CLINICAL TRIAL PLANNING GRANTS TO GUIDE AND IMPROVE TIMING, INTENSITY, DURATION AND OUTCOMES OF PEDIATRIC CRITICAL CARE AND REHABILITATION THERAPEUTIC INTERVENTIONS IN CHILDHOOD CARDIOPULMONARY ARREST RELEASE DATE: July 26, 2002 RFA: HD-02-026 National Institute of Child Health and Human Development (NICHD) (http://www.nichd.nih.gov) LETTER OF INTENT RECEIPT DATE: October 31, 2002 APPLICATION RECEIPT DATE: November 25, 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 purpose of the Clinical Trial Planning Grant is to provide support for the initial development and organization of an effective research team and the elements essential for conducting successful clinical trials. The National Center for Medical Rehabilitation Research (NCMRR) of the National Institute of Child Health and Human Development (NICHD) wishes to use its program in pediatric critical care and rehabilitation research (PCCR) to support clinical trials focused on evaluating the timing, intensity, duration and outcomes of pediatric critical care and rehabilitation interventions for childhood cardiopulmonary arrest. RESEARCH OBJECTIVES Background Outcomes after childhood cardiopulmonary arrest remain suboptimal, despite attempts to standardize rapid intervention and advanced pediatric life support. Neurodevelopmental devastation after restoration of cardiopulmonary function is too common. The effects on the family unit of caring for children after such an occurrence are well known to every pediatric intensivist, rehabilitation specialist and general pediatrician. Both profound neurodevelopmental change and persistent vegetative state are common, enduring, and expensive in terms of financial and social costs to the larger community, as well as to the family. In the United States, 16,000 children are estimated to die of unexpected cardiopulmonary arrest (CPA) each year. Remarkably, overall incidence in children (survivors and non-survivors) remains somewhat difficult to assess, although one recent prospective study found an overall annual incidence of 19.7/100,000 children. Although the data set created by the current literature remains somewhat ambiguous, the current figures assigned to survival to hospital discharge among children arriving at the hospital in both cardiac and pulmonary arrest is reported as two to eight percent. Of survivors of combined cardiac and respiratory arrest, neurological devastation is likely in a high proportion of children: some studies find poor functional outcomes in virtually all such survivors. One study of children discharged from the hospital in a persistent vegetative state showed that death or only minimal awareness was the uniform outcome in subsequent years, and substantial costs (greater than $90,000 per year per patient) were sustained. The prognosis is better for children who experience a respiratory arrest alone. A collective review of available studies shows that there is a 75 percent survival to discharge rate among children arriving at the hospital apneic but with a palpable pulse. The same study showed a much higher percentage of children with a good neurologic outcome, as compared to those with both cardiac and pulmonary arrest. In-hospital cardiopulmonary arrest is also known to carry a better prognosis, but there is considerable variability in reported outcomes. As the initiation and withdrawal of resuscitation, critical care and rehabilitative strategies in childhood cardiopulmonary arrest take place in the context of tragedy, decision making is exceptionally difficult, and the lack of substantial data and uniformity of practice standards adds to the agony for patients, families and practitioners. The challenge for the health care system is to develop and universally adopt guidelines to avoid futile resuscitation and to improve the outcomes in survivors. The emerging discipline of pediatric rehabilitation is providing interventions for some special needs children that may be beneficial in promoting improvements in functional areas such as cognition, mobility, performance of self-care, community and school integration, and family/caregiver education and support. Important questions, however, remain regarding the effectiveness of individual treatment strategies, as well as the organization and intensity of pediatric rehabilitation services that realistically can be offered. Similarly, innovative strategies to improve outcomes in the acute setting and minimize organ damage are needed. Hypothermia, institution of extracorporeal life support systems, and development of new therapies for the prevention and treatment of hypoxic-ischemic encephalopathy are a few of the newer therapeutic avenues under discussion in the literature. The roles of excitotoxic amino acids, proteolytic enzymes, free radicals, nitric oxide and leukocyte biology are not precisely understood. The importance of reperfusion injury after anoxic-ischemic encephalopathy is emerging in the critical care literature. As injury and cellular repair mechanisms, especially neuronal apoptosis and necrosis and neuronal stem cell biology, are better understood, potential avenues for therapeutic interventions are developed. Such therapeutic strategies may be of different value in immature vs. mature animals and humans. The increasing presence of comorbidities in childhood cardiopulmonary arrest parallels the increased numbers of children with special needs in our communities. The increasing numbers of children with impaired pulmonary function, immunologic disability, post-surgical cardiac conduction and functional limitations, and impaired cognition and mobility, impose additional complexity. In planning for clinical research addressing improvement for childhood victims of cardiopulmonary arrest, investigators should take into account the differences in appropriate strategies for special needs children, and how comorbidities may influence therapeutic outcome. Treatments delivered by rehabilitation specialists can dramatically increase the quality of life and functional independence for individuals following devastating illnesses. There is presently inadequate evidence in the pediatric and rehabilitation literature to substantiate the use of rehabilitation treatment as effective for minimizing disability in survivors of cardiopulmonary arrest. These factors underscore the need to determine efficacious rehabilitation strategies for these disorders. Such evidence is urgently needed as the population of childhood cardiopulmonary arrest survivors increases. Central to rehabilitation is the primary goal of functional independence and return to pre-injury or pre-surgical status. Where such goals are unrealistic, or adequate data to support realistic goal- setting is lacking, the choice, timing, intensity and duration of therapeutic interventions must be subjective, and the influence of socioeconomic disparities maximal. Although these issues underlie medical rehabilitation practice, few studies have demonstrated the most appropriate treatment course to help guide clinical practice in cohorts of cardiopulmonary arrest survivors. Similarly, there is a lack of adequate evidence to demonstrate which components in the resuscitation continuum are most critical in preventing neurological devastation in childhood arrests. It might be hypothesized that oxygenation must be restored to pre-arrest levels, but is this to be prioritized over restoration of circulation or metabolic manipulation (hypothermia, substrate)? Is enhanced oxygen delivery of benefit in the child in cardiopulmonary arrest? Some studies suggest that increased oxygen concentration in the injured brain may exacerbate reperfusion injury via oxygen radical formation and lipid peroxidation. In a few animal models, neurologic outcome was less favorable in subjects resuscitated with higher inspired oxygen concentrations. Inadequate data exist regarding the timing, intensity, and duration of resuscitation treatment interventions and outcomes after childhood cardiopulmonary arrest. For the community of clinical rehabilitation practitioners, the techniques and therapies to maximize functional ability in cohorts of childhood cardiopulmonary arrest survivors have not been demonstrated empirically. Additionally, the data substantiating the time frame of rehabilitation interventions to maximize outcome is vital to planning for such services. Due, in part, to the diversity of the needs and goals of the post-arrest population, there is little agreement among professionals as to treatment strategies, the efficacy of rehabilitation, or desired or achievable outcomes. What is the sequence by which different areas of function recover following arrest, and how can this information be used to design/guide intervention? Should rehabilitation begin in the pediatric intensive care unit (PICU)? If so, which interventions can or should be implemented in the intensive care unit? If rehabilitation intervention is initiated in the PICU immediately after resuscitation, is outcome enhanced? Is there an optimum time for aggressive intervention? Is twice-a-day physical therapy more effective than once-a-day therapy? Is there a point in time when one or the other is more effective? The relationship between the choice, timing, intensity and duration of treatment and subsequent follow up is an issue that pervades all pediatric critical care and rehabilitation practice. The importance and timeliness of this topic was highlighted at the NICHD Patient Learning During Medical Rehabilitation Conference (1998), the NICHD Neonatal Follow-up Conference (June, 2002), and the NICHD Pediatric Critical Care Research Planning Conference (May, 2002). The purpose of this initiative is to encourage studies that evaluate models of providing pediatric critical care and rehabilitation that consider choice, timing, intensity and duration of treatment. In addition, current practice has evolved in response to reimbursement guidelines, rather than clinical evidence. This RFA builds on the recommendations of these workshops, and encourages clinical research studies that will establish optimal delivery schedules and the kinds and amounts of pediatric critical care and rehabilitation services for patients in different diagnosis groups or categories. Research Scope Current constraints on clinical researchers make the complex and time- consuming process of planning Phase III clinical trials problematic, especially in the fields of pediatric critical care and rehabilitation where there is not a well-established clinical research infrastructure. These planning grants will provide a mechanism for early peer review of the rationale and design of the potential clinical trial, and provide successful applicants resources to assist them in the development of detailed clinical trial study plans and collaborations. It is hoped that these Planning Grants will help to facilitate the development of clinical trial projects in the NCMRR pediatric critical care and rehabilitation research (PCCR) program. The range of activities that may be supported by this Clinical Trial Planning Grant includes: 1. Development of a detailed experimental design, including: translation of the clinical question into a statistical hypothesis; determination of the sample size and duration of the trial; selection of endpoint(s) and data to be collected; creation of inclusion/exclusion criteria. 2. Development of specific protocols, including: patient selection and informed consent procedures; randomization and masking procedures; data collection techniques; treatment administration and dose/quantity measurements; follow-up and quality control procedures. 3. Development of detailed plans for patient recruitment and retention, including women and minority individuals, and plans for recruitment outreach. 4. Identification of other personnel necessary to perform the proposed research, including statisticians, data managers, and study coordinators. 5. Identification of the physical resources necessary to perform the proposed research, including clinical space and equipment that is accessible to subjects and researchers with disabilities. 6. Selection of specific methods of data analysis. 7. Evaluation of models of the pediatric critical care and rehabilitation treatment processes, including: involvement of various professional disciplines, team approaches and treatment settings, coordination of health care systems and resources. 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. This RFA uses just-in-time concepts. It also uses the modular budgeting format (see https://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 intends to commit approximately $1 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. An applicant may request a project period of up to two years and a budget for direct costs of up to $100,000 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 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 issues. o Direct your questions about scientific/research issues to: Carol E. Nicholson, M.D., M.S. Program Director, Pediatric Critical Care and Rehabilitation Research National Center for Medical 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 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 6100 Executive Boulevard, 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 6100 Executive Boulevard, Room 8A14H, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 435-6996 FAX: (301) 480-4783 Email: cm143g@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 E. Nicholson, M.D., M.S. 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 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. 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 https://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 https://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: 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 must be sent to: Robert H. 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) 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. Incomplete and/or nonresponsive 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 the goals discussed in this request for applications (RFA). o Scientific and clinical significance of the proposed clinical intervention, including analysis of the need and potential impact on health care, comparison with competitive therapies, and relevance of the proposed clinical trial to outcomes desired by the target patient population; o Basis or grounding of the project in the relevant literature, including biological mechanisms and supporting clinical data; o Qualifications and research experience of the Principal Investigator and, for multi-center trials, a core of potential center investigators, and a clear statement of the leadership and proposed organization and committee structures of the clinical trial; o The potential of the proposed planning activity to lead to a full-scale clinical trial, including: (a) adequacy of collaborative linkages, (b) likelihood of successfully recruiting research participants, (c) the likelihood of sustaining participant cooperation throughout the trial, and (d) the capability to standardize data collection and follow- up procedures. 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 25, 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: 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 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 (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. 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 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. 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, 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 https://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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