BOTANICAL/DRUG INTERACTIONS Release Date: August 7, 2000 RFA: AT-00-004 National Center for Complementary and Alternative Medicine http://nccam.nih.gov National Cancer Institute http://www.nci.nih.gov Letter of Intent Receipt Date: November 10, 2000 Application Receipt Date: January 12, 2001 THIS RFA USES THE MODULAR GRANT AND JUST-IN-TIME CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA. PURPOSE The National Center for Complementary and Alternative Medicine (NCCAM) is committed to ensuring that the healthcare profession and the American public are provided with the best possible information about the safety and efficacy of botanicals. However, there is a paucity of reliable, research-based data available to guide choices about the use of botanicals simultaneously with over-the-counter and prescription drugs. The widespread usage of botanicals, the high probability that botanicals and pharmaceutical drugs are being used concomitantly, the generic concern that potential drug-drug interactions should always be a cause for caution, and the recently published reports of adverse botanical/drug interactions support the need for this initiative. The main objective of this initiative is to encourage biomedical research in order to prevent adverse botanical/drug interactions during therapy or anesthesia, to establish possible synergistic combinations of botanicals with pharmaceutical drugs, and to increase our knowledge of the mechanisms of action of botanicals. 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), Botanical/Drug Interactions, 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/. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non- profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) R01 and the NCCAM R21 award mechanisms. 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 two years for the R21 applications or three years for the R01 applications. 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 anticipated award date is August 2001. FUNDS AVAILABLE The NCCAM intends to commit approximately $4.3 M in FY 2001 to fund ten R21 and five R01 new and/or competitive continuation grants in response to this RFA. An R21 applicant may request a project period of up to two years and a budget for Direct Costs of up to $125,000 per year. An R01 applicant may request a project period of up to three years and a budget for Direct Costs of up to $375,000 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 plans of the NCCAM provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. At this time, it is not known if this RFA will be reissued. RESEARCH OBJECTIVES Background Eisenberg et.al. (1998) reported that 18 percent of individuals taking prescription drugs were concurrently using herbals or high dose vitamin products, or both. They estimated that 15 million adults are at risk for potential drug-dietary supplement interactions. The frequency and extent of adverse drug reactions or even positive, synergistic efficacy due to concurrent use is unknown. Since the Eisenberg study also revealed that fewer than 40 percent of those surveyed disclosed their use of complementary and alternative medicines to their physicians, the difficulty of gathering information about botanical/drug interactions is further compounded. The use of anesthetics on patients who are concurrently taking botanicals and other supplements may pose acute risks for the patient (Norred and Finlayson, 2000). Botanical products, as used by the public, are usually complex mixtures. Since both the putative active ingredient(s) and other constituents (i.e., "inert" ingredients and contaminants) in the mixture have the potential for interactions with pharmaceutical drugs or anesthetics, studies of standardized botanical products (even when available) may have significant methodological limitations. Thus, purified components of botanical products, used singly or in combination, may be the most suitable reagents for some studies of botanical/drug interactions. These studies in turn will allow subsequent investigations of whole products or unrefined botanical extracts. Despite the experimental difficulties engendered by the relative lack of standardized botanicals available as reference reagents, more studies investigating botanical/drug interactions are needed immediately to better inform the American public and the healthcare profession. Moreover, since the NCCAM has recently initiated Phase III clinical trials to study the efficacy of some botanicals (i.e. Ginkgo and Hypericum) that are already in widespread public use, and since additional trials with other botanicals are being carried out at NCCAM Centers and are being contemplated, there is an imperative for additional research on possible botanical/drug interactions. Goals The proposed initiative is expected to stimulate investigator-initiated biomedical research on botanical/drug interactions in vitro, in animal models, and in phase I/II or case control clinical studies. The phase I/II clinical studies are expected to examine the uptake, bioavailability, or pharmacodynamics of the botanical/drug combination in contrast to these parameters when the herbal or drug is administered alone. This RFA invites proposals designed to explore the cellular and molecular effects of botanicals in interactive paradigms with proprietary drugs, or studies which may help to predict the effects of the botanicals on drug action and metabolism in vivo. The case control studies should be aimed at elucidating the relationship between a botanical product and specific adverse events in the presence of a proprietary drug. SPECIAL REQUIREMENTS The NCCAM does not usually accept research applications in the botanical category that focus on the isolation of active ingredients from herbal preparations, except when this is necessary for identification and standardization of optimal whole products or when comparisons are being made to the complex product or to investigate metabolic pathways and mechanisms of action as part of the proposed research project. Conventional drug discovery and drug development approaches using botanicals as the source are not considered to be within the scope of this RFA. Research projects can be basic (mechanistic) and/or clinical studies other than a Phase III trial (defined below). Case control studies WILL be accepted in response to this RFA. Applications that do not meet one or more of these requirements will be ineligible for funding. Health services studies or surveys and epidemiological studies except for case control studies 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 ). The NIH has also released "Further Guidance On A Data And Safety Monitoring For Phase I and Phase II Trials", NIH Guide, June 5, 2000: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html. In addition, NCCAM requires that all masked clinical trials, regardless of size, establish an independent data and safety monitoring board. The Data Safety Monitoring Guidelines for NCCAM-supported clinical trials are available at: http://nccam.nih.gov/research/policies/datasafety/index.htm. Funds should be budgeted for these activities. They should not duplicate internal review and monitoring systems that are already in place at the institution. 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 are 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 was 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, and is available on the web at: 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. 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. 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 NCCAM staff to estimate the potential review workload and plan the review. Mail/Fax letters of intent on or before November 10, 2000 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: westn@od.nih.gov 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: 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 Institute staff. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted in BUDGET INSTRUCTIONS below. Applicants wishing to submit R21 applications are encouraged to contact the Program Staff listed under INQUIRIES prior to submission. The NCCAM has guidelines for the preparation and submission of these applications as outlined in R21 APPLICATION GUIDELINES below. Applications for R21 grants that do not meet the requirements as outlined in these guidelines will not be accepted by the NCCAM. R21 APPLICATION GUIDELINES o The purpose of the NCCAM's Exploratory/Developmental Research (R21) grant mechanism is to provide investigators, at all career levels, with a funding opportunity for exploring the feasibility, as well as the development, of projects investigating botanical/drug interactions. The R21 mechanism is specifically intended to support innovative ideas where preliminary data as evidence of feasibility are sparse or do not exist. These grants are not intended for large-scale undertakings or to support or supplement ongoing research. Rather, R21-supported projects are intended to serve as a basis for planning and strengthening future investigator-initiated research project grant applications (R01). It is important to note that, while originality of approach and potential significance of the proposed research are major considerations in evaluation for funding R21 grants, the applicant is also responsible for presenting the background literature that provides some basis for the approach and developing a rigorous research plan. o For R21 applications, Direct Costs are limited to a maximum of $125,000 per year for a maximum of two years. Direct Costs requested for the proposed period may not exceed $250,000. Direct costs should be requested in increments of $25,000. Total Costs should equal the modular Direct Costs plus Facilities and Administrative (F&A) costs. The award is nonrenewable and may not be used to supplement an ongoing project. o Do not exceed a total of fifteen pages for Items a-d in the Research Plan. Tables and figures are included in the page limitation. Applications that exceed the page limitation or NIH requirements for type size and margins (refer to PHS 398 application for details) will be returned to the applicant without further consideration. The fifteen-page limitation does not include Items e-I (Human Subjects, Vertebrate Animals, Literature Cited, Consortia, and Consultants). o Color illustrations or original photographs may be included in an Appendix. These are allowed only if there are copies of black and white figures appearing in the body of the application. No other appendix material is permitted. o Applications not following the above instructions will be returned to the applicant without review. BUDGET INSTRUCTIONS Modular Grant applications will request Direct Costs in $25,000 modules, up to a total Direct Cost request of $250,000 per year for R01s and $125,000 per year for R21s. Applications that request more than $250,000 direct costs in any year must follow the traditional PHS 398 application instructions. The total Direct Costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: PHS 398 o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the total Direct Costs requested for each year. This is not a Form page. o Under Personnel, List ALL project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of Total Costs (direct plus Facilities and Administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of key personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The Total Cost for a consortium/contractual arrangement is included in the overall requested modular Direct Cost amount. Include the Letter of Intent to establish a consortium. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by reviewers in the assessment of each individual's qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm - Complete the educational block at the top of the form page; - List position(s) and any honors; - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years. - List selected peer-reviewed publications, with full citations; o CHECKLIST - This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. o The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. The title and number of the program announcement must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label available in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application. 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 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, including the Checklist, and four 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, one additional copy of the application must be sent to: Dr. Richard L. Nahin Director, DERTR National Center for Complementary and Alternative Medicine 9000 Rockville Pike Building 31, Room 5B58 Bethesda, MD 20892-2182 Telephone: (301) 496-4792 FAX: (301) 402-4741 Email: nahinr@od.noh.gov Applications must be received by January 12, 2001. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS 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 review criteria stated below. As part of the initial merit review, all applications will receive a written critique and may 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 NCCAM 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? Because the exploratory grant mechanism (R21) is designed to support innovative ideas, preliminary data as evidence of feasibility of the project are not required. However, the applicant does have the responsibility for developing a sound research plan approach, including appropriate statistical analyses and sample size calculations where appropriate. Innovation of the project and potential significance of the proposed research will be major considerations in the evaluation of this mechanism. 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. Schedule Letter of Intent Receipt Date: November 10, 2000 Application Receipt Date: January 12, 2001 Council Review: May 2001 Earliest Anticipated Start Date: August 2001 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. 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: 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: westn@od.nih.gov Dr. Jeffrey D. White Director, Office of Cancer Complementary and Alternative Medicine National Cancer Institute Executive Plaza North, Suite 102 National Institutes of Health Bethesda, MD 20892 phone: 301-435-7980 fax: 301-480-0075 e-mail: jeffreyw@mail.nih.gov http://occam.nci.nih.gov Direct inquiries regarding review issues to: Dr. Richard L. Nahin Director, DERTR National Center for Complementary and Alternative Medicine 9000 Rockville Pike Building 31, Room 5B58 Bethesda, MD 20892-2182 Telephone: (301) 496-4792 FAX: (301) 402-4741 Email: nahinr@od.noh.gov Direct inquiries regarding fiscal matters 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: WhiteS@gwgate.nhlbi.nih.gov * 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 No. 93.213. 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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