ASTHMA CLINICAL RESEARCH NETWORK RELEASE DATE: July 15, 2002 RFA: HL-02-029 National Heart, Lung, and Blood Institute (NHLBI) (http://www.nhlbi.nih.gov) LETTER OF INTENT RECEIPT DATE: September 24, 2002 APPLICATION RECEIPT DATE: October 24, 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 National Heart, Lung, and Blood Institute invites applications to compete for participation in a cooperative research network to evaluate current and novel therapies and management strategies for adult asthma. One anticipated outcome will be rapid dissemination of the findings to the medical community. The objective of this Request for Applications (RFA) is to establish (1) a network of 6 to 7 clinical centers to design and perform multiple therapeutic trials for treatment of adult asthma, and (2) a Data Coordinating Center for the network. This is a one time solicitation to support clinical research centers and the Data Coordinating Center for 5 years. RESEARCH OBJECTIVES Background Asthma is a chronic inflammatory disease of the airways. Over the past 15 years, the number of Americans afflicted with asthma has more than doubled to over 14 million. Symptoms not severe enough to require a visit to the emergency room or to a physician can still substantially impair quality of life. Asthma results in many lost nights of sleep, disruption of family and caregiver routines, and restricted activities for over one third of people with the disease. It imposes financial burdens on patients and their families, including lost work days and income. Asthma is the leading work-related lung disease, accounting for at least 21 percent of all adult onset asthma. Asthma has great impact in the U.S. economy, currently costing $18 to $20 billion yearly, with the majority of the expense attributed to emergency room visits and hospitalization. There is an urgent need to rapidly evaluate new and existing therapeutic approaches for patients with asthma, and to disseminate the findings to health care professionals, patients and the public. In order to address this major public health problem, the NHLBI established an Asthma Clinical Research Network (ACRN) in 1993 to conduct short-term (e.g. 12 to 18 months) trials to evaluate therapeutic approaches to asthma. The current ACRN consists of six clinical centers and one Data Coordinating Center. To date, the ACRN has completed six clinical trials. There are currently three trials underway and two more are expected. Since its establishment the ACRN has published 24 papers and 12 abstracts. Some of the completed and ongoing trials include: The Addition of Regular-Use to Intermittent Rescue Beta-Agonist for Patients with Mild Asthma, Colchicine In Moderate Asthma, Salmeterol Off Corticosteroids, Salmeterol plus or minus Inhaled Corticosteroids, Dose of Inhaled Corticosteroids with Equisystemic Effects, Measuring Inhaled Corticosteroid Efficacy, Beta Adrenergic Response by Genotype, Improving Asthma Control Trial, and Smoking Modulates Outcomes of Glucocorticoid Therapy in Asthma. Additional information on these trials can be found at the ACRN website http://www.acrn.org The results from the ACRN studies have had a major impact on the treatment and management of asthma. For example, in the mid 1990s several small studies demonstrated that regularly scheduled use of inhaled beta agonists compared to as needed use was associated with a deleterious effect on asthma control. In an attempt to resolve the controversy surrounding the most commonly prescribed asthma medication, the ACRN conducted a clinical trial on the comparison of regularly scheduled with as needed use of the beta agonist albuterol in mild asthma. The results showed that in patients with mild asthma, the regularly scheduled use of inhaled albuterol was not associated with either a beneficial or deleterious effect. An NHLBI-supported asthma network is the ideal environment to address the above and many other timely clinical topics. As the list of possible future studies changes over time, the opportunity to collaborate in a network provides flexibility to rapidly respond to new and emerging concepts. There are several reasons why an asthma clinical research network will accelerate clinical research to meet this need, some of these are: (1) to accumulate a large number of comparable patients that otherwise would be difficult for one center to recruit, (2) to standardize treatment protocols, which may result in reduction of the number of patients needed at each clinical center, (3) to combine the necessary clinical expertise and administrative resources to facilitate multiple trials in a timely and efficient manner, and (4) to promote rapid dissemination of research findings to health care professionals and the public. Organization of the Asthma Clinical Research Network The Asthma Clinical Research Network will be a cooperative network of 6 to 7 adult asthma Clinical Centers, one Data Coordinating Center, and the Division of Lung Diseases, NHLBI. Clinical Centers will be responsible for proposing and prioritizing protocols, participating in protocol development, conducting the research, and disseminating research findings. All individual Clinical Centers will be required to participate in a cooperative and interactive manner with one another and with the Data Coordinating Center in all aspects of the network. The Data Coordinating Center will support protocol development and provide sample size calculations, statistical advice, common questionnaires, data analysis, coordinating the activities of the Steering Committee, Protocol Review Committee, Data and Safety Monitoring Board, and overall study coordination and quality assurance. A Steering Committee composed of the principal investigators of the Clinical Centers and the Data Coordinating Center and the NHLBI Project officer will be the main governing body of the ACRN. Each Clinical Center, the Data Coordinating Center and the NHLBI will have one vote. The Steering Committee may meet as often as three to six times in the first 12 months of the project period and two to four times per year thereafter. All major scientific decisions will be determined by majority vote of the Steering Committee. The Steering Committee will have primary responsibility for the general organization of the network, finalizing common clinical protocols, facilitating the conduct and monitoring of the studies, and reporting study results. Topics for the protocols will be proposed and prioritized by the Steering Committee. For each protocol, one Clinical Center will take the lead responsibility for drafting the protocol, although the entire Steering Committee will provide input and will be responsible for assuring development of a common protocol to be implemented by the Clinical Centers. Subcommittees of the Steering Committee will be established as necessary, for example, it is envisioned that a Publications and Presentations Committee will prioritize, facilitate and supervise preparation and review of manuscripts prior to submission for publication. Data collections will be monitored in a manner consistent with Guidelines for Data Quality Assurance in Clinical trials and Observational Studies http://www.nhlbi.nih.gov/funding/policies/dataqual.htm. An independent Protocol Review Committee, established by NHLBI with input from the Steering Committee, will provide peer review for each protocol. A Data and Safety Monitoring Board (DSMB), similarly established, will monitor patient safety and review performance of each study approximately semi-annually. As a part of its monitoring responsibility, the DSMB will submit recommendations to NHLBI regarding the continuation of each study and prepare a report for principal investigators to provide to their institutional review boards (IRBs.) It is required that each protocol will be conducted in at least four or more of the Clinical Centers. As specific protocols are developed, support will depend on the availability of funds and will be provided on a per patient basis. All the Clinical Centers must be willing to pursue this funding arrangement for each new protocol conducted. Clinical protocols must be approved by the local IRBs and the Protocol Review Committee before initiation. The exact number of protocols supported in the 5-year program will depend on the nature and extent of the investigations proposed by the Steering Committee and the availability of funds. Research Scope The overall goal of this program is to establish a Clinical Research Network to identify the best possible asthma therapies with original ideas and improve overall asthma control. The emphasis will be on clinical trials 12-18 months in duration that help identify optimal therapy for patients with different asthma phenotypes, genotypes, ethnic background and asthma severity. Therapeutic trials may involve investigational drugs, drugs already approved but not currently used, and drugs currently used in treatment of asthma. All projects must be completed within the 5-year duration of this research program. Examples are provided to indicate the range of research areas appropriate for this RFA. They include, but are not limited to the following: o Evaluation of novel treatments such as anti-cytokine, anti-IgE, or other innovative approaches of specific immunotherapy in asthma. o Evaluation of the role of macrolides altering the progression of asthma. o Development of management strategies and characterization of particular asthma phenotypes (e.g. steroid-resistant severe asthma, sudden onset and severe exacerbations in otherwise mild asthma, cough variant asthma, adult onset asthma, non-atopic asthma, nocturnal asthma, obesity and asthma). o Exploration of the implications of genotype-phenotype correlations in determining a patient"s response to a particular pharmacologic agent. o Evaluation of markers of inflammation appropriate for clinical practice to monitor patient"s response to treatment. o Evaluation of the effectiveness of various medications (e.g. theophylline, anti-histamines) in combination with other asthma drugs for controlling, preventing and altering the progression of asthma. o Identification of optimal management strategies in different ethnic and cultural settings, as well as in elderly patients. THESE ARE EXAMPLES ONLY. APPLICANTS SHOULD NOT FEEL LIMITED TO THE SUBJECTS MENTIONED ABOVE AND ARE ENCOURAGED TO SUBMIT OTHER TOPICS PERTINENT TO THE OBJECTIVES OF THE RFA. It is not the intent of this network to provide support for only one or two protocols that run for the entire 5 years. Multiple trials will need to be conducted, possibly 2 to 4 a year. It is anticipated that in the initial year, trials will be selected from the studies proposed by the successful applicants. However, a decision to fund a particular Clinical Center will not commit the ACRN to develop that group"s clinical protocol. MECHANISM OF SUPPORT This RFA will use the cooperative agreement (U10) award mechanism. Under the cooperative agreement mechanism, 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." The anticipated award date is September 30, 2003. This RFA uses just-in-time concepts. It also uses the modular as well as the non-modular budgeting formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular format. Otherwise follow the instructions for non-modular research grant applications. The NIH (U10) is a 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." FUNDS AVAILABLE A maximum of up to seven awards for Clinical Centers and one award for a Data Coordinating Center will be made under this RFA. A maximum of about $43.4 million (total costs) over a five year period will be awarded for the Clinical Centers and the Data Coordinating Center. An applicant for a Clinical Center may request a project period of up to five years and a budget for total costs of up to $823,000 per year. An applicant for a Data Coordinating Center may request a project period of up to five years and a budget for total costs of up to $1,332,000 per year. Because the nature and scope of the research proposed in response to this RFA may vary, it is anticipated that the size of an award will also vary in all years. Future year costs will be distributed based on the final approved protocols. Although the financial plans of the NHLBI provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of applications of appropriate scientific and technical merit. Designated funding levels are subject to change at any time prior to award, due to unforeseen budgetary, administrative, or scientific developments. It is not known if competing renewal applications will be accepted or if this RFA will be re-issued. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. Among the disciplines and expertise that may be appropriate for this program are pulmonary medicine, allergy and immunology, pharmacology, pharmacogenetics, molecular and cellular biology, biostatistics, therapeutic development, and clinical trials management. SPECIAL REQUIREMENTS Studies contemplated in this program require a significant number of patients be enrolled in a uniform manner before individual research studies are initiated. Thus, this program is designed to be a collaborative effort. Applicants will be responsible for proposing research studies and common guidelines that will be shared across the program for patient diagnosis, enrollment, testing, sampling, and data collection. All individual investigators/centers will be required to participate in a collaborative and interactive manner with one another in all aspects of the program. This mechanism should include common definitions, common procedures for patient selection and enrollment, standardization of common procedures, tests and reporting forms. 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 NHLBI purpose is to support and/or stimulate the recipient"s activity by involvement in and otherwise facilitating the activity in a "partner" role, but 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 toward achieving 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 their protocols, 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 another NHLBI scientist may serve on other study committees, when appropriate. The NHLBI Project Scientist (and the other cited 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 potential changes in the 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 and the NHLBI Project Scientist. 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, MD. A NHLBI staff person (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 protocol. 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 (i.e., cooperative agreement awardees). 6. Support or other involvement of industry or any other third party in the study - e.g., participation by the third party, involvement of project resources or citing the name of the project or the NHLBI support, or special access to project 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 publicly to release and disseminate results, data and other products of the study, concordant with the study protocol and governance and the approved plan for making data and materials available to the scientific community and 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, quality control, or other major breach of the protocol, (c) substantive changes in the agreed upon protocol with which NHLBI cannot concur, (d) reaching a major study endpoint substantially before schedule with persuasive statistical significance, or (e) human subject ethical issues that may dictate a premature termination. 9. Upon completion of the project, the Data Coordinating Center is expected to put all study 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: Hector G. Ortega, M.D., Sc.D. Division of Lung Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 1008, MSC795 Bethesda, MD 20892 Telephone: (301) 435-0202 FAX:(301) 480-3557 Email: ortegah@nhlbi.nih.gov o Direct your questions about peer review issues to: Anne P. Clark, Ph.D. Chief Review Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7178, MSC 7924 Bethesda, MD 20892 Telephone: (301) 435-0270 FAX: (301) 480-0730 Email: clarka@nhlbi.nih.gov o Direct your questions about financial or grants management matters to: Ray Zimmerman Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7156 Bethesda, MD 20892 Telephone: (301) 435-0171 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 IC 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 in the inquiries section. 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 Grants Info, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. SUPPLEMENTAL INSTRUCTIONS: Clinical Center Applicants: o Qualifications and experience. Participation in this Network will be a complex and time-consuming undertaking. Applicants for Clinical Centers must have the necessary experience and expertise to conduct clinical studies in patients with asthma. Prospective Clinical Centers must have an established research program in asthma, and demonstrated access to a sufficient number of patients to accomplish their portion of the proposed protocols. An appropriate time commitment is expected from the investigator leadership (Principal Investigator and any Co-investigators) at each Clinical Center. o Study population. The application should include a description of the pool of potential study participants, including the age range, ethnic/racial and gender distribution (approximately 50 percent women and 25 percent minorities), and recruitment sources. It is not anticipated that all eligible patients will be enrolled in research protocols at any one time, and it is possible that an individual patient may be enrolled in more than one study. Patient access may be accomplished by establishing links with other groups in addition to the applicant"s institution. If this is planned, there must be a well-described and documented plan to link the individual Clinical Centers with other community health care providers, such as pulmonary/allergy practices, general practitioners, pediatricians, and health maintenance organizations, as appropriate, to ensure adequate numbers of patients for clinical studies. o Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. In such a case, a letter of agreement from either the GCRC Program Director or Principal Investigator should be included with the application. o Willingness to participate in the Asthma Clinical Research Network. Applicants should state their general support of collaborative research, any special expertise they can offer and willingness to interact with other Clinical Centers, the NHLBI, and the Data Coordinating Center through this Network concept. Applicants should discuss their willingness, and that of the institutions involved, to pursue a per-patient basis (capitation) of operational costs for each protocol. Clinical Center applicants must be able to interact with the Data Coordinating Center to transmit and edit data and should discuss their capability to participate in a distributed data entry system. o Research Plan: Each Clinical Center applicant should propose a research plan that includes two protocols. These two protocols must be short-term (12-18 months) clinical trials on asthma patients and involve sufficient subjects to require the use of a network with multicenter participation. The research plan should follow the instructions in the PHS 398 application form (revised 5/2001, http://grants.nih.gov/grants/forms.htm), and should include: a one page overview of the proposed two investigations that presents the key research objective of each investigation and a diagram depicting the initiation and duration of the two investigations, a description of each of the two protocols that includes the rationale, research aims, outcome measures, and study design, a description of the patient populations with an estimate of the expected distribution of minority and female patients, ages, and levels of asthma severity, and assurances of the applicant"s access to the patient populations. Applicants are encouraged to explore, within the context of their proposed protocols, new technologies that could lead to improved treatments, monitoring of disease progression, predicting or evaluating response to therapy. It will also be important to include strategies to assure adherence to therapy as part of the protocol. The applicant should indicate for each protocol how many patients are available in the applicant"s center and how many will be required for the entire Network. In the discussion of outcome measures, it will be important to indicate appropriate objective measures of primary and secondary outcomes. The entire Research Plan, including protocols, should not exceed the Form 398 Research Plan instructions of 25 pages. o Clinical Research Skills Development Core: The NHLBI is interested in ensuring that the full potential of clinical research networks and multicenter clinical studies foster the clinical research careers of new investigators. The Clinical Skills Development Core presents a rich environment for young clinical investigators to be exposed to and develop additional research skills. The individual centers can be expected to include among their research staffs clinical personnel who are newly trained and relatively inexperienced in research. To assist the centers in enhancing the developmental environment for their new clinical investigators, the NHLBI will permit applicants to request up to $100,000 in direct costs per year for a Clinical Research Skills Development Core. The objective of the Core is to support activities to assist new clinical investigators in progressing to more senior status by enhancing their research skills. This support is in addition to the infrastructure and protocol costs for the network mechanism. A Clinical Research Skills Development Core is not required, however, and its absence will not disadvantage an applicant. The priority score of the Core will have no effect on the overall score of an application. 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 involve translational research. 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. The Core should also address other skills necessary for a successful research career, such as grant writing, ethical conduct of research, biostatistics, 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: 1. A summary of the types of skills that would be developed and a description of proposed project-specific activities, 2. 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, 3. 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, 4. A plan for coordinating the activities of participating senior investigators, 5. A plan for monitoring the progress of the new clinical investigators, 6. 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 7. A detailed development plan for each proposed new investigator (or a representative plan and proposals for tailoring it to the 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 application. Since the Core is intended to serve new clinical investigators who occupy positions and receive salary support from other sources, salary support for the new investigators is neither needed nor allowable as a Core cost. All new clinical investigators supported by any grant are 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. 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 required application components identified above. Additional information is available at http://www.nhlbi.nih.gov/funding/policies/ntwk_skill.htm. o Budget: Clinical Center applicants should consider the following issues regarding budgets. The underlying concept of the Asthma Clinical Research Network is that a group effort is essential to maintain the infrastructure required to perform multiple clinical trials. Based on this approach, it is estimated that the individual Clinical Centers will require a minimum level of effort to sustain the organizational aspects of the Asthma Clinical Research Network. Therefore, individual Clinical Centers should submit requests for a CORE BUDGET not to exceed $175,000 total costs per year. It is anticipated that this budget will cover a minimum of 25% total 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), and travel costs for approximately six trips each year to attend Steering Committee meetings in Bethesda, MD, and other travel related to Network operations. These costs should include appropriate justification. Total costs for the core budget can be escalated at three percent annually for future years. It should be noted that funds would not be provided for the purchase of expensive equipment. In addition to the core budget, each Clinical Center will be provided funds for implementation of protocols. This support will be provided for each protocol on a per-successfully-enrolled-patient basis. The precise number of protocols conducted over the five years will be determined by the Asthma Clinical Research Network Steering Committee and will depend on a number of factors including availability of funds, length of the protocols, and ease of recruitment. It is anticipated that after the first year, two to four protocols may be active each year. Clinical Centers should request protocol enrollment funds as PATIENT CARE costs not to exceed $648,000 per year. This amount should be placed in the patient care category. Patient care costs can be escalated at three percent annually for future years. Maximum allowable total costs for each clinical center (core costs, costs per patient to conduct the protocols, and facilities a nd administrative costs) will be $823,000 a year. Applicants for the Clinical Centers should present the following information: o For each year, the Clinical Centers should include the core budget costs (not to exceed $175,000 total costs) and patient care costs (not to exceed $648,000 total costs). Estimated protocol implementation costs for Year 1 should be based on the two proposals presented in the applicant"s research plan. A table should be included showing estimated costs per patient for conducting each protocol. o The budget for each clinical protocol in the PATIENT CARE category should be developed on a cost-per-patient-basis and include all direct costs and the associated protocol facilities and administrative costs at a rate not to exceed 28%. Costs of drugs or laboratory tests that are not clinically indicated (i.e., are not eligible for third-party reimbursement as part of routine clinical care) should be part of the per-patient cost of conducting a protocol. Applications should identify the potential source(s) for any drugs or substances that are being considered for clinical protocols that are currently unavailable commercially. If either of the protocols proposed by a Clinical Center applicant includes obtaining blood or tissue samples, the applicant should delineate how such specimens will be handled and analyzed. In the event that a central laboratory is required to analyze specimens, the Clinical Centers will be responsible for obtaining the sample(s) and the cost of obtaining them will be part of the Clinical Center"s per-patient expense. The cost of shipping, analyzing, and storing them, as well as training of personnel and quality control will be the responsibility of the Data Coordinating Center. o Investigators should prepare budgets only for their own Clinical Center to conduct the proposed trial, and not for the entire Asthma Clinical Research Network. The applicant should state the total number of patients required by the entire Network to complete each proposed trial. The yearly budget for the applicant"s Center should include the number of patients available for the proposed protocol at the applicant"s Center. A budget based on the costs per patient for recruiting and maintaining the specified number of subjects at the applicant"s Center should be included for each protocol. Note that ongoing annual budgets for protocols will be based on the protocols approved by the Protocol Review Committee and the Asthma Clinical Research Network Steering Committee. The individual Clinical Centers will be expected to project patient enrollment for a specific protocol during a specified time frame, continuation and level of funding for each Clinical Center will be based on actual recruitment and overall performance. Awards will be subject to administrative review annually. Data Coordinating Center Applicants: o Qualifications and experience. Applicants for a Data Coordinating Center must demonstrate experience in asthma and in coordinating multi-center clinical studies in all phases: protocol and manual of operations development, data collection and management, data safety and confidentiality, quality assurance, data entry, data analysis, electronic communications, administrative management and coordination. A significant commitment is expected from the Principal Investigator of the Data Coordinating Center. o Study design and management. Data Coordinating Center applicants should discuss various aspects of study design that would be important in developing clinical protocols, for example: eligibility criteria, baseline and outcome measures, methods of randomization, important considerations for making sample size and power calculations, methods and frequency of data collection and entry, monitoring accuracy of data collection, quality control procedures including training and certification for multiple protocols, some of which may occur simultaneously, managing labeling and handling of specimens (see below), and plans for statistical analysis. Applicants should also describe their experience with asthma patients and their ability to provide leadership in this field to support the clinical studies envisioned under this RFA. In addition, they should describe their plans for administrative management of the DSMB, the Protocol Review Committee, the Steering Committee, and associated subcommittees. The proposed Data Coordinating Center budgets should stipulate and justify the amount included for managing the DSMB and other Committees. Travel expenses for the clinical center PI to attend the Steering Committee will be included in the budgets prepared by the Clinical Centers. o The Data Coordinating Center should describe how laboratory specimens (e.g., blood or tissue samples) will be handled. Laboratories responsible to the Data Coordinating Center will manage specimens and laboratory studies as required by the Steering Committee. The costs of performing specific laboratory tests that are not clinically indicated (i.e., will not be reimbursed through third-party payers as part of routine clinical care) will be budgeted as a part of the per-patient costs of each Clinical Center. The costs of specimen shipment as well as laboratory data acquisition and management will be a part of the budget of the Data Coordinating Center. Estimated shipping and handling expenses for specimens should be justified and included in the budget of the Data Coordinating Center. For the purposes of planning, the Data Coordinating Center should assume about 2,000 patients over the course of the 5-year study period. o The Data Coordinating Center will be responsible for one or more central labs that will analyze data from clinical testing. It is understood that the specific central lab(s) needed will depend on the protocols ultimately selected. However, for purposes of the application, Data Coordinating Center applicants should describe in detail how they will identify and secure the necessary central lab(s) once specific protocols are approved. The costs of performing specific tests (i.e., tests that are not eligible for third-party reimbursement) will be budgeted as a part of the per-patient costs of each Clinical Center. The format of transfer of data to the Data Coordinating Center should be specified. The expense of transferring the data on the clinical studies to the central lab(s), training technicians to obtain the data in a uniform manner, and instituting quality control measures (e.g., provision for re-reading a proportion of the studies to determine accuracy of interpretation) will be included in the Data Coordinating Center budget. o Budget: Applicants for the Data Coordinating Center should prepare budgets for five 12-month periods that roughly correspond with the standard coordinating center responsibilities outlined elsewhere in this RFA. Data Coordinating Center applicants may request a project period of up to five years and a budget for total costs of up to $1,332,000 per year. Total costs can be escalated at three percent annually for future years. For budget purposes, Data Coordinating Center applicants should assume that in the first year, all administrative aspects of the Asthma Clinical Research Network will be organized and at least one protocol will be developed and started. For subsequent years, applicants may assume that two to four protocols a year will be active, i.e., either in the protocol development, implementation, or analysis and writing phase. Data Coordinating Center applicants should include costs for managing the DSMB, the Protocol Review Committee, and the Steering Committee including the cost of DSMB meetings two times per year in Bethesda, the cost of Protocol Review Committee conference calls and meetings, and the administrative expenses of Steering Committee conference calls and meetings. Travel of Steering Committee members will be budgeted by Clinical Centers. The Data Coordinating Center also should include costs for site visits of each of the Clinical Centers over the five-year study period, assuming seven Clinical Centers throughout the U.S., and a five-member site visit team, for purposes of budget preparation. The award will be subject to administrative review annually. It is expected that all protocols will be performed in a manner consistent with United States Food and Drug Administration guidelines. 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 Appendix material must be sent to Dr. Anne P. Clark at the address listed in the inquiries section. 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. Principle 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 at the address listed under Where to Send Inquiries. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the Institutes and Centers (IC). 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 Division of Extramural Affairs, NHLBI in accordance with the review criteria stated below. The roster of the initial review group will be posted on the NHLBI home page approximately two weeks prior to the review. 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 Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NHLBI. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NHLBI in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed, assigned a priority score, and receive a second level review by the National Heart, Lung, and Blood Advisory Council. Review Criteria for Core Clinical Center Applications o Research plan. Appropriateness of proposed protocol(s), need for the network to accomplish the proposed protocol, relevance and importance of the research questions, preliminary results that justify the proposed end points and sample size, and likelihood that accrual could be accomplished on time. o Qualifications and experience. The expertise, training, and experience of the investigators and staff in asthma clinical trials, evidence of understanding of randomized, multi-center trials, administrative abilities of the Principal Investigator, study nurse and/or data coordinator, and the level of commitment to the program for the effective function of the Asthma Clinical Research Network. o Patient access and study population. The access to at least 200 patients with asthma, plans for the recruitment and retention of subjects, plans to ensure appropriate representation by ethnic group, age, and gender, the description of competing protocols, and the strategy for allocating patients between them. o Willingness and ability to participate in the Network. Applicant institution"s history of collaborative research, depth of commitment, willingness to randomize patients, and ability to work with other Network Centers and NHLBI. o Institutional resources for patient care and follow-up. Adequacy of institutional resources including personnel, space, and special laboratory facilities. Review Criteria for Data Coordinating Center Applications o Research plan. Demonstrates understanding of the scientific, statistical, logistical, and technical issues underlying multi-center studies, including issues relating to assessment of outcomes relating to use of novel treatments of patients with asthma, and demonstrates leadership in study design and statistics, data acquisition and management, data quality control, data analysis, handling and quality control of laboratory specimens, and network coordination. o Qualifications and experience. The expertise, training, and experience of the investigators and staff, including the administrative abilities of the Principal Investigator, co-investigator, and the time they plan to devote to the program for the effective coordination of the Network. o Study management. The administrative, supervisory, and collaborative arrangements for achieving the goals of the program, including willingness to cooperate with the participating Clinical Centers and the NHLBI. This includes the ability to assist Core Clinical Centers with recruitment problems to meet accrual goals. o Willingness and ability to participate in the Network. Applicant institution"s history of collaborative research, depth of commitment, and ability to work with other Network Centers and the NHLBI. o Environment. Facilities, equipment, and organizational structure to effectively coordinate Clinical Research Network activities and assist Clinical Centers in implementing the Clinical Research Network protocols, providing for specialized laboratory testing, and collecting data. This includes but is not limited to development of repositories, conduct of lab tests and studies, and obtaining study drugs or investigational agents or products. In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research. o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: September 24, 2002 Application Receipt Date: October 24, 2002 Peer Review Date: February/March 2003 Council Review: May 29-30, 2003 Earliest Anticipated Start Date: September 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://grants1.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. 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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