PILOT CLINICAL TRIALS IN THE EPIDEMIOLOGY, PREVENTION AND TREATMENT OF RESPIRATORY FAILURE IN CHILDREN RELEASE DATE: July 26, 2002 RFA: HD-02-027 National Institute of Child Health and Human Development (NICHD) (http://www.nichd.nih.gov/) National Institute of Nursing Research (NINR) (http://www.ninr.nih.gov) LETTER OF INTENT RECEIPT DATE: October 31, 2002 APPLICATION RECEIPT DATE: November 26, 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 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 Institute of Child Health and Human Development (NICHD) and the National Institute of Nursing Research (NINR) solicit applications for clinical studies designed to enhance understanding and prevention and treatment of respiratory failure in children. The present clinical literature documents the efficacy of various treatment modalities, including mechanical ventilation strategies employing conventional and innovative techniques, over a wide range of parameters, manipulated with both invasive and non-invasive maneuvers. Survival of children mechanically ventilated for a wide variety of indications is now the rule. This RFA solicits clinical studies to 1) define and characterize acute and chronic respiratory failure of various etiologies in children, 2) develop new approaches to prevent the development of chronic functional disability in children who have been mechanically ventilated for any cause, and 3) ameliorate the effects of mechanical ventilation on child development (cognitive and interpersonal), cardiovascular stability, pulmonary function, and integration into school and home care. A separate RFA solicits basic and clinical research specifically addressing the problem of improving outcomes after childhood cardiopulmonary arrest, specifically, the effects of choice, timing and duration and intensity of therapies on functional outcomes. RESEARCH OBJECTIVES Background The ARDSnet trial, in adults, and other smaller, more descriptive studies in children, have underscored with empiric data the importance of carefully chosen mechanical ventilation strategies in order to minimize, prevent, and control the devastating complications that result from acute respiratory failure. However, innovative ventilatory modalities (equipment and strategies), are evolving rapidly. As more children survive mechanical ventilation in the pediatric intensive care unit, data that evaluate the incidence of long-term complications are needed. Whether the incidence of such complications is related to mechanical ventilatory (equipment and strategy) modalities remains unknown. Long term oxygen and diuretic dependence, sleep hypoventilation, the need for persistent tracheostomy, and the emerging use of less invasive technologies have not been linked to child health outcomes in the literature in sufficiently powered studies. Similarly, children with special needs and complex medical disorders represent an increasing proportion of the pediatric critical care patient population. Special needs children may need pediatric surgical intervention to correct congenital anomalies, or ameliorate the course of disabilities that are traumatically sustained. The effects of such intervention on child health parameters remain understudied. This contributes to the increase in the number of children with suboptimal respiratory function at the time of discharge from the critical care unit, and into the chronic care and outpatient setting. Acute and chronic ventilatory modalities (strategies and equipment) that produce optimal outcomes for special needs children are reported only anecdotally in the literature. Exercise tolerance, vital capacity, chronic fibrotic or reactive airway disease, as sequelae of mechanical ventilation outside the neonatal age group remain understudied. To achieve and maintain independence from invasive mechanical ventilation, patients and their caregivers (physicians, nurses, respiratory therapists) must walk a tight rope, balancing reduction of support against the danger of hypoxia. Another facet of this balance is evident when the effect of increased respiratory work is considered in the disabled child, however, these considerations also apply to children who were physically and functionally normal before critical illness, but are left with decreased pulmonary reserve. Integration into educational programs, and the ability to live in the family unit must be balanced with the need to provide oxygenation and mechanical support which will optimize growth and development, cognition, emotional health, normal sleep patterns. Indeed, for many children with respiratory compromise and their families, the need for prolonged ventilatory support is the major obstacle to maximizing child health outcomes in this setting. The potential of failure of mechanical ventilation and oxygenation systems is frightening to children, their families, and schools. In fact, for some children and families, fear of abrupt respiratory failure may outweigh motivation to maximize developmental outcome. Children are then deprived of their full potential for development, maturation and successful integration into adult society. Fear of hypoxia and ventilatory failure is well founded, as both confer significant morbidity and mortality acutely. Acutely, diminished brain function during a hypoxemic episode poses potential dangers to children with already diminished functional abilities and reserves. In addition, recurrent hypoxemia may impose long-lasting damaging effects on the brain, resulting in impairment of memory or other cognitive functions. This is especially a concern in the early childhood years when the nervous system is still developing, and children are adapting to their disability. Recurrent hypoxemia and hypercarbia may eventually also impair the body"s defense mechanisms against hypoventilation and hypoxia, creating a vicious cycle for the patient. The progressive decline in effective physiologic responses to hypoventilation and hypoxia may precipitate or substantially worsen chronic disability. Young children cannot reliably report or interpret symptoms of hypoxemia and hypoventilation. Chronic use of inhaled beta agonists is common in such children and complicates assessment by children and their parents and clinicians. Unrecognized decline in respiratory sufficiency over time may contribute to catastrophic outcomes in otherwise treatable respiratory infections, a too-frequent outcome in special needs children. To address this critical problem for children, the National Center for Medical Rehabilitation Research (NCMRR), NICHD, and National Institute of Nursing Research (NINR), cosponsored a workshop on mechanical ventilation in the disabled, prior to founding the new program in pediatric critical care and rehabilitation research. Most recently, a planning conference of subspecialists (May 3-4, 2002) identified the need to study critical care interventions and long-term outcomes in children. Basic research is needed to enhance understanding of the central and peripheral control mechanisms that counteract acute and chronic respiratory failure, and the pathogenic mechanisms involved in loss of counter-regulatory control. In addition, clinical studies are needed to better define the scope of the problem and develop new prevention and therapeutic approaches to maximize outcomes for childhood survivors of mechanical ventilation. As a first step toward addressing the problem of respiratory failure in children, the NICHD has issued this RFA as part of the new program at the NCMRR in pediatric critical care and rehabilitation research. The National Heart, Lung, and Blood Institute (NHLBI) has interest in research related to acute lung injury and critical care. Therefore, applications that are of mutual interest may be given a secondary assignment to NHLBI in accordance with the NIH referral guidelines. Scope and Objectives This RFA solicits clinical studies to 1) define the scope and nature of respiratory failure in children, especially those with special needs, and 2) develop and evaluate acute and chronic management strategies to prevent or minimize the development of chronic respiratory failure in children or to ameliorate its effects. Recent scientific and engineering advances, including the availability of innovative approaches and techniques that potentially open up new avenues of exploration, might be utilized to enhance management and quality of life for children with respiratory failure. While this RFA focuses on clinical studies of respiratory failure, basic research to evaluate cellular and tissue mechanisms of respiratory insufficiency in children is also of interest, particularly as it relates to long term adaptation in survival from critical illness in young animals. Appropriate topics for investigation under this RFA would include, but are not limited to: o Studies to determine the prevalence of respiratory insufficiency in children with special needs, with a focus on delineating differences among various age groups (e.g., infants, children and adolescents). o Studies to delineate the role of age, gender, race/ethnicity, socioeconomic status and other factors in the risk of respiratory insufficiency, and the adaptation to home ventilatory support. o Studies to identify factors, including acute and chronic modes and strategies of ventilatory support, which optimize child health outcomes. o Studies to establish normative data for respiratory parameters (pulmonary function, oxygen saturation levels and indices of ventilation)particularly in special needs children requiring ventilatory support, throughout a 24-hour period. o Studies to determine whether there are changes in respiratory regulatory mechanisms with age. o Studies to determine whether novel strategies that minimize the need for obtrusive and invasive mechanical ventilatory support result in more optimal short and long-term outcomes in children. o Studies to assess the reliability and utility of continuous oximeters/sensors in detecting hypoxia during sleep, or in situations where it may be less apparent in children, particularly those with special needs. o Studies to determine whether the occurrence of hypoxemia and hypoventilation, as well as the need for ongoing ventilatory support, can be minimized by altering the choice of drugs, or timing of drug administration, or drugs with altered kinetics. o Studies to determine whether different therapeutic modalities (strategies and equipment) regimens for respiratory failure in childhood affect central and peripheral regulatory mechanisms. o Studies to develop and test strategies for minimizing the risk of impairment due to subtle alterations in oxygenation and ventilation in survivors of critical illness in childhood. MECHANISM OF SUPPORT This RFA will use the NIH Exploratory/Developmental Research Grant (R21) award mechanism. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one- time solicitation. The anticipated award date is July 1, 2003. The R21 awards are intended to demonstrate feasibility and to obtain preliminary data testing innovative ideas that represent clear departure from ongoing research interests. These grants are intended to 1) provide initial support for new investigators, 2) allow exploration of possible new directions for established investigators, and 3) stimulate investigators from other areas to lend their expertise to research within the scope of this solicitation. These R21 grants will not be renewable, continuation of projects developed under this program will be through the regular research grant (R01) program. Applicants from institutions which 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. This RFA uses just-in-time concepts. It also uses the modular budgeting format (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. FUNDS AVAILABLE The NICHD and NINR intend to commit approximately $1.15 million in total costs [Direct plus Facilities and Administrative (F & A) costs] in FY 2003 to fund four to six new grants in response to this RFA. NINR intends to commit funds for one project by a nurse researcher. An applicant may request a project period of up to two years and a budget for direct costs of up to $125,000 per year. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the NICHD and NINR provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. ELIGIBLE INSTITUTIONS You may submit an application 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 or foreign o Faith-based organizations 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. 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: Carol Nicholson, M.S., M.D. Program Director, Pediatric Critical Care and Rehabilitation Research National Institute of Child Health and Human Development National Center for Medical Rehabilitation Research 6100 Executive Boulevard, Room 2A03, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301)435-6843 Email: nicholca@mail.nih.gov Hilary D. Sigmon Ph.D., R.N. Program Director National Institute of Nursing Research 6701 Democracy Boulevard, Room 710, MSC 4870 Bethesda, MD 20892-4870 Telephone: (301) 480-8260 FAX: (301) 480-8260 Email: hilary.sigmon@nih.gov o Direct your questions about peer review issues to: Robert H. Stretch, Ph.D. Director, Division of Scientific Review National Institute of Child Health and Human Development Building 6100 Room 5B01, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-1485 FAX: (301) 402-4104 Email: STRETCH@NIH.GOV o Direct your questions about financial or grants management matters to: Christopher Myers Grants Management Branch National Institute of Child Health and Human Development Building 6100 Room 8A14H, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 435-6996 FAX: (301) 480-4783 Email: cm143g@nih.gov Tara Mowery Grants Management Specialist National Institute of Nursing Research 45 Center Drive MSC 6300 Bethesda, MD 20892-6300 Telephone: (301) 594-5979 FAX: (301) 480-8260 Email: tara-mowery@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 NICHD 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: Carol Nicholson, M.S., M.D. Program Director, Pediatric Critical Care and Rehabilitation Research National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 2A03, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301)435-6843 Email: nicholca@mail.nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at http://grants.nih.gov/grants/funding/modular/modular.htm. 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 must be sent to: Robert H. Stretch, Ph.D. Director, Division of Scientific Review (DSR) National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 5B01, MSC 7510 Bethesda, MD 20892-7510 Rockville, MD 20852 (for courier/express service) 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. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NICHD and NINR. 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 NICHD in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Receive a second level review by the National Advisory Child Health and Human Development Council. REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application"s overall score, weighting them as appropriate for each application. Your application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, you may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) SIGNIFICANCE: Does your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? What will be the effect of these studies on the concepts or methods that drive this field? (2) APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: o PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. o INCLUSION: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below) o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: October 31, 2002 Application Receipt Date: November 26, 2002 Peer Review Date: February/March 2003 Council Review: June 2003 Earliest Anticipated Start Date: July 1, 2003 AWARD CRITERIA 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 is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research, updated racial and ethnic categories in compliance with the new OMB standards, clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398, and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable, and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at http://grants.nih.gov/grants/funding/children/children.htm. 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. 93.929 (NICHD) and 93.361 (NINR), 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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