COPD CLINICAL RESEARCH NETWORK RELEASE DATE: August 22, 2002 RFA: HL-03-002 National Heart, Lung, and Blood Institute (NHLBI) (http://www.nhlbi.nih.gov) LETTER OF INTENT RECEIPT DATE: October 16, 2002 APPLICATION RECEIPT DATE: November 13, 2002 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism 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 Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The purpose of this initiative is to establish a Clinical Research Network (CRN) to investigate disease management approaches in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). The COPD CRN, which will consist of 4-6 Clinical Centers and a Data and Coordinating Center, will provide an infrastructure for conducting multiple, collaborative therapeutic trials with relative speed and efficiency. These trials may evaluate existing or new medications, combinations of medications and/or devices, and defined management strategies. RESEARCH OBJECTIVES Background. Chronic obstructive pulmonary disease (COPD) is a serious public health problem that is responsible for more than 500,000 hospitalizations, 100,000 deaths, and $15 billion in direct costs of medical care in the U.S. each year. In addition, millions of Americans are disabled by this disease. While smoking cessation is of clear benefit in slowing the progressive loss of lung function that is characteristic of COPD, management of established disease is largely limited to supportive measures that do not interfere with the disease process itself. More effective management strategies are needed. There is particular need for better prevention and management of exacerbations of COPD since these are associated with a substantial portion of the hospitalizations, deaths, and costs of care attributable to the disease. Notably, nearly half of patients hospitalized for exacerbations of severe COPD are dead within a year, these patients having a one-year survival rate similar to that associated with a diagnosis of Stage IIIA lung cancer. Need for Research. While certain supportive measures (such as long term oxygen therapy) are of established benefit in selected patients, there remains considerable uncertainty regarding the effectiveness of many treatment modalities that are routinely used in COPD, indications for specific therapies, the usefulness of novel therapeutic approaches, and the best means for management of common comorbid conditions. Improvements in management might also derive from better characterization of disease progression in those with severe COPD using newer tools of clinical assessment such as chemical biomarkers and high resolution computed tomography (CT) of the lung. Other important management issues include therapeutic stratification of subjects by phenotype, the validity of surrogate markers of therapeutic response, selection of outcome measures, muscle dysfunction, mental status, and quality of life. Scientific Aims. The general aim of the COPD CRN will be to perform short-term, collaborative, therapeutic intervention trials in patients with moderate-to-severe COPD, with emphasis on the prevention and management of exacerbations of the disease. These studies will use common protocols and address the knowledge deficits described above. The primary objective of each study carried out by the COPD CRN will be to: o Strengthen the knowledge base for therapeutic decision-making by testing particular approaches to the management of moderate-to-severe COPD and evaluating indications for specific therapies. Secondary objectives of the COPD CRN will be to: o Improve the management of comorbid conditions, o Develop methods for predicting individual responsiveness to treatments, and o Evaluate and correlate various outcome measures. Research Approaches. It is expected that the Clinical Centers of the COPD CRN will collectively perform approximately 5 short-term, randomized, controlled clinical trials during the 5-year project period. Each protocol will be implemented at all Clinical Centers. The specific protocols to be carried out by the COPD CRN will be determined according to procedures detailed below, after the network is established. The primary objective of each protocol will be to test whether a defined treatment approach favorably alters outcome in a population of patients with moderate-to-severe COPD. Better prevention and management of disease exacerbations are particularly important treatment goals in this group of patients. Examples of treatment approaches that might be tested include, but are not limited to o Chronic administration of beta-adrenergic and/or anticholinergic bronchodilators, o Treatment with an antibiotic in specific circumstances, o Chronic administration of an inhaled corticosteroid, o Treatment with a mucus-altering drug, o Oxygen supplementation in individuals with nocturnal oxyhemoglobin desaturation, o Use of a novel agent or approach, or o A program of drugs, nutritional supplements, and exercise designed to improve skeletal and respiratory muscle function. Tests of rational combinations of treatments may be appropriate, as may the targeting of therapies to specific subpopulations of COPD patients (e.g. those with pronounced bronchitic symptoms) or the utilization of a therapy only under certain circumstances (e.g. during or after an exacerbation). COPD CRN protocols may also address one or more of the secondary aims of the COPD CRN listed above. Secondary research topics that might be addressed include, but are not limited to o The reliability and sensitivity of various indices of outcome (e.g., survival, disease severity, frequency or severity of exacerbations, medication requirements or health care utilization, pulmonary function, lung radiographic density, exercise capability, mental status, or quality of life) for assessing therapeutic benefit, o Usefulness of patient characteristics (e.g., clinical parameters, radiographic or laboratory measures, biomarkers, genomic or proteomic profiles, or genetic factors) as predictors of individual responsiveness to a particular therapy, and o Appropriateness of standard approaches for the management of comorbid conditions (e.g., cardiovascular diseases) in patients with moderate-to-severe COPD. Project Organization. The COPD CRN will consist of the following components: the NHLBI, 4-6 Clinical Centers, a Data and Coordinating Center (DCC), a Steering Committee and its subcommittees, a Protocol Review Committee, and a Data and Safety Monitoring Board (DSMB). The responsibilities of each component of the COPD CRN are described below. NHLBI. The NHLBI will be responsible for organizing and providing support for the COPD CRN and will be involved substantially with the awardees as a "partner", consistent with the Cooperative Agreement mechanism. A designated NHLBI Project Scientist will monitor subject recruitment and study progress, ensure disclosure of conflicts of interest and adherence to NHLBI policies, and serve as Executive Secretary for the Protocol Review Committee. The NHLBI Project Scientist, together with the NHLBI Grants Management Specialist, will be responsible for fiscal management of the network, including calculation of capitation budget rates and awards. The NHLBI will appoint the Chairperson of the Steering Committee and all members of the Protocol Review Committee and the DSMB. Clinical Centers. The Principal Investigator at each Clinical Center will have primary responsibility for study design and implementation, including subject recruitment and safety. With the assistance of Co- Investigators as appropriate, the Principal Investigator will hire and supervise relevant personnel, obtain Institutional Review Board (IRB) approval for CRN protocols, oversee data collection and adherence to quality assurance measures, and prepare budgets and annual reports. The Principal Investigator (or designated alternate) will serve as a voting member of the Steering Committee. A Clinical Coordinator at each clinical center will set up training systems, certify personnel, and establish procedures to ensure adherence to protocols, collection of high quality data, and accurate transmission of data to the DCC. Data Coordinating Center (DCC). The DCC will assist protocol development, provide statistical consultation for study design, and prepare operational timetables. The DCC will develop data collection forms and manuals of operations, determine sampling and randomization schemes, and assist in defining primary and secondary outcomes and analytical approaches for the protocols. The DCC will subcontract to external laboratories, as needed, coordinate with suppliers of drugs, and arrange for the preparation and packaging of medications. The DCC will develop procedures for quality control, training and certification, and data management. It will monitor the quality and quantity of data received from the Clinical Centers, provide relevant reports to the NHLBI, Clinical Centers, and Steering Committee, and serve as a central repository for study data. The DCC will prepare protocols for submission to the Protocol Review Committee and prepare confidential data analyses and reports for the DSMB. It will support manuscript preparation through data analysis, statistical consultation, editorial support, and meeting coordination. The DCC will schedule and make arrangements for all meetings of COPD CRN committees and boards. The DCC will be subject to annual administrative review. Steering Committee. Voting members of the Steering Committee will include the Principal Investigator from each Clinical Center (or designated alternate), the Principal Investigator from the Data Coordinating Center (or designated alternate), the NHLBI Project Scientist, and a Chairperson appointed by the NHLBI. The Chairperson of the Steering Committee (who may or may not be a Principal Investigator of a participating Clinical Center) will plan network activities, oversee its functions, conduct the Steering Committee meetings, and cast tie-breaking votes in that committee. The Steering Committee will develop and ensure compliance with COPD CRN policies and procedures, identify and prioritize topics for investigation, evaluate protocols proposed by the Clinical Centers, and develop consensus protocols for submission to the Protocol Review Committee. The Steering Committee will ensure that studies are properly conducted and monitored, that data are appropriately analyzed and interpreted, and that study results are reported in the scientific literature in a timely manner and disseminated to physicians involved in the care of COPD patients. Subcommittees, consisting of qualified individuals from the clinical centers, the DCC, and the NHLBI, may be established by the Steering Committee to perform specific functions such as Publications and Presentations or Quality Control. Protocol Review Committee. The Protocol Review Committee will be appointed by, and responsible to, the NHLBI. It will consist of a Chairperson and scientists with expertise in basic and clinical research, clinical trial design, biostatistics, and outcome measures. The Protocol Review Committee will evaluate protocols proposed by the Steering Committee based on the importance of the question to be addressed, scientific merit of the experimental design, feasibility, appropriateness to a CRN, and consistency with NHLBI mission and policies. The Protocol Review Committee will provide a written critique of each protocol and a final recommendation to the NHLBI. All study protocols performed by the COPD CRN must be recommended by the Protocol Review Committee and approved by the NHLBI. Data Safety and Monitoring Board (DSMB). The NHLBI will establish a DSMB in accordance with established policies (see http://www.nhlbi.nih.gov/funding/policies/dsmb_inst.htm) to ensure data quality and participant safety and to provide independent advice to the NHLBI regarding progress and the appropriateness of study continuation. MECHANISM OF SUPPORT This RFA will use the NIH U10 cooperative agreement award mechanism in which the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the section "Cooperative Agreement Terms and Conditions of Award", below. The project period for studies supported through this RFA will be 5 years. The anticipated award date is July 1, 2003. This RFA uses just-in-time concepts. It does not use the modular budgeting format. FUNDS AVAILABLE The NHLBI intends to commit approximately $25 million (Total Costs) over a 5-year period to the support of the COPD CRN. (Total Costs include Direct Costs and Facility & Administrative Costs, also called indirect costs or overhead). It is anticipated that 4 to 6 Clinical Centers and one Data and Coordinating Center will be established under this program. Additional funds may be provided to support Clinical Research Skills Development Cores in one or more of the Clinical Centers. The proposed budget of a Clinical Center applicant may not exceed $600,000 Direct Costs in any year ($700,000 if applying for a Clinical Research Skills Development Core). The proposed budget of a Data and Coordinating Center applicant may not exceed $800,000 Direct Costs in any year. Specific instructions for budget preparation are in the SUPPLEMENTAL INSTRUCTIONS, below. Awards made to a particular center under this RFA will depend in part on the protocols carried out by the COPD CRN and may be more or less than the requested budget. Although the financial plans of the NHLBI provide support for the COPD CRN, 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 award, due to unforeseen budgetary, administrative, or scientific developments. At this time it is not known if the RFA will be reissued. 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 Foreign institutions are not eligible. An institution may apply for both a Clinical Center and the Data and Coordinating Center, but there must be no overlap of key personnel to ensure that data acquisition is independent of data analysis. More than one application for a Clinical Center may be submitted from the same institution. 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. Women, individuals in underrepresented racial and ethnic groups, and individuals with disabilities are always encouraged to apply for NIH programs. SPECIAL REQUIREMENTS The COPD CRN will be a collaborative effort that will require frequent interactions of awardees among themselves and with the NHLBI. Applicants should explicitly indicate their willingness to o Participate in Steering Committee meetings (expected to occur approximately 6 times per year in or near Bethesda, Maryland), site visits required by the NHLBI, and regular telephone conference calls, o Cooperate with other awardees in the development and design of research protocols, o Abide by common definitions, common methods for patient selection and enrollment, and common protocols, procedures, tests, and reporting forms as chosen by majority vote of the Steering Committee, o Actively seek to implement each network-wide protocol approved by the Protocol Review Committee and the NHLBI, o Comply with study policies and quality assurance measures approved by the Steering Committee, o Agree to oversight of the study by a Data and Safety Monitoring Board (DSMB), o Accept awards for the support of research based on per-patient (capitated) rates and the actual numbers of subjects enrolled, followed, and completing the study (Clinical Centers only), o Accept awards for the support of research based on the number of protocols developed, initiated, and carried out (Data and Coordinating Center only), o Transmit study data to the Data and Coordinating Center in a timely and accurate manner (Clinical Centers only), o Report all adverse events in accordance with procedures established by the Steering Committee and NHLBI policies, o Cooperate with other awardees in the publication of study results and the eventual release to the scientific community of study procedures and other resources, o Develop and implement plans for the dissemination of study results to physicians involved in the care of patients with COPD, o Participate in studies of the cost effectiveness of therapeutic interventions should the NHLBI choose to implement such research within the COPD CRN, and o Accept the Cooperative Agreement Terms and Conditions of Award given below. Cooperative Agreement Terms and Conditions of Award The cooperative agreement is an award instrument establishing an "assistance" relationship (in contrast to an "acquisition" relationship) between NHLBI and a recipient, in which substantial NHLBI scientific and/or programmatic involvement with the recipient is anticipated during performance of the activity. The purpose of NHLBI involvement is to support and/or stimulate the recipient"s activity by acting as a "partner", while avoiding a dominant role, direction, or prime responsibility. The terms and conditions below, elaborate on these actions and responsibilities, and the awardee agrees to these collaborative actions with the NHLBI Project Scientist to achieve the project objectives. It is anticipated that these terms and conditions will enhance the relationship between the NHLBI staff and the principal investigator(s), and will facilitate the successful conduct and completion of the study. These agreements will be in addition to, and not in lieu of, the relevant NIH procedures for grants administration. The terms will be as follows: 1. The awardee(s) will have lead responsibilities in all aspects of the study, including any modification of study design, conduct of the study, quality control, data analysis and interpretation, preparation of publications, and collaboration with other investigators, unless otherwise provided for in these terms or by action of the Steering Committee. 2. The NHLBI Project Scientist will serve on the Steering Committee, he/she or other NHLBI scientists may serve on other study committees, when appropriate. The NHLBI Project Scientist (and other NHLBI scientists) may work with awardees on issues coming before the Steering Committee and, as appropriate, other committees, e.g., recruitment, intervention, follow-up, quality control, adherence to protocol, assessment of problems affecting the study and possible changes in protocol, interim data and safety monitoring, final data analysis and interpretation, preparation of publications, and development of solutions to major problems such as insufficient participant enrollment. 3. Awardee(s) agree to the governance of the study through a Steering Committee. Steering Committee voting membership shall consist of the Principal Investigators (i.e., cooperative agreement awardees), the NHLBI Project Scientist, and the Chairperson. Meetings of the Steering Committee will ordinarily be held by telephone conference call or in the metropolitan Washington Area. 4. A Data and Safety Monitoring Board will be appointed by the Director, NHLBI to provide overall monitoring of interim data and safety issues, the Steering Committee will nominate members for this Board. Meetings of the Data and Safety Monitoring Board will ordinarily be held in Bethesda. An NHLBI scientist other than the NHLBI Project Scientist shall serve as Executive Secretary to the Board. An independent Protocol Review Committee, established by the NHLBI, will provide peer review for each network protocol. Because the Board serves as an independent group advisory to the NHLBI, study investigators will not communicate with Board members regarding study issues, except as authorized by the Board"s Executive Secretary. 5. Awardees will retain custody of and have primary rights to their data developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. The collaborative protocol and governance policies will call for the continued submission of data centrally to the coordinating center for a collaborative database, the submittal of copies of the collaborative datasets to each principal investigator upon completion of the study, procedures for data analysis, reporting and publication, and procedures to protect and ensure the privacy of medical and genetic data and records of individuals. The NHLBI Project Scientist, on behalf of the NHLBI, will have the same access, privileges and responsibilities regarding the collaborative data as the other members of the Steering Committee. 6. Support or other involvement of industry or any other third party in the study – e.g., participation by the third party, involvement of study resources or citing the name of the study or NHLBI support, or special access to study results, data, findings or resources – may be advantageous and appropriate. However, except for licensing of patents or copyrights, support or involvement of any third party will occur only following notification of and concurrence by NHLBI. 7. Awardees are encouraged to publish and to publicly release and disseminate results, data and other products of the study, concordant with study protocols and governance, and the approved plan for making data and materials available to the scientific community and to the NHLBI. However, during or within three years beyond the end date of the project period of NHLBI support, unpublished data, unpublished results, data sets not previously released, or other study materials or products are to be made available to any third party only with the approval of the Steering Committee and in accordance with paragraph 6. 8. The NHLBI reserves the right to terminate or curtail the study (or an individual award) in the event of (a) failure to develop or implement a mutually agreeable collaborative protocol, (b) substantial shortfall in participant recruitment, follow-up, data reporting, or quality control, (c) major breach of the protocol or substantive changes in the agreed-upon protocol with which NHLBI cannot concur, (d) attaining of a major study endpoint before schedule with persuasive statistical significance, or (e) human subject ethical issues that may dictate a premature termination. 9. Upon completion of the project, awardees are expected to put their intervention materials and procedure manuals into the public domain and/or make them available to other investigators, according to the approved plan for making data and materials available to the scientific community and the NHLBI, for the conduct of research at no charge other than the costs of reproduction and distribution. 10. Any disagreement that may arise in scientific/programmatic matters (within the scope of the award), between award recipients and the NHLBI may be brought to arbitration. An arbitration panel will be composed of three members--one selected by the Steering Committee (with the NHLBI member not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by NHLBI, and the third member selected by the two prior members. This special arbitration procedure in no way affects the awardee"s right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR part 50, Subpart D and HHS regulation at 45 CFR part 16, or the rights of NHLBI under applicable statutes, regulations and terms of the award. 11. These special terms of award are in addition to and not in lieu of otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR part 74, and other HHS, PHS, and NIH grant administration policy statements. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues to: Dr. Tom Croxton Division of Lung Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 10208 Bethesda, MD 20892-7952 Telephone: (301) 435-0202 FAX: (301) 480-3557 Email: croxtont@nhlbi.nih.gov o Direct your questions about peer review issues to: Dr. Anne Clark Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7214 Bethesda, MD 20892-7924 Telephone: (301) 435-0270 FAX: (301) 480-0730 Email: clarka@nhlbi.nih.gov o Direct your questions about financial or grants management matters to: Mr. Ray Zimmerman Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7156 Bethesda, MD 20892 Telephone: (301) 435-0171 FAX: (301) 480-3310 Email: zimmermr@nhlbi.nih.gov 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 Dr. Anne Clark at the address listed under WHERE TO SEND INQUIRIES, above. SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). 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) 435-0714, Email: GrantsInfo@nih.gov. SUPPLEMENTAL INSTRUCTIONS: Clinical Centers. Applications for Clinical Centers should describe the expertise of study personnel in COPD, their clinical research experience in pulmonary disease, the research environment of the applicant institution, their access to the necessary populations, and the availability of resources needed to conduct clinical trials. In addition, the application must include a Research Plan describing two short-term (12-18 month) protocols that could be used as models for the development of CRN-wide study protocols. Clinical Centers selected to participate in the COPD CRN will be asked to present their proposed protocols to the Steering Committee for consideration, but the COPD CRN may choose not to implement either of the protocols proposed by a participating center. The proposed protocols should address important questions in the clinical management of moderate-to-severe COPD and have practical implications for patient care. Randomized, controlled trials that require more subjects than would be available at a single center are preferred. Both protocols must be feasible within the 5-year project period. The Research Plan should describe the specific aims of the research, relevant background information, preliminary data, the two proposed protocols, plans for data analysis and interpretation, and methodological details. The background information and preliminary data should support the rationale and feasibility of the studies and provide justification for the proposed end points and sample sizes. The protocol descriptions should include the expected subject population demographics, inclusion and exclusion criteria, methods for subject characterization, details of the therapeutic and control interventions, outcome measures to be employed, plans for data analysis and interpretation, timelines, and plans for data sharing and dissemination of study results. Sample size calculations may assume availability of 4 times the number of subjects expected to be enrolled at the applicant center. Recruitment estimates for the center should be justified on the basis of the number of COPD patients seen each year at the applicant institution and the documented history of success in recruiting similar subjects for previous clinical trials at that institution, including data on the participation of women and underrepresented minority and ethnic populations in previous studies. A Clinical Center applicant should request a project period of 5 years. The budget request for the first year may include up to $115,000 Direct Costs to support core research activities, up to $500,000 Direct Costs for per-patient costs associated with specific protocols, and up to $100,000 Direct Costs for the support of a Clinical Research Skills Development Core (optional, see below). The core research activities budget should cover a minimum of 25% effort for the combined physician leadership (Principal Investigator and any Co-Investigators), appropriate percentages of effort for other key personnel (e.g., Clinical Coordinator, data entry clerk), travel costs for approximately six trips each year to attend Steering Committee meetings in Bethesda, MD, and other travel costs related to CRN operations. Direct cost requests for the core research budget may be escalated at three percent annually in future years. Facilities and Administration costs associated with the per-patient costs may be requested at a rate not to exceed 28%. Facilities and Administration costs other than those associated with per-patient costs may be requested in accordance with the grantee"s established Facilities and Administration cost (indirect cost) rate covering the applicable activities and period of time. Budget requests for per-patient costs should be based on the two specific protocols proposed in the application and reflect anticipated costs for simultaneous implementation of these protocols in the first year. A table should be included showing estimated Total Costs per patient for conducting each protocol. Direct Costs should include drugs or laboratory tests that are not clinically indicated (i.e., are not eligible for third-party reimbursement as a part of routine clinical care). Applicants should identify the potential source(s) for all drugs or devices involved in the protocols that are not commercially available. If donations (e.g., from a pharmaceutical company) are anticipated, applicants should provide documents that indicate the willingness of the source to contribute to the study and should also describe contingency plans and anticipated extra costs should the arrangements not develop as expected. Per-patient costs for years 2-5 may be escalated at a rate of 3% per year. Funding may not be requested for the purchase of expensive equipment. The funding level for a Clinical Center will be based on the protocols actually carried out by the COPD CRN (not necessarily those proposed) and may be more or less than the budget requested in the application. Clinical Centers of the COPD CRN are likely to include among their research staffs relatively inexperienced clinical investigators. CRNs can promote progression of these individuals to established investigators by providing experiences that develop clinical research skills and involve interaction with leading clinical investigators, mentoring in clinical investigation, and participation in multi- institutional research experiences. To ensure the full potential of the COPD CRN to foster the clinical research careers of new investigators, the NHLBI will allow applicants for Clinical Centers of the COPD CRN to request up to $100,000 in Direct Costs per year and associated Facilities and Administrative Costs for a Clinical Research Skills Development Core. The objective of the Core is to support activities that will assist new clinical investigators in progressing to more senior status by enhancing their research skills. A Clinical Research Skills Development Core is not required, and its absence will not disadvantage an applicant. If proposed, the quality of the Core will be evaluated as a separate part of the initial peer review process, and the priority score of the Core will have no effect on the overall score of the application. Up to four pages may be used to describe the proposed Clinical Research Skills Development Core. This text will not be counted toward the 25-page limit for the total Research Plan specified by the Form 398 instructions. Applicants should read the specific requirements and other instructions for applying at http://www.nhlbi.nih.gov/funding/policies/ntwk_skill.htm. Data and Coordinating Center (DCC). DCC applicants should document experience and expertise in the many aspects of coordinating multi-center clinical trials, including development of data forms, protocols, and manuals of operations, staff training, data collection and management, quality assurance, data analysis, distributed data entry, electronic communications, and administrative management and coordination. Experience in coordinating studies of lung disease and the availability to the DCC of expertise in pulmonology are desirable. DCC applications should discuss the familiarity and experience of the Principal Investigator and other Key Personnel with clinical trial design and implementation, including issues of IRB approvals, eligibility criteria, baseline and outcome measures, methods of randomization, sample size and power calculations, data collection, entry, and transmission, monitoring the accuracy of data collection, quality control, labeling and handling of specimens and drugs, approaches for statistical analysis, and procedures required to ensure that all protocols are performed in a manner consistent with United States Food and Drug Administration guidelines. The DCC application should also describe plans for communications and interactions with the NHLBI, Clinical Centers, the Protocol Review Committee, and the DSMB. Applicants for the DCC should prepare categorical budgets for five 12- month periods (not to exceed $800,000 Direct Costs in each year) that would support the coordinating center responsibilities outlined herein and in other sections of this RFA. The budget justification for each year must include a table that apportions the total Direct Cost request among the following categories: 1) core costs, 2) costs of protocol initiation (per protocol), and 3) costs of protocol support (per protocol). Core costs should include support for essential personnel and facilities and the costs for meetings in Bethesda, Maryland of the Protocol Review Committee (10 members, 2 meetings per year) and the DSMB (8 members, 3 meetings per year). Costs of protocol initiation should include the costs of expanding the manual of procedures and of developing questionnaires, forms, and database structures. Protocol support costs should include the costs of pharmaceutical handling, data entry and analysis, quality control, and manuscript preparation. The total first year budget request should provide for the organization of all administrative aspects of the COPD CRN and for the development and initiation of two protocols. Budget requests for years 2-5 should assume that one additional protocol will be initiated and that 3-4 protocols will be active (i.e., recruiting subjects and collecting data). The funds released for DCC operations in each year will be based in part on the number of protocols actually carried out by the COPD CRN and may be more or less than the budget requested in the application. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. SENDING AN APPLICATION TO THE NIH: Submit the original application with both required signatures on the Face Page, the Checklist, and three photocopies made after both individuals have signed the Face Page so that their signatures are present on the copies, 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 five collated sets of any Appendix material must be sent to Dr. Anne P. Clark at the address listed under WHERE TO SEND INQUIRIES, above. APPLICATION PROCESSING: Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. The 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 your application has been received. If you have not received such a letter within three weeks after submitting the application, contact Dr. Anne Clark as the address listed under WHERE TO SEND INQUIRIES, above. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and for 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: o Receive a written critique 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 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 discuss the following aspects of your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment o Recruitment experience and capabilities The scientific review group will address and consider each of these criteria in assigning your application"s overall score, weighting them as appropriate for each application. Your 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, you 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 your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? 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? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the Principal Investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your 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) RECRUITMENT EXPERIENCE AND CAPABILITIES: What is the likelihood, based on experience and patient base, that you will be successful in recruiting an adequate number of research subjects with the desired clinical characteristics and with an acceptable level of participation by women and individuals from racial and ethnic minority populations. (Clinical Centers only) ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: o PROTECTIONS: 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 INCLUSION: 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 included in the section on Federal Citations, below) (Clinical Centers only) o DATA SHARING: The adequacy of the proposed plans to share data and disseminate study results. o 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: October 16, 2002 Application Receipt Date: November 13, 2002 Peer Review Date: February/March 2003 Council Review: May 2003 Earliest Anticipated Start Date: July 1, 2003 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 MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (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 AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html), a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm The amended policy incorporates: the use of an NIH definition of clinical research, updated racial and ethnic categories in compliance with the new OMB standards, clarification of language governing NIH- defined Phase III clinical trials consistent with the new PHS Form 398, and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable, and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: Because COPD is primarily a disease of middle-aged and older adults, it is expected that the studies supported through this RFA will not involve children as research subjects. Nonetheless, all investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research (available at http://grants.nih.gov/grants/funding/children/children.htm) and must explicitly address this issue in Section 8.e. Human Subjects of their application under a heading entitled "Inclusion of Children". 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. 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. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.838, and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. 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 described at http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 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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