CONSORTIUM ON DEEP BRAIN STIMULATION FOR THE TREATMENT OF PARKINSON'S DISEASE AND OTHER NEUROLOGICAL DISORDERS Release Date: September 27, 1999 RFA: NS-99-006 National Institute of Neurological Disorders and Stroke National Institute on Aging Letter of Intent Receipt Date: November 15, 1999 Application Receipt Date: February 16, 2000 THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA. PURPOSE In response to the resurgence of interest in the application of neurosurgical approaches to the treatment of movement disorders and especially Parkinson's disease, the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (NIA) invite qualified investigators to submit grant applications for a broad range of studies aimed at improving the use of deep brain stimulation as a therapy. The purpose of this Request for Applications (RFA) is to encourage additional basic and clinical studies into the mechanisms of a potentially reversible, adjustable and long term electrical treatment of neurological disorders. It is expected that this research will produce a greater understanding of the circuitry involved in movement and related disorders, the development of improved electrodes for use in deep brain stimulation, and improved treatment. This RFA will create a consortium of research programs in deep brain stimulation that will serve as a focal point for collaboration and expansion of the field. Investigators in the consortium will conduct research within their areas of expertise and will also collaborate with other consortium members to develop interdisciplinary projects that pool results and expertise available in the individual projects. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This RFA, "Deep Brain Stimulation for the Treatment of Parkinson's Disease and other Neurological Disorders" is related to the priority area of chronic disabling conditions. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 17-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202/512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. Complete and detailed instructions and information on Modular Grant applications can be found at https://grants.nih.gov/grants/funding/modular/modular.htm The mechanism of support for this initiative is the regular research grant (R01). Responsibility for planning, direction and execution of the proposed research will rest solely with the applicant. Because the nature and scope of the research proposed in response to this RFA may vary, it is anticipated that the size of the award may also vary. This RFA is a one-time solicitation. Future applications will compete with all investigator-initiated applications and be reviewed according to the customary peer-review procedures. Investigators seeking to carry out pilot studies of clinical research in preparation for a clinical trial are encouraged to make use of the "NINDS Pilot Clinical Trial Grant (R01) For Neurologic Disease" as described in Program Announcement PAR-97-103, August 29, 1997. FUNDS AVAILABLE The NINDS and NIA will allocate up to 5 million dollars in total costs to support applications responding to this RFA in FY 2000. Applicants may request up to five years of support. In all cases, facilities and administrative (indirect) costs will be awarded based on the negotiated rates. The award of grants pursuant to this RFA is contingent upon the receipt of a sufficient number of high quality applications and the availability of funds for this purpose. Policies that govern research grant programs of the National Institutes of Health are applicable to all procedures in the receipt, review and support of this RFA. RESEARCH OBJECTIVES The overall purpose of this initiative is to continue to support and stimulate the progress on deep brain stimulation as a treatment for Parkinson's disease and related neurodegenerative disorders. Chronic electrical stimulation through electrodes implanted deep in the brain can relieve the symptoms of Parkinson's disease. Based on results from only about 30 patients, the FDA recently approved deep brain stimulation (DBS) within the thalamus for relief of tremor of Parkinson's disease and also for non-Parkinsonian "essential tremor." Tremor is often not the most troublesome symptom of Parkinson's disease. Now, evidence, mostly from Europe, suggests that DBS can relieve other, more debilitating symptoms of Parkinson's disease such as bradykinesia and rigidity. Not only does the benefit appear to be long lasting, but also there is tantalizing evidence that chronic stimulation may slow progression of the disease. Side effects of chronic stimulation seem to be less problematic than drugs, and stimulation therapy is less destructive than surgical ablation therapies, and thus potentially reversible if more complete treatments become available. The promise of DBS emphasizes in a dramatic way the importance of electrical activity in reorganizing neural circuits and brain function. DBS may also alter the response of cells to intrinsic signaling molecules and, perhaps, to drugs. How activity modifies the nervous system is among the most active and important areas in neuroscience. The National Institute of Neurological Disorders and Stroke convened a Workshop on Deep Brain Stimulation for Parkinson's Disease on March 3, 1999 in Bethesda, MD to evaluate the current information and identify the need for future research. The Workshop concluded that DBS is one of the most dramatic advances in decades for treatment of neurological disorders. It provides a powerful effect with obvious benefit in the treatment of Parkinson's disease, and with potential benefit in the treatment of other neurological disorders. Accordingly, the following suggestions are made for further work: O Studies that are appropriately scaled, prospective, controlled, randomized clinical trials to obtain longitudinal data on the effect of DBS on cognition and mood, and to examine the difference of stimulation on various targets. O Studies, including the development of models, to further refine the understanding of the functional organization of basal ganglia and its circuits and their role in the control of behavior, including planned movement. O Studies of the mechanisms of action of DBS, including local and distant alterations such as, respectively, micro-physiological changes occurring at the electrode tip and changes in the neural networks. O Studies of the effect of short and long term stimulation on motor control circuitry. O The development of improved and more versatile implantable microelectrodes and stimulators to provide more somatotopic and focal information that is better customized for certain regions. O The development of microelectrodes that can simultaneously stimulate and record, do microdialysis, or infuse chemicals. O The development of smaller, multiple-site electrodes, that can stimulate and record from different brain structures simultaneously, such as the subthalamic nucleus and the globus pallidus. O The development of stimulators that are rechargeable and that have a wider range of frequencies, voltages, and pulse widths, and that might provide random pulses. O The design of better methods of placing electrodes that reduce placement time, expense, and morbidity, and increase accuracy. O The development of improved animal models showing progressive degeneration that allow the study of the physiology of brain stimulation in the normal and diseased or injured brain and the changes chronic stimulation evokes in cells and circuits including plasticity of synaptic connections, modulation of gene expression, and the influences of activity on trophic factor release and sensitivity. O The development of rodent models to study the behavioral manifestations of different movement disorders and for acute drug screening. O Studies of the purported neuroprotective effect of long-term DBS. O Studies to compare DBS with surgical ablation in earlier stage Parkinson's disease patients and in less compromised Parkinsonian animal models. O Clinical and basic studies to determine the effect of DBS on symptoms that are resistant to treatment with levodopa or dopaminergic drugs. O Studies to examine the effects of DBS on the treatment of other neurological problems, including pain, epilepsy, spinal cord injury, traumatic brain injury, and stroke, and psychiatric disorders related to Parkinson's disease. O Studies of the ethical issues in proposing surgery for earlier stage patients who presently are adequately treated by drugs. SPECIAL REQUIREMENTS Annual Meeting: Synthesis of the component projects of the consortium will require multidisciplinary collaboration and communication of research results and opportunities. To facilitate such interactions, the NINDS and NIA will hold a yearly DBS Workshop. The PI and one other representative from each project will attend this meeting in Rockville, Maryland. This meeting will also be open to interested members of the research community. The cost of participating in the annual meeting should be built into the proposed budget. Collaborative Studies: The consortium structure is put in place to facilitate collaboration among investigators. A mission of the consortium is to foster joint collaborative initiatives among members. To this end, a Steering Committee composed of the NINDS and NIA Program Directors, invited consultants, and the Principal Investigators will review and approve plans for collaboration. The cost of participating in collaborative studies should be estimated at 20% of the basic cost of the grant for years beyond year one. Allocation of some or all of these funds will be optional and will depend upon approval by the Program Directors at the recommendation of Steering Committee based on proposed collaborations. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided 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 research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994. NIH POLICY AND GUIDELINES ON THE INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH 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 is scientific or ethical reasons not to include them. This 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 was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: https://grants.nih.gov/grants/guide/notice-files/not98-024.html LETTER OF INTENT Prospective applicants are asked to submit, by November 15, 1999 a Letter of Intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although a Letter of Intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows Institute staff to estimate the potential review workload and avoid conflict of interest in the review. The Letter of Intent is to be sent to: Eugene J. Oliver, Ph.D. Program Director National Institute of Neurological Disorders and Stroke National Institutes of Health Neuroscience Center 6001 Executive Blvd., Room 2203 Bethesda, MD 20892-9525 APPLICATION PROCEDURES The Research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research; from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, Room MSC 7910, Bethesda, MD 20892, telephone 301/710-0267;email: GrantsInfo@nih.gov. 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. In addition, the RFA label available in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. The sample RFA label available at: https://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and Institute staff. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $250,000 per year. (Applications that request more than $250,000 direct costs in any year must follow the traditional PHS398 application instructions.)The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: PHS 398 o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative page. (See https://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the total direct costs requested for each year. This is not a Form page. o Under Personnel, List key project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of key personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by reviewers in the assessment of each individual's qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: https://grants.nih.gov/grants/funding/modular/modular.htm - Complete the educational block at the top of the form page; - List position(s) and any honors; - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years. - List selected peer-reviewed publications, with full citations; o CHECKLIST - This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. o The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. Submit a signed, typewritten original of the application, including the Checklist, and three If they only want one copy we should get 4; or we can get three copies and they get two 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) In order to facilitate the review of applications, please mail or deliver one copy of the application when completed to: Dr. Lillian Pubols Chief, Scientific Review Branch, NINDS, NIH Neuroscience Center 6001 Executive Blvd., Room 3208 Bethesda, MD 20892-9525 Applications must be received by February 16, 2000. 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. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by CSR and responsiveness by NINDS. Incomplete applications will be returned to the applicant without further consideration. As part of the initial merit review, all applications will receive a written critique, undergo a process in which only those applications deemed to have the highest scientific merit (generally the top half of the applications received for review) will be discussed, assigned a priority score, and receive a second level review by the NINDS Advisory Council. What about NIA Council? The next sentence should be deleted. Site visits are not anticipated for these Center grant applications. REVIEW CRITERIA FOR RESEARCH GRANT APPLICATIONS: 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 review, comments on the following aspects of the application will be made in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in the assignment of the overall score. (1) Significance. Does this study address an important problem? If the aims of the application 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? (2) 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? (3) Innovation. Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) 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)? (5) 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? AWARD CRITERIA Funding decisions will primarily be based on scientific and technical merit as determined by the Initial Review Group, review by the National Advisory Neurological Disorders and Stroke Council and by the National Advisory Council on Aging, and the availability of funds. In selection of applications for award, consideration will also be given to the need for program balance across the areas of research outlined in this RFA. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Eugene J. Oliver, Ph.D. Program Director National Institute of Neurological Disorders and Stroke National Institutes of Health Neuroscience Center 6001 Executive Blvd., Room 2203 Bethesda, MD 20892-9525 Telephone: 301/496-5680 FAX: 301/480-1080 E-mail: eo11c@nih.gov William Heetderks, M.D., Ph.D. Program Director National Institute of Neurological Disorders and Stroke National Institutes of Health Neuroscience Center 6001 Executive Blvd., Room 2207 Bethesda, MD 20892-9525 Telephone: 301/496-1447 FAX: 301/480-1080 Email: heet@nih.gov Judith A. Finkelstein, Ph.D. Sensory/Motor Disorders of Aging Program Neuroscience and Neuropsychology of Aging National Institute on Aging Gateway Building, Suite 3C307 7210 Wisconsin Avenue Bethesda MD 20892-9205 Telephone: (301) 496-9350 FAX: (3020 496-1494 Email: jf119k@nih.gov Direct inquiries regarding fiscal matters to: Kimberly Pendleton Grants Management Specialist Grants Management Branch, DEA Neuroscience Center 6001 Executive Blvd., Room 3254 Bethesda, MD 20892-9525 Telephone: (301) 496-9231 FAX: 301-402-0219 EMAIL: kp33e@nih.gov Joe Ellis Grants and Contracts Management Office Gateway Building, Suite 2N212 7201 Wisconsin Avenue Bethesda MD 20892-9205 Telephone: (301) 496-1472 FAX: (301) 402-3672 Email: je14j@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.853 and 93.866. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-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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