RFA-AT-00-001: CENTERS FOR COMPLEMENTARY AND ALTERNATIVE MEDICINE RESEARCH

Department of Health
and Human Services (HHS)

NIH... Turning Discovery Into Health^®

CENTERS FOR COMPLEMENTARY AND ALTERNATIVE MEDICINE RESEARCH Release Date: November 29, 1999 RFA: AT-00-001 National Center for Complementary and Alternative Medicine National Cancer Institute National Heart, Lung, and Blood Institute Letter of Intent Receipt Date: January 7, 2000 Application Information Meeting: January 21, 2000 Application Receipt Date: March 14, 2000 PURPOSE Despite the broad use of complementary and alternative medicine (CAM) treatments (Eisenberg et al., 1998) there is a relative paucity of data available to demonstrate convincingly the safety, efficacy, effectiveness and mechanisms of these CAM practices. A similar conclusion was reached in a 1990 report on unconventional cancer treatments by the U.S. Office of Technology Assessment. This report urges a systematic analysis of alternative treatments and their effect on major disease, health and wellness (U.S. Office of Technology Assessment, OTA-H-405, 1990, p.225). In order to promote high-quality research of CAM, the National Center for Complementary and Alternative Medicine (NCCAM), the National Cancer Institute (NCI), and the National Heart, Lung, and Blood Institute (NHLBI) invite applications for Centers for CAM Research using the P50 Specialized Center grant mechanism. Such Centers will provide the resources necessary for the rigorous scientific investigation of CAM. It is expected that research conducted at these Centers will examine the potential efficacy, effectiveness, safety and validity of CAM practices, as well as the physiological or psychological mechanisms underlying or contributing to the effects of these practices. HEALTHY PEOPLE 2000 The Public Health Service is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," an initiative for setting national health policy and priorities. Although "Healthy People 2000" does not specify a CAM objective, this RFA reflects several different priority areas within the Healthy People 2000 objectives, such as cancer and chronic disabling conditions. 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, D.C. 20402-9325 (Telephone: 202-783-3238). Applicants may also obtain a copy of "Healthy People 2000" at http://odphp.osophs.dhhs.gov/pubs/hp2000/. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and nonprofit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Applications may include foreign components, but foreign organizations are not eligible to apply. To be considered, applicant organizations must have: (1) a minimum of three independent investigators who together represent experience in both basic and clinical research; (2) access to a patient care and service facility; and (3) the capacity to design, conduct, and evaluate three to four research projects that include at least one basic (mechanistic) study and one clinical study; Phase III trials (see ASPECIAL REQUIREMENTS - Research Projects for definition) and surveys will not be considered. Although applications must be submitted from one institution, they may include subcontracted collaborative scientific and clinical arrangements with scientists from other institutions, including foreign institutions, as long as these arrangements are clearly delineated, and formally and officially confirmed by signed statements from the responsible officials of each institution. However, a full institutional commitment must come from the parent institution receiving the award. NIH staff (See INQUIRIES below) should be consulted if there are questions regarding any of the above requirements or exclusions. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC Program Director or Principal Investigator should be included within the application. MECHANISM OF SUPPORT Support of this program will be through the NIH P50 Specialized Center Grant mechanism. This mechanism supports the full range of research and development from basic to clinical and intervention studies. P50 Centers assemble critical masses of basic and clinical scientists to work together collaboratively. The essential characteristics of a P50 Center include: (1) a strong, focused scientific program encompassing basic and clinical research that will have a clear impact on human disease and associated quality-of-life or disability issues; (2) a strong, innovative program to establish and monitor developmental and feasibility studies that can respond quickly to new research opportunities; (3) a strong career development program to develop and expand the scientific cadre of investigators dedicated to research on a specific disease entity or biomedical problem; (4) shared core facilities that increase the functional capacity of the Center; and (5) a willingness and commitment to work with other Centers and scientists in order to maximize research progress. Applicants will be responsible for the planning, direction, and execution of the proposed Center program. Awards will be administered under the NIH Grants Policy Statement. FUNDS AVAILABLE NIH anticipates making up to three awards with an estimated commitment from the NCCAM of $4.5 million total costs for the initial year’s funding. In addition, NCI and NHLBI may provide support to other meritorious applications that fit their program objectives. Funding levels are dependent on the receipt of applications of high technical and scientific merit, and the continued availability of funds. Because the nature and scope of applications may vary, it is anticipated that the award size will vary. Although this program is provided for in the financial plans of NCCAM, the award of grants pursuant to this RFA is contingent upon the availability of funds. Applicants may request three to five years of support. Applications submitted in response to this RFA are limited to $1.5 million total costs (direct costs and Facilities and Administration costs) in the first year of the award. Future increases are limited to three percent per year. RESEARCH OBJECTIVES 1. Background The demographics, prevalence, and patterns of use of CAM in the United States have been described (Eisenberg et al., 1998). The most relevant findings are the following: a) extrapolation to the population of the United States suggests that Americans made approximately 629 million visits to providers of CAM therapy during 1997; and b) expenditures associated with CAM therapies exceeds non-reimbursed expenses incurred for all hospitalizations in the United States. These findings indicate that CAM occupies a larger role in the health care of U.S. citizens than previously understood. Despite this broad use, there are, in general, insufficient scientific data that address safety and efficacy questions for CAM therapies. The NCCAM currently supports eight NIH P50 Centers for CAM Research. The Centers are designed to identify and evaluate promising CAM approaches by establishing mechanisms for investigators to have their research ideas reviewed, developed and executed in a scientifically rigorous manner. It is expected that work begun at the Centers will provide the basis for subsequent investigator-initiated research grant applications to the NIH. 2. Goals A. General: This RFA seeks to expand the current NIH Centers for CAM Research program with the addition of up to three new P50 Centers. Centers for CAM Research will provide focal points for initiating and maintaining state-of-the-art research that will contribute to improved treatment and prevention of human disease, or that address the risk factors, rehabilitation or quality-of-life issues associated with these conditions. Centers will not only be expected to conduct a wide spectrum of research activities, but also to contribute significantly to the development of core research resources, career development of new investigators, and the expansion of the research base through collaborative research with scientists and clinicians (both CAM and conventional) in other institutions locally and nationwide. Developmental research funds provide support for innovative developmental projects that take maximum advantage of new research opportunities, or that establish the methodological feasibility and strengthen the scientific rationale for proceeding to trials on the use of CAM. This provides a flexible means for responding quickly to new research opportunities. Career development of new and established investigators will generate a cadre of scientists who could leave the Center with research experience to develop independent CAM research programs. In order to facilitate achievement of Center program goals, it is expected that each center will develop specialized multi-user resource activities, such as basic or clinical laboratories, database and data management facilities, and/or biostatistical cores. Requirements for all Centers are annual meetings of the Principal Investigators (and other key Center staff) coordinated by the NCCAM. The purposes of these meetings are to share scientific information, assess scientific progress, identify new research opportunities, and establish priorities that will accelerate the study of CAM. B. Specific Objectives: Specific objectives for the current Center applications include: o Performing research related to CAM treatments in one of the listed research theme areas (see RESEARCH ACTIVITIES below); o Investigating basic mechanisms of CAM therapeutic and diagnostic interventions; o Conducting feasibility studies or Phase I and II trials of sufficiently developed CAM interventions to facilitate the design and eventual conduct of randomized, masked, controlled trials; o Acting as an institutional focus for training in research methodology, bioethics, biostatistics, clinical trial design, epidemiology, health services studies and basic laboratory methods that relate to CAM. This could be satisfied by concurrent training supported by other NIH funding mechanisms (e.g., K30, T32); o Provide plans for establishing an advisory committee (see ASPECIAL REQUIREMENTS@ for AC composition) to provide program direction and advice to the Principal Investigator of the Center, including prioritization of developmental and feasibility studies, and utilization of core facilities; o Developing a mechanism for scientific/technical merit review of developmental or feasibility studies from investigators; o Developing workshops, seminars, etc. for training purposes; and o Establishing a system to identify and support basic and clinical investigators in their career development, including promotions and tenure. RESEARCH ACTIVITIES The overall goals and objectives of the Center’s research agenda for the requested funding period should be explicitly stated in the application. This should include identification of the Center’s research direction, as well as specific disease entities and target populations to be studied. 1. Research Theme Areas Applicants should develop a multidisciplinary research focus that incorporates basic and clinical research in one of the two following themes. The application should describe how the Research Theme will be integrated with one or more of the high priority CAM Program Areas (item 2 below). A. Asthma: A number of CAM therapies have been reported to be of use in the treatment of asthma. However, controlled clinical trials are often lacking, and the mechanisms of action are not clearly understood. Further studies are needed to assess the efficacy of CAM remedies in allergic disease and asthma. Since the symptoms and clinical findings in chronic asthma fluctuate over time and can often appear to improve with placebo, larger, well-designed, double-blind, placebo-controlled trials appear warranted, as well as careful assessment of objective and immunological endpoints. Although Phase III trials will not be considered for this RFA, applicants are encouraged to address methodological and other design issues necessary for the development, design, and eventual conduct of such trials. Moreover, the mechanism of action of these alternative therapies needs to be investigated and defined. Examples of some potential areas of interest include the following: Phase II trials are needed to evaluate the efficacy and physiological correlates of hypnotic suggestion in allergic disease and asthma, and the pathophysiological pathway mediating the effects. Phase II trials are needed to evaluate the efficacy and physiological correlates of acupuncture in the treatment of asthma. The mechanisms mediating the effects of acupuncture on asthma require clarification. Phase II trials are necessary to assess the efficacy and physiological correlates of homeopathy in asthma, and pharmacologic studies are necessary to identify mechanisms of action. Herbal remedies, administered as powders or teas, have been popular. Controlled clinical trials are needed to assess their effectiveness and physiological consequences, and pharmacologic studies are needed to determine their potential interactive effect with standard asthma medications. Ayurvedic medicine is a complex system of health care consisting of numerous components that include transcendental meditation, herbal preparations, pulse diagnosis, and yoga. Studies of an Ayurvedic approach to asthma management, as well as studies of its separate components would be of considerable interest. The rigorous study of breathing techniques (e.g., yoga breathing exercises such as pranayama; and diaphragmatic breathing) in asthma management would enhance understanding of asthma self-management techniques and their potential role in therapy. B. Cancer: Centers are sought to conduct and promote basic and clinical research on CAM approaches for the treatment of cancer. Any of the relevant areas of CAM listed below (see item 2 below: CAM Program Areas) could be included. The rationale for the choice of a particular CAM modality, as well as the reason for its selection instead of other CAM or non-CAM approaches, should be provided. Research topics may include, but are not limited to: 1) prevention; 2) modification of disease course; 3) supportive care or symptom management (including pain control); 4) management of chemotherapy, surgery or radiation induced side-effects; and 5) issues involved in improving quality of life of cancer survivors. Multidisciplinary approaches to study the molecular and cellular basis of the mechanism of action of CAM therapies in cancer are encouraged, as are collaborations with investigators doing basic research in cancer. The establishment and use of animal and other models to study biological effect and mechanism of action of CAM approaches and agents is encouraged. Examples of some potential areas of interest include but are not limited to the following: Phase I/II clinical trials of botanicals. The conduct of these trials should be supported by some preliminary evidence of efficacy. This evidence might include, for example, patterns of traditional use and case series, as well as preclinical or pilot clinical data against cancer or for palliation of symptoms or side-effects. Unconventional adjuvant nutritional approaches that either augment the therapeutic effect of conventional therapies or ameliorate side effects. These approaches should be consistent with the description of CAM modalities listed below (see item 2: CAM Program Areas). Elucidation and systematic evaluation of the mechanisms of action and potential clinical significance of drug-botanical interactions. Comparative analyses of therapeutic indexes of whole botanical products versus specific isolated compounds from these products with known anticancer activity. Studies of the potential effect of mind-body modalities (e.g., relaxation, imagery, meditation, psychosocial support groups, or psychotherapy) on physiologic endpoints (e.g., immune parameters) or disease parameters (response rate to conventional therapy, disease-free survival, overall survival). Mental health assessments are not allowed as primary outcome measures. Cancer chemoprevention studies that are oriented to unpurified, whole natural substances (e.g., soya products, herbal extracts, etc.). Studies to evaluate the potential interaction of antioxidant compounds and conventional chemotherapy and/or radiation therapy. 2. CAM Program Areas: For the purpose of this RFA, investigators must include modalities from the following broad program areas in CAM: o Alternative Medical Systems (e.g., oriental medicine, Ayurvedic, homeopathy, naturopathy); o Manipulative and Body-based Systems (e.g., chiropractic, osteopathic, massage therapy or unconventional applications of integrated conventional and physical therapies); o Biofield (e.g., energy healing, intentional effects on living systems); o Bioelectromagnetics (e.g., diagnostic and therapeutic application of electromagnetic (EM) fields including pulsed EM fields, magnetic fields, Direct Current (DC) fields, artificial light therapy, etc. Note: This category does not include the study of electromagnetic fields as risk factors for disease); o Pharmacologic Therapies (e.g., metabolic therapies and immunoaugmentative therapies as used by CAM practitioners or the public such as antineoplastons, Coley’s toxin, Enzyme therapies, the Livingston-Wheeler system, the Revici system or 714-X) o Herbal Medicine (Note: This category DOES NOT include the study or isolation of active ingredients from herbal preparations except where identification and standardization of optimal whole product are the specific aim -- e.g., optimal ratio of glycosides and terpenoids in Ginkgo biloba -- or comparisons are being made to the whole product); (NOTE: Studies incorporating the following three CAM program areas MUST focus on the more unconventional uses of these approaches and MUST involve collaborations with expert practitioners of these approaches. In addition compelling arguments that the interventions fall outside the purview of conventional medicine MUST be provided in the application. It is strongly recommended that applicants interested in these three areas should contact one of the program officers listed under INQUIRIES prior to submission) o Mind-Body Medicine: This RFA is limited to those mind-body approaches that address unconventional explanatory models with a focus on their NOVEL scientific and clinical use, or that are usually used by the public or practitioners outside of a conventional medicine setting (e.g., transcendental meditation, imagery, hypnosis, biofeedback, music therapy, yoga, spirituality, biological effects of consciousness). Mind-body approaches that are relatively integrated into conventional medicine (e.g., patient education, psychotherapy, cognitive-behavioral approaches, mindfulness meditation, etc.) will NOT be considered unless physiologic endpoints (e.g., immune parameters) or disease parameters (response rate to conventional therapy, disease-free survival, overall survival) are the primary outcome measures; o Orthomolecular Medicine - This category includes the use of products, many of which may be used as nutritional and food supplements (e.g., ultra- high doses of magnesium, Co-enzyme Q, carnitine, melatonin, vitamins) when investigated for therapeutic or preventive purposes. These products are usually used in combinations and at very high doses (5-10 fold) well above the Recommended Daily Allowance (RDA) when such RDAs have been defined. For the purposes of this RFA, orthomolecular medicine may be integrated within comprehensive lifestyle changes based on indigenous or non-orthodox systems of medicine (e.g., Ornish or Pritikin programs). SPECIAL REQUIREMENTS Applications must include ALL the following elements to be considered responsive to the RFA. Unresponsive application will not be reviewed: 1. A strong institutional commitment: An institution receiving this award should incorporate the Center high within its institutional priorities. The institution should demonstrate a strong commitment to the program's stability and success. The application must provide a plan that addresses how the institutional commitment will be established and sustained, how it will maintain accountability for promoting scientific progress, and how the Center research effort will be given a high priority within the institution relative to other research efforts. The institution should demonstrate commitment to the scientific value of the proposed research and willingness to consider this research as support for tenure and promotion. This institutional commitment may be in the form of commitments to recruit scientific talent, provision of discretionary resources to the Center director, faculty appointments for Center investigators, assignment of clinical and research space, cost sharing of resources, or other ways to be proposed by the applicant. 2. A qualified principal investigator (PI): A leader should be selected as principal investigator who can oversee and conduct planning activities and provide direction to the Center. The PI should have documented experience both as a scientist and as administrator of a research program. The PI is required to commit a minimum of 30% effort and has to be primary investigator on one (but not more than two) subprojects. 3. Linkages to the CAM community: The applicant needs to document that linkages to the relevant CAM communities exist and that certified or licensed CAM practitioners provide appropriate input to, and participate in, Center research projects. 4. A substantial patient population: The grant application must demonstrate and document access to a patient population that is able to participate in, and can benefit from, the innovative research activities of the Center. 5. Research projects: Each Center application should include three to four research projects. At least three projects are required to start in year-01 of the award. Start of the fourth project can be postponed until the second or third year of the award. Each of these projects must request at least three, but not more than five, years of support in the application. At least three of the submitted projects that begin in year-01 of the award must be judged meritorious by the peer-review panel for the application to meet the minimal requirements of a P50 Center. Failure to meet this requirement will remove the application from funding consideration. Subproject principal investigators are each required to commit at least 15% time to these projects. The research must be oriented toward the most critically needed areas of CAM research, and toward collaborative activities that address new innovative possibilities in CAM research. Whenever feasible, collaborations with appropriate certified, licensed or otherwise qualified CAM practitioners are required. Projects should be interactive with each other whenever possible. At least one of the approved subprojects has to be a basic (mechanistic) study and one has to be a clinical study other than a Phase III trial (defined below). Applications that do not meet this basic requirement will be ineligible for funding. While epidemiological and health services studies that can be completed in five years are permissible, surveys WILL NOT be accepted under this RFA. For the purpose of this RFA, a Phase III trial is defined as: a broadly based prospective investigation usually involving a substantial number of human subjects either at a single site or at multiple sites. The primary objective of such trials is to evaluate an experimental intervention in comparison with a standard or control intervention, or to compare two or more existing treatments. In Phase III trials, the primary endpoint is usually a significant change in some clinical outcome. The definition includes interventions given for disease prevention, prophylaxis, diagnosis, or therapy. 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: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). In addition, NCCAM requires that all masked clinical trials, regardless of size, establish an independent data and safety monitoring board. Funds should be budgeted for these activities. They should not duplicate internal review and monitoring systems that are already in place at the institution. Collaborative arrangements within the Center, within the parent institution and with other institutions are encouraged. All collaborations with scientists outside the immediate Center should be documented with appropriate letters of commitment as applicable. Collaborations with other institutions, including foreign institutions, may involve subcontracting arrangements but an award will be made to one institution only; that institution is expected to demonstrate the full institutional commitment noted in item 1 above (Strong Institutional Commitment). 6. Resource Cores: A core is defined as a resource shared by multiple investigators that should enhance research productivity and increase the functional capacity of the Center. Subproject utilization of these cores is essential and needs to be specified in the application. At a minimum, the Center is required to have an administrative core that is responsible for the day-to-day administrative details, as well as program coordination and ongoing evaluation of the Center. Also falling within the administrative core would be the Career Development Program, the Developmental Research Program and the Advisory Committee (items # 7-9 below). Other cores that benefit the specific research activities of the Center may be added as appropriate. Examples of cores would include data management cores, biostatistical cores, clinical trial coordinating cores, and laboratory-based cores. These resources should not duplicate resources already available to Center investigators. However, fee-for-service cores (i.e., Center use of existing facilities) are acceptable with adequate justification. 7. Career Development: The Center should demonstrate a consistent commitment to career development. Up to $150,000 (total costs) of the first year budget may be dedicated to the salaries and research activities of investigators who wish to pursue careers investigating alternative medicine. Candidates are expected to devote full-time to research and appropriate supplemental training. Recruitment should encourage the participation of CAM practitioners (with, or without previous research experience) and of qualified women and minorities where possible. To this end, each applicant should include a clear policy and plans for recruiting minorities and women and scientists with disabilities. The Center application should propose the number of slots available, and describe the criteria for candidate eligibility, and the selection process. It is expected that the Advisory Committee (item #9) will be involved in this selection process. Also, the application should indicate prospective mentors who are already in place at the proposed Center, briefly describe their research programs, and describe CAM activities that contribute to the environment for career development (e.g., existing training grants, other career development mechanisms and relevant programs). Highly experienced CAM practitioners should be among the prospective mentors. Prospective mentors should document their knowledge of CAM. Career development research projects should adhere to the list of CAM program areas appearing in this announcement. Rebudgeting of Center funds to, or from, the career development program will only be permitted with prior approval by NIH staff. 8. Developmental Research Program: In each year of the award, Centers will allocate a minimum of $100,000 (total costs) to developmental and feasibility projects that explore innovative ideas, or that establish the methodological feasibility and strengthen the scientific rationale for proceeding to phase III trials on the use of particular CAM modalities. It is important that Centers use developmental funds to stimulate projects that take maximum advantage of new research opportunities. These projects may be collaborative among scientists within one or more Centers, or with scientists outside the Center environment. Developmental research projects should adhere to the list of CAM program areas appearing in this announcement. Rebudgeting of Center funds to, or from, the developmental program will only be permitted with prior NIH staff approval. It is not expected or required that feasibility and developmental projects will be identified by the time of submission. However, the Center application should include an institutional review process for supporting projects that represent the most innovative ideas and that are likely to have the greatest impact on CAM research. These funds are intended to remain flexible and to support feasibility and developmental studies of a limited duration (two years or less), rather than the duration of the entire grant period. The expectation is that successful feasibility studies will become fully developed projects within the Center, or supported through other research funding mechanisms, e.g., R01, R21. NIH staff must be notified before the start of each developmental project, such that human and animal subject assurances, and Advisory Committee approval can be verified. 9. Advisory Committee: Scientific and administrative Center oversight is charged to a multidisciplinary Advisory Committee (AC) to be appointed on a rotating basis by the Principal Investigator. The AC shall not be chaired by the Principal Investigator who will serve in an ex officio capacity only. The AC should meet at least twice a year and minutes of the meeting should be kept. These minutes shall be made available to NIH staff within 6 weeks of the meeting. The AC should consist of at least nine individuals familiar with the Center's research activities. The AC shall include both a biostatistician and epidemiologist to assist with the review of projects and the optimal approaches for subsequent data analysis. The AC MUST have representation from the scientific, practitioner and lay communities in BOTH CAM and conventional medicine. Members SHOULD NOT be identified until after an award is made. However, the process by which members will be chosen should be specified. Besides prioritizing developmental research projects submitted by Center or, if applicable, Consortium investigators, the AC should periodically review Center operations to ensure that Center resources, especially core facilities, are used for the most scientifically worthy projects. The AC should take an active role in encouraging younger faculty members to perform research and assist them in applying appropriate research concepts and methods. The AC should also be involved in the selection of candidates for the career development program. Support for the AC should be explicitly budgeted and justified. 10. Annual Meeting of Centers: Centers will be expected to participate in annual meetings with NCCAM and Institute staff to share positive and negative results with other Centers, share materials, assess progress, identify new research opportunities, and establish interactions, research priorities and collaborations that will maximize the impact of the research. Travel funds for the Principal Investigator and selected Project Investigators should be budgeted for this purpose. This may include Project Investigators from other institutions who are actively collaborating with Centers investigators. It is expected that the meeting locations will rotate among the active NCCAM Centers. 11. Investigational New Drug (or Device) applications (INDs): It is the sole responsibility of the applicant to obtain all necessary clearances from the Food and Drug Administration as required. It is expected that applicants will have started the IND process, if required, well before submission. In addition, applicants are strongly encouraged to consult their local Institutional Review Boards (IRBs) concerning IND status and the IRB approval process. 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 available on the web at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not94-100.html 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. LETTER OF INTENT Applicants are asked to submit, by January 7, 2000, a letter of intent that includes the number and title of this RFA; the name, address, and telephone number of the Principal Investigator; the identities of other key personnel and participating organizations or institutions, if any; the title of the overall proposal. Although a letter of intent is not required, is not binding, and does not enter into the review of applications, the information that it contains will be especially helpful to the NIH in planning for the review of applications, estimating the potential workload, and avoiding conflicts of interest in the review process. Mail/Fax letters of intent to: Dr. Neal B. West Program Officer National Center for Complementary and Alternative Medicine Building 31/ Room 5B58 Bethesda, MD 20892-2182 Telephone: (301) 402-5867 FAX: (301) 402-4741 Email: [email protected] APPLICATION INFORMATION MEETING In order to improve the quality of applications submitted in response to this RFA, as well as to give potential applicants the opportunity to clarify any issues or questions concerning the RFA, a meeting will be held. At the meeting, potential applicants will have the opportunity to discuss application concepts and outlines of proposed applications with NIH staff and other relevant scientific experts. The meeting will be held at, or in close proximity to NIH on Friday, January 21, 2000. Although a registration fee is not associated with this meeting, pre-registration is encouraged. NIH has not allocated funds to pay for attendee travel to the workshop; all travel costs are the responsibility of the attendee. Additional information on the meeting, as well as registration materials can be obtained from the NCCAM Program Officer listed under INQUIRIES. A summary of the presentations and issues discussed at the meeting will be made available through the NCCAM Web-site about one week after the meeting. Hard copies will be available for those applicants without Web access. 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 and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 710-0267, Email: [email protected]. The application is also available at http://grants.nih.gov/grants/funding/phs398/phs398.html. The total page limitation of the application, as specified in the instructions of the Form PHS 398, does not apply to this RFA. Instead, the following stipulations apply: Table of Contents: Disregard the Table of Contents page from PHS 398 and, instead, write a Table of Contents appropriate for this Center grant application. The Table of Contents should list all items for which funding is sought, in addition to each specific activity required of the Center as outlined under Special Requirements. Specifically list the locations of the checklist and the various supporting documents, including bibliographic sketches and other support pages. Each page of the application should be numbered consecutively. This numbering should be reflected in the Table of Contents. Budget: For preparation of the budget, the applicant should present a composite budget for all years of support. This composite budget should include the direct costs for each required Center activity (e.g., Advisory Committee, Developmental Research Program, Career Development, etc.), as well as each research project and each core facility. This composite budget should be in tabular format, with each budget year being listed in a separate column and each Center activity, core or subproject being listed in a separate row. Budget Form pages 4 and 5 of PHS Form 398 should be completed for each Center activity, core or subproject listed in the composite budget. These pages should be clearly labeled as to which Center activity, subproject or core they address. In addition, the utilization relationships between the projects and the core(s) should be presented in a table of direct costs, with the columns being the projects and the rows being the core(s). NOTE: A signed, completed face page (PHS 398, page A) must be provided for each subcontract associated with the application, as well as for the applicant institution. Bibliographic Sketches: Bibliographic sketches and other support pages are required for all proposed Center personnel and for all investigators associated with the mandatory research projects and cores. These pages should be in alphabetical order following the budget pages and should not be duplicated in the descriptions of individual component projects and cores. Research Projects and Core Facilities: Each research project and each core facility is allowed 25 pages, excluding bibliographies. NOTE: The section on the Administrative Core is to include descriptions and justifications of the Advisory Committee, the Developmental Research Program, the Career Development Program, and the Center’s overall goals and objectives; this combined section is limited to 25 pages. Descriptions of the research projects and the core facilities should follow the PHS 398 format, section 9 (Research Plan) with the addition that each project and each core should have its own title page and abstract. The title page should list all investigators (or core staff) and their associated institutions, as well as the direct and total costs for the project for each year of the award. In addition, each project must provide a detailed description of core utilization, and each core must document its contributions to Center research projects. Each of the six points listed under Human Subjects in the PHS 398 application must be addressed for those studies involving human subjects. Although not required at the time of the application, Institutional Review Board and Institutional Animal Care and Use Committee approval must be obtained for each project listed, if appropriate, within 60 days of submission. The RFA label available in the PHS 398 application package must be affixed to the bottom of the face page of the application. The affixed label should clearly display the RFA number: AT-00-001. Failure to use this label could result in delayed processing of the application. 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 sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. Submit a typewritten, signed original of the application, four signed photocopies, and the completed checklist in one package to: Center for Scientific Review National Institutes of Health Suite 1040 6701 Rockledge Dr. MSC 7710 Bethesda, MD 20892-7710 Applicants who prefer to use express mail or courier service should change the zip code above to 20817. At the time of submission, mail one additional complete copy of the application to the following RFA program administrator: Dr. Richard L. Nahin National Center for Complementary and Alternative Medicine 9000 Rockville Pike Bldg. 31, Room 5B-58 Bethesda, MD 20892-2182 Applications must be received by March 14, 2000. If an application is received after the date, it will be returned to the applicant without review. The CSR will not accept any application that is essentially the same as one previously reviewed. This does not preclude the submission of a substantial revision of an application already reviewed, but such an application must follow the guidance in the PHS Form 398 application instructions for preparation of revised applications, including an introduction addressing the previous critique. Individual subprojects from the P50 Center application may be simultaneously submitted to the Center for Scientific Review (CSR) as investigator- initiated applications (e.g., R01); this fact must be clearly documented in the Center application under pending support. If, following review, both the Center application and the R01 application are found to be in the fundable range, the subproject investigator must relinquish the R01 and will not have the option to withdraw from the Center grant. This is an NIH policy intended to preserve the scientific integrity of a multi-project grant, which may be seriously compromised if a strong component project(s) is removed from the program. Investigators wishing to participate in a multi-project grant must be aware of this policy before making a commitment to the Principal Investigator and awarding institution. 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 NCCAM in accordance with the NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a process, streamlined review, in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate National Advisory Council. Review Criteria All applications submitted in response to this RFA will be reviewed according to the following review criteria. Reviewers will consider these criteria when assigning a single overall score to each application. This single score should reflect their judgement that the proposed center will have a substantial impact on the pursuit of its goals. Major factors to be considered in evaluation of applications will include: 1. How the proposed Center combines basic and clinical research with the research theme and CAM program areas. 2. Incorporation of appropriate CAM expertise, including certified or licensed practitioners. 3. The integration of appropriate CAM and conventional expertise. 4. Scientific merit of each proposed subproject. Each research project will be reviewed according to the explicitly-stated set of five review criteria recently adapted by the NIH: (a) 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? (b) 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? (c) Innovation: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (d) 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)? (e) 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. Each subproject will receive a priority score. The score reflects not only the feasibility of the project and the adequacy of the experimental design, but also its relevance to the overall goals of the Center, the appropriate utilization of Center resources (e.g., cores), and the integration of CAM practitioners. Each subproject also will be reviewed for the adequacy of plans to include both genders, minorities, children and their subgroups as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects also will be evaluated. In addition, the adequacy of the proposed protection for humans, animals or the environment will be evaluated to the extent they may be adversely affected by the project proposed in the application. 5. Scientific merit of combining the component parts into a Center (e.g., the whole is greater than the sum of its parts); 6. Technical merit and justification of each core unit; 7. Adequacy of facilities to perform the proposed research, including laboratory and clinical facilities, instrumentation, and data management systems, when needed; 8. Adequacy of plans for interaction among investigators, and the integration of the various projects and core units; 9. Qualifications, experience and commitment of the PI and his/her ability to devote time and effort to provide effective leadership; 10. Scientific and administrative structure, including internal and external procedures for monitoring and evaluating the proposed research and for providing ongoing quality control and scientific review; 11. Institutional commitment to the program, and the appropriateness of resources and policies for the administration of a Center; 12. The proposed organization and activities of the Advisory Committee will be evaluated, including the process to prioritize developmental/feasibility research proposals and the process to choose Committee members after an award is made; 13. Career Development Program including adequacy of the process for selecting candidates for career development and plans for recruiting minority and women candidates; and adequacy of the individuals available to serve as possible mentors of career development candidates; 14. Developmental Research Program including adequacy of the proposed process for continuously reviewing and funding projects for their quality, innovativeness and potential impact; and potential of the program to generate innovative, high-quality projects on a consistent basis. 15. Demonstration of an effective relationship among Consortium institutions, if any, including documentation of current relationships, as well as the functions, commitments and contributions each Consortium member will bring to the proposed Center; 16. The appropriateness of the budget for the proposed program and its individual components will be considered independently of the factors indicated above. A single numerical priority score will be assigned to the application as a whole. Although primary emphasis will be placed on scientific merit, innovativeness, and past progress (where applicable), significant consideration will be given to administrative structure, multidisciplinary interactions including those with CAM practitioners, potential for impacting on the disease/condition in question, and institutional commitment. AWARD AND REPORTING REQUIREMENTS Applications recommended by the NIH Initial Review Group and by the appropriate national advisory council will be considered for award based on: 1) scientific and technical merit as determined by peer review; 2) program relevance and balance; 3) availability of funds; and 4) responsiveness to the goals and objectives of the RFA. Letter of Intent Due: January 7, 2000 Application Information Meeting: January 21, 2000 Application Receipt Date: March 14, 2000 Review by Advisory Council: August/September 2000 Anticipated Award Date: September 2000 INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Inquiries regarding programmatic issues should be directed to: Dr. Neal B. West Program Officer National Center for Complementary and Alternative Medicine Building 31/ Room 5B58 Bethesda, MD 20892-2182 Telephone: (301) 402-5867 FAX: (301) 402-4741 Email: [email protected] Virginia S. Taggart, M.P.H Division of Lung Diseases (Asthma) National Heart, Lung, and Blood Institute National Institutes of Health Two Rockledge Center , Suite 10018 6701 Rockledge Dr. MSC 7952 Bethesda, MD 20892-7952 Phone: (301) 435-0202 Fax: 301-480-3557 Email: [email protected]; Dr. Jeffrey D. White Division of Clinical Sciences National Cancer Institute National Institutes of Health 9000 Rockville Pike Bldg. 10, Room 3B38 Bethesda, MD 20892 Phone: (301) 402-2912 Fax: (301) 402-1001 Email: [email protected] Inquiries regarding budget issues should be directed to: Suzanne White* Grants Operations Branch National Heart, Lung and Blood Institute National Institutes of Health Two Rockledge Center, Suite 7154, MSC 7926 6701 Rockledge Drive Bethesda, MD 20892-7952 Phone: 301-435-0170 Fax: 301-480-3310 Email: [email protected] * Note: NHLBI is the Grants Management Service Center for the NCCAM AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Nos. 93.213 (NCCAM, 93.396 (NCI), and 93.837 and 93.838 (NHLBI). 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 PHS grants policies and Federal Regulations 42 FR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The Public Health Service (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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