IDIOPATHIC PULMONARY FIBROSIS CLINICAL RESEARCH NETWORK RELEASE DATE: March 17, 2004 RFA Number: RFA-HL-04-021 EXPIRATION DATE: June 22, 2004 Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov/) COMPONENT OF PARTICIPATING ORGANIZATION: National Heart, Lung, and Blood Institute (NHLBI) (http://www.nhlbi.nih.gov/) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.838 LETTER OF INTENT RECEIPT DATE: May 22, 2004 APPLICATION RECEIPT DATE: June 21, 2004 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism(s) of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Supplementary Instructions o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The purpose of this initiative is to: 1) establish a Clinical Research Network (CRN) of 6 to 7 clinical centers to design and perform multiple therapeutic trials for treatment of patients with newly diagnosed idiopathic pulmonary fibrosis usual interstitial pneumonitis variety (termed IPF), and (2) establish a Data Coordinating Center for the network. This RFA is a one time solicitation to support these clinical centers and Data Coordinating Center for 5 years. This CRN will create the infrastructure for conducting multiple, collaborative therapeutic trials with relative speed and efficiency. These trials may evaluate existing or new medications, combinations of medications, and defined management strategies. RESEARCH OBJECTIVES Background IPF has a prevalence of approximately 100,000 persons, and an incidence of about 30 - 50,000 new cases per year in the United States. IPF has an especially severe course with a 5 year mortality of about 50% and no predictably effective treatment. Lung transplantation, often single lung, is an option for only a few patients, and the complications from an allograft are significant. Management of established IPF disease has relied on giving corticosteroids in conjunction with immunosuppressive drugs, such as cyclophosphamide, plus use of other supportive measures, but these do not seem to halt the disease process. More effective management strategies are needed. Recent basic research in animal models of lung fibrosis and on affected human lung tissue has found an oversecretion of tissue growth factor beta (TGF?) produced by myofibroblasts in fibrotic foci which contributes to an excessive fibrotic response. This basic research was translated quickly into patient treatment using interferon gamma (INF?) as an agent to inhibit TGF? and suppress and minimize fibrotic changes. Even though as important derangement occurs in IPF lung tissue driven by TGF?, a selective strike at inhibiting this molecule with INF? has not produced a significant cure. Recently, NHLBI has funded research to search for novel molecular targets involved in the IPF disease process, so other potential new therapeutic agents could be in the pipeline. However, there is a need now to conduct treatment trials with combinations of presently available drugs or novel therapies in an attempt to halt this relentless illness in patients with IPF. Specific Objectives for an IPF-CRN Given the complexity of the immunopathologic process in IPF, a multi-pronged attack with several medications and novel therapeutic approaches is required. This is an empirical clinical strategy now to treat IPF with a combination of agents having low toxicity and cost that might retard progression of this illness. These approaches need to be evaluated carefully with rigorously randomized, multi-drug therapeutic trials for stabilizing disease which can only be achieved through a collaborative effort such as an IPF-CRN that can enroll 250 to 350 patients/year. Approach This initiative will establish a clinical network consisting of 6 or 7 clinical centers that will enroll 40-50 patients per center per year with newly diagnosed IPF for multiple trials using common protocols that will evaluate treatment and follow up. A data coordinating center will be created, also. To recruit an adequate number of patients, a center could subcontract with one or more clinical facilities to obtain suitable IPF patients to include in the trial. Clinical trials in this network need to be completed in a reasonably short period of time. Each clinical center must have access to a relatively large number of research subjects, personnel experienced in clinical research, and have an appropriate laboratory infrastructure. An efficient framework for such trials is the multi-center, multi-study research network model currently in use in several NHLBI clinical treatment networks. For patients who require a bronchoscopy and/or open lung biopsy for diagnosis, living lung tissue, blood and/or other biological products, such as bronchoalveolar lavage cells, will be stored for future ancillary studies that investigate cellular genomic, proteomic, and other immunopathogenic changes. The IPF CRN will include an independent Protocol Review Committee, and a Data and Safety Monitoring Board that will be advisory to the NHLBI. A Steering Committee, composed of the Principal Investigator from each Clinical Center and the Data Coordinating Center, and the NHLBI Project Scientist, will select the specific trials to be performed, establish standards for subject selection and characterization, develop detailed protocols for the trials, and analyze and publish the results. Through the collaborative effort of the IPF-CRN, approaches with multi-drug treatment, including combination therapy, and other treatment modalities can be carefully evaluated. Examples of possible treatment trials, but not limited to these, may utilize several drugs with anti-inflammatory and anti-fibrotic actions that are currently available; most have minimal toxicity and have been used for other illnesses. Possible drugs to be considered include: corticosteroids, colchicine, pirfenidone, Lovastatin, anti-leukotriene inhibition and interferon gamma. Use of a drug for dissolution of clotting (fibrinolysis) might be considered. Later, novel agents in the pipeline from ongoing human lung research may be found and become appropriate to include. The Clinical Centers of the IPF CRN will collectively perform multiple 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 IPF 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 clinical outcome in a population of patients with newly diagnosed IPF. Project Organization The IPF CRN will consist of the following components: the NHLBI program office, 6 or 7 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 IPF CRN are described below. NHLBI. The NHLBI will be responsible for organizing and providing support for the IPF CRN and will be involved substantially with the awardees as a partner , consistent with the Cooperative Agreement funding 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 will 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 Chair 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 IPF 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 IPF CRN committees and boards. The DCC will manage and distribute protocol funds to participating Clinical Centers as a fee for service arrangement after a protocol has been approved and the NHLBI has released the funds for distribution. 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 Chair appointed by the NHLBI. The Chair 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, and conduct the Steering Committee meetings. The Steering Committee will develop and ensure compliance with IPF 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 IPF 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 Chair and scientists with expertise in basic and clinical research, clinical trial design, biostatistics, and outcome measures. Clinical scientists knowledgeable about IPF but who are not participating at a designated Clinical Center could be invited to help develop and assess treatment protocols. 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 IPF 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 April 1, 2005. This RFA uses just-in-time concepts. Uses nonmodular budget. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part2.htm FUNDS AVAILABLE The NHLBI intends to commit approximately $3 million (total costs) in FY 2005, and approximately $31 million (Total Costs) over a 5-year period to the support of the IPF CRN. Total Costs include Direct Costs and Facility & Administrative Costs, also called indirect costs or overhead. It is anticipated that 6 to 7 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 for a Clinical Center applicant may not exceed $125,000 Direct Costs dollars associated with the core cost activities with future year escalations of 3%. If applying for a Clinical Research Skills Development Core, a clinical center can add $100,000 direct costs (but without future year escalations). The proposed budget of a Data and Coordinating Center applicant may not exceed $850,000 Direct Costs with future year escalations of 3%. In addition, the DCC should request not more than $ 4,000,000 per year in years 2 through 5 in the patient care category for the distribution of approved protocols. The final amount will be determined by NHLBI. 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 IPF CRN and may be more or less than the requested budget. Although the financial plans of the NHLBI provide support for the IPF 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. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Foreign institutions are not eligible to apply. 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 IPF 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 4 times in the first year and 3 times per year in subsequent years 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 each 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 IPF, o Participate in studies of the cost effectiveness of therapeutic interventions should the NHLBI choose to implement such research within the IPF 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 with bi- monthly telephone conference calls, and perhaps 3 meetings in the metropolitan Washington area per year. 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 data sets 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. Study investigators are encouraged to publish and to release publicly and disseminate results and other products of the study, in accordance with study protocols and governance. Within three years of the end of the period of NHLBI support for the project, data not previously released and other study materials or products not previously distributed, are to be made available to individuals who are not study investigators, provided such release is consistent with the study protocol and governance and with paragraph 6. In addition, study investigators must establish a plan for making data sets and materials available to the scientific community and to the NHLBI immediately upon completion of the three year period following the end of the period of NHLBI support. 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: Herbert Y. Reynolds M.D. Division of Lung Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 10112 Bethesda, MD 20892-7952 Telephone: (301) 435-0218 FAX: (301) 480-3557 Email: Reynoldh@nhlbi.nih.gov o Direct your questions about peer review issues to: Chief, Review Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute National Institutes of Health 6701 Rockledge Drive, Room 7214 MSC7924 Bethesda, MD 20892-7924 Bethesda, MD 20817 (for express / courier service) Telephone: (301) 435-0270 FAX: (301) 480-0730 o Direct your questions about financial or grants management matters to: Mr. Robert A. Pike Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7154 Bethesda, MD 20892 Telephone: (301) 435-0182 FAX: (301) 480-3310 Email: piker@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). Applications must have a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. SUPPLEMENTARY INSTRUCTIONS: Clinical Centers. Applications for Clinical Centers should describe the expertise of study personnel with IPF, their clinical research experience in pulmonary disease, the research environment of the applicant institution, their access to the necessary patient populations, and the availability of resources needed to conduct clinical trials. Details should be given for developing any collaborative arrangements to recruit the requiste number of study IPF patients. An application must include a Research Plan describing one multi-drug clinical protocol and one other therapeutic trial that could be used as models for the development of CRN-wide study protocols. Clinical Centers selected to participate in the IPF CRN will be asked to present their proposed protocols to the Steering Committee for consideration, but the IPF 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 newly diagnosed IPF 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 if available, the two proposed protocols, plans for data analysis and interpretation, and methodological details. The background information and any 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 new IPF 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 $125,000 Direct Costs to support core research activities, and up $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 four trips the first year to develop treatment protocols and, thereafter, three 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. A separate budget table to identify the per-patient costs and total costs should be included with each protocol proposal. These budgets should be based on the two specific protocols proposed in the application and reflect anticipated costs for simultaneous implementation in the first year. Applicants should indicate for each protocol how many patients are available in the applicant’s center and how many will be required from the network. The center’s estimate of eligible patients should be based on the actual number of patients with that particular clinical problem treated in the year 2003. Protocol Direct Costs should include drugs or laboratory tests that are not clinically indicated, or are not eligible for third-party reimbursement as a part of routine clinical care. Applicants should identify the potential source(s) for all drugs involved in the protocols. If donations 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. Funding may not be requested for the purchase of expensive equipment. Distribution of protocol funds will be based on the approved protocols actually carried out by the IPF CRN and may be more or less than the budget identified in the application. Protocol funds are not to be included in the budget requests for the clinical sites. They are to be identified as proposed costs in a separate table. Therefore, the total costs on the application face page should reflect the core costs. Protocol funds will be distributed by the DCC once the per patient costs have been established for approved protocols. CLINICAL RESEARCH SKILLS DEVELOPMENT CORE Clinical Centers of the IPF CRN are likely to include among their research staffs relatively junior 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 IPF CRN to foster the clinical research careers of new investigators, the NHLBI will allow applicants for Clinical Centers of the IPF CRN to request up to $100,000 in Direct Costs per year (but without future year escalations) 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. Developmental opportunities that provide experience with new technologies and skills are encouraged for inclusion in the Core. Innovative strategies should be proposed for cross-disciplinary career development to achieve the goal of exposing new clinical investigators to additional research techniques and opportunities. Examples include a program of seminars focusing on scientific topics that include an integration of basic and clinical studies or an "exchange" program wherein clinical investigators spend time in basic science laboratories. In addition to developing the research skills of new clinical investigators, the Cores must ensure that the participating new clinical investigators receive the mentoring they need to foster their research careers. The Clinical Research Skills Development Core is intended for staff investigators with limited clinical research experience, including fellows and junior faculty members. Investigators who have had a previous K series award are not eligible to participate as new investigators under this program. Individuals with an active K grant can participate until the end of the award period for the K grant, but may not receive salary on the Skills Development Core. The Core should also address other skills necessary for a successful research career, such as grant writing, ethical conduct of research, and clinical trial design. If a Clinical Research Skills Development Core is proposed, it must be directed by an investigator with strong educational and mentoring credentials who will devote a minimum of 5 percent effort as its Leader. To facilitate mentoring and multidisciplinary developmental activities, active involvement by the principal investigator and other senior investigators within the program is strongly encouraged. An application for a Clinical Research Skills Development Core will be evaluated in terms of its potential effectiveness in developing the skills and research capabilities of new clinical investigators as reflected in the following required elements of the application: o A summary of the types of skills that would be developed and a description of proposed project-specific activities; o A detailed discussion of how mentoring and the professional development of the new clinical investigators will be achieved, including their progression to more independent status; o The credentials and track records of the Clinical Research Skills Development Core Leader, the Principal Investigator, and other participating senior staff in developing new investigators; o A plan for coordinating the activities of participating senior investigators; o A plan for monitoring the progress of the new clinical investigators; o A description of existing opportunities within the applicant's institution for supporting investigator development and steps taken to avoid overlap with or duplication of these efforts; and o A detailed development plan for each proposed new investigator (or a representative plan and proposals for tailoring it to needs of multiple new investigators) including required course work and scientific enrichment activities such as special lectures, visiting scientist symposia, seminars, and workshops. Costs allowable for inclusion within the $100,000 direct costs per year limit for the Clinical Research Skills Development Core include salary support for the Core Leader and other participating senior investigators and staff, travel costs for new investigators, supplies and equipment to be used in support of developmental activities, and costs for courses, seminars, workshops, and other activities directly related to the development plan. All costs requested in this Core must be justified with respect to developmental activities and may not be used to supplement the costs of research proposed in the rest of the project. Since the Core is intended to serve new clinical investigators, salary support for the new investigators is neither needed nor allowable as a Core cost. All new clinical investigators should be eligible to participate in Core-sponsored activities so long as they have not attained independent status. However, attaining independent status should be an objective of the Core activities so participating new investigators should be encouraged to apply for either a Career Development Award, a patient-oriented regular research grant, or any other source of independent research or career development support. Although the participating new investigators will be expected to devote essentially full-time effort to research during this period, they may devote an appropriate percentage of their time to maintaining clinical skills. However, 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 including a separate budget for this 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 $850,000 Direct Costs in the first year but with future year escalations of 3% that would support the coordinating center responsibilities outlined herein and in other sections of this RFA. In addition, the DCC should request not more than $ 4,000,000 per year in years 2 through 5 in the patient care category for the distribution of approved protocols. The final amount will be determined by NHLBI. These funds will be managed by the DCC and distributed to each participating Clinical Center as a fee for service arrangement after a protocol has been approved and the NHLBI has released the funds for distribution. A half-time position should be budgeted to cover costs associated with the management and distribution of approved protocol dollars to each IPF CRN for all five years. 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 DCC budget must include support for the chair over the 5 years (20% effort needed and travel expenses), and also for 2 sight visits made to all the clinical centers during the 5 year interval. The total first year budget request should provide for the organization of all administrative aspects of the IPF CRN and for the development and initiation of at least 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 IPF 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 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 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. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA, it is to be prepared as a NEW application. That is, the application for the RFA must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application. 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 Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Receive a written critique o Receive a second level review by the National Heart, Lung, and Blood Advisory Council. REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to 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 the application’s overall score, weighting them as appropriate for each application. The application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. SIGNIFICANCE: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? INNOVATION: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? INVESTIGATOR: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? ENVIRONMENT: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? RECRUITMENT EXPERIENCE AND CAPABILITIES: What is the likelihood, based on experience and patient base, that the project 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) REVIEW CRITERIA FOR CLINICAL RESEARCH SKILLS DEVELOPMENT CORE The Clinical Research Skills Development Core will receive a priority score based on the review criteria below, but the priority score will not enter into the overall priority score. Review Criteria for Clinical Research Skills Development Core The Clinical Research Skills Development Core will be evaluated for its effectiveness in developing the skills and clinical research capabilities of new investigators. This will include an evaluation of: o Credentials and track record of the Principal Investigator, Clinical Research Skills Development Core Project Leader, and other participating senior investigators. o Methods by which new investigators are to be recruited and selected including plans to recruit women and minority individuals. o Plans for developing the skills of new investigators; the types of skill and technologic development proposed. o Means by which the new investigators' professional development will be achieved. ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the application will also be reviewed with respect to the following: INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below). CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. ADDITIONAL REVIEW CONSIDERATIONS Sharing Research Data Applicants requesting more than $500,000 in direct costs in any year of the proposed research must include a data sharing plan in their application. The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or priority score. BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. REVIEW CRITERIA FOR DATA COORDINATING CENTER For evaluation purposes of DCC Applications, the following technical criteria will be considered by the Review Committee in the order of relative importance: 1. Personnel: Documented training, expertise, experience, and availability of the Principal Investigator for planning and directing the Data Coordinating Center. Expertise of personnel in preparation of data forms, electronic transmission of data, data management, and biostatistics. Experience of personnel in coordination of multi- center clinical research projects. Documented training, experience, competence, and availability of administrative staff. Documented experience and availability of proposed personnel for website development and maintenance. 2. Methods and Procedures: Merit of the proposed plans for Consortium coordination and for data collection, processing, entry, transmission, storage, statistical analysis, and reporting. Merit of proposed plans for training of CC personnel in data collection and handling. Merit of quality control and quality assurance plans and proposed monitoring of CC performance. Adequacy of plans for protecting the privacy of research subjects. 3. Facilities and Organizations: Availability and adequacy of the facilities and resources necessary to carry out the proposed functions of the DCC. Adequacy of the organizational and administrative structure, including the means of assuring quality control of data, data entry, confidentiality of data, and plans for day-to-day coordination. Institutional commitment to the DCC RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: May 22, 2004 Application Receipt Date: June 21, 2004 Peer Review Date: October, 2004 Council Review: February, 2005 Earliest Anticipated Start Date: April 1, 2005 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds oProgrammatic priorities. REQUIRED FEDERAL CITATIONS DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required for all types of clinical trials, including physiologic, toxicity, and dose-finding studies (phase I); efficacy studies (phase II); efficacy, effectiveness and comparative trials (phase III). The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risk to the participants. (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). SHARING RESEARCH DATA: Starting with the October 1, 2003 receipt date, investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible. http://grants.nih.gov/grants/policy/data_sharing Investigators should seek guidance from their institutions, on issues related to institutional policies, local IRB rules, as well as local, state and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score. 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 IPF 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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