating in the design of the activities; advising in the selection of sources or resources (e.g., determining where a particular organism can be found); coordinating or participating in the collection and/or analysis of data; advising in management and technical performance; or participating in the preparation of publications. The Scientific Coordinator will serve as a liaison/facilitator between the awardee, pharmaceutical and biotech industries, and other government agencies (e.g., FDA, USDA, CDC), and will serve as a resource of scientific and policy information related to the goals of the awardee's research. However, the role of NIAID will be to facilitate and not entirely to direct the activities. It is anticipated that decisions in all activities will be reached by consensus and the NIAID program staff will be given the opportunity to offer input into this process. The manner of reaching this consensus and the final decision-making authority will rest with the Principal Investigator. An NIAID Program Official will be responsible for the normal program stewardship of this award. For clinical studies, a mandatory milestone is the approval of the final clinical protocol by NIAID. The Program Official may also serve as the Scientific Coordinator. 4. Collaborative Responsibilities The specific timelines, interim objectives and funding levels agreed to by the Principal Investigator and the NIAID shall be included in the terms and conditions of award. Given the nature of product development, it is recognized that timelines and interim objectives may require revision and renegotiation during the course of the project period. The Principal Investigator and NIAID must agree to all such revisions. Release of each funding increment by NIAID will be based on a NIAID review of progress towards achieving the previously agreed upon interim objective. Where scientifically appropriate NIAID may ask recipients to collaborate or cooperate with other NIAID funded projects and/or US government agencies, for example CDC, FDA and USDA. 5. Arbitration Any disagreement that may arise on scientific/programmatic matters (within the scope of the award), between award recipients and the NIAID may be brought to arbitration. An arbitration panel will be composed of three members - one selected by the Steering Committee (with the NIAID representation not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by NIAID, and the third member selected by the two prior selected members. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 16. These special Terms of Award are in addition to and not in lieu of otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR Parts 74 and 92, and other HHS, PHS, and NIH Grant Administration policy statements. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct questions about scientific/research issues to: Carolyn D. Deal, Ph.D. Division of Microbiology & Infectious Diseases National Institute of Allergy and Infectious Diseases Room 5039, MSC-6604 6610 Rockledge Drive Bethesda, MD 20892-6604 Telephone: (301)402-0443 FAX: (301) 480-3617 Email: cd128z@nih.gov o Direct questions about peer review issues to: Hagit David Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 3137, MSC-7616 6700-B Rockledge Drive Bethesda, MD 20892-7616 Telephone: (301) 402-4596 FAX: (301) 402-2638 Email: hd29e@nih.gov o Direct questions about financial or grants management matters to: Lesia Norwood Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 2117, MSC-7614 6700-B Rockledge Drive Bethesda, MD 20892-7614 Telephone: (301) 402-7146 FAX: (301) 480-3780 Email: ln5t@nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NIAID staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: Hagit David Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 3137, MSC-7616 6700-B Rockledge Drive Bethesda, MD 20892-7616 Telephone: (301) 402-4596 FAX: (301) 402-2638 Email: hd29e@nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). Applications must have a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The D&B number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package by commercial carrier to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional exact copies of the grant application and all five sets of any appendix material must be sent to: Hagit David Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 3137, MSC-7616 6700-B Rockledge Drive Bethesda, MD 20892-7616 BETHESDA, MD 20817 (for express mail or courier service) APPLICATION PROCESSING: Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. The NIH will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA, it is to be prepared as a NEW application. That is the application for the RFA must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes. While the investigator may still benefit from the previous review, the RFA application is not to state explicitly how. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIAID. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration or review. Applications submitted by an academic institution alone without an industrial partner will be considered non-responsive and will be returned without review. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by one or more appropriate peer review groups convened by the NIAID in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Undergo a selection process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed and assigned a priority score o Receive a written critique o Receive a second level review by the National Advisory Allergy and Infectious Diseases Council 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 evaluate the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. The scientific review group will address and consider each of the following criteria in assigning the application’s overall score, weighting them as appropriate for each application: o Significance o Approach o Innovation o Principal Investigator and Other Staff o Environment The scientific review group will address and consider each of these criteria in assigning the application's overall score, weighting them as appropriate for each application. 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. 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? 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? Are the interim objectives (developmental milestones) appropriate and feasible? Are the criteria for go/no go decision making clearly defined and reasonable? INNOVATION: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? PRINCIPAL INVESTIGATOR AND OTHER STAFF: 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)? Are the other scientific and technical staff appropriate and qualified? Are the project management and administrative staff appropriate and qualified? 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? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score: PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below) INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below). CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. ADDITIONAL REVIEW CONSIDERATIONS SHARING RESEARCH DATA: Applicants requesting $500,000 or more in direct costs in any year of the proposed research are expected to include a data sharing plan in their application. The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data-sharing plan into the determination of scientific merit or priority score. (See instructions and URL to policy in the Federal Citations, below.) BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: November 19, 2004 Application Receipt Date: December 20, 2004 Peer Review Date: April, 2005 Council Review: June, 2005 Earliest Anticipated Start Date: August, 2005 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit of the proposed project as determined by peer review o Availability of funds o Programmatic priorities. REQUIRED FEDERAL CITATIONS ANIMAL WELFARE PROTECTION: Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf), as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm), as applicable. HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required for all types of clinical trials, including physiologic, toxicity, and dose- finding studies (phase I); efficacy studies (phase II), efficacy, effectiveness and comparative trials (phase III). The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risk to the participants. (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). SHARING RESEARCH DATA: Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible. http://grants.nih.gov/grants/policy/data_sharing Investigators should seek guidance from their institutions, on issues related to institutional policies, local IRB rules, as well as local, state and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score. INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: 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 clinical research projects unless a clear and compelling justification is provided indicating 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 clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy 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. 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 is available at http://grants.nih.gov/grants/funding/children/children.htm. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. This policy announcement is in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide, in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s) to be used in the proposed research. Applications that do not provide this information will be returned without review. 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 RFA 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. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the Standards for Privacy of Individually Identifiable Health Information , the Privacy Rule, on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on Am I a covered entity? Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html. 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. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. 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 RFA 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. AUTHORITY AND REGULATIONS This program is described in the Catalogue of Federal Domestic Assistance at http://www.cfda.gov/ in the following citations: No. 93.855, Immunology, Allergy, and Transplantation Research and No. 93.856, Microbiology and Infectious Diseases Research. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (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 NIH Grants Policy Statement is available at http://grants.nih.gov/grants/policy/policy.htm. This document includes general information about the grant application and review process; information on the terms and conditions that apply to NIH Grants and cooperative agreements; and a listing of pertinent offices and officials at the NIH. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the 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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