ADVANCED NMR SPECTROSCOPY INSTRUMENTATION Release Date: December 23, 1998 RFA: RR-99-004 P.T. National Center for Research Resources Letter of Intent Receipt Date: February 17, 1999 Application Receipt Date: March 17, 1999 PURPOSE It is the purpose of this Request for Applications (RFA) to stimulate advanced NMR instrumentation development, particularly for liquid phase protein and solid state membrane protein applications, and their effective integration into high- field NMR spectrometer systems. The Small Business Innovation Research (SBIR) program has supported such development efforts; however, the extent of such support has been limited. Recently, the NIH has announced that applicants may request a larger budget and period of support if necessary for completion of the project (See NIH Guide for Grants and Contracts, February 13, 1998 (https://grants.nih.gov/grants/guide/notice-files/not98-014.html). This RFA provides a means within the SBIR program to more fully accommodate the high expenses involved in such technology development, particularly multidisciplinary staffing, custom-fabrication, and long-term project support through the prototype development stage. The contribution of NMR to structural studies of macromolecules in the tens of kDalton molecular weight range is well-recognized, and new pulse sequences promise to substantially raise existing upper molecular weight limits on NMR solution structure determination. Nevertheless, the contribution of NMR to structural biology is presently limited by both sensitivity and spectral resolution. NMR structure studies are time-intensive, but essential, particularly for biological structures which cannot be crystallized and for studies of the dynamical behavior of biomolecules. A recent report (High Field NMR: A New Millennium Resource; (http://www.magnet.fsu.edu/NMRcoll) points out the virtual revolution in biological NMR which would occur if an order of magnitude gain in sensitivity could be achieved, bringing many experiments within the feasible envelope and increasing the throughput of current studies. To accomplish this, it is essential to stimulate innovative new research and development efforts in the following areas: design of 1GHz+ superconducting magnets for NMR spectroscopy, development of flexible probes for such high-field spectrometers, and related preamplifier design. 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, Advanced NMR Spectroscopy Instrumentation, is related to several of the priority areas. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 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 Eligibility requirements are described in the SBIR OMNIBUS SOLICITATIONS. Any small business, independently owned and operated by United States citizens or permanent resident aliens may apply. The business must be organized for-profit, cannot be dominant in its field of expertise, and must have its principal place of business in the United States. Including any affiliates, the company can be the employer of no more than 500 people. MECHANISM OF SUPPORT Support for this RFA is through the SBIR mechanism, which is a set-aside program. Applications can be submitted for support as Phase I SBIR (R43) or Phase II SBIR (R44) grants; or under the SBIR FAST-TRACK option as described in the OMNIBUS SOLICITATIONS. Phase II applications in response to this RFA will only be accepted as competing continuations of previously funded NIH Phase I SBIR awards. The Phase II proposal must be a logical extension of the Phase I research. Information on the FAST-TRACK process and the SBIR OMNIBUS SOLICITATIONS are available at: https://grants.nih.gov/grants/funding/sbir.htm. Awards will be administered under NIH grants policy as stated in the National Institutes of Health Grants Policy Statement issued October 1, 1998 (https://grants.nih.gov/grants/policy/nihgps/). FUNDS AVAILABLE It is expected that two to six awards will be made in FY99, and approximately $2 million from the SBIR set-aside will be designated for this purpose. However, the number of awards will be dependent upon receipt of a sufficient number and diversity of applications with high scientific merit. RESEARCH OBJECTIVES Along with X-ray crystallography, multi-dimensional NMR spectrometry provides the structural foundation of biomedical science. Our understanding of the catalytic, structural, and control roles of proteins and nucleic acids is based on our ability to relate, at atomic levels of detail, macromolecular structure and dynamics to function. NMR provides essential dynamical insights, which are rarely available utilizing X-ray-based approaches. NMR spectroscopy is now making an important transition to magnetic field strengths of greater than 1GHz in order to capture both sensitivity and resolution advantages, which translate into higher molecular weight limits on three dimensional structure determinations and lower macromolecule concentration requirements. Higher magnetic fields, combined with improved probe designs and new pulse sequences, promise to open a wide range of biological systems to study using NMR spectrometry. While much progress has recently been made in the development of NMR probes, particularly superconducting and new MAS designs, there continues to be much untapped potential, including, for instance: high temperature superconducting probe designs with triple resonance and pulsed field gradient capabilities, microcoil probe design, and technological developments associated with application of dynamic nuclear polarization. New magnet technology is itself an active area of development, involving materials as well as engineering aspects. It is also recognized that preamplifier development is a critical component of any high-sensitivity NMR system. The objective of this RFA is to support the development of advanced high-field NMR components or systems, such as magnets, probes, and low-noise preamplifiers; their implementation in functioning prototypes; their evaluation, and ultimate commercialization. These components will ultimately be integrated into high- sensitivity and potentially high-throughput NMR systems. This RFA recognizes that such technology development efforts require the sustained focus of multidisciplinary groups, potentially involve utilization of expensive fabrication processes, and as a consequence require a wide range of financial resources. 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 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 has been published in the Federal Register of March 20, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators may also obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. 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 clear and compelling 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: https://grants.nih.gov/grants/guide/notice-files/not98-024.html. 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 NCRR staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be sent to Ms. Joellen Harper at the address listed under INQUIRIES by the letter of intent receipt date listed in the heading of this RFA. APPLICATION PROCEDURES This RFA must be read in conjunction with the OMNIBUS SOLICITATION OF THE PUBLIC HEALTH SERVICE FOR SMALL BUSINESS INNOVATION RESEARCH GRANT (SBIR) APPLICATIONS. All of the instructions within the omnibus solicitation apply with the following exceptions: o Special Receipt Date o Additional review considerations o More flexible time and budget specifications o Different page limits Applications received in response to this RFA are to be prepared as described in the OMNIBUS SOLICITATIONS for the SBIR program. OMNIBUS SOLICITATIONS are available electronically through the NIH, Office of Extramural Research "Small Business Funding Opportunities" website: https://grants.nih.gov/grants/funding/sbir.htm. Hard copies, subject to availability, may be obtained from the PHS SBIR/STTR Solicitation Office, phone (301) 206-9385; FAX (301) 206-9722; email a2y@cu.nih.gov. Helpful information in preparation of the application can be obtained at: https://grants.nih.gov/grants/funding/sbirsttradvice.htm. Applications in response to this RFA are to be submitted on the applicable grant application forms as follows: SBIR Phase I PHS 6246-1 (1/98) https://grants.nih.gov/grants/funding/sbir1/SBIR.htm SBIR Phase II PHS 6246-2 (1/98) https://grants.nih.gov/grants/funding/sbir2/index.htm The application forms are also located in the back pages of the OMNIBUS SOLICITATIONS. Applications will be accepted on March 17, 1999. The RFA title and number must be typed in line 2 on the face page of the application form. If an application is received after the application receipt 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 review, unless the applicant withdraws the pending application. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. SBIR projects submitted for Phase II support in response to this RFA must demonstrate successful Phase I feasibility prior to a Phase II award. Applications can be submitted for Phase I or Phase II support, or as a combined Phase I and II (Fast Track). Phase II applications will only be accepted as continuations of previously funded Phase I grants. The Phase II proposal must be a logical extension of the Phase I research, but not necessarily a Phase I supported in response to this RFA. PHASE I: Demonstration of feasibility for the next step in the NMR technology development process. It would be expected, but not required, that Phase I would support relatively early discovery and evaluation projects. Phase I projects should focus on research required to advance to the next stage in the development process and present a plan and time line outlining accomplishments and milestones to be achieved at each stage. Applicants should emphasize innovative aspects of the proposed technology development and the nature of the new capabilities which will follow from a successful development effort. Applicants should include a general plan for the complete development project and clearly state how the proposed Phase I fits into this plan. The complete application (including all form pages and "continuation" pages suggested by the OMNIBUS SOLICITATIONS instructions or application form pages) may not exceed 50 pages, excluding: cover letters; the one-page "Introduction" required when submitting a revised (amended) application; letters of commitment from collaborators and consultants; the "Checklist" (form page 6); and the "Personal Data on Principal Investigator" form page. For this RFA, projects normally will be supported in Phase I for up to two years with a budget of up to $700,000, total costs, per year. Budgets proposed must be commensurate with the research, design, and construction efforts described in the application. Larger budgets could be considered if required for conduct of the research and appropriately justified in the application. The second year of support will be contingent upon NCRR programmatic evaluation to ensure that investigators are accomplishing milestones and time lines presented in the original application. PHASE II: Full prototype development leading to Phase III commercialization. Support can be requested for development work leading to full-scale prototypes, their testing, development of software for data transfer, and evaluation of user interfaces. It is not possible for the SBIR program to provide full funding for the commercialization of advanced detectors. Thus, a co-funding partner or other sources of support should be identified prior to a Phase II award. The funds and/or resources to be dedicated to activities directly related to the commercialization of detectors by the partner/company, including details of the commitment contingencies, must be clearly specified in the application. Appropriate documentation of the commitment must be provided. Phase II awards can be for up to four years and $750,000 total costs, per year. As with Phase I, requests for larger budgets may be considered, and support for years two to four is dependent upon NCRR programmatic review of progress including achievement of proposed milestones and evaluation of additional information not required in the original application. As for Phase I, the Phase II application page limit is 50 pages. FAST TRACK: Applications may be submitted for combined Phase I and Phase II FAST TRACK consideration as described in the OMNIBUS SOLICITATIONS. However, due to the complex nature of NMR technology development, it is recommended that only well defined and more advanced projects be proposed for support through this mechanism. Phase I, FAST TRACK applications must specify clear, measurable goals that should be achieved prior to Phase II funding. Failure to provide measurable goals in the Phase I application and/or sufficient detail in the Phase II application may be sufficient reason for the peer review committee to exclude the Phase II from consideration. Special provisions described in this RFA pertaining to Phase I and Phase II also apply to FAST TRACK applications. An additional requirement of the FAST TRACK mechanism is the commitment of funds and/or resources for commercialization of the product to ensure a rapid transition to the market. These funds are in addition to the funds required for research support in Phase II described above. A Commitment Appendix to the Phase II application must be included which specifies the amount of funds and/or nature of resources that will be dedicated to the SBIR project and must describe those activities. If such commitment is from an investor or partner organization, a copy of the agreement or a letter describing the details of the agreement must be provided. The small business concern must also submit a concise Product Development Plan (limited to five pages) as an Appendix to the Phase II application addressing the four areas described in the instructions for FAST TRACK applications in the OMNIBUS SOLICITATIONS. The Fast Track application page limit is 60 pages (excluding the required pages described above). Potential applicants are encouraged to contact program staff for guidance and to read the advice and information on the web sites. However, responsibility for planning, direction, and execution of the proposed research will be solely that of the applicant. The completed original application and two legible copies must be sent or delivered 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) The submission, review, and award schedule for this Request for Applications is: Application receipt date: March 17, 1999 CSR Committee Review: June/July 1999 Council Review: September 1999 Earliest Funding: September 1999 REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed by the CSR for completeness and by NCRR for responsiveness. Applications not adhering to application instructions described above and those applications that are incomplete or non-responsive will be returned to the applicant without review. Applications will be reviewed for scientific and technical merit and the documented ability of the investigators to meet the RESEARCH OBJECTIVES of this RFA by an initial review group convened by the Center for Scientific Review, in accordance with the standard NIH peer review procedures. 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 National Advisory Research Resources Council. REVIEW CRITERIA Review criteria are essentially as described in the OMNIBUS SOLICITATIONS with the additional considerations specified for this RFA. o The soundness and technical merit of the proposed approach. o The qualifications of the proposed principal investigator, supporting staff, and consultants. o The scientific, technical, or technological innovation of the overall magnet/probe technology development plan. o The potential of the proposed research for commercial application. o The appropriateness of the budget requested. o The adequacy and suitability of the facilities and research environment. o Where appropriate, the adequacy of assurances detailing the proposed means for (a) safeguarding human or animal subjects and/or (b) protecting against or minimizing any adverse effect on the environment. o Potential impact of the developed technology on structural biology research. Phase I applications should specify clear, measurable goals (milestones) that should be achieved prior to initiating Phase II. Failure to provide clear, measurable goals may be sufficient reason for the initial review group to judge the application non-competitive. The initial review group will also examine the adequacy of plans to include both genders and minorities, and their subgroups, as appropriate for the scientific goals of the research, plans for the recruitment and retention of subjects; the adequacy of plans for including children as appropriate for the scientific goals of the research, or justification for exclusion; the provisions for the protection of human and animal subjects and the safety of the research environment. AWARD CRITERIA Funding decisions for Phase I or Phase II applications will be based on the quality of the proposed project as determined by peer review, program priorities, potential impact on structural biology research, and availability of funds. FAST TRACK, Phase II applications may be funded following submission of the Phase I progress report and other documents necessary for continuation. Phase II applications will be selected for funding based on the initial priority score, NCRR's assessment of the Phase I progress and determination that Phase I goals were achieved, the project's potential for commercial success, and the availability of funds. 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: Dr. Abraham Levy Biomedical Technology National Center for Research Resources 6705 Rockledge Drive, Room 6160, MSC 7965 Bethesda, MD 20892-7965 Telephone: (301) 435-0755 FAX: (301) 480-3659 Or send an email inquiry to: BTAdir@ep.ncrr.nih.gov Direct inquiries regarding fiscal matters to: Ms. Joellen Harper Office of Grants and Contracts Management National Center for Research Resources 6705 Rockledge Drive, Room 6086, MSC 7965 Bethesda, MD 20892-7965 Telephone (301) 435-0844 Harperj@ncrr.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.371. Awards are made under authorization of the Public Health Service Act, Title III, Part A (Public Law 78-410), as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR 74. 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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