COLLABORATIVE PEDIATRIC CRITICAL CARE RESEARCH NETWORK RELEASE DATE: April 16, 2004 RFA NUMBER: RFA-HD-04-004 - (Reissued as RFA-HD-08-025) EXPIRATION DATE: August 10, 2004 Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov) COMPONENT OF PARTICIPATING ORGANIZATION: National Institute of Child Health and Human Development (NICHD) (http://www.nichd.nih.gov/) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.865 LETTER OF INTENT RECEIPT DATE: July 12, 2004 APPLICATION RECEIPT DATE: August 9, 2004 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 Institute of Child Health and Human Development (NICHD) invites applications from investigators willing to participate with the NICHD under a cooperative agreement (U10) to initiate a multi-center program designed to investigate the safety and efficacy of treatment and management strategies to care for critically ill children, as well as the pathophysiological bases of critical illness and injury in childhood. This network will promote the efficient comparison of novel critical care treatment methods and management strategies of potential benefit for children who are critically ill. The objective of this Request for Applications (RFA) is to establish and maintain the infrastructure required for a network of approximately six clinical centers to perform multiple clinical trials as well as pertinent descriptive and translational research for children who are critically ill. An RFA for a Data Coordinating Center to support the network is separately published (RFA HD-04-015). The established network of academic centers will be able to study the required numbers of patients using rigorous common protocols and can provide answers more rapidly than individual centers acting alone. RESEARCH OBJECTIVES Background Several convergent developments in critical care medicine, as well as in the larger medical, scientific, and national communities, underlie the decision to develop and maintain strong collaborative infrastructure in the form of a national pediatric critical care research network. The intent is to support a substantial range of research activities that reach across traditional disciplinary lines, transcending customary thinking and organizational structures in order to achieve innovative research in the care of the critically ill child. Modern critical care medicine has introduced a number of principles of management and innovative methodologies without rigorous use of the controlled observation necessary for their objective evaluation. A major problem has been the balance between assuring prompt implementation of new technologies, procedures, treatments, and drugs, and evaluation of their safety, efficacy, and cost/risk/benefit ratios. Indeed, because of the urgent demands of critically ill children, care is based on limited knowledge of new modalities not subjected to critical studies prior to introduction and use. In a critically ill child, for example, an innovative idea may be tried, which, if the child's condition improves, may rapidly start a new trend, and become the standard of care, expected and demanded by critically ill patients, their families, and the professionals caring for them. As a result, incorporation into the arsenal of critical care therapies frequently is based on limited experience, with efficacy and/or safety virtually unevaluated scientifically. Earlier attempts to address this need by the community of pediatric critical care investigators, while productive of smaller studies, suffered from under- funded, non-sustainable infrastructure. Recent threats of bioterrorism, utilizing infectious and chemical agents to induce critical illness in diverse organ systems, and the potential for deployment of weapons systems which induce burns and trauma, have heightened the need for adequately powered studies that evaluate the efficacy and cost/risk/benefit ratios of innovative modalities and strategies in pediatric critical illness. Even in the instance that such events are rare (either occurring individually or in clusters) and unpredictable, an infrastructure to conserve and analyze data in critical illness in children is an essential research capacity; it is hoped that, for the needs of pediatric preparedness, this collaborative research network, will be an important national resource. Recent discoveries across a broad range of basic science research areas have greatly expanded the options for the critically ill child. Current advances in understanding of the molecular biology underlying organ system failure offer the possibility of manipulating otherwise poorly controlled processes, including inflammation, cell and organ death, and regeneration of tissues and functional organ system capacity. Modalities of mechanical ventilation, non- invasive ventilation, circulatory support, organ transplantation, and extracorporeal life support have extended therapeutic options to children previously thought to be beyond the reach of state-of-the-art therapy. The use of less invasive techniques in neurosurgery, general, orthopedic, reconstructive, vascular, and cardiovascular surgery, as well as the implementation of newer techniques of respiratory and circulatory support, have been central to the radical changes in mortality achievable with state of the art pediatric critical care medicine. As a result, children in higher risk groups who are victims of critical illness and/or injury, and those who might benefit from surgical interventions once not feasible, are benefiting from critical care in increasing number. Often, in the present context of critical care, children with complex illnesses, combinations of medical, surgical, and traumatic processes are surviving to discharge from multidisciplinary critical care units. As mortality from pediatric critical illness and injury declines, survival of children with disabling residuals of the critical pathology increases, and chronic medical conditions become more common. In children, it is well known that such conditions make the risk of subsequent critical illness greater than that for age-peers who have not sustained such illness or injury. There are several reasons that a collaborative clinical research network would accelerate pediatric critical care research, and lead to evaluation of promising new approaches to life support and critical decision-making in complex illnesses. The heterogeneity of critically ill children makes it difficult to accumulate a large number of comparable patients in one center. Multi-center trials have the potential to reduce the number of patients needed at each clinical center, and allow subject accrual and meaningful research to be completed more rapidly. Further, common treatment protocols would reduce variables that contribute to patient outcome and allow valid comparisons between treatments. Finally, the Network approach will increase the number of comparative trials and meaningful translational descriptive studies that are conducted by providing a framework for rapid initiation of important studies, a focus on randomized studies, and efficient use of pooled clinical expertise and data management resources. Research Scope The Collaborative Pediatric Critical Care Network will achieve its objective through conducting clinical trials, as well as translational and descriptive studies. Therapeutic trials may involve investigational drugs, drugs already approved but not currently used, and drugs currently used, as well as diverse innovative and more traditional management strategies. Patients might be randomized between different doses, as well as modes and techniques of novel treatment or novel treatment versus standard therapy. It is also recognized that not all studies can proceed directly to Phase III clinical trials. Pilot clinical trials and adequately powered descriptive studies are essential to the development of the database necessary to conduct successful Phase III trials. Indeed, the unique complexity of multiple organ system pathophysiology in the young is not well understood. Some examples of research appropriate for this RFA include, but are not limited to, the following: o Trials of methods of ventilatory support in various critical illnesses, including less invasive methods. o Trials of agents and strategies which may prevent progression of respiratory infection or compromise to respiratory failure. o Descriptive studies of the epidemiology of the complications of critical care which may be disabling, and the relationship of such complications to critical care methodologies: agents, technical apparatus, and strategies. o Descriptive studies of the epidemiology of critical illness among specific high risk populations (for example, neonatal intensive care survivors, disabled children, and children with ongoing chronic conditions such as asthma or diabetes). o Trials of innovative methods of circulatory support in defined populations of children where benefit is postulated: in overwhelming sepsis, cardiopulmonary arrest, or after complex surgical therapy. o Descriptive studies of the biological processes underlying critical illness in childhood, and progression to organ failure, such as genetic polymorphisms, and signal transduction. o Descriptive studies and trials that are directed at the critical care needs of pediatric oncology patients, especially those who have undergone bone marrow transplantation and chemotherapeutic agents. Examples include indications, modalities, and strategies for support in respiratory and circulatory compromise. o Trials of novel interventions and decision-making strategies for pediatric trauma patients, based on translational research, applying recent basic science findings to the bedside care of the critically injured child. o Trials of regimens or modalities of care that may prevent, ameliorate, or reverse the cascade of multiple organ system failure (MOSF) in children who are critically ill or injured. o Trials of novel interventions and strategies that may prevent or ameliorate the course of MOSF in children who are not critically ill, but are at increased risk to become unstable (immunocompromised and disabled children, children with genetic polymorphisms that place them at risk, trauma and burn patients who initially appear stable). o Descriptive studies and experimental trials of novel informatics-based decision making, to evaluate efficacy and safety in allocating resources for children with illness and injury whose future course is uncertain, and are at risk to become critically ill, or to be left with disability. o Follow-up studies to evaluate the link between acute interventions and chronic illness and disability. For example, various surgical and critical care modalities to correct congenital anomalies, critical injury and other situations where the risk of compromise of developmental outcome and/or functional success may be substantial. o Studies of transfusion therapy, including clinical trials, that evaluate the risk/benefit ratio of conservative and liberal transfusion in defined groups of critically ill and injured children. o Trials of new or more traditional immunosuppressive drugs, monoclonal antibodies, or cytokines in immunomodulation during sepsis and the systemic inflammatory response. In addition, the Network will conduct patient management trials in collaboration with other research groups that have an interest in critically ill children: for example, the cooperative cancer research groups and those groups studying ventilation strategies. These are examples only. Applicants are not limited to the subjects mentioned above, and are encouraged to submit proposals for other studies pertinent to the objectives of the RFA. MECHANISM OF SUPPORT This RFA will use the NIH Cooperative Clinical Research (U10) award mechanism. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. The anticipated award date is April 1, 2005. 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 The NICHD intends to commit approximately $1 million in total costs [Direct plus Facilities and Administrative (F & A) costs] in FY 2005 to support up to six new grants in response to this RFA. An applicant may request a project period of up to five years and a budget for direct costs of up to $100,000 for the first year and up to $450,000 per year thereafter. 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 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. At this time, it is not known if this RFA will be reissued. 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 o Foreign institutions are not eligible to apply Applications may be submitted from organizations located in the United States of America. This geographic constraint is necessary because of the need for close communication among members of the program, the requirement for frequent Steering Committee meetings, and the necessity of site visits for data verification. Participants must be based in a multidisciplinary pediatric intensive care unit (or units), in an academically oriented department of pediatric critical care medicine, that admits both medical and surgical patients. 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 his/her 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. The Principal Investigator must be a pediatric intensivist. SPECIAL REQUIREMENTS Organization of the Collaborative Pediatric Critical Care Research Network The Collaborative Critical Care Research Network (Network) will be a cooperative network of approximately six Clinical Centers, one Data Coordinating Center, and the National Institute of Child Health and Human Development (NICHD). Clinical Centers will be responsible for proposing protocols that are appropriate and feasible for adoption by the Network, guiding protocol development, enrolling patients, analyzing results, and disseminating research findings. All Clinical Centers will be required to participate in a cooperative and interactive manner with one another and with the Data Coordinating Center. Divisions and departments of pediatric critical care medicine have the option to form a consortium and apply as a single entity for a Clinical Center award. In the case of a consortium, there will be one Principal Investigator who will serve on the Steering Committee and represent the other centers, and the maximum direct costs per year will be limited to $100,000 ($450,000 in Years 02 -05). Participants must be based in a multidisciplinary pediatric intensive care unit (or units), in an academically oriented department of pediatric critical care medicine, that admits both medical and surgical patients. Physician staffing of the Clinical Center should include at least four full-time board- certified pediatric intensivists. Complete descriptions of the training and qualifications of each in both clinical care and research should be provided. The Principal Investigator should be a practicing pediatric intensivist: her/his clinical, academic, administrative, and research commitments should be described in detail. A centralized Data Coordinating Center will support the activities of the Network. The functions of the Data Coordinating Center will include developing protocol data management aspects, devising novel comparative study designs, providing sample size calculations and statistical advice, developing data forms, performing data analyses, coordinating the activities of the Steering Committee, Protocol Review Committee, and Data and Safety Monitoring Board, and overall study coordination and quality assurance. In addition, in order to hasten accrual in Network studies, the Data Coordinating Center, along with NICHD and the Steering Committee, will have the responsibility to identify qualified and interested investigators at non-Network centers who wish to enroll patients in these studies. Arrangements for data collection and reimbursement of trial-related data collection costs at non-Network centers will be the responsibility of the Data Coordinating Center. Awards for a Clinical Center and a Data Coordinating Center to support the network will not be made to the same Principal Investigator to ensure that data analysis is conducted 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. A Steering Committee will be the main governing body of the Network and, at a minimum, will be composed of the Principal Investigators of the Clinical Centers and the Data Coordinating Center and the NICHD Project Scientist. The structure and role of the Steering Committee are described below under Cooperative Agreement Terms and Conditions of Award. The costs of travel to Washington DC (up to six times per year) for the Principal Investigator should be included in the application budget request. In addition, funds should be budgeted to provide for travel of the research nurse to two of the Steering Committee meetings per year. Data collection will be monitored in a manner consistent with NICHD Policy for Data and Safety Monitoring (http://www.nichd.nih.gov/funding/datasafety.htm). A Data and Safety Monitoring Board (DSMB) will monitor the activities of the Network semi-annually. As a part of its monitoring responsibility, the DSMB will submit recommendations to NICHD regarding the continuation of each study, and prepare a report for Principal Investigators to provide to their institutional review boards (IRBs). It is anticipated that each protocol will be implemented in all of the Clinical Centers. As specific protocols are developed, support will depend on the availability of funds, and per patient (capitation) funding made available. All the Clinical Centers must be willing to pursue this funding arrangement for each new protocol conducted. Clinical protocols must be approved by local IRBs and the Protocol Review Committee before initiation. The exact number of protocols supported in the five-year program will depend on the nature and extent of the investigations proposed by the Steering Committee. Both short- and longer-term projects should be considered. Required Expertise and Institutional Resources Each clinical center selected will be supervised by a Principal Investigator who is a pediatric intensivist. The disciplines and expertise that will be sought for the research undertaken in this program include but are not limited to the areas of pediatric critical care medicine, pediatric surgical critical care, pediatric trauma, biostatistics, bioengineering, informatics, immunology, pulmonology, cardiology, pharmacology, therapeutic development, and clinical trials management. Organizations should have academically-oriented divisions of pediatric critical care medicine. The Clinical Center must be located in an institution with a full spectrum of pediatric specialists and subspecialists in medicine and surgery to support the activities of Network studies. Because assessment of outcomes in survivors is so central to the Network purpose, all of the specialties involved in pediatric critical care should be available. These should include (but are not limited to): pediatric rehabilitation or general pediatric long term follow- up, pediatric surgery and trauma surgery, pediatric cardiovascular surgery, pediatric neurology and developmental medicine, pediatric cardiology, pediatric pulmonology and pediatric immunology. A history of cooperation between pediatric critical care medicine and surgery towards excellence in clinical care, maintenance of a database, and research productivity should be documented. A pediatric surgeon, neurosurgeon, or cardiothoracic surgeon interested in pediatric critical care research willing to participate in the Collaborative Pediatric Critical Care Research Network should be designated. Such individuals must commit to serve as consultants, and possibly as collaborators, in Network research. The research productivity of the surgical consultants should be documented. Applicant Clinical Centers should have a full range of state-of-the-art facilities, clinical capabilities, and excellent support staff. Laboratory facilities, imaging capabilities, research pharmacies, and qualified staff in respiratory therapy are essential requirements that should be documented in the application. Patient Population Requirements Clinical Center applicants should include a table in their applications providing the number of non-neonatal (older than 28 days) critically ill children at their institution. The table should include a breakdown by age of surgical (trauma and non-trauma), medical, oncology, and bone marrow transplant admissions to the pediatric critical care unit in 2003. An example of such a table can be found at http://www.nichd.nih.gov/RFA/HD-04-004/HD-04-004.htm. While consideration of the applicant Center's qualification in census will be an important criterion for inclusion in the Network, relevant expertise and productivity will be evaluated as well. The capacity to follow children and capture data about their status for up two years after admission is strongly recommended for all applicants, and will be central in the review of the proposed Center's qualifications; no applications will be considered where the capacity to follow children as outpatients and capture pertinent outcome data is not evident. Specific plans to work collaboratively with professionals in pediatric rehabilitation, general pediatrics, and pediatric subspecialty disciplines providing care to children with special health care needs are specifically solicited. Applications should also indicate the willingness of the pediatric critical care and pediatric surgical divisions to work collaboratively. Participation in Studies It is the intent of this network that multiple trials and descriptive studies will be conducted during the five-year project period. It is anticipated that in the initial year, one trial will be selected from the studies proposed by the successful applicants. However, a decision to fund a particular Clinical Center will not commit the Network to develop that center's clinical protocol. Nevertheless, awardees must agree to actively enroll patients in at least one Network trial and/or descriptive study in the first year after the award. Applicants should plan that, after the first year, at least three studies will begin enrolling patients each year. All applicants should propose a strategy to streamline protocol development and acceptance among centers, given this ambitious pace for initiating studies. Initiation of trials in future years will depend on satisfactory progress in previous trials. Additionally, eligibility for clinical centers includes provision for the evaluation of outcomes in children surviving critical illness and injury. Cooperative Agreement Terms and Conditions of Award The following Terms and Conditions will be incorporated into the award statement. They are to be followed in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Parts 74 and 92, and other HHS and NIH grant administration policies. The administrative and funding instrument used for this program will be the U10, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH scientific and/or programmatic involvement with the PI is anticipated during performance of the activities. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the PI's activities by involvement in and otherwise working jointly with the PI in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the PI for the project as a whole, although specific tasks and activities may be shared between the awardee and the NICHD Project Scientist. Facilities and Administrative cost (indirect cost) award procedures apply to cooperative agreements in the same manner as for grants. Business management aspects of these awards will be administered by the NICHD Grants Management Branch in accordance with HHS and NIH grant administrative requirements. 1. Awardee Rights and Responsibilities The Collaborative Pediatric Critical Care Research Network (Network) will be a cooperative network of approximately six Clinical Centers, one Data Coordinating Center, and the National Institute of Child Health and Human Development (NICHD). Clinical Centers will be responsible for proposing protocols that could be adopted by the Network, guiding protocol development, enrolling patients, analyzing results, and disseminating research findings. All Clinical Centers will be required to participate in a cooperative and interactive manner with one another and with the Data Coordinating Center. All awardees are required to submit annual progress reports to NICHD, as appropriate, and to provide study and site performance information as stipulated by NICHD. A centralized Data Coordinating Center will support the activities of the Network. Functions of the Data Coordinating Center include advice and assistance in developing protocols, devising novel comparative study designs, providing sample size calculations and statistical advice, developing data forms, performing data analyses, coordinating the activities of the Steering Committee, Protocol Review Committee, and Data and Safety Monitoring Board, and overall study coordination and quality assurance. In addition, in order to ensure accrual in protocols, the Coordinating Center will have the responsibility to identify to the NICHD and the Steering Committee, qualified and interested investigators at non-Network clinical centers who wish to enroll patients in Network studies, or to propose protocols for consideration by the Steering Committee. Arrangements for data collection and reimbursement of trial-related data collection costs at non-Network centers, once approved by the Steering Committee, will be the responsibility of the Data Coordinating Center. o Development of Network Research Agenda and Protocols It is the responsibility of the awardee(s) to develop the details of the research design, including definition of objectives and approaches, the planning, implementation, and analysis of studies, any modification of study design, quality control, collaboration with other investigators, interpretations, and conclusions of studies, unless otherwise provided for in these terms or by action of the Steering Committee. Modifications of study protocols will be approved by the Data and Safety Monitoring Board. Ancillary studies will not be funded by this grant mechanism. o Coordination and Internal Oversight of Network Activities Awardee(s) agree to the governance of the study through a Steering Committee. Meetings of the Steering Committee will ordinarily be held in the Washington, D.C. metropolitan area or by telephone conference call. The Steering Committee, with the assistance of the Data Coordinating Center, is responsible for coordinating protocol development, descriptive study design, protocol submission, study conduct, quality control and study monitoring, drug ordering, data management, statistical analysis, protocol amendments/status changes, adherence to requirements regarding investigational drug management and federally mandated regulations, and protocol and performance reporting. The Data Coordinating Center will be responsible for communication with the appropriate NICHD staff. The Steering Committee Chairperson, who will be someone other than an NICHD staff member and may be someone other than a Principal Investigator, will be selected by NICHD. The Clinical Centers, the Data Coordinating Center, and NICHD each will have one vote. The Chairperson will vote in the case of ties. The Steering Committee may meet as often as three to six times in the first 12 months of the Network, 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 publishing study results. Topics for the protocols will be proposed and prioritized by the Steering Committee; protocols from the wider pediatric critical care community of investigators may be submitted for Steering Committee review as well. For each protocol, one investigator (or small group) will take the lead responsibility for drafting the protocol along with the Data Coordinating Center, although the Steering Committee will provide input and will be responsible for assuring development of a common protocol to be implemented by the network's Clinical Centers, as well as centers or consortia from outside the network. Some of the major considerations relevant to protocol review by the Steering Committee include: (a) the strength of the scientific rationale supporting the study, (b) the medical importance of the question being posed, (c) the avoidance of undesirable duplication with other ongoing studies, (d) the appropriateness of study design including interim monitoring plans if appropriate, (e) a satisfactory projected accrual rate and follow-up period, (f) patient safety, (g) compliance with federal regulatory requirements, (h) adequacy of data management, (i) appropriateness of patient selection, evaluation, assessment of toxicity and risk, response to therapy and follow- up, (j) adherence to NIH guidelines. 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. Subcommittees to oversee study protocol development in regard to the complications of critical care treatments, such as pneumothoraces, line erosion and placement complications, and nosocomial infection are also envisioned. o Network Compliance with Federally Mandated Regulatory Requirements The Network must comply with all FDA regulatory requirements for studies involving investigational devices and agents and NIH policies applying to the conduct of research involving human subjects and be consistent with Office of Human Research Protections guidelines http://www.hhs.gov/ohrp/. These regulations include but are not limited to CFR 21 Parts 50, 56 and 312 and CFR 45 Part 46. o Data Collection and Management The Network shall establish and implement mechanisms for data collection and management that are: (a) adequate for quality control and analysis, and (b) as simple as possible in order to encourage maximum participation of physicians entering patients and to avoid unnecessary expenses. Awardees are required to follow Network procedures for data collection and management, which will be developed by the Steering Committee. o Study Monitoring and Quality Assurance The Network shall establish and implement mechanisms for study monitoring and quality assurance, as well as policies and procedures for protocol implementation. Awardees are required to follow Network procedures for study monitoring. The Network is responsible for assuring accurate and timely knowledge of the progress of each study through: a. tracking and reporting of patient accrual and adherence to defined accrual goals; b. ongoing assessment of case eligibility and availability; c. timely medical review and assessment of patient data; d. rapid reporting of treatment-related morbidity and measures to ensure communication of this information to all parties; e. interim evaluation and consideration of measures of outcome as consistent with patient safety and good clinical trials practice; f. timely communication of results of studies; and g. an on-site monitoring program. The NICHD is responsible for ensuring that all participating sites receive routine audits by the Data Coordinating Center. In the event that an awardee fails to comply with these guidelines, the accrual of new patients to the Network's protocols at the affected site shall be suspended immediately upon notice of the determination. The suspension will remain in effect until the awardee conducts the required audit and the audit report or remedial action is accepted by the NICHD. The Data Coordinating Center and the Institute will be responsible for notifying any affected site of the suspension. During the suspension period, no funds from this award may be provided to the site for new accruals, and no charges to the award for new accruals will be permitted. Awardees will retain custody of and have primary rights to the data developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. 2. NIH Responsibilities NICHD Project Scientist: The NICHD Project Scientist will have substantial scientific-programmatic involvement during conduct of this activity, through technical assistance and participation as one voting member of the Steering Committee. NICHD Project Officer: The NICHD will appoint a Project Officer, apart from the Project Scientist, who will: o Carry out continuous review of all activities to ensure that the objectives are being met and that all regulatory, fiscal, and administrative matters are handled according to NIH guidelines. o Have the option to withhold support to a participating institution if technical performance requirements are not met. o Perform other duties required for normal program stewardship of grants. 3. Collaborative Responsibilities The management of the National Pediatric Collaborative Critical Care Research Network includes three committees whose functions are as follows: o A Steering Committee will be responsible for protocol development and selection. Protocols that originate with investigators outside the Steering Committee may be presented for review as well, if two of the Principal Investigators and the NICHD Project Scientist concur. The structure of the Steering Committee is outlined above. o An Advisory Board will advise the Steering Committee in the identification and prioritization of topics for Network research. The Advisory Board, chosen by the NICHD with the advice of the Steering Committee, will be composed of individuals with expertise in clinical trials, biostatistics, epidemiology, pediatric rehabilitation, pediatric pulmonology, developmental pediatrics, and pediatric surgery. o A Protocol Review Committee will review and approve all clinical protocols before initiation. 4. Arbitration Process Any disagreements that may arise in scientific or programmatic matters within the scope of the award between grantees and the NIH may be brought to arbitration. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D, and HHS regulation at 45 CFR Part 16. An Arbitration Panel will help resolve both scientific and programmatic issues that develop during the course of work that restrict progress. The Arbitration Panel will be composed of three members: a member selected by the Steering Committee without NIH staff voting, a member selected by NICHD, and a member with expertise in the relevant area selected by the other two members. 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 E. Nicholson, M.D., M.S. Pediatric Critical Care and Rehabilitation Program National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 2A03, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 435-6843 FAX: (301) 402-0832 Email: firstname.lastname@example.org o Direct your questions about peer review issues to: Robert Stretch, Ph.D. Director, Division of Scientific Review National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 5B01, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-1485 FAX: (301) 402-4104 Email: email@example.com o Direct your questions about financial or grants management matters to: Chris Robey Grants Management Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, 8A17, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 435-6996 FAX: (301) 451-5510 Email: firstname.lastname@example.org 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: Carol E. Nicholson, M.D., M.S. Pediatric Critical Care and Rehabilitation Program National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 2A03, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 435-6843 FAX: (301) 402-0832 Email: email@example.com SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). Applications must have a Dun and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document is available at https://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. SUPPLEMENTARY INSTRUCTIONS: Each applicant Principal Investigator for a Clinical Center should prepare an application that reflects two fundamental components: 1) the qualifications of the Principal Investigator and research nurse to be supported at the center, as well as the qualifications of the applicant institution to participate fully in the Network described in this RFA. In addition, it is appropriate to include support for a half-time administrative or data entry/collation employee. 2) a proposal for an experimental or descriptive study to be implemented by the network within the first 18 months after award. The proposal must be for a study term of no greater than 18 months, so that the first Network study will be completed within 36 months of the award. The budget for the study should reflect its implementation at all six centers. 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: https://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 and all copies of the appendix material must be sent to: Robert Stretch, Ph.D. Director, Division of Scientific Review National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 5B01, MSC 7510 Bethesda, MD 20892-7510 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-1485 FAX: (301) 402-4104 Email: firstname.lastname@example.org APPLICATION PROCESSING: Applications must be received on or before 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. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within eight weeks. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA, it is to be prepared as a NEW application. That is, the application for the RFA must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NICHD. 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 Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Receive a written critique o Receive a second level review by the National 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 the 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 the application's overall score, weighting them as appropriate for each application. The application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. PROPOSED NETWORK STUDY: SIGNIFICANCE: Does this proposed network study address an important problem? If the aims of the study are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? Can the proposed study be completed within 36 months of the award? INNOVATION: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? INVESTIGATOR: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the Principal Investigator and other researchers (if any)? ENVIRONMENT: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score: QUALIFICATIONS AND EXPERIENCE: The expertise, training, and experience of the investigators and staff, including the administrative abilities of the Principal Investigator and Research Nurse; especially evidence that her/his time can realistically be devoted to the program for the effective development of the Network. PEDIATRIC CRITICAL CARE STAFFING: Quality of the clinical care and research experience of the physicians staffing the Clinical Center pediatric intensive care unit. WILLINGNESS TO PARTICPATE IN A COLLABORATIVE RESEARCH NETWORK: Applicant institution's history of collaborative research, the Principal Investigator's depth of commitment and ability to work with other Network Centers, NICHD, and the Network Data Coordinating Center. FULL SPECTRUM OF PEDIATRIC SPECIALISTS AND SUBSPECIALISTS IN MEDICINE AND SURGERY: Evidence of staffing and collaboration of the full spectrum of pediatric medical and surgical specialists and subspecialists, as detailed under SPECIAL REQUIREMENTS. A HISTORY OF COOPERATION BETWEEN PEDIATRIC CRITICAL CARE MEDICINE AND SURGERY TOWARDS EXCELLENCE: Evidence and quality of collaborative activities and research productivity between the specialties involved in pediatric critical care, including the research productivity of the surgical consultants. FACILITIES AND CAPABILITIES: Quality of the support staff, laboratory facilities, imaging capabilities, pharmacies with research capability and experience, and qualified staff in respiratory therapy. Capacity of the applicant Center to follow children as outpatients and capture pertinent outcome data for up to two years after admission. PROTOCOL DEVELOPMENT: Quality of proposed strategy to streamline protocol development and acceptance among Centers in the network. PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below.) INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below.) CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. ADDITIONAL CONSIDERATIONS 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: July 12, 2004 Application Receipt Date: August 9, 2004 Peer Review Date: October/November 2004 Council Review: January 2005 Earliest Anticipated Start Date: April 01, 2005 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 HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm). DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required for all types of clinical trials, including physiologic, toxicity, and dose- finding studies (phase I); efficacy studies (phase II); efficacy, effectiveness and comparative trials (phase III). The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risk to the participants (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: https://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 "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 (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at https://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. 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 https://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 https://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 https://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. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule," on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html. 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 at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at https://grants.nih.gov/grants/policy/policy.htm. 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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