Full Text HL-94-009 CARDIOVASCULAR CONSEQUENCES OF SLEEP APNEA NIH GUIDE, Volume 23, Number 7, February 18, 1994 RFA: HL-94-009 P.T. 34 Keywords: Cardiovascular Diseases Sleep Disorders Clinical Medicine, General National Heart, Lung, and Blood Institute Letter of Intent Receipt Date: April 1, 1994 Application Receipt Date: May 23, 1994 PURPOSE The Division of Lung Diseases, Division of Epidemiology and Clinical Applications, and the National Center on Sleep Disorders Research are undertaking the development of a collaborative clinical study of cardiovascular consequences of sleep apnea, to be conducted in well characterized, existing population-based cohorts. Goals include determining the degree to which sleep apnea and milder degrees of sleep-related breathing disorders (SRBD) are independent or contributing risk factors for the development of cardiovascular and cerebrovascular disease, as well as examining possible associations with other cardiovascular risk factors. This request for applications (RFA) is both for clinical centers and the data coordinating center. It is estimated that the study will involve five to six clinical centers, each recruiting approximately 900 to 1,000 participants for in-depth studies of sleep apnea and SRBD from existing epidemiological cohorts; there will be a single Data Coordinating Center. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This RFA, Cardiovascular Consequences of Sleep Apnea, is related to the priority areas of heart disease and stroke, clinical prevention services, diabetes and chronic disabling diseases. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic, for-profit, and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of state and local governments, and eligible agencies of the Federal government. Foreign organizations are not eligible to apply and any international component of a domestic application must be minor in its magnitude and critical in what it would contribute. Applications from minority individuals and women are encouraged. Awards for a Clinical Center and a Data Coordinating Center under this RFA will not be made to the same Principal Investigator (PI) to ensure that data analysis is done independently of data acquisition. The same institution may apply for both a Clinical Center and the Data Coordinating Center award, but the applications for each must be from different individuals. Data coordinating centers currently participating in epidemiology cohort studies are eligible. MECHANISM OF SUPPORT The administrative and funding instrument to be used for this program will be a cooperative agreement (U01), an assistance mechanism, in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility or a dominant role in the activity. Details of the responsibilities, relationships, and governance of the study to be funded under cooperative agreement(s) are discussed later in this document under the section Terms and Conditions of Award. The total project period for applications submitted in response to the present RFA may not exceed five years. The anticipated award date is September 30, 1994. Awards and level of support depend on receipt of a sufficient number of applications of high scientific merit. Although this program is provided for in the financial plans of the NHLBI, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. Because the nature and scope of the research proposed in response to this RFA may vary, it is anticipated that the sizes of awards will also vary. At this time, the NHLBI anticipates that there may be a renewed competition after five years. However, the final decision will depend upon experience with the program during the first five years as well as financial considerations. FUNDS AVAILABLE An estimated five to six awards for Clinical Centers and one award for a Data Coordinating Center will be made under this RFA. A maximum of about $16.3 million (including direct and indirect costs) over a five-year period will be awarded for the Clinical Centers and the Data Coordinating Center. Approximately $3.0 million will be available for the first year, $3.1 million for the second year, $3.3 million for the third year, $3.4 million the fourth year and $3.5 million for the last year. It is anticipated that the award for each Clinical Center will be about $400,000 total costs for the first year and the award for the Data Coordinating Center will be about $600,000 total costs for the first year. RESEARCH OBJECTIVES Background Snoring, the most common symptom of sleep disordered breathing, has been implicated as a risk factor for the development of hypertension, ischemic heart disease and cerebral infarction. Many of these adverse cardiovascular effects of snoring have been attributed to the substantial prevalence of obstructive sleep apnea among habitual snorers. Obstructive sleep apnea is characterized by loud snoring and disrupted breathing during sleep. It is associated with a number of adverse clinical consequences, including daytime sleepiness, impaired performance, accidents and cardio/cerebrovascular morbidity and mortality. The relative risks of cerebrovascular accidents, ischemic heart disease, and myocardial infarctions range from 1.5 to 4 in snorers as compared to non-snorers. Hypertension is common in patients with sleep apnea, with studies suggesting that up to 40 percent of hypertensive patients may have significant sleep apnea. Improvement in hypertension control has been reported to occur in patients with both conditions following treatment of their apnea. Vascular mortality may be significantly higher among untreated or conservatively treated patients with sleep apnea compared to patients treated aggressively. In addition, patients with sleep apnea or heavy snoring may have up to a 50 percent decrease in brain blood flow during rapid eye movement (REM) sleep and as high as a 50 percent increase in the incidence of stroke. These findings raise the intriguing possibility of a potential etiologic relationship between sleep apnea and thrombotic stroke. Sleep apnea may be an independent vascular disease risk factor, a concomitant of established vascular or cerebral diseases or other risk factors (such as obesity or hypertension), but this remains to be determined. Similarly, little is known regarding potential interactions between sleep apnea and other risk factors, or whether specific population subgroups may be particularly susceptible to adverse cardiovascular and cerebrovascular consequences potentially associated with sleep apnea. Further elucidation of the relationship between sleep apnea and hypertension in African-Americans may be particularly important. Severe hypertension is more common and its consequences more severe in African-Americans than in whites, but the reasons for this are not clear. Risk factors for sleep apnea such as obesity and macroglossia are also common in African-Americans, and preliminary data suggest that, among young subjects, sleep apnea may be more prevalent among African-Americans than among whites. Sleep apnea could help elucidate the marked racial differences in hypertension and its consequences. Sleep apnea is also known to increase markedly in prevalence following menopause. Examining cardiovascular disease events and sleep apnea in post-menopausal women may provide insight into any possible changes in cardiovascular disease risk among women. Sleep apnea has been described in 30 percent or more of elderly subjects. The bases for strong relationships between aging and increased apneic activity are not understood, but may be related to changes in sleep quality, cerebral function, muscle tone, obesity, cardiac function and lung function with aging. Due to their reduced functional reserves and co-existing morbidity, elderly persons may be at greatest risk for exacerbation of underlying cardiovascular and cerebrovascular disease when exposed to the physiologic stresses associated with apnea and arousal from sleep. The profound physiological derangements (hypoxemia, severe hypertension, tachycardia, fragmentation of sleep, arrhythmias) that often occur in association with sleep disordered breathing provide biologically plausible explanations for associations between sleep apnea and cardiovascular morbidity. The increased risk of cardiovascular events shortly after awakening has been linked to sympathetic discharge associated with arousal, which can occur dozens of times each night in patients with sleep apnea. The use of cardiovascular medications may also be an important effect modifier on the relationship of CVD, its risk factors, and SRBD, since some of these agents have known side effects related to sleep and breathing. Identification of factors that predispose to increased risk for SRBD is important for public health policy, potentially enabling specific high risk populations to be targeted, as well as for developing an improved understanding of disease pathogenesis that may include interactions among a number of risk factors in causing morbidity. This program seeks to accomplish this with an interactive, coordinated group of clinical centers working under a common protocol in a multidisciplinary setting. A separate Data Coordinating Center will support protocol development, sample size calculations, common questionnaires, complete data analysis, data management, standardization of procedures, quality control and overall study coordination. Objectives and Scope The overall objective of this program (sleep study) is to utilize existing, well characterized, established population-based epidemiologic cohorts (parent studies) to determine the degree to which sleep apnea is an independent or contributing risk factor for the development of cardiovascular and cerebrovascular disease. It is also aimed at examining possible associations between sleep apnea, hypertension and stroke among different age, gender and ethnic groups. This program has five specific aims; however, other important areas may be appropriate for inclusion into this program and it is not restricted to only these five aims: o Determining the risk of CVD associated with sleep apnea and other sleep related breathing disorders independent of other cardiovascular disease risk factors; o Assessing potential interactions between sleep apnea, SRBD, and other vascular disease risk factors, particularly obesity and hypertension, in relation to CVD risk; o Examining the contribution of sleep apnea and SRBD to the development of other CVD risk factors, particularly hypertension; o Identifying population subgroups at greatest risk for adverse clinical outcomes from sleep apnea and SRBD, including those defined by age, gender and race; o Estimating the extent of medical care utilization, health care costs, and measures of quality of life associated with sleep apnea and SRBD. Although these five aims are identified, others may be appropriate. The design of the experimental protocol and identification of specific populations targeted for this program remain in the hands of the investigators. A number of possible components are listed for illustrative purposes. Study Population and Design This program is to be built upon established epidemiologic programs. It is anticipated that the sleep study would make use of data previously collected in existing cohort studies as well as any outcome information. For example, a number of studies supported by NHLBI, other components of NIH, National Center for Health Statistics and other agencies have already collected much of the baseline information on hypertension, obesity, and other cardiovascular risk factors needed to examine relationships with sleep apnea and SRBD. These studies together cover a wide age span, concentrated in single communities or distributed among multiple sites. Information on cardiovascular outcomes and development of risk factors such as obesity and hypertension is also being collected. Several epidemiology studies also include questionnaires on snoring and sleep-related breathing disorders, which could be used to identify persons at high risk of sleep apnea. Sleep Study Cohort A total population of approximately 6,000 participants (50 percent women and appropriate minority representation) is anticipated. The sleep study population may include a wide range of samples. For example, for ages 40 years and above: (a) subjects at increased risk for CVD because of other known risk factors (e.g., family history, hypertension, obesity, etc.); (b) subjects at risk for sleep apnea (but without severe apnea at entry); and/or (c) subjects with mild to moderate levels of apnea, but without known CVD. It is not essential that all Clinical Centers have access to the full age range of subjects since certain established cohorts may be particularly suited to provide a unique aspect (age, gender, race) of their population for this program. For data that are already collected or planned to be collected in the parent study, applicants should demonstrate availability, adequacy of the data set, standardization and reliability of data on the cohort to be included in the sleep study. Study Design It is envisioned that the sleep study will require approximately 900 to 1,000 well characterized participants recruited from established cohort studies or clinical trials in each of five to six clinical sites, which may themselves consist of more than one site. It is possible for one or more sites from a multicenter study to collaborate in recruiting a subset of their participants into the sleep study. It is expected that the sleep study design would include, as a minimum, baseline and repeated measures, as needed, of sleep-disordered breathing, sleep state, pulmonary and cardiac function, oxygen saturation, lipid and lipoprotein levels, endocrine function, blood pressure, obesity, and other cardiopulmonary risk factors. Given the cost of conducting laboratory polysomnography in the number of participants needed for this study and the difficulty with participants accepting additional measurements, applicants should probably utilize ambulatory measurements of sleep disordered breathing in non-laboratory settings. Polysomnography may be used to validate the ambulatory measurements in a subset of the population or in selected cases. Morbid outcomes may be defined with the use of several measures, such as evidence of left ventricular dysfunction, sustained hypertension, atherosclerosis, cognitive impairment, hospital admissions for treatment of ischemic heart disease, health care expenditures associated with CVD and cerebrovascular disease, measures of functional status, quality of life, and death. For any activities to be conducted through subcontracts, applicants should develop and describe such operational factors as access to subjects, organization of the facility, means of assuring quality control, data entry, plans for coordination, and a process for filing human subject assurances. Applicants should also provide all details of the experimental design, methods and procedures to be used in the proposed sleep studies. The proposed studies of successful applicants will be submitted to the Steering Committee for further consideration once the cooperative agreements have been awarded. It is anticipated that the final sleep protocol (including standardized data collection procedures) will be developed from among the highly meritorious studies proposed by the successful applicants. However, a decision to fund a particular Clinical Center will not commit the steering committee to conduct that Center's specific protocol. Timetable The timetable for the sleep study may be roughly subdivided into three phases over a five year period. There may be some overlap of functions within each of the phases, and the time estimates are only approximations. The purpose of the phases is to provide broad guidelines for the collaborative endeavor. Phase I: Planning and protocol months 0-12 development Phase II: Subject recruitment, protocol months 12-48 implementation, examinations, and follow-up. Phase III: Data analysis and report months 48-60 preparation The first twelve months of the study may be devoted to planning and protocol development, for example, to determine participant eligibility criteria; train staff in diagnostic procedures and sleep studies; help set up data acquisition and consent forms; define terms and outcome measures; develop a manual of operations, standardized protocol, questionnaires, forms, and procedures for quality control; and pretest data collection forms and procedures. The Data Coordinating Center will also play a key role in the planning and protocol development stage. Possible objectives in addition to assisting Clinical Centers in their planning and organization of the steering committee, are to help develop the study protocol and analytic plans; select a data acquisition, transfer, and management system; plan for any subcontracts for chemical analysis; establish a reading center for evaluating and interpreting sleep records collected or validated by ambulatory methods and polysomnography; develop procedures for quality control, training, standardization of procedures and certification; print the protocols and data forms; develop and produce a Manual of Operations, and take the lead for the orderly accumulation and transmission of data for the sleep study. In Phase II, the Clinical Centers will proceed with subject recruitment, protocol implementation, examinations and follow-up. The Data Coordinating Center will assist the Clinical Centers with respect to implementing the protocol, subject recruitment, data acquisition, and ongoing quality control. In Phase III, Clinical Centers and the Data Coordinating Center will conduct data analysis and prepare reports. SPECIAL REQUIREMENTS Characteristics of Existing Epidemiological Cohorts To promote and facilitate development of a collaborative program among the award recipients, and to permit assessment according to review criteria, a number of issues discussed below need to be addressed in each application for a Clinical Center. Applicants must have access to established, well characterized populations that include measures of CVD risk factors and outcomes. These may include studies supported by the National Institutes of Health or other federal, state, or private agencies. This program is primarily aimed at cohorts in ongoing epidemiological studies. However, those from recently completed studies may be proposed if they are in every way suitable for the study as specified in this RFA, including considerations of cost as discussed earlier under FUNDS AVAILABLE and subsequently under Budget and Related Issues, as well as under Review Criteria and Award Criteria. Applicants must describe plans for providing data from the parent study to the sleep study Data Coordinating Center and the concurrence of the parent study data source with these plans. Applicants should describe and document access to study participants and provide a brief, clear description of the characteristics, age distribution, other relevant baseline information of the potential population, and any unique features for use of their particular cohort in the sleep study. Applicants should also describe current procedures for collecting and classifying information on deaths, cardiovascular events, and other health outcomes. As described under study design, it is expected that the sleep study will require a number of cardiopulmonary and sleep measurements. Therefore, it is expected that the subjects of the established epidemiology cohort will have had measurements of certain minimum characteristics, such as blood lipids, glucose, insulin, cholesterol, hematocrit, blood pressure, ECG, body size and fatness, smoking status, medical/family history, as well as outcome measures such as left ventricular dysfunction, myocardial infarction, sustained hypertension, atherosclerosis, stroke, hospital admissions for treatment of ischemic heart disease, and cause specific mortality. The existing study should also have the means to re-contact and follow-up the identified cohort for CVD events. The parent study data that will be utilized in the sleep study should have been collected according to up-to-date and standard methods within five years of Phase II (on or about September 30, 1995) of the sleep study, as agreed to during protocol development. If such data are not available from the parent study or if certain minor baseline measurements are missing, investigators may propose methods for collecting these data as part of the sleep study. It is the responsibility of the principal investigators to provide documentation from appropriate parent study Steering Committees, Data and Safety Monitoring Boards and sponsoring agencies for use of their population for this program. Additional Material to Include in the Application It is envisioned that the Principal Investigator (PI) will be an established investigator in cardiovascular, pulmonary or sleep disorders research. Either the PI or a co- investigator should have demonstrated experience in sleep disorders research. For example, it would be desirable for the PI and Co-PI to have combined expertise in CVD risk factors, epidemiology and sleep disorders medicine. It is not essential that this investigative team be from the same institution. However, if applications involve investigators from different institutions there must be well documented plans for adequate communication, interactions and facilities to conduct the sleep aspects of the protocol. Clinical Center applicants must be able to interact effectively with the Data Coordinating Center to transmit and edit data and should discuss their capability to participate in a distributed data entry system if this approach is selected. Clinical Center applicants should also state their willingness, and that of the institutions involved, to participate in a cooperative and interactive manner with other Clinical Centers, the NHLBI and the Data Coordinating Center within the context of this collaborative research program. 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. If so, a letter of agreement from either the GCRC Program Director or Principal Investigator should be included with the application. Data Coordinating Center applicants should discuss various aspects of study design that would be important in developing the sleep study protocol, their familiarity with sleep disorders and cardiopulmonary risk factors and diseases, eligibility criteria, important considerations for making sample size and power calculations, baseline and outcome measures, methods and frequency of data collection and entry, monitoring accuracy of data collection, methods of data acquisition and transfer, quality control procedures including training and certification, chemical analysis of blood samples, centralized reading of sleep records, and plans for statistical analysis of results. Budget and Related Issues Applicants are expected to be able to complete the sleep study with the funding available through this RFA in conjunction with any already committed funding. A decision to award a sleep study application does not constitute a continued commitment to the parent study beyond its current project and budget period. Applications for the Clinical Centers and the Data Coordinating Center should present five budget periods of 12 months each. Applicants should provide adequate budget justification for each phase of the study and all applicable direct and indirect costs should be included. Estimates of staffing needs, including the Principal Investigator, Co-Investigator, other professional and support staff must be included. The suggested level of commitment for the Principal Investigator and Co-Investigator should be not less than 20 percent each. Other personnel such as clinic coordinator, sleep technician, research assistants and secretary should be carefully outlined and justified in the application. Travel costs for approximately three to four trips to Bethesda for two people should be included in the first year budget with reductions to two trips for two people in subsequent years. Any major equipment items should be well justified. If collaborations or subcontracts are involved which require transfer of funds from the grantee to other institutions, it is necessary to establish formal subcontract agreements with each collaborating institution. Budgets for subcontracts should be prepared using the same guidelines as for the main grant. Budgets can be escalated four percent for the remaining future years. Future year awards may be redistributed based on the final protocol, enrollment of subjects into the sleep protocol during a specified time frame and overall performance. The individual clinics are expected to project subject enrollment into the sleep protocol. Applicants for the Data Coordinating Center should prepare budgets that allow for roughly the standard coordinating center activities and responsibilities related in timing and scope to the above mentioned phases. Terms and Conditions of Award 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. [Part 92 applies when state and local governments are eligible to apply as a "domestic organization."] The administrative and funding instrument used for this program is a cooperative agreement (U01), an assistance mechanism (rather than an acquisition mechanism) in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility or a dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the activity resides with the awardee(s) for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and the NHLBI Project Scientist. Awardees will have the usual responsibilities of award recipients, including protocol development, participant recruitment and follow-up, data collection, quality control, interim data and safety monitoring, final data analysis and interpretation, and preparation of publications, as well as responsibilities for collaboration with other awardees, and collaboration with the NHLBI Project Scientist. The NHLBI Project Scientist (Branch Chief, Airways Diseases Branch, Division of Lung Diseases), in addition to the usual stewardship responsibilities, will have responsibilities in protocol development, quality control, interim data and safety monitoring, final data analysis and interpretation, preparation of publications, collaboration with awardees, and project coordination. Awardees will have lead responsibilities for the project as a whole and it is anticipated that the awardees will have lead responsibilities in all joint tasks and activities, except it is anticipated that the NHLBI Project Scientist will have lead responsibilities in quality control and catalyzing interim monitoring of data and safety and may, consistent with publication policy to be adopted by the Steering Committee, have lead responsibilities in the preparation of some publications. A Steering Committee, composed of the principal investigator(s) of each Clinical Center, the principal investigator(s) of the Coordinating Center, and the NHLBI Project Scientist will be the main governing body of the study and will have primary responsibility for developing common protocols, facilitating the conduct and monitoring of studies, and reporting study results. Each Field Site, the Coordinating Center and the NHLBI Project Scientist will have one vote. The Chairperson, who will be someone other than an NHLBI staff member, will be selected by the Steering Committee. Subcommittees will be established by the Steering Committee, as it deems appropriate; an NHLBI scientist (or where necessary, scientists) will serve on subcommittees as deemed appropriate by the NHLBI Project Scientist. The collaborative protocol will be developed by the Steering Committee. This protocol may be reviewed by an external committee convened by NHLBI. The protocol will be implemented only with the concurrence of the awardees and NHLBI. Data will be submitted centrally to the Coordinating Center. The protocol will define rules regarding access to data and publications. An independent Data and Safety Monitoring Board, to be appointed by NHLBI, will review progress at least annually and report to NHLBI. 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 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. 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. STUDY POPULATIONS SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDY POPULATIONS NIH policy is that applicants for NIH clinical research grants and cooperative agreements are required to include minorities and women in study populations so that research findings can be of benefit to all persons at risk of disease, disorder, or condition under study; special emphasis must be placed on the need for inclusion of minorities and women in studies of diseases, disorders, and conditions which disproportionately affect them. This policy is intended to apply to males and females of all ages. If women or minorities are excluded or inadequately represented in clinical research, particularly in proposed population-based studies, a clear compelling rationale must be provided. The composition of the proposed study population must be described in terms of gender and racial/ethnic group. In addition, gender and racial/ethnic issues must be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. This information must be included in the form PHS 398 (rev. 9/91) in Sections 1-4 of the Research Plan, and summarized in Section 5, Human Subjects. Applicants are urged to assess carefully the feasibility of including the broadest possible representation of minority groups. However, NIH recognizes that it may not be feasible or appropriate in all research projects to include representation of the full array of United States racial/ethnic minority populations (i.e., Native Americans [including American Indians or Alaskan Natives], Asian/Pacific Islanders, Blacks, Hispanics). The rationale for studies on single minority population groups should be provided. For the purpose of this policy, clinical research includes human biomedical and behavioral studies of etiology, epidemiology, prevention (and preventive strategies), diagnosis, or treatment of diseases, disorders or conditions, including but not limited to clinical trials. The usual NIH policies concerning research on human subjects also apply. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are not subject to these policies. However, every effort should be made to include human tissues from women and racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. If the required information is not contained within the application, the application will be returned. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women in a study design is inadequate to answer the scientific question(s) addressed AND the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and will be reflected in assigning the priority score to the application. All applications for clinical research submitted to NIH are required to address these policies. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. LETTER OF INTENT Prospective applicants are asked to submit, by April 1, 1994, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, the information that it contains is helpful in planning for the review of applications. It allows NHLBI staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be sent to: C. James Scheirer, Ph.D. Division of Extramural Affairs National Heart, Lung, and Blood Institute Westwood Building, Room 648 Bethesda, MD 20892 Telephone: (301) 594-7452 FAX: (301) 594-7407 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 9/91) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research; from the Office of Grants Information, Division of Research Grants, National Institutes of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892, telephone (301) 710-0267; and from the NIH Project Scientist(s) listed under INQUIRIES. The RFA label available in the PHS 398 application form must be affixed to the bottom of the face page of the application. 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 in line 2a of the face page of the application form and the YES box must be marked. Send or deliver the original, signed application and three legible complete photocopies to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** Send two additional copies of the application to: C. James Scheirer, Ph.D. Division of Extramural Affairs National Heart, Lung, and Blood Institute Westwood Building, Room 648 Bethesda, MD 20892 Telephone: (301) 594-7452 It is important to send these two copies at the same time as the original and three copies are sent to the division of research grants. Otherwise, the NHLBI cannot guarantee that the application will be reviewed in competition for this RFA. Applications must be received by May 23, 1994. If an application is received after this date it will be returned to the applicant without review. The Division of Research Grants (DRG) 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 DRG 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 reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS General Considerations All applicants will be judged on the basis of the scientific merit of their proposed research project and their documented ability to conduct the essential study components as broadly outlined in the RESEARCH OBJECTIVES of this RFA. Review Method Upon receipt, applications will be reviewed by the DRG for completeness and by NHLBI staff for responsiveness to this RFA. Incomplete applications will be returned to the applicant without further consideration. If the application is judged unresponsive, the applicant will be contacted and given an opportunity to withdraw the application. If the application submitted in response to this RFA is substantially similar to a grant application already submitted to the NIH for review, but has not yet been reviewed, the applicant will be asked to withdraw either the pending application or the new one. Simultaneous submission of identical applications will not be allowed, nor will essentially identical applications be reviewed by different review committees. Therefore, an application cannot be submitted in response to this RFA that is essentially identical to one that has already been 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. Applications judged to be responsive by NHLBI staff will be reviewed for scientific and technical merit by an initial peer review group, which will be convened by the Division of Extramural Affairs, NHLBI, solely to review these applications. The initial review will include a preliminary evaluation to determine scientific merit relative to the other applications received in response to this RFA (triage); the NIH will remove from further consideration applications judged to be noncompetitive and promptly notify the Principal Investigator and the official signing for the applicant organization. Those applications judged to be competitive will be further evaluated for scientific/technical merit by the usual peer review procedures, including, if deemed appropriate, an applicant interview in or near Bethesda at the applicant's expense. Subsequently, they will be reviewed by the National Heart, Lung, and Blood Advisory Council. Review Criteria Applicants are encouraged to submit and describe their own ideas on how best to meet the goals of the RFA and their specific protocol, but they are expected to address issues identified under SPECIAL REQUIREMENTS of this Request for Applications. Applications will be judged primarily on the scientific quality of the application, the appropriateness, facilities and access to subjects from existing, established epidemiology studies, adequacy of existing data, multidisciplinary nature of the study and group, approach to cost containment, the discussion of considerations relevant to this RFA, expertise of the investigators, their capability to perform the work proposed, and a demonstrated willingness to work as part of the collaborative group and with the NHLBI Project Scientist. The review group will assess the scientific merit of the applications and related factors, including: Clinical Centers o Ability to utilize existing, established epidemiological cohorts to address the goals of this program; adequacy of the population, data set, and access to recruit the required numbers of subjects, including appropriate representation of minorities and women. o Importance and scientific merit of the proposed sleep study protocol, including adequacy of the methodology to carry out the proposed research plan. o Availability of adequate facilities and other resources including a plan for the administrative structure within the Clinical Center. o Rationale and cost-effectiveness of the research approach proposed and appropriateness of the budget. o Adequacy of data collection, preliminary analysis, reporting procedures, monitoring of study recruitment and subject follow-up, ability to process the volume of data expected within their Center and manage the individual study databases. Plans to ensure quality control of data. o Expertise, training, and experience of the investigators and staff, including the scientific and administrative abilities of the PI and co-investigators; their potential to accomplish the proposed research goals; the time they plan to devote to the program for the effective conduct of the study; their previous experience conducting clinical or population based research; their ability, experience and willingness to participate collaboratively with other Clinical Centers, the Data Coordinating Center, and the NHLBI in the manner summarized in the RFA. o Facilities, equipment, and organizational structure to effectively implement the proposed research. Data Coordinating Center o Understanding of the scientific, statistical, logistical, and technical issues underlying multicenter studies, including taking a leadership role in the area of study design, statistics, logistics, data acquisition and management, quality control, data analysis, and overall coordination. o Adequacy of the proposed plans for acquisition, transfer, management, and analysis of data; sleep reading center; quality control of data collection and monitoring, and overall coordination of Center activities. o The expertise, training, and experience of the investigators and staff, including the administrative abilities of the Principal Investigator and co-investigators, and the time they plan to devote to the program for effective coordination. o 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. o Facilities, equipment, subcontracts, and organizational structure to effectively assist Clinical Centers in implementing the protocol and in data collection procedures and in overall coordination of study-wide activities. o Appropriateness of the budget for the work proposed. AWARD CRITERIA Applications recommended by the National Heart, Lung, and Blood Advisory Council will be considered for award based on (a) scientific and technical merit; (b) program balance, including in this instance, sufficient compatibility of features to make a successful collaborative program a reasonable likelihood; and (c) availability of funds. Letter of Intent Receipt Date: April 1, 1994 Application Receipt Date: May 23, 1994 Review by NHLBI Advisory Council: September 1-2, 1994 Anticipated Award Date: September 30, 1994 INQUIRIES Written and telephone inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Inquiries regarding programmatic issues may be directed to: James P. Kiley, Ph.D. Division of Lung Diseases National Heart, Lung, and Blood Institute Westwood Building, Room 6A15 Bethesda, MD 20892 Telephone: (301) 594-7443 FAX: (301) 594-7487 Inquiries regarding review and application procedures may be directed to: C. James Scheirer, Ph.D. Division of Extramural Affairs National Heart, Lung, and Blood Institute Westwood Building, Room 648 Bethesda, MD 20892 Telephone: (301) 594-7452 FAX: (301) 594-7407 Inquiries regarding fiscal and administrative matters may be directed to: Mr. Raymond Zimmerman Division of Extramural Affairs National Heart, Lung, and Blood Institute Westwood Building, Room 4A11C Bethesda, MD 20892 Telephone: (301) 594-7420 FAX: (301) 594-7492 AUTHORITY AND REGULATIONS This project is described in the Catalog of Federal Domestic Assistance No. 93.837. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR 74. This project is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. .
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Office of Extramural Research (OER) |
National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892 |
Department of Health and Human Services (HHS) |
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