PHARMACOLOGICAL APPROACHES TO ENHANCE NEUROMODULATION IN REHABILITATION RELEASE DATE: July 22, 2002 RFA: HD-02-023 National Institute of Child Health and Human Development (NICHD) (http://www.nichd.nih.gov) National Institute on Deafness and Other Communication Disorders (NIDCD) (http://www.nidcd.nih.gov) National Institute of Neurological Disorders and Stroke (NINDS) (http://www.ninds.nih.gov) LETTER OF INTENT RECEIPT DATE: September 27, 2002 APPLICATION RECEIPT DATE: October 25, 2002 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanisms 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 Pharmacological compounds have the potential to enhance functional recovery in rehabilitation, especially when used in conjunction with behavioral and physical therapy. This Request for Applications (RFA) supports studies relevant to the treatment of neurological conditions such as stroke, brain trauma, spinal cord injury, neurodevelopmental and neurodegenerative disorders, infections, and neurosurgery. Applications in response to this RFA must focus on rehabilitative strategies rather than the reduction of acute pathology. They may include studies involving synaptic plasticity, neurotransmitter interactions, neurotrophic mechanisms, pain or fatigue, or any other neurological mechanisms that accelerate the recovery process, enhance function or reduce disability. Studies in validated animal models may be proposed, provided they include appropriate functional outcomes. Pilot clinical trials in humans may also be considered. RESEARCH OBJECTIVES Background Several studies over the last few decades have examined the influence of environmental activity on the neural substrate. Proper activity is necessary for the development of appropriate connections in motor, cognitive, and behavioral systems. Animals raised in enriched environments develop more elaborate synaptic connections with corresponding functional benefits. Conversely, sensory deprivation has adverse effects on synaptic development with lasting functional consequences. These same principles have been applied to clinical and educational settings where early experience and enriched environments are used to enhance development and learning in children. More recently, these principles have been extended into the rehabilitative setting, for many of the mechanisms that drive initial neuronal development reappear during regeneration and recovery. Therapeutic exercise is used to enhance existing and regenerating neuronal pathways. The NIH is currently supporting clinical trials to examine the use of weight-supported treadmill training to stimulate gait in individuals with spinal cord injury and constraint-induced therapy to enhance the use of impaired limbs by stroke patients. Other rehabilitative approaches involve the use of therapeutic training to improve cognitive and behavioral function. Pharmacological compounds could further enhance the benefits of rehabilitative therapies through several possible mechanisms. Psychoactive drugs that stimulate appropriate neurotransmitter pathways have the potential to enhance or modulate synaptic function. Similar approaches have been used to delay cognitive decline in neurodegenerative disorders (e.g., cholinergic treatments for Alzheimer disease) or to sharpen attention in childhood behavioral disorders. Another possibility is the use of neurotrophic compounds to stimulate synaptic regeneration, improve synaptic efficacy or enhance other neurocellular processes. Drugs that reduce pain or fatigue could enhance the benefits of exercise and improve compliance. Neuroendocrine factors have been shown to influence recovery from traumatic brain injury and may explain gender differences. This RFA provides incentive for multidisciplinary groups to develop proposals to extend these promising findings into clinical rehabilitation. Research Scope Applications submitted in response to this RFA should examine strategies for using pharmacological agents to enhance rehabilitation. The focus must be on the rehabilitative phase, rather than on preventing injury, minimizing acute pathology or reducing ongoing degeneration. Studies in animal models may be included if they have the potential for developing rehabilitative strategies. Rehabilitative strategies may target motor or sensory function, behavior, cognition, and/or memory. The focus should be on neurological conditions rather than those primarily involving muscle, cardiovascular function or metabolism. Applicants are encouraged to provide a mechanistic basis for the use of pharmacological interventions in a rehabilitative context and to discuss the potential for incorporation into clinical settings. A major priority in the NIDCD strategic plan is the development and improvement of devices, pharmacologic agents, and strategies for habilitation/rehabilitation of human communication disorders. The NIDCD would be specifically interested in applications responsive to this RFA focused in the areas of hearing (e.g., cochlear implants), balance, voice (e.g., spasmodic dysphonia), speech, language (e.g., aphasia), and the chemical senses of taste and smell (e.g., anosmia and ageusia). Applications responsive to this RFA may include studies in animal models or pilot clinical trials in humans. Research topics may include, but are not limited to, the following: o Anatomical correlates of functional recovery, plasticity, and adaptation to evaluate pharmacological interventions, o Use of pharmacotherapy to accelerate recovery of sensory or motor functions following disease or injury (e.g., vestibular compensation), o Interaction of pharmacological compounds with behavioral and/or physical therapy approaches, o Use of pharmacological approaches to enhance the efficacy of or compliance with behavioral and physical therapy regimes, o Improved models for evaluating the interaction of neuroactive compounds and therapeutic approaches in rehabilitation, o Studies of focal delivery of pharmacological agents to target specific areas of central nervous system and studies to investigate the effects of localized neuromodulation, MECHANISM OF SUPPORT This RFA will use the NIH Research Project Grant (R01) and the Exploratory/Developmental Research Grant (R21) award mechanisms. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing continuation R01 applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is July 1, 2003. The R01 mechanism is recommended for proposals in well-established areas, especially where there is significant preliminary data. The R21 mechanism is used for support of creative, novel, and/or high risk/high payoff approaches that could produce innovative advances in this field. This includes feasibility studies, protocol planning, and the incorporation of new disciplines and technologies. The R21 provides the means to acquire the necessary pilot information, to attract talented new investigators from related disciplines, and to foster the development of interdisciplinary, inter-institutional collaborative efforts among investigators with diverse training and expertise. R21 grants are non-renewable, and may not be used to supplement an ongoing project. 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 participating institutes intend to commit approximately $2.4 million (NICHD $1.5 million, NIDCD $500,000 and NINDS $400,000) in total costs [Direct plus Facilities and Administrative (F & A) costs] in FY 2003 to fund new and/or competitive continuation grants in response to this RFA. An applicant for an R01 may request a project period of up to five years and a budget for direct costs of up to $250,000 per year. An applicant for an R21 may request a project period of up to three years and a budget of $100,000 per year in direct costs. 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, NIDCD, and NINDS 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 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: Ralph M. Nitkin, Ph.D. Program Director, Biological Sciences and Career Development 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) 402-2242 FAX: (301) 402-0832 Email: rn21e@nih.gov Lana Shekim, Ph.D. Program Director, Voice and Speech Scientific Programs Branch, DER National Institute on Deafness and Other Communication Disorders 6120 Executive Blvd., EPS-400-C, MSC 7180 Bethesda, MD 20892-7180 Telephone: (301) 496-5061 FAX: (301) 402-6251 Email: shekiml@nidcd.nih.gov Daofen Chen, Ph.D. Program Director, Channels/Synapses/Circuits National Institute of Neurological Disorders and Stroke 6001 Executive Boulevard, Room 2131, MSC 9523 Bethesda, MD 20892-9523 Telephone: (301) 496-1917 FAX: (301) 402-1501 Email: daofen_chen@nih.gov 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: rs365s@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 8A17H, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-6996 FAX: (301) 496-0915 Email: cm143g@nih.gov Sara Stone Chief, Grants Management Branch National Institute on Deafness and Other Communication Disorders 6120 Executive Boulevard, Room 400B, MSC 7180 Bethesda, MD 20892-7180 Telephone: (301) 402-0909 FAX: (301) 402-1758 Email: stones@nidcd.nih.gov Aricia Cottman Grants Specialist National Institute of Neurological Disorders and Stroke 6001 Executive Boulevard, Room 3290, MSC 9537 Bethesda, MD 20892-9537 Telephone: (301) 496-8072 FAX: (301) 402-0219 Email: ac195q@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: Ralph M. Nitkin, Ph.D. National Center for Medical Rehabilitation Research National Institute of Child Health and Human Development Building 6100E, Room 2A03, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 402-2242 FAX: (301) 402-0832 Email: rn21e@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. SUPPLEMENTAL INSTRUCTIONS: The Research Plan for an R21 application need not include preliminary data and should be limited to 15 pages. Appendices may not be submitted. 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 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 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 for responsiveness by the NICHD, NIDCD, and NINDS. 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, the National Advisory Deafness and Other Communications Disorders Council, and the National Advisory Neurological Disorders and Stroke 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 DATA SHARING: The adequacy of the proposed plan to share data. 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: September 27, 2002 Application Receipt Date: October 25, 2002 Peer Review Date: February/March 2003 Council Review: May/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. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at https://grants.nih.gov/grants/stem_cells.htm and at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide the official NIH identifier(s)for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. 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 Nos. 93.929, 93.173, and 93.853 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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