FOOD ALLERGY RESEARCH CONSORTIUM AND STATISTICAL CENTER RELEASE DATE: August 24, 2004 RFA Number: RFA-AI-04-034 Update: The following update relating to this announcement has been issued: July 7, 2009 - This RFA has been reissued as (RFA-AI-09-039). EXPIRATION DATE: December 17, 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 16, 2004 APPLICATION RECEIPT DATE: December 16, 2004 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanisms of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Supplementary Instructions o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The National Institute of Allergy and Infectious Diseases (NIAID) invites applications from single institutions or consortia of institutions to establish the Food Allergy Research Consortium, a collaborative research program designed to develop new approaches to treat and prevent food allergy. Applications are also invited to establish a Statistical and Clinical Coordinating Center (SACCC) to support the clinical research projects undertaken by the Consortium. The goals of the program are to: (1) develop immune intervention strategies for preventing and treating food allergy; (2) identify the mechanisms of development, loss and re-emergence of oral tolerance; (3) determine the molecular and functional characteristics of food allergens; and (4) determine the role of the gastrointestinal (GI) tract in development and loss of oral tolerance. RESEARCH OBJECTIVES Background Food allergy is an immunologic disease responsible for substantial morbidity and mortality. Food allergy occurs in 6 – 8% of children and 2% of adults, and prevalence is increasing. Severe food allergic reaction may cause anaphylaxis and death. In the United States, approximately 30,000 anaphylactic episodes and 150 deaths per year are due to food allergy. Six foods (milk, egg, peanuts, tree nuts, fish, shellfish) cause 90% of all allergic reactions to foods, and peanuts and tree nuts are the most common food allergens causing anaphylaxis. Food allergic disorders encompass IgE-mediated immediate hypersensitivity and cell-mediated hypersensitivity. Both immune mechanisms contribute to the gastrointestinal (GI), cutaneous, respiratory and systemic symptoms associated with food allergy. The GI tract is responsible for digestion and absorption of nutrients essential for survival of the organism, and GI mucosal immunity provides critical functions that support distinctions between nutrients and pathogens. Oral tolerance describes the immunosuppressive mechanism that prevents individuals from developing an allergic response to foods. Failure to develop or maintain oral tolerance precedes food allergy in children and adults. Delayed maturation of GI mucosal immunity and oral tolerance in newborns is linked to the high incidence of food allergy in children under 3 years of age. Several common childhood food allergies (cow’s milk and egg) are frequently transient, whereas other allergies (peanut) often persist throughout adulthood. Limitations of and lack of consensus on methods for diagnosis and management of food allergy hinder development of best clinical practices. Diagnosis is confirmed by the double-blind, placebo-controlled food challenge, a test with inherent risk of severe reactions. The most effective strategy to prevent an allergic episode is strict food avoidance. Compliance with strict food avoidance is complicated by the ubiquitous presence of certain foods, such as peanut, soy, milk, and egg, in processed foods, poor food labeling practices and cross-contamination of food products during processing. Recent advances in food allergy research suggest that new, focused research directions will advance our understanding of the pathophysiology of food allergy and translate these findings into new options for identification and treatment of susceptible individuals. In June 2003, the NIAID convened an Expert Panel on Food Allergy Research to evaluate the current state of IgE-mediated food allergy and to make recommendations for targeted basic science and clinical research. The Expert Panel concluded that the field of food allergy research is poised to make significant advances in the prevention and treatment of food allergies and anaphylactic reactions to foods and recommended new initiatives to eliminate critical gaps in understanding GI physiology, immunology and the mechanism of oral tolerance; the pathophysiology of food allergy and food allergy- associated anaphylaxis and the molecular characteristics of food allergens. The panel also recommended targeted research to define the natural history of childhood and adult-onset food allergy, including the importance of understanding spontaneous reestablishment of tolerance following development of allergy; and to develop new immune-based therapies to prevent and treat food allergy. The summary of this meeting is posted at http://www.niaid.nih.gov/dait/pdf/11-20-03FAreport1.pdf. Objective and Scope The objectives of this research program are to: explore the pathobiology underlying the development and loss of oral tolerance and the development and reversal of food allergies; translate these findings into new immune-based approaches to prevent and treat food allergy; and explore the molecular and functional characteristics of food allergens. Close interaction between basic scientists and clinical investigators should promote utilization of patient materials in research and accelerate the translation of basic research advances to clinical application. Food Allergy Research Consortium To be deemed responsive, applications must contain at least two projects organized around a central hypothesis: o One project, termed “immune intervention project,” must focus on an immune intervention in either human food allergic subjects, an animal model of food allergy, or both. The project must test the intervention selected in either: (a) a clinical trial; (b) a pre-clinical study with strong likelihood of leading to a clinical trial; or (c) both a pre-clinical study and a clinical trial. The intervention may include mechanistic and/or biomarker studies. Additional details are found in “Supplementary Instructions.” o The second project, termed “immune mechanisms in observational study,” must study immune mechanisms in food allergic subjects during an observational study without interventions. This project must utilize clinical samples from food allergic individuals. One example is to utilize specimens and clinical data from food-allergic subjects in a longitudinal study and also evaluate immune parameters accompanying the development and reversal of food allergy. The study may include biomarker studies. Additional details are found in “Supplementary Instructions.” o If additional projects are proposed, each one must also be organized around the same central hypothesis. This program is milestone-based and funding beyond the first year will be contingent upon satisfactory progress in meeting negotiated milestones (see “SPECIAL REQUIREMENTS” and “COOPERATIVE AGREEMENT TERMS AND CONDITIONS OF AWARD” for additional information on this requirement). For the purposes of this RFA, pre-clinical studies are defined as research projects testing immune intervention strategies to prevent or treat food allergy using animal models such as, but not limited to, inbred and genetically-modified mice, pigs and non-human primates. For the NIH definition of clinical research and clinical trials, see http://grants.nih.gov/grants/funding/phs398/instructions2/p3_definitions.htm. Studies involving genetically-modified foods will not be supported under this RFA. Research areas considered responsive to this RFA include, but are not limited to, the following: o Delineation of the unique properties of the gastrointestinal tract that promote oral tolerance and the failure of tolerance, including the role of innate immunity, the Th1/Th2 microenvironments, and regulatory T cells in the pathogenesis of food allergy; o Analysis of the molecular and functional characteristics of food allergens and the role that food processing may have in the development of antigenicity and in the severity of food allergic reactions; o Investigation of the natural history of food allergy, including analysis of the immunologic parameters underlying development and reversal of food allergy and the acquisition of new food sensitivities; and o Testing or development of new immunologic approaches to prevent and treat food allergy with either clinical trials, preclinical studies that have the potential to lead to new clinical trials, or both preclinical studies and clinical trials. Statistical and Clinical Coordinating Center (SACCC) The SACCC will provide coordination, assistance, centralized data management, and analytical support for all human studies within the first and second projects of the Food Allergy Research Consortium, that is, for all clinical trials and for all immune mechanisms in observational studies involving food allergic patients funded under this RFA. SACCC responsibilities include statistical design, data collection and analysis, and logistical support for the Consortium Steering Committee and the NIAID Data and Safety Monitoring Board (DSMB). Specifically, the SACCC will provide assistance in the following areas: o Clinical Trial Design, Implementation and Management: Develop and implement plans for the statistical design, analysis and management of clinical trials, including monitoring clinical sites, implementing Standard Operating Procedures, and training of site clinical, technical and data management staff. o Protocol Development: Assist in developing clinical protocols, protocol modifications, case report forms, consent forms and Manual of Operations. o Regulatory Requirements: Assist in the preparation of Investigational New Drug (IND) applications to the Food and Drug Administration, as well as interim and annual reports; track IND applications; and provide data to IND sponsors (NIAID, pharmaceutical company or other entity). o Computerized Data and Communication Systems: Establish and manage a secure and confidential computerized system to collect study data; provide quality assurance for and report on study data; establish electronic communication linkages between clinical sites and the SACCC; and provide a computerized system for clinical site registration and for the receipt, follow-up, report and disposition of adverse events. o Distribution of Study Medications: Receive, package and deliver study medications to clinical sites, and maintain an inventory and tracking system for all study medications. o Prepare reports and analyses to be used for presentations and publications. o Consortium Steering Committee and NIAID DSMB: Provide logistical support for meetings and teleconferences of the Consortium Steering Committee and the NIAID DSMB including budgeted support for travel, lodging, meeting venues and teleconferences as required by the Consortium, as specified in the “Cooperative Agreement Terms and Conditions of Award”. o The Principal Investigator of the SACCC shall be a member of the Steering Committee. MECHANISM OF SUPPORT This RFA will use the NIH single project (U01) and NIH multi-project cooperative agreement (U19), "assistance" mechanisms, rather than "acquisition" mechanisms. 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 July, 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 and U19 are cooperative agreement award mechanisms 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. 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. Applicants for U19 grants must follow special application guidelines in the NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS; this brochure is available via the WWW at:http://www.niaid.nih.gov/ncn/grants/multibron.htm. FUNDS AVAILABLE The NIAID intends to commit approximately $3.6 million in FY 2005 to fund two to three new U19 grants for the Food Allergy Research Consortium, and $0.9 million in FY 2005 to fund one new U01 grant for the Statistical and Clinical Coordinating Center. An applicant may request a project period of up to five years. 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, the NIAID has not determined whether or how this solicitation will be continued beyond the present RFA. 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 o Faith-based or community-based 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 U.S. paper size of 8.5" x 11”. o Funds for up to 8% administrative costs can 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 1. Meetings – Food Allergy Research Consortium and Statistical and Clinical Coordinating Center The Steering Committee will serve as the main governing body for the Consortium and will consist of the following voting members: the Principal Investigators, two additional scientists from each awardee appointed by the Principal Investigator, the Director of the SACCC, and the NIAID Scientific Coordinator. The Committee shall meet twice each year in the Bethesda, MD area. At the first meeting of the Steering Committee, a Chair will be selected from among the non-Federal members. All Steering Committee members of the Food Allergy Research Consortium and the Statistical and Clinical Coordinating Center must agree to participate in the meetings and teleconferences of the Steering Committee and other subcommittees to be established by the Steering Committee. Each awardee agrees to work collaboratively with the Consortium, its Steering Committee and the SACCC, abide by the policies, procedures, recommendations and decisions of the Steering Committee, and participate in all Steering Committee activities. Additional details of the Steering Committee are found in “Cooperative Agreement Terms and Conditions of Award,” item 4, Collaborative Responsibilities. Applications for a SACCC should budget for travel and lodging for all non- government Steering Committee members, to attend two Steering Committee meetings per year, and also budget for arranging teleconferences of the Steering Committee and other subcommittees to be established by the Steering Committee. 2. Milestones - Food Allergy Research Consortium This program is milestone-based and funding beyond the first year will be contingent upon satisfactory progress in meeting milestones. These milestones should be in the form of concrete accomplishments whose attainment represents significant advancement toward the overall goals of each project. The milestones in the initial application will serve as examples for purposes of review of the scientific merit. Final milestones will be negotiated between the awardee and the NIAID. 3. Statistical and Clinical Coordinating Center The Principal Investigator of the SACCC may not serve as a U19 Principal Investigator or as a Project Leader for a U19 project funded under this RFA. Applications for the SACCC should include in their budget request support for travel and lodging of all members of the Steering Committee to attend the Committee meetings in Bethesda, MD, to be held as specified in the “Cooperative Agreement Terms and Conditions of Award” section. In addition, the budget should include support for arranging teleconferences of the Steering Committee and other subcommittees to be established by the Steering Committee, and for meetings and teleconferences of the Data and Safety Monitoring Board (DSMB). It is anticipated that the DSMB will consist of five to seven members, who will have one meeting per year in Bethesda, MD and one meeting per year by teleconference. Additional details on the DSMB are provided under “Cooperative Agreement Terms and Conditions of Award,” item 4. Collaborative Responsibilities. 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 instruments used for this program are the single project (U01) and multi-project (U19) cooperative agreements, "assistance", rather than "acquisition" mechanisms, in which substantial NIH scientific and/or programmatic involvement with the awardees 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. This award provides support for one or more NIH-defined clinical trials. The NIH Policy for research supported as an NIH Clinical Trial, “NIH Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research”, was updated October 9, 2001 (URL listed below under REQUIRED FEDERAL CITATIONS). A description of plans to conduct analyses, as appropriate, by sex/gender and/or racial/ethnic groups must be included in clinical trial protocols and the results of the subset analyses must be reported to NIH in Progress Reports, Competitive Renewal Applications, and in the required Final Progress Report, as stated in the Guidelines. 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. Consortium Principal Investigators and the Director of the SACCC, as voting members of the Steering Committee, shall be responsible for establishing and following the policies of the committee and for the development and review of milestones of progress. Principal Investigators will be expected to participate in two Steering Committee meetings each year, in the Bethesda vicinity or by teleconference. Meetings will be organized by the Chair of the Steering Committee. 3. NIAID Staff Responsibilities An NIAID Program Official will be responsible for the normal program stewardship, including monitoring program progress, approving changes and concurring in proceeding into study implementation stage. Release of each yearly funding increment for U19s will be based on a review of progress towards achieving the previously agreed upon milestones, and for the SACCC, evaluation will be based on achieving effective support of clinical trials and the DSMB. The Government, via the NIAID Program Official, will have access to data generated under this Cooperative Agreement and may periodically review the data and progress reports. NIAID staff may use information obtained from the data for the preparation of internal reports on the activities of the study. However, awardees will retain custody of and have primary rights to all data developed under these awards, subject to Government rights of access consistent with HHS, PHS, and NIH policies. 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. This includes providing guidance and support in the development, assembly, and submission of all required regulatory documents, e.g., those regarding the use of investigational drugs, to the Food and Drug Administration. As a member of the Steering Committee, the NIAID Scientific Coordinator will serve as a resource for protocol design and development and provide scientific/programmatic support during the accomplishment of the research by participating in the design of the activities, advising in the selection of sources or resources (e.g., determining where a particular reagent can be found), advising in management and technical performance, or participating in the preparation of publications. The NIAID Scientific Coordinator will be a voting member of the Steering Committee and participate in all Steering Committee activities, including, but not limited to, conference calls, subcommittees and special committees. An NIAID Medical Officer will monitor the clinical trials and serve as the Medical Monitor. Should a pharmaceutical or biotechnology company sponsoring a clinical trial choose to name its own Medical Monitor, then the NIAID Medical Officer will work with the company-assigned Medical Monitor. 4. Collaborative Responsibilities Steering Committee The Steering Committee will serve as the main governing body for the Consortium and will consist of the following voting members: the Principal Investigators of each funded U19 application, two additional members appointed by the Principal Investigators of each funded U19 application, the Director of the SACCC, and the NIAID Scientific Coordinator. The Committee shall meet twice each year in the Bethesda, MD area. At the first meeting of the Steering Committee, a Chair will be selected from among the non-Federal members. All members of the Steering Committee must agree to participate in all Steering Committee meetings and teleconferences. The Steering Committee will be responsible for: (1) reviewing and prioritizing the research projects to be undertaken by the Consortium; (2) making recommendations on funding of Consortium research projects; (3) reviewing and determining project milestones; (4) establishing appropriate methods/measures to assess progress and the attainment of milestones; (5) evaluating progress of Consortium research projects, recommending modifications in research goals and milestones, and, when appropriate, curtailing projects for lack of progress; and (6) coordinating all activities of the Consortium. The Steering Committee may also recommend that the clinical, pre-clinical, mechanistic and biomarker studies proposed by the awardees require modification, coordination/consolidation with other projects, or will not be carried out by the Consortium. Therefore, the specific projects proposed in applications may not necessarily be those that are implemented by the Consortium. The Steering Committee will establish priorities and set milestones for the Consortium within 6 months of the award. Review of milestones shall be linked to the annual funding cycle and submission of the annual progress report. The NIAID Scientific Coordinator will monitor accomplishment of milestones and work with the Steering Committee to redirect, replace and/or curtail research projects that do not meet negotiated milestones during the funding period. Any re-budgeting that will result in a change of scope of the individual projects undertaken by the Consortium must be approved by the Grants Management Specialist in consultation with the NIAID Program Official. Each awardee agrees to work collaboratively with the Consortium, its Steering Committee and the SACCC, abide by the policies, procedures, recommendations and decisions of the Steering Committee, and participate in all Steering Committee activities. Data and Safety Monitoring Board The NIAID will appoint five to seven individuals to an independent Data and Safety Monitoring Board (DSMB) to advise the Institute on issues pertaining to appropriateness of clinical protocols and the conduct and safety of clinical research and clinical trials. Information is also provided to the Principal Investigator, Co-Investigators and the Steering Committee. The DSMB will meet at least twice a year, by teleconference or in the Bethesda, MD vicinity. The SACCC will be responsible for organizing DSMB meetings and teleconferences. 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 chosen by the awardee, a second member selected by the 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: Marshall Plaut, M.D. Division of Allergy, Immunology, and Transplantation National Institute of Allergy and Infectious Diseases Room Number 3093, MSC-6601 6610 Rockledge Drive Bethesda, MD 20892-6601 Telephone: 301.-435-4425 FAX: 301-402-0175 Email: email@example.com o Direct questions about peer review issues to: Geetha Bansal Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 3145, MSC-7616 6700-B Rockledge Drive Bethesda, MD 20892-7616 Telephone: (301) 402-1464 FAX: (301) 402-2638 Email: firstname.lastname@example.org o Direct questions about financial or grants management matters to: Michael Fato Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 2247, MSC-7614 6700-B Rockledge Drive Bethesda, MD 20892-7614 Telephone: (301) 451-2690 FAX: (301) 480-3780 Email: email@example.com 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: Geetha Bansal Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 3145, MSC-7616 6700-B Rockledge Drive Bethesda, MD 20892-7616 Telephone: (301) 402-1464 FAX: (301) 402-2638 Email: firstname.lastname@example.org SUBMITTING AN APPLICATION Applicants for U19 grants must follow special application guidelines in the NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS; this brochure is available via the WWW at: http://www.niaid.nih.gov/ncn/grants/multibron.htm. Applications for U01 grants use the same format as R01 applications. 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) 435-0714, 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 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: Geetha Bansal Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 3145, MSC-7616 6700-B Rockledge Drive Bethesda, MD 20892-7616 BETHESDA, MD 20817 (for express mail or courier service) Applications that are not received as a single package on or before the December 16, 2004 or that do not conform to the instructions contained in PHS 398 (rev. 5/01) Application Kit (for the U19 application: as modified in, and superseded by, the NIAID BROCHURE ENTITLED "INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS"), will be judged non-responsive and will be returned to the applicant. It is highly recommended that the appropriate NIAID program contact be consulted before submitting the letter of intent and during the early stages of preparation of the application. (See program contact under INQUIRIES). SPECIAL INSTRUCTIONS FOR COMPLETION OF APPLICATIONS IN RESPONSE TO THIS RFA: Applicants for U19 cooperative agreements must follow special application guidelines in the NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS; this brochure is available from NIAID listed under INQUIRIES via the WWW at: http://www.niaid.nih.gov/ncn/grants/multibron.htm. This brochure presents specific instructions for sections of the PHS 398 (rev. 5/01) application form that should be completed differently than usual. For all other items in the application, follow the usual instructions in the PHS 398. 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 from the previous unfunded version of the application. While the investigator may still benefit from the previous review, the RFA application is not to state explicitly how. CONCURRENT SUBMISSION OF AN R01 AND A COMPONENT PROJECT OF A MULTI-PROJECT APPLICATION: Current NIH policy permits a component research project of a multi-project grant application to be concurrently submitted as a traditional individual research project (R01) application. If, following review, both the multi-project application and the R01 application are found to be in the fundable range, the investigator must relinquish the R01 and will not have the option to withdraw from the multi-project grant. This is an NIH policy intended to preserve the scientific integrity of a multi-project grant, which may be seriously compromised if a strong component project(s) is removed from the program. Investigators wishing to participate in a multi-project grant must be aware of this policy before making a commitment to the Principal Investigator and awarding institution. 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. SUPPLEMENTARY INSTRUCTIONS Food Allergy Research Consortium Applications (U19) Research Plan for Immune Intervention Project o Each application must contain a project that is either a clinical trial of a food allergy therapy, a pre-clinical study with strong potential to lead to a food allergy therapy, or both a pre-clinical study and a clinical trial. o Clinical Trials: Applications proposing a clinical trial must include: the scientific rationale for the therapeutic intervention; confirmation of the ability to acquire the drug and the timetable for drug availability; study design including statistical analyses; target population; primary and secondary outcomes; and, if applicable, associated mechanistic and/or biomarker studies. o Pre-clinical Studies: Applications proposing a pre-clinical study should include not only a full description of such a study, but also, in the experimental design section, a brief synopsis describing a proposed phase I clinical trial that would follow successful completion of the pre-clinical study. The synopsis should include a brief description of the same elements described above for clinical trials. o Pre-clinical Studies plus Clinical Trials: Applications proposing a pre- clinical study may also propose an actual phase I clinical trial. If both a pre-clinical study and a phase I clinical trial are proposed, then not only full details of the pre-clinical study, but also full details of the trial, not just a synopsis, are required. Research Plan for Immune Mechanisms in Observational Study Project The Immune Mechanisms Project must include the scientific rationale for the study; study design including statistical analysis; target population; retention of the population for the duration of the study; primary and secondary outcomes; conceptual framework for selecting and designing the mechanistic studies and, if applicable, biomarker studies. Milestones Each U19 project must propose annual milestones that form the basis of progress evaluation by the Steering Committee. These milestones should be in the form of concrete accomplishments whose attainment represents significant advancement toward the overall goals of each project. The milestones in the initial application will serve as examples for purposes of review of the scientific merit. As stated in the “Cooperative Agreement Terms and Conditions of Award,” the final milestones are negotiated with the Steering Committee and may be different from the milestones in the initial application. Statistical and Clinical Coordinating Center Applications (U01) Applications for the Statistical and Clinical Coordinating Center should include the following: o A plan for statistical design and analyses of clinical trials and observational studies which should include a summary of overall strategy and approaches to overcoming anticipated obstacles for the type of clinical trials and observational studies that may be undertaken by the Food Allergy Research Consortium; o A plan for management of clinical trials and observational studies that includes: - clinical site monitoring; - collection, storage, and reporting of data; - a system for adverse event reporting; - assistance in development, implementation, and modification of clinical protocols, including preparation of Manual of Operations; - assistance in the preparation and tracking of Investigational New Drug applications; and - preparation of reports and analyses for review and publication. o Provision of statistical, technical and logistical support to the Steering Committee and the NIAID DSMB. Budget – Statistical and Clinical Coordinating Center For the purpose of budget development and project planning, applicants should assume that, at any one time, there will be protocols at some stage of development (from early protocol design and development, through post- treatment data analysis), involving no more than three Phase I clinical trials, three Phase II clinical trials and three immune mechanisms observational studies Steering Committee The voting membership of the Steering Committee will include the Principal Investigator of each U19 and two additional members appointed by the Principal Investigator for each funded application, the Director of the SACCC, and the NIAID Scientific Coordinator. The NIAID Program Official, if different from the NIAID Scientific Coordinator, may attend the Steering Committee meetings, as a non-voting participant. The NIAID Scientific Coordinator has one vote. The chairmanship of the Steering Committee will be determined at the first meeting. The Steering Committee will convene at least twice a year. One meeting will be in the Bethesda, MD vicinity; the second meeting may be in the Bethesda vicinity or by a teleconference. 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 that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group 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 Review Criteria for the U19 Food Allergy Research Consortium The general review criteria for U19 multi-project cooperative agreement applications are presented in the NIAID brochure entitled "INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS” at http://www.niaid.nih.gov/ncn/grants/multibron.htm. Review Criteria for the U01 Statistical and Clinical Coordinating Center These include standard NIH criteria: o Significance o Approach o Innovation o Investigator o Environment 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 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? 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? 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)? 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: Additional review criteria for the Statistical and Clinical Coordinating Center include: 1. Qualifications and experience of the Director of the Center and the staff to manage clinical trials and clinical observational studies. - documentation of training, expertise, relevant experience, leadership/management skills 2. Ability to provide statistical leadership in the design and analysis of clinical trials. 3. Quality of the management plan for supporting the conduct clinical trials, including: - site monitoring and the collection, storage and reporting of data - experience assisting with regulatory activities, including Investigational New Drug applications - a system for adverse event reporting - preparation of reports and analyses for review and publication. 4. Ability to provide statistical, technical and logistical support to the Steering Committee and to the DSMB. 5. Appropriateness of the staffing plan. 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. However, reviewers will not factor budget considerations into the determination of scientific merit or priority score. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: November 16, 2004 Application Receipt Date: December 16, 2004 Peer Review Date: April, 2005 Council Review: June, 2005 Earliest Anticipated Start Date: July, 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. 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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