CAUSES AND MECHANISMS OF COPD EXACERBATIONS RELEASE DATE: September 16, 2004 RFA Number: RFA-HL-04-036 EXPIRATION DATE: January 12, 2005 Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov) COMPONENT OF PARTICIPATING ORGANIZATION: National Heart, Lung, and Blood Institute (NHLBI) (http://www.nhlbi.nih.gov) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER No. 93.838, Lung Diseases Research LETTER OF INTENT RECEIPT DATE: December 13, 2004 APPLICATION RECEIPT DATE: January 11, 2005 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism(s) 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 NHLBI invites applications for research projects that will investigate the causes of and molecular pathways involved in acute exacerbations of chronic obstructive pulmonary disease (COPD). Clinical and basic research supported through this program must seek new knowledge that may lead to the development of more effective approaches to the prevention and treatment of exacerbations in COPD. While the studies may be descriptive in part, all research projects supported through this RFA must include hypothesis-based, mechanistic investigations that lead toward the identification of molecular targets for therapeutic intervention. RESEARCH OBJECTIVES Moderate-to-severe COPD is characterized by periods of profound worsening of respiratory symptoms that may occur up to several times per year. Most exacerbations are idiopathic, though some are due to viral or bacterial infections. Some exacerbations are mild and may not be reported by the patient, but others produce striking clinical deterioration and require hospitalization. While recovery is essentially complete in most cases, treatment failures account for many of the 120,000 COPD deaths in this country each year. Approximately $10 billion per year, or nearly two thirds of the total direct costs of medical care in the U.S. related to COPD, is expended for the treatment of exacerbations. Despite this, medical interventions appear to have only a modest effect on the intensity, duration, and mortality of COPD exacerbations. Hence, new approaches for preventing and treating exacerbations are urgently needed to increase the quality and length of life for COPD patients and possibly reduce the overall cost of their care. Little is known about what causes COPD exacerbations, what individual factors determine risk or susceptibility, what cellular and molecular mechanisms are involved, what mechanisms contribute to remission, or how exacerbations may hasten the progressive loss of pulmonary function seen in COPD. Better understanding of why exacerbations develop and what pathways mediate their manifestations is needed to identify targets for prevention strategies and more effective therapies. This initiative will support a variety of studies related to the causes of and pathways contributing to exacerbations of COPD. All research projects supported through this RFA will include mechanistic studies of molecular hypotheses. By improving understanding of the molecular events involved in the initiation, development, and resolution of exacerbations, these studies will aid in identifying specific targets for more effective preventive and therapeutic interventions. Anticipated approaches include development of novel methods for detection and grading of exacerbations; clinical investigations of instigating factors, manifestations, outcomes, and effects of treatments; correlation of microbiological and biomarker measures with clinical course; characterization of inflammatory cells and mediators; assessments of host defense mechanisms before, during, and after an exacerbation; testing of genotype associations; and in vitro and animal studies of the molecular pathways involved. Research goals that are relevant to this solicitation include, but are not limited to, the following: o Evaluate methods for detection and measurement of exacerbations; possibly involving pulmonary mechanics, microphonic monitoring of cough frequency, biomarkers in exhaled breath, and patient scoring of dyspnea and sputum volume and color. o Identify predisposing factors (e.g., immune dysfunction, comorbidity, airway bacterial colonization) and triggers (e.g., upper respiratory tract infection, exposure to airborne pollutants or allergens, improper use of medications, or stress) of exacerbations. o Study molecular pathways through which airway inflammation produces worsening of respiratory symptoms during an exacerbation. o Examine the involvement of specific molecules and pathways in the onset, perpetuation, and remission of exacerbations. o Perform genomic and proteomic surveys of molecular events that occur in airways during the course of an exacerbation. o Conduct genetic association studies of susceptibility to frequent exacerbations. o Test the contributions of specific viral proteins, bacterial products, inflammatory cells and cytokines, proteases, mediators of mucous secretions, endogenous bronchoconstrictors (e.g., endothelin-1), or systemic mediators (e.g., tumor necrosis factor ?, fibrinogen) to the progression and clinical manifestations of exacerbations. o Carry out animal studies of the regulation and pathophysiological effects of molecular pathways that are activated during a COPD exacerbation. MECHANISM OF SUPPORT This RFA will use the NIH R01 award mechanism. As an applicant you 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 September 30, 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. This RFA uses just-in-time concepts. It also uses the modular budgeting as well as the non-modular budgeting formats (see https://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are 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 https://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm. FUNDS AVAILABLE The NHLBI intends to commit approximately $2,500,000 in FY 2005 to fund 5 to 7 new grants in response to this RFA. An applicant may request a project period of up to 5 years and a budget for direct costs of up to $275,000 in the first year, $500,000 in years 02-04, and $275,000 in the fifth year. 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. Applications requesting 5 years of support must provide a specific justification for that project duration. Although the financial plans of the NHLBI 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. ELIGIBLE INSTITUTIONS You may submit (an) application(s) 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 institutions/organizations o Foreign institutions that offer unusual talent, resources, populations, or environmental conditions that are not readily available in the United States or that augment existing U.S. resources. o Faith-based or community-based organizations 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 Applicants must propose an operational definition of COPD exacerbations and a system for grading the severity of exacerbations. The NHLBI will coordinate discussions among investigators and convene a meeting during the first year of the program to encourage the development of a consensus definition and grading system for use in all clinical studies of this program. The proposed research plan may include the validation of methods for detecting and grading COPD exacerbations and descriptive studies that seek to demonstrate associations between exacerbations and predisposing or aggravating factors. However, the research projects supported through this solicitation may not be entirely methodological and descriptive in nature. All applications must include studies that are based on stated hypotheses that involve particular molecular pathways or events. All studies must be relevant to COPD exacerbations in humans. The new knowledge to be gained must serve to enable the development of better approaches for the prevention and/or clinical management of COPD exacerbations. Studies of animal models or in vitro systems will be allowed only if their relevance to human COPD exacerbations is established. 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 your questions about scientific/research issues to: Tom Croxton, Ph.D., M.D. Division of Lung Diseases National Heart, Lung, and Blood Institute Rockledge II, Room 10208 6701 Rockledge Drive Bethesda, MD 20892-7952 Telephone: (301) 435-0202 FAX: (301) 480-3557 Email: firstname.lastname@example.org o Direct your questions about peer review issues to: Valerie Prenger, Ph.D. Chief Review Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute Rockledge II, Room 7194 6701 Rockledge Drive Bethesda, MD 20892-7924 Telephone: (301) 435-0288 FAX: (301) 480-4755 Email: email@example.com o Direct your questions about financial or grants management matters to: Mr. John Diggs Grants Management Specialist Grants Operations Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute Rockledge II, Room 7155 6701 Rockledge Drive Bethesda, MD 20892-7926 Telephone: (301) 435-0159 FAX: (301) 480-0422 Email: firstname.lastname@example.org 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 NHLBI 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: Valerie Prenger, Ph.D. Chief Review Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute Rockledge II, Room 7194 6701 Rockledge Drive Bethesda, MD 20892-7924 Telephone: (301) 435-0288 FAX: (301) 480-4755 Email: email@example.com 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 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 the PHS 398 form. The PHS 398 document is available at https://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. SUPPLEMENTARY INSTRUCTIONS: SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a modular grant format. The modular 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 https://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 https://grants.nih.gov/grants/funding/modular/modular.htm. 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: https://grants.nih.gov/grants/funding/phs398/labels.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 copies of the application and all copies of the appendix material must be sent to: Valerie Prenger, Ph.D. Chief Review Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute Rockledge II, Room 7194 6701 Rockledge Drive Bethesda, MD 20892-7924 APPLICATION PROCESSING: Applications must be received on or before 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. 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. The Center for Scientific Review (CSR) 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. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NHLBI. Incomplete applications will not be reviewed. If the application is not responsive to the RFA, NIH staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next appropriate NIH review cycle. 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 NHLBI in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the 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 Heart, Lung, and Blood Advisory 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 Investigator o Environment 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: 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 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: December 13, 2004 Application Receipt Date: January 11, 2005 Peer Review Date: May-June 2005 Council Review: September 1, 2005 Earliest Anticipated Start Date: September 30, 2005 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic 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 the participants. (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: https://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 (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at https://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. Because COPD is a disease of adults, it is anticipated that studies supported through this program will not include children as research participants. 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 https://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 https://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 https://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 https://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). 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 https://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.healthypeople.gov/. 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 https://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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