and Human Services (HHS)
EXPIRED
NOVEL BIOMARKERS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) Release Date: July 24, 2001 RFA: RFA-HL-02-005 National Heart, Lung, and Blood Institute (http://www.nhlbi.nih.gov) Letter of Intent Receipt Date: January 25, 2002 Application Receipt Date: February 26, 2002 PURPOSE The National Heart, Lung, and Blood Institute (NHLBI) invites applications for research grants to identify novel biomarkers of chronic obstructive pulmonary disease (COPD). COPD is a complex group of conditions associated with progressive airway obstruction for which no disease-modifying therapy is currently known. The purpose of this Request for Applications (RFA) is to promote the identification and characterization of biomarkers that might eventually be useful for studies of COPD pathogenesis, for diagnosis, for therapeutic stratification of patients, or for testing of potential drug treatments. Such biomarkers might reflect the presence or severity of COPD, the rate of disease progression, or exacerbations of the disease. A variety of techniques might be employed, ranging from chemical assays of exhaled air condensate to proteomic analysis of blood to functional imaging of lungs by positron emission tomography (PET). The focus of this RFA is on novel biomarkers for COPD that can be determined by minimally invasive means. 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, Novel Biomarkers of Chronic Obstructive Pulmonary Disease (COPD), is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non- profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) Research Project (R01) award mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this RFA may not exceed four years. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. The anticipated award date is September 30, 2002. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts that have been adopted by the NIH. Complete and detailed instructions and information on Modular Grant applications have been incorporated into the PHS 398 (rev. 5/2001). Additional information on Modular Grants can be found at http://grants.nih.gov/grants/funding/modular/modular.htm FUNDS AVAILABLE The NHLBI intends to commit approximately $3.5 million in FY 2002 to fund eight to ten new grants in response to this RFA. An applicant may request a project period of up to four years and a budget for direct costs of up to $350,000 per year. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. 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. At this time, it is not known if this RFA will be reissued. RESEARCH OBJECTIVES Background COPD is a progressive disease, usually related to cigarette smoking, that affects 15 million Americans and is the fourth leading cause of death in this country. Attempts to reduce rates of smoking have been only minimally successful and COPD will likely be an increasingly important cause of disability and premature death in the future. There is remarkable heterogeneity among affected individuals with regard to the severity, rate of progression, and clinical manifestations of their disease. There is currently no reliable way to predict which individuals will develop COPD or which patients with COPD will experience rapid loss of lung function. Improvements are needed in our understanding of the disease process and in methods for characterizing subjects with this disease. Identification of biomarkers could lead to better understanding of the mechanisms of COPD and could facilitate the development of innovative therapies. Previous studies of chemical biomarkers in COPD, while typically involving only a small number of subjects, have yielded several encouraging findings. Individuals with stable COPD had increased markers of oxidative stress in exhaled air and plasma, increased levels of myeloperoxidase and eosinophil cationic protein in serum, and increased levels of eosinophil peroxidase and human neutrophil lipocalin in sputum. Urinary concentrations of desmosine and isodesmosine, degradation products of elastin, were correlated with both the presence of COPD and with disease exacerbation. Various inflammatory mediators and products of inflammatory cells were increased in serum during periods of exacerbation of COPD. Microsatellite DNA instability was detected in sputum cells of one fourth of smokers with severe COPD but in none of smokers without COPD. Validation and extension of these findings is needed in larger groups of subjects with COPD that are stratified by disease expression and severity. There has been little use of advanced techniques in studies of potential biomarkers for COPD. In one preliminary report involving measurements by positron emission tomography, activation of neutrophils and uptake of macrophages were greater in the lungs of subjects with COPD than in normal controls. No studies involving proteomic analysis or gene expression profiling by microarray analysis have been reported. Other This RFA invites studies to examine associations between specific aspects of COPD and novel biomarkers that are measured by minimally invasive methods. A biomarker is defined in the RFA as a physiological or anatomical measurement or the quantitative result of a physical, chemical, or cellular analysis of a biological specimen obtained from a human subject. This definition includes, but is not limited to, the following: o Measurements of chemicals or biochemicals in biological fluids, o Quantitation of specific cell types by histological or chemical characteristics, o Proteomic analysis, o Gene expression profiles, o Innovative physiological measures such as airway impedance, o High resolution computed tomography, and o Functional imaging technologies such as positron emission tomography (PET). A biomarker to be evaluated through this RFA must be novel, i.e. it must reasonably be expected to capture information about the disease state that is substantially different from or substantially more detailed than that which can be obtained through established methods for characterizing subjects with COPD. These established methods include spirometry, measurements of gas diffusing capacities, and radiographic measures of lung tissue density. A biomarker to be evaluated through this RFA must involve only minimally invasive methods for measurements or sample collection. Examples of minimally invasive techniques are sampling of exhaled air, sputum induction, peripheral venous blood draws, urine collection, plethysmography, and use of radiographic imaging methods. Proposed studies must involve characterizations of human subjects and must include individuals who have COPD. Studies of individuals with alpha-1 antitrypsin deficiency will be allowed. It is expected that studies will attempt to correlate particular biomarkers with specific aspects of COPD. Examples of aspects of COPD include, but are not limited to: o Presence or absence of stable COPD in smokers, o Degree of airflow limitation, o Symptoms of chronic bronchitis, o Severity and/or distribution of emphysema, o Responsiveness to therapies for COPD, o Frequency of exacerbations, or o Disease exacerbation. Measurements of multiple biomarkers in individual subjects and testing of multivariate correlations are encouraged. However, applicants should explain their rationale for the choice of each putative biomarker, should clearly define the aspect of COPD that is hypothesized to be correlated with the biomarker, and should justify the selection of the group(s) of human subjects that will be studied in the context of the underlying hypothesis. Examples of possible comparisons, depending upon the biomarker and the hypothesis, include: o Between smokers with and without COPD, o Between current smokers and non-smokers with COPD, o Between members of a single group of COPD subjects with varying rates of decline in FEV1 over time, o Between subjects with COPD and subjects with asthma, and o Between samples obtained in a single group of subjects during stable COPD and during exacerbations. Other comparisons not listed may also be appropriate. Plans for subject recruitment and characterization should be described in detail. The use of previously characterized cohorts of subjects is encouraged, particularly for studies attempting to correlate biomarkers with the rate of disease progression. SPECIAL REQUIREMENTS Studies of animals and in vitro models will not be funded through this RFA. Studies supported through this RFA must not employ invasive methods for the collection of specimens to be assayed for biomarkers. Proposals involving biomarkers in bronchoalveolar lavage fluid, in biopsies, or in surgical specimens will be judged as nonresponsive and returned to the applicant without scientific review. Applications to study physiological measurements or x-ray images will be considered responsive to the RFA only if the proposed measurements are likely to yield information that is substantially different from that which can be obtained by standard methods of pulmonary function testing and computed tomography (CT). This restriction does not preclude comparisons of standard measures (e.g. spirometry, lung CT) to the proposed novel biomarkers. In fact, measurements using established methods will generally be necessary for the characterization of the research subjects. It is recognized that certain characterizations of human subjects that might be obtained through this RFA could also serve as phenotypes in studies testing associations of candidate gene polymorphisms with COPD. While it is not the intent of this RFA to support genetic studies, funds may be requested for the collection and storage of DNA specimens. Funds will not be provided for genotyping of study participants. Any applicant wishing to make use of this option must describe briefly the planned use of study data and DNA specimens, must specify what costs for DNA collection and storage are included in the proposed budget, and must obtain Institutional Review Board approval for the collection and storage of these biological specimens. Upon initiation of the program, periodic meetings will be organized to encourage the exchange of information among investigators who participate in this program. Travel funds for a two day meeting each year, most likely to be held in Bethesda, Maryland, must be included in the module calculation. Applicants must include a statement indicating their willingness to participate in these meetings. Applicants are encouraged to contact the program official listed under INQUIRIES for further information. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are 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 research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to 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) all investigators to report accrual, and to conduct and report analyses, as appropriate, of sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the Inclusion of Children as Participants in Research Involving Human Subjects that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL: http://grants.nih.gov/grants/guide/notice-files/not98-024.html Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. 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 found in the NIH Guide for Grants and Contracts Announcement dated June 5, 2000, at the following website: 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. LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. 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 to Dr. Deborah Beebe at the address listed under INQUIRIES by January 25, 2002. APPLICATION PROCEDURES The PHS 398 research grant application instructions and forms (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html are to be used in applying for these grants. This version of the PHS 398 is available in an interactive, searchable PDF format. Although applicants are strongly encouraged to begin using the 5/2001 revision of the PHS 398 as soon as possible, the NIH will continue to accept applications prepared using the 4/1998 revision until January 9, 2002. Beginning January 10, 2002, however, the NIH will return applications that are not submitted on the 5/2001 version. For further assistance contact GrantsInfo, Telephone 301/710-0267, Email: [email protected]. It is expected that most grant applications submitted in response to this RFA will request no more than $250,000 direct costs in any year. Such applications must use a Modular Budget Format. Applications involving exceptional costs such as those associated with characterization of a large number of research subjects or use of advanced technologies may request up to $350,000 direct costs per year. Applications requesting greater than $250,000 direct costs in any year are required to include a categorical budget request using Form Page 4 and Form Page 5 of the PHS 398 (rev. 05/01). SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and NIH staff. The research grant application form PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html is to be used in applying for these grants, with modular budget instructions beginning on page 13 of the application instructions. SUBMITTING YOUR APPLICATION The RFA label available in the PHS 398 (rev. 05/01) 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 sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. 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 as well as all five collated sets of Appendix material must be sent to Dr. Deborah Beebe at the address listed under Inquiries. 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 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. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. Principal investigators should not send supplementary material without first contacting the Scientific Review Administrator (SRA). The SRA will be identified in the letter sent to you indicating that your application has been received. If you have not yet received such a letter, contact Dr. Deborah Beebe at the address listed under Inquiries. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NHLBI. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. 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 receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed, assigned a priority score, and receive a second level review by the NHLBI National 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 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. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? (2) Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? (3) Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? (5) Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and its duration in relation to the proposed research. o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. Schedule Letter of Intent Receipt Date: January 25, 2002 Application Receipt Date: February 26, 2002 Peer Review Date: June/July, 2002 Council Review: September 5-6, 2002 Earliest Anticipated Start Date: September 30, 2002 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. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or answer questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Tom Croxton, Ph.D., M.D. Division of Lung Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 10208, MSC 7952 Bethesda, MD 20892-7952 Telephone: (301) 435-0202 FAX: (301) 480-3557 Email: [email protected] Direct inquiries regarding review issues to: Deborah Beebe, Ph.D. Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7178, MSC 7924 Bethesda, MD 20892-7924 Telephone: (301) 435-0270 FAX: (301) 480-3541 Email: [email protected] Direct inquiries regarding fiscal matters to: Marsha Mathis Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7158, MSC 7926 Bethesda, MD 20892-7926 Telephone: (301) 435-0170 FAX: (301) 480-3510 Email: [email protected] AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.838. 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 PHS strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.
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