SEVERE ASTHMA RESEARCH PROGRAM Release Date: January 17, 2001 RFA: RFA-HL-01-012 (Notice of limited competion request for competing applications, see NOT-HL-05-125) National Heart, Lung, and Blood Institute Letter of Intent Receipt Date: February 9, 2001 Application Receipt Date: March 12, 2001 PURPOSE The National Heart, Lung, and Blood Institute (NHLBI) invites applications to participate in an interactive Severe Asthma Research Program. Severe asthma affects a small subset of asthma patients but uses a disproportionate amount of health care resources. It is also responsible for a significant amount of the morbidity and mortality associated with asthma. The purpose of this RFA is to establish a collaborative program to investigate the mechanistic basis for severe asthma and how it differs from mild-to-moderate asthma. The objective of this Request for Applications (RFA) is to establish a collaborative program to perform research investigating the pathophysiology of severe asthma. 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 Request for Applications (RFA), Severe Asthma Research Program, 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 foreign and domestic, 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. Among the disciplines and expertise that may be appropriate for this program are pulmonary medicine, molecular and cellular biology, allergy and immunology, pharmacogenetics, genetics, and imaging. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) regular research project (R01) award mechanism. The total project period for an application submitted in response to this RFA may not exceed five 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, 2001. FUNDS AVAILABLE The NHLBI intends to commit approximately $4.5 million dollars in FY 2001 to fund up to eight awards in response to this RFA. An applicant may request a project period of up to five years and a budget for direct costs of up to $350,000 per year. Facilities and Administrative (indirect) costs will be awarded based on the negotiated rates. Because the nature and scope of the research proposed in response to this RFA may vary, it is anticipated that the size of an award may also vary in all years. Future year costs may be distributed based on the final projects agreed upon by the principal investigators. 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. Designated funding levels are subject to change at any time prior to final award, due to unforeseen budgetary, administrative, or scientific developments. RESEARCH OBJECTIVES Background A small percentage of asthma patients (10 percent or less) has severe disease that is refractory to conventional treatment modalities, including treatment with systemic corticosteroids. Although severe asthmatics represent only a small percentage of the asthmatic population, their disease has a major impact on the health care system, consuming resources disproportionately, in terms of time and health care dollars. In addition, this patient subgroup bears the most significant burden in relation to poor quality of life, high risk for mortality, and a high investment of health care costs for marginal management. Yet, we have very little knowledge of the pathophysiology of severe asthma and how it differs from mild-to-moderate asthma. This information is critical for the development of effective treatment modalities for severe asthma patients. Although there has been a considerable increase in our understanding of the mechanisms involved in the inception and maintenance of mild-to-moderate asthma over the past 20 years, a paucity of clinical, physiologic, and pathologic data exists on severe asthma. While there is overwhelming evidence to indicate that airway inflammation underlies the pathophysiology of asthma, its relationship to disease severity remains unclear. Although atopy is one of the strongest risk factors for the development of asthma in childhood, it is not an associated finding in severe asthma, thus its role in the pathology of severe asthma requires clarification. Virtually nothing is known of the genetic, environmental, and other factors that are associated with disease progression and severity. Once established, it is not known whether severe asthma can be completely reversed. Corticosteroids are highly effective anti-asthma drugs acting to reduce airway inflammation. However, there are many patients with severe asthma in whom only partial improvement is achieved even at high doses. Although very few long term longitudinal epidemiologic studies exist, the scant evidence available suggests that severe and poorly controlled asthma progresses to an increasingly irreversible component. Severe and prolonged inflammation is almost always accompanied by tissue remodeling, however, the mechanism(s) involved and their contribution to the pathophysiology of severe asthma remain poorly understood. The functional importance of remodeling to airway narrowing, or for the development of airways hyperresponsiveness, remains unclear, as well as the potential ramifications of these changes for airway function and therapeutic management. Given the recent findings demonstrating the persistence of inflammation in patients with severe asthma despite high dose glucocorticoid treatment, a comprehensive assessment of severe asthma is clearly warranted to define the cellular and molecular events underlying the pathophysiology of severe asthma. The number of severe asthma patients at any one site, along with differing diagnosis guidelines make it difficult to obtain clear data on the pathophysiology of severe asthma. There is a critical need to evaluate a significant population of patients in a uniform manner to elucidate how the pathophysiology of severe asthma differs from that of mild-to-moderate asthma. Because of the small number of patients with severe asthma at any one institution, meaningful comparison and investigation into the underlying causes of severe asthma necessitate recruitment of patients through a collaborative research program. Investigators in this program will agree on a definition of severe asthma and diagnosis guidelines in order to obtain a sufficiently homogeneous patient population to answer research questions that may require more patients than can be recruited at any one institution. In addition, the collaborative nature of the program will help pool the necessary expertise and resources to facilitate the conduct of novel research in a timely and efficient manner. Research Scope The objective of this RFA is to establish a Severe Asthma Research Program in order to accelerate research on the pathophysiology of severe asthma. The fundamental question to be addressed by each investigator is how the pathophysiology of severe asthma differs from that of mild-to-moderate asthma. The final definition of severe asthma, for the purposes of this RFA, will be decided upon by a steering committee composed of the principal investigators from each institution and the NHLBI Project Officer. Each applicant must propose a research project in humans characterized with severe asthma. Applicants should provide a definition of severe asthma in the application along with standard diagnosis guidelines for patients. All investigators must agree to utilize the common guidelines developed by the Steering Committee for all investigator-initiated studies performed under this RFA. Animal models, intervention-based clinical studies and long-term epidemiology studies are not appropriate for this RFA. Robust disease definitions will need to be developed and used as entry criteria for research studies to enable meaningful comparisons between groups of patients in the program. Studies may be combined or patients pooled to address common questions. Comparisons with mild-to-moderate asthmatics should be included as controls. Emphasis should be placed on research that will help elucidate the underlying pathophysiologic mechanisms that contribute to the initiation and progression of the severe asthma phenotype. Some examples of research areas appropriate for this RFA include, but are not limited to the following: o Investigation of the risk factors for severe asthma versus mild-to- moderate asthma. This may include investigation into environmental, genetic, pharmacogenetic and other factors that may predispose a patient towards the development of severe asthma as compared to mild-to-moderate asthma. Determine whether disease begins in early life and progresses or whether there is a defining event(s) that changes the course of illness. o The genetics and pharmacogenetics of severe asthma. o Determination of whether there are physiologic abnormalities that are specific to severe asthma. Evaluate the relationship between progressive remodeling and declining FEV1 and lack of reversibility. Definition of the morphologic and histologic findings of patients with severe asthma as compared with those who have mild to moderate asthma and to those with airway remodeling. o Investigation of the role of infection and atopy in severe asthma. The role of both respiratory infections and allergy in the development and exacerbation of mild-to-moderate asthma has been established. However, their roles in the initiation and/or progression of severe asthma is unclear and needs to be clarified. o Definition of the immune, inflammatory and neuroregulatory mechanisms that contribute to the pathogenesis of severe asthma and their impact on lung function. Particular attention needs to be given to how these mechanisms differ in severe asthmatics as compared to patients with milder disease. The relationship between the innate and acquired immune systems of the airways and their relationship to severe asthma needs to be established. The relationship of lymphocytes (e.g., neutrophils) and their effector functions as they relate to ongoing inflammation and airway remodeling specifically in severe asthma needs to be more fully explored. o Establish the effect of inhaled and/or oral corticosteroids on basic pathophysiologic manifestations of severe asthma, e.g., modulation of airway cell function, disease progression, airway remodeling and lung function. o Application of new technologies to study the composition and dynamics of the airways in chronic severe disease with increased discrimination and resolution. THESE ARE EXAMPLES ONLY. APPLICANTS SHOULD NOT FEEL LIMITED TO THE SUBJECTS MENTIONED ABOVE AND ARE ENCOURAGED TO SUBMIT OTHER TOPICS PERTINENT TO THE OBJECTIVES OF THE RFA. Applications utilizing animals, clinical interventions or long-term epidemiology studies will be judged non- responsive. SPECIAL REQUIREMENTS In order to gain insight into the pathophysiology of severe asthma it is critical that a significant number of patients be evaluated in a uniform manner before individual research studies are initiated. Thus, this program is designed to be a collaborative effort. Applicants will be responsible for proposing research studies and common guidelines that will be shared across the program for patient diagnosis, enrollment, testing and sampling and sharing of materials and data. All individual investigators will be required to participate in a collaborative and interactive manner with one another in all aspects of the program, including sharing of patients, samples and data. The investigators in the Program will be responsible for collaboratively developing a common mechanism by which patient data, samples and materials can be collected and shared as needed for the research studies proposed. This mechanism should include common definitions, common procedures for patient selection and enrollment, standardization of common procedures, tests and reporting forms. A Steering Committee will coordinate the efforts of the Severe Asthma Research Program and will be composed of the principal investigators of the Program and the NHLBI Project Officer. The Steering Committee may meet as often as three to six times in the first 12 months of the study, and two times per year thereafter. Meetings will be held in the greater Baltimore- Washington area. The Steering Committee will have primary responsibility for the general organization of the program, finalizing the common definitions, common measures, standardization of common procedures and common reporting formats, so that studies are comparable and complementary, to be implemented at each institution, facilitating the conduct and monitoring of the studies. Definitions and procedures must be agreed upon by the Steering Committee before research studies are initiated. Research funds will be restricted until such agreement is reached. Subcommittees of the Steering Committee may be established as necessary. Applicants must include sufficient travel funds in order for the principal investigator, at a minimum, at each institution to attend all meetings of the Steering Committee. Designated funds will be restricted for travel to Steering Committee meetings only. Applicants must also include sufficient funds for shipment of samples. 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 (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a complete copy of the updated Guidelines are available at https://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 studies 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, by 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 address: https://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. 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 February 9, 2001. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: GrantsInfo@nih.gov. Because we expect that there will not be any applications requesting less than $250,000 in direct costs for every year, applications should be in the standard (non-modular) format with a detailed budget. Additional Material to Include in the Application To promote development of a collaborative program among the award recipients, the issues discussed below need to be addressed in each application for the Research Program. This material is in addition to the submission of a research plan, as described in the section entitled Research Scope. o Willingness to participate in the Severe Asthma Research Program. Applicants should provide a written statement describing their general support of collaborative research and interaction with other institutions participating in the Program and specifically state their willingness to implement common guidelines developed by the Steering Committee as well as share patients, samples and data when appropriate as determined by the Steering Committee. APPLICATIONS NOT CONFORMING TO THESE GUIDELINES WILL BE CONSIDERED UNRESPONSIVE TO THIS RFA AND WILL BE RETURNED WITHOUT FURTHER REVIEW. The RFA label available in the PHS 398 (rev. 4/98) 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: https://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 must be sent to: Dr. Deborah Beebe at the listing 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. 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 or Board. 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: Applicants must have experience and expertise to conduct research studies in patients with severe asthma. Prospective institutions must have an established clinical research program on the pathogenesis of asthma. (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? (6) Study population. Applicants must have the ability to enroll over the 5 years at least 25-50 patients with severe asthma. The pool of potential study participants in the Severe Asthma Research Program should consist of appropriate gender and minority representation. The application must include a description of the pool of potential study participants--the age range, ethnic/racial distribution, estimated distribution of patients with different levels of asthma severity, and recruitment source. Access to at least 25-50 patients for research studies over the 5 year period is expected, but it is not anticipated that all patients will be enrolled in research studies at any one time, and it is possible that an individual patient may be enrolled in more than one study. Patient access may be accomplished by establishing links with other groups besides the applicant"s institution. There must be a well described plan to link the individual institutions with community health care providers such as HMOs, asthma clinics, or private practice physicians to ensure adequate numbers patients. 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 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. o The adequacy of the proposed plan to share data, if appropriate. Applications will be judged primarily on the scientific quality of the application, however, the scientific merit of the proposed research plan will not be the sole criterion for selection of successful applicants. Applicants are encouraged to submit and describe their own ideas on how best to meet the goals of the Severe Asthma Research Program, but they are expected to address issues identified under APPLICATION PROCEDURES of the RFA. Schedule Letter of Intent Receipt Date: February 9, 2001 Application Receipt Date: March 12, 2001 Peer Review Date: July 2001 Council Review: September 6-7, 2001 Earliest Anticipated Start Date: September 30, 2001 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: Patricia Noel, Ph.D. Division of Lung Diseases National Heart, Lung and Blood Institute 6701 Rockledge Drive, Room 10018, MSC7952 Bethesda, Maryland 20892-7952 Telephone: (301)-435-0202 FAX: (301)-480-3557 Email: noelp@nih.gov Direct inquiries regarding review issues to: Deborah Beebe, Ph.D. Division of Extramural Affairs National Heart, Lung and Blood Institute 6701 Rockledge Drive, Room 7418, MSC 7924 Bethesda, MD 20892-7924 Telephone: (301) 435-0270 FAX: (301)-480-3541 Email: (beebed@nhlbi.nih.gov) Direct inquiries regarding fiscal matters to: Tanya McCoy Division of Extramural Affairs National Heart, Lung and Blood Institute 6701 Rockledge Drive, Suite 7154, MSC 7926 Bethesda, MD 20892-7926 Telephone: (301)-435-0171 FAX (301)-480-3310 email: mccoyt@nhlbi.nih.gov 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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