RFA-NS-02-004: TECHNOLOGY DEVELOPMENT FOR SAFE AND EFFECTIVE DEEP BRAIN STIMULATION

Department of Health
and Human Services (HHS)

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TECHNOLOGY DEVELOPMENT FOR SAFE AND EFFECTIVE DEEP BRAIN STIMULATION Release Date: July 27, 2001 RFA: RFA-NS-02-004 National Institute of Neurological Disorders and Stroke, NINDS (http://www.ninds.nih.gov/) Letter of Intent Receipt Date: September 20, 2001 Application Receipt Date: November 20, 2001 THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. MODULAR INSTRUCTIONS MUST BE USED FOR RESEARCH GRANT APPLICATIONS REQUESTING LESS THAN $250,000 PER YEAR IN ALL YEARS. MODULAR BUDGET INSTRUCTIONS ARE PROVIDED IN SECTION C OF THE PHS 398 (REVISION 5/2001) AVAILABLE AT http://grants.nih.gov/grants/funding/phs398/phs398.html. PURPOSE Deep brain stimulation (DBS) in the thalamus for the treatment of tremor was approved by the FDA in 1997 following the pioneering work of Benabid and colleagues in France. Subsequently it has been found that stimulation in the subthalamic nucleus (STN) or globus pallidus (GPi) can relieve multiple symptoms of Parkinson"s disease (PD). DBS has been successful in restoring significant mobility to a large number of patients with advanced PD. During the past year, GPi and STN stimulation underwent review at the FDA for potential use to decrease symptoms of dyskinesia, tremor, postural instability, and/or bradykinesia in individuals with advanced PD. Over two thousand patients have been implanted with DBS systems and the number is growing rapidly. Using the current guidelines, estimations are that as many as 15,000 individuals per year will be candidates for this procedure. This number could increase as the population ages and/or if the indications are expanded to include PD patients with less advanced symptoms. Despite the success of this therapy in some patients, there is significant room for improvement. Complications such as breakage of the electrode lead wires or movement of the stimulating electrode occur. Untoward effects arising from electrical stimulation of neural tissue other than the target tissue can limit stimulation and limit the beneficial effects in some cases. The optimal methods for positioning the electrode and the optimal number and size of the stimulating electrodes has not been determined. In addition, placement of these electrodes carries a small risk of significant complications such as intracranial hemorrhage or infection with potential persistent neurological disability including hemiplegia or cognitive dysfunction. One other limitation to further study of DBS is the lack of suitable stimulation and electrical recording systems that would permit study of DBS in appropriate animal models. Improvement in this treatment modality should be possible through research and development to advance techniques for delivering electrical stimulation to STN, GPi and other brain structures. This announcement will support research to position electrodes in the appropriate target areas, to devise ways to make electrode placement more stable, to increase reliability of electrodes and electrode lead wires, to develop electrodes and systems capable of recording as well as stimulating, to develop electrodes capable of more selective stimulation, to develop better stimulators, and to improve the safety of implanted systems. RESEARCH OBJECTIVES A workshop on DBS was held on the NIH campus on March 3, 1999 to discuss the opportunities and needs for further research in DBS. As a result of the recommendations from this workshop the NIH issued an RFA "CONSORTIUM ON DEEP BRAIN STIMULATION FOR THE TREATMENT OF PARKINSON"S DISEASE AND OTHER NEUROLOGICAL DISORDERS" in September 1999. The initial RFA called for research on animal models, better electrodes and stimulator technology, clinical studies and trials, and studies of the mechanism of action of DBS. In response to the RFA, we have awarded several grants to investigators and have recruited a core group of investigators into a DBS consortium. This follow-up RFA is seeking applications that will expand the consortium and strengthen the research effort by developing advanced methods and hardware for safe and effective stimulation of deep brain structures. A companion RFA will be issued to request additional research on mechanisms of action of DBS. As the third arm of the consortium, investigators interested in clinical trials of DBS are encouraged to contact NINDS staff to discuss opportunities to conduct clinical studies and trials in this area. Research Goals and Topics: The goal of this announcement is to expand research in the area of technology development for DBS. Research is sought in areas of electrode placement, electrode stability, stimulator design, lead wire reliability, and other factors related to providing safe, reliable DBS therapy. Studies with human volunteers are not within the scope of this RFA. Examples of potential research topics include: o The development and validation of better methods of placing electrodes that reduce placement time, expense, and morbidity, and that increase accuracy of placement. o The development and validation of better DBS electrodes and lead wires that are more reliable, safer to implant and/or provide greater control of the stimulation site. o The development of stimulators that are rechargeable and/or that have a wider range of stimulation rates, stimulation currents, pulse widths, pulse waveforms, and that permit recording from electrodes as well as stimulation. o The development of microelectrodes and implantation systems for use in animal models of PD and DBS that can simultaneously stimulate and record, do microdialysis, or infuse chemicals at multiple sites in multiple brain structures involved in the control of movement. o Studies of the safety of DBS stimulation, including acute effects of electrode placement and long-term effects of electrode placement and stimulation. SPECIAL REQUIREMENTS Consortium and Annual Meeting: Investigators who participate in this RFA will collaborate with other investigators in the previously established consortium for DBS. Synthesis of the individual investigator’s research projects into an integrated research effort on Deep Brain Stimulation will require multidisciplinary collaboration and communication of research results and opportunities. To facilitate such interactions, the NINDS, NIMH 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 traveling to the annual meeting should be built into the proposed budget. Collaborative Studies: The consortium structure is put in place to facilitate collaboration among participating investigators. A mission of the consortium is to foster joint collaborative initiatives among members. To this end, a Steering Committee composed of the NINDS, NIMH 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. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) R01 award mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this RFA may not exceed 5 years. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. The earliest anticipated award date is July 1, 2002. FUNDS AVAILABLE NINDS intends to commit approximately $1,500,000 in FY 2002 to fund 2-5 new and/or competitive continuation grants in response to this RFA. An applicant may request a project period of up to 5 years and a budget for direct costs of up to $400,000 per year. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plan of NINDS provides 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. 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. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or answer questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: William J. Heetderks, M.D., Ph.D. Repair and Plasticity, NINDS Neuroscience Center 6001 Executive Blvd Room 2207, MSC 9525 Bethesda, MD 20892-9525 Telephone: (301) 496-1447 Fax: (301) 480-1080 Email: heet@nih.gov Eugene J. Oliver, Ph.D. Neurodegeneration, NINDS Neuroscience Center 6001 Executive Blvd Room 2203, MSC 9525 Bethesda, MD 20892-9525 Telephone: (301) 496-5680 FAX: (301) 480-1080 E-mail: eo11c@nih.gov Direct inquiries regarding review issues to: Lillian M. Pubols, Ph.D. Chief, Scientific Review Branch National Institute of Neurological Disorders and Stroke Neuroscience Center Suite # 3208 6001 Executive Blvd. Bethesda, MD 20892-9529 Tel.: 301-496-5324/9223 e-mail: LP28E@NIH.GOV Direct inquiries regarding fiscal matters to: Brenda Kibler Grants Management Branch, NINDS Neuroscience Center 6001 Executive Blvd Room 3290, MSC 9537 Bethesda, MD 20892-9525 Telephone: (301) 496-9231 EMAIL: kiblerb@ninds.nih.gov LETTER OF INTENT Prospective applicants are asked to submit 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 IC staff to estimate the potential review workload and plan the review. The Letter of Intent is to be sent to: William J. 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 Email: Heet@nih.gov SCHEDULE SUMMARY Letter of Intent Receipt Date: September 20, 2001 Application Receipt Date: November 20, 2001 Peer Review Date: March, 2002 Council Review: May, 2002 Earliest Anticipated Start Date: July, 2002 APPLICATION PROCEDURES The PHS 398 research grant application instructions and forms (rev. 5/2001) available at http://grants.nih.gov/grants/funding/phs398/phs398.html are to be used in applying for these grants. This version of the PHS 398 is available in an interactive, searchable PDF format. Although applicants are strongly encouraged to begin using the 5/2001 revision of the PHS 398 as soon as possible, the NIH will continue to accept applications prepared using the 4/1998 revision until January 9, 2002. Beginning January 10, 2002, however, the NIH will return applications that are not submitted on the 5/2001 version. For further assistance contact GrantsInfo, Telephone 301/710-0267, Email: GrantsInfo@nih.gov. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS 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 NIH staff. The research grant application form PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html is to be used in applying for these grants, with modular budget instructions provided in Section C of the application instructions. Applicants are permitted, however, to use the 4/1998 revision of the PHS 398 for scheduled application receipt dates until January 9, 2002. If you are preparing an application using the 4/1998 version, please refer to the step-by-step instructions for Modular Grants available at http://grants.nih.gov/grants/funding/modular/modular.htm. Additional information about Modular Grants is also available on this site. The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. 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: Lillian M. Pubols, Ph.D. Chief, Scientific Review Branch National Institute of Neurological Disorders and Stroke Neuroscience Center Suite # 3208 6001 Executive Blvd. Bethesda, MD 20892-9529 (For Fed Ex or other courier use Rockville, MD 20852) Upon receipt, applications will be reviewed for completeness by the Center for Scientific Review and responsiveness by Institute staff. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. 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 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 NINDS in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and 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, assigned a priority score, and receive a second level review by the NINDS National Advisory 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. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that 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. (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? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research. o 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. AWARD CRITERIA Award 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. 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 sub-populations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are 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 research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to 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) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. 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 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 was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. 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. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. 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. This policy announcement is found in the NIH Guide for Grants and Contracts Announcement dated June 5, 2000, at the following website: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at: http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm Applicants may wish to place data collected under this RFA (PA) 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. 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 Request for Applications (RFA), TECHNOLOGY DEVELOPMENT FOR SAFE AND EFFECTIVE DEEP BRAIN STIMULATION, 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. 93.853. 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 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 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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