EXPLORATORY AND DEVELOPMENTAL RESEARCH GRANTS FOR INVESTIGATIONS IN RARE DISEASES (R21) RELEASE DATE: September 16, 2003 PA NUMBER: PA-03-171 March 2, 2006 (NOT-OD-06-046) Effective with the June 1, 2006 submission date, all R03, R21, R33 and R34 applications must be submitted through Grants.gov using the electronic SF424 (R&R) application. This announcement will stay active for only the May 1, 2006 AIDS and AIDS-related application submission date. The non-AIDS portion of this funding opportunity expires on the date indicated below. Parent R03 (PA-06-180) and R21 (PA-06-181) funding opportunity announcements have been issued for the submission date of June 1, 2006 and submission dates for AIDS and non-AIDS applications thereafter. Applications relating to R33 and R34 activities must be in response to NIH Institute/Center (IC)-specific announcements. nnouncements. EXPIRATION DATE for R21 Non-AIDS Applications: March 2, 2006 EXPIRATION DATE for R21 AIDS and AIDS-Related Applications: May 2, 2006 Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATIONS: National Institutes of Health (NIH) (http://www.nih.gov/ COMPONENTS OF PARTICIPATING ORGANIZATIONS: National Heart, Lung, and Blood Institute (NHLBI) (http://www.nhlbi.nih.gov) Office of Rare Diseases (ORD) (http://rarediseases.info.nih.gov) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.233, 93.837, 93.838, 93.839 THIS PA CONTAINS THE FOLLOWING INFORMATION o Purpose of the PA o Research Objectives o Mechanism of Support o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Where to Send Inquiries o Submitting an Application o Supplementary Instructions o Peer Review Process o Review Criteria o Award Criteria o Required Federal Citations PURPOSE OF THIS PA The purpose of this announcement is to define the scope of exploratory and developmental grant applications to the National Heart, Lung, and Blood Institute (NHLBI) for support of investigators with novel approaches to understanding, treating, and preventing rare diseases in the areas of heart, lung, and blood disease as well as sleep disorders. The Office of Rare Diseases at NIH (ORD) will co-fund applications in these rare diseases. Availability of R21 awards for these individuals is expected to allow investigators with novel ideas to obtain research support without the need for large amounts of preliminary data that often serves as a barrier to entry into the NIH grants system. It is anticipated that these efforts will ultimately result in an increased pipeline of therapeutic approaches to treatment and prevention of rare diseases. Such diseases are often referred to as "orphan" diseases since there is a general lack of interest among industries to invest resources in diseases that in aggregate comprise too small a population to guarantee return on investment. Potential applicants may wish to review the information available through the Office of Rare Diseases http://rarediseases.info.nih.gov/. The R21 is intended to encourage exploratory and developmental research projects by providing support for the early and conceptual stages of projects dealing with heart, lung, and blood diseases and sleep disorders. RESEARCH OBJECTIVES The National Institutes of Health has received a substantial increase in research funding from Congress for the purpose of expanding the national investment of the United States in behavioral and biomedical research. Notwithstanding such increases, funding for rare diseases and disorders at the National Institutes of Health has not increased appreciably. The Rare Disease Act of 2002 (Public Law 107- 280) established the Office of Rare Diseases to encourage collaboration and new research endeavors for rare diseases. For these reasons and because of the number of such diseases in the areas of heart, lung, and blood disease along with sleep disorders, the NHLBI and ORD invite applications utilizing the R21 funding mechanism in the area of rare diseases. The R21 mechanism is intended to encourage new exploratory and developmental research projects. Such projects should be designed to provide preliminary results to demonstrate feasibility of novel approaches to heart, lung, and blood diseases and sleep disorders. Studies may involve considerable risk with the expectation that the results to be obtained lead to a breakthrough in a particular area, or to the development of novel techniques, agents, methodologies, or approaches that could have major impact reducing the burden of rare diseases in the areas of cardiovascular, respiratory, and blood disease. New activities that promote the formation of new research collaborations and explore novel approaches to test imaginative new ideas while providing preliminary data to demonstrate concept feasibility are especially encouraged. Potential areas of application could include but are not limited to the following: o Heart and Vascular Diseases: arrhythmogenic right ventricular dysplasia, Brugada's Syndrome, congenital heart disease, familial homozygous hypercholesterolemia, Liddle's Syndrome, Long QT Syndrome. o Lung Diseases: alpha1-antitrypsin deficiency, berylliosis, bronchopulmonary dysplasia, Churg-Strauss Syndrome, cystic fibrosis, LAM, primary pulmonary fibrosis, sarcoidosis. o Blood Diseases: aplastic anemias, the hemophilias, hereditary, hemorrhagic telangiectasia, lymphatic diseases, myelodysplastic syndromes, myeloproliferative disorders, sickle cell disease, stem cell therapies for rare diseases such as inborn errors of metabolism, the thalassemias, the thrombocytopenias. o Sleep Disorders: congenital central hypoventilation syndrome (Ondine's Curse), circadian rhythm disorders such as advanced sleep phase syndrome. MECHANISM OF SUPPORT Applicants responding to this PA must use the NIH Exploratory/ Developmental Research Grant (R21) award mechanism. The applicant will be solely responsible for planning, directing, and executing the proposed project. Guidelines for this mechanism are available at (http://grants.nih.gov/grants/guide/pa-files/PA-03-107.html) The applicant may request a project period of up to two years with a combined budget for direct costs of up $275,000 for the two year period. For example, the applicant may request $100,000 in the first year and $175,000 in the second year. The request should be tailored to the needs of the project. Normally, no more than $200,000 may be requested in any single year. Each new investigator will be solely responsible for planning, directing, and executing the proposed research. This PA uses just-in-time concepts. It also uses the modular budgeting format. (see http://grants.nih.gov/grants/funding/modular/modular.htm). All applications submitted in response to this announcement must use the modular budget format. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm. Under this PA exploratory/developmental grant support is for new investigators with new projects only; competing continuation applications will not be accepted. Two revisions of a previously reviewed exploratory/developmental grant application may be submitted as defined in NIH Policy at http://grants.nih.gov/grants/policy/amendedapps.htm. ELIGIBLE INSTITUTIONS You may submit an application if your 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 INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any investigator with the skills, knowledge, and resources necessary to carry out the proposed research is eligible to serve as the principal investigator of an award through this program. Investigators representing underrepresented racial and ethnic groups as well as those with disabilities are always encouraged to apply for NIH programs. WHERE TO SEND INQUIRIES We encourage your inquiries concerning this PA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into two areas: scientific/research and financial or grants management issues: o Direct your questions about scientific/research issues to: David A. Lathrop, Ph.D. Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 9142 (MSC 7940) Bethesda, MD 20892-7940 (20817 for Courier) Telephone: (301) 435-0529 FAX: (301) 480-1454 Email: LathropD@nhlbi.nih.gov Elizabeth L. Wagner, M.P.H. Division of Blood Diseases and Resources National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 10159 (MSC 7950) Bethesda, MD 20892-7950 (20817 for Courier) Telephone: (301) 435-0065 FAX: (301) 480-0868 Email: WagnerE@nhlbi.nih.gov Mary Beth Clark Division of Epidemiology and Clinical Applications National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 8108 (MSC 7938) Bethesda, MD 20892-7938 (20817 for Courier) Telephone: (301) 435-0405 FAX: (301) 480-1864 Email: ClarkM@nhlbi.nih.gov Giovanna M. Spinella, M.D. Director, Extramural Research Program Office of Rare Diseases, OD, NIH 6100 Executive Blvd. Rm. 3B01-MSC 7518 Bethesda, MD 20892-7518 Telephone: 301 402-4336 Fax: 301 480-9655 E-mail: spinellg@od.nih.gov Carol E. Vreim, Ph.D. Division of Lung Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 10120 (MSC 7952) Bethesda, MD 20892-7952 (20817 for Courier) Telephone: (301) 435-0233 FAX: (301) 480-3547 Email: VreimC@nhlbi.nih.gov o Direct your questions about financial or grants management matters to: Kieran Kelley Grants Operations Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7156, MSC 7926 Bethesda, Maryland 20892-7926 Telephone: (301) 435-0171 FAX: (301) 480-3310 Email: KelleyK2@mail.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 number (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the face page of thr PHS 398 form. The PHS 398 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. APPLICATION RECEIPT DATES: Beginning with the October 1, 2003 receipt date, applications submitted in response to this program announcement will be accepted at the standard application deadlines, which are available at http://grants.nih.gov/grants/dates.htm. Application deadlines are also indicated in the PHS 398 application kit. SUPPLEMENTARY INSTRUCTIONS: All instructions for the PHS 398 (rev. 5/2001) must be followed, with these exceptions: o Research Plan Items a - d of the Research Plan (Specific Aims, Background and Significance, Preliminary Studies, and Research Design and Methods) may not exceed a total of 15 pages. No preliminary data is required but may be included if it is available. Because competing continuation applications for an exploratory/developmental grant are ineligible and will not be accepted, a Progress Report may not be included. Appendix. Use the instructions for the appendix detailed in the PHS 398 except that no more than 5 manuscripts, previously accepted for publication, may be included. SPECIFIC INSTRUCTIONS FOR MODULAR BUDGET GRANT APPLICATIONS: All investigator initiated R21 applications must be submitted in a modular budget grant format. The modular budget grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at http://grants.nih.gov/grants/funding/modular/modular.htm. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the checklist, and five signed photocopies in one package to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) APPLICATION PROCESSING: Applications must be received by or mailed on or before the receipt dates described at http://grants.nih.gov/grants/funding/submissionschedule.htm. The CSR will not accept any application in response to this PA that is essentially the same as one currently pending initial review unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of a substantial revision of an unfunded version of an application already reviewed, but such application must include an Introduction addressing the previous critique. 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 Applications submitted for this PA will be assigned on the basis of established PHS referral guidelines. Appropriate scientific review groups, convened in accordance with the standard NIH peer review procedures http://www.csr.nih.gov/refrev.htm), will evaluate applications for scientific and technical merit. 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 appropriate national advisory council or board REVIEW CRITERIA The NIH R21 exploratory/developmental grant is a mechanism for supporting novel scientific ideas or new model systems, tools or technologies that have the potential to significantly advance our knowledge or the status of health-related research. Because the research plan is limited to 15 pages, an exploratory/developmental grant application need not have extensive background material or preliminary information as normally expected in an R01 application. Reviewers will be instructed to focus their evaluation on the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Reviewers will thus place less emphasis on methodological details and certain indicators traditionally used in evaluating the scientific merit of R01 applications including supportive preliminary data. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Preliminary data are not required for R21 applications. The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. 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. o Significance o Approach o Innovation o Investigator o Environment The application does not need to be strong in all categories to be judged likely to significantly advance current knowledge and thus deserve a meritorious 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: 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 of either gender, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. 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 BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. AWARD CRITERIA Applications submitted in response to this PA will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: o Scientific merit of the proposed project as determined by peer review o Availability of funds o Relevance to program priorities REQUIRED FEDERAL CITATIONS 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 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). 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 "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. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that 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. You will find this policy announcement 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 PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. 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). Those who must comply with the Privacy Rule (classified under the Rule as "covered entities") must do so by April 14, 2003 (with the exception of small health plans which have an extra year to comply). 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 PA 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 Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm 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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