BOTANICAL PRODUCTS DEVELOPMENT: SBIR AND STTR Release Date: June 22, 2000 RFA: AT-00-003 National Center for Complementary and Alternative Medicine http://nccam.nih.gov/ National Institute of Diabetes and Digestive and Kidney Diseases http://www.niddk.nih.gov/ Letter of Intent Receipt Date: September 7, 2000 Application Receipt Date: November 14, 2000 PURPOSE The purpose of this Request for Applications (RFA) is to support projects that could lead to development of appropriate standardized products and provision of a reliable constant supply of these products as reference reagents for clinical research, including human trials, as well as basic research. The NCCAM has identified at least four herbs (feverfew, valerian root, echinacea, and milk thistle) that warrant further testing in Phase II and/or Phase III trials. Before supporting such trials, several issues regarding the choice of the clinical trial material require special attention, for example: (1) use of different parts of the plants (e.g., roots, aerial parts, whole plant); (2) use of different cultivars and species; (3) optimal growing and harvest conditions; (4) whether to use whole extract or a specific fraction; (5) the method of extraction (e.g., alcoholic, tea, pressed juice); (6) chemical standardization of the product; (7) presentation of the medication (e.g., extract, tablet, capsule); and (8) the dose and length of administration. The goal of each project would be to develop a well-defined product the next step for which would be scaled up to satisfy research needs. This RFA provides a flexible system within the Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) programs to accommodate the extensive needs and complex development process. It invites grant applications for SBIR and STTR projects with award duration and amounts greater than those routinely allowed under the SBIR/STTR program. This RFA provides a flexible system within the SBIR/STTR program to cover the extensive needs and complex development processes needed to identify/characterize and develop a botanical product. This RFA must be read in conjunction with the Omnibus Solicitation of the National Institutes of Health, Centers for Disease Control and Prevention, and Food and Drug Administration for Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) Grant Applications (PHS 2000-2) (http://grants.nih.gov/grants/funding/sbirsttr1/index.htm). 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, January 12, 2000) at: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-012.html All of the instructions within the Omnibus SBIR/STTR Solicitation apply with the following exceptions: o Special receipt dates o Initial review convened by the NCCAM Division of Extramural Research, Training and Review o Modification of review criteria and/or application instructions o Increased award amount and duration o Additional award consideration o Opportunity for 1 year of Phase I support and 3 years of Phase II support 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. AHealthy People 2010" does not specify a complementary and alternative medicine (CAM) objective, although this RFA, Botanical Products Development: SBIR/STTR, may be applied to several different priority areas with "Healthy People 2010". Potential applicants may obtain a copy of "Healthy People 2010" at http://health.gov/healthypeople/ ELIGIBILITY Eligibility requirements for SBIR and STTR are described in the NIH Omnibus Solicitation for SBIR/STTR grant applications (http://grants.nih.gov/grants/funding/sbir.htm). Any small business, independently owned and operated by United States citizens or permanent resident aliens may apply. It 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. Eligibility is determined at the time of award of Phase I and Phase II The NCCAM will pursue SBIR/STTR funding mechanisms for the four projects described by this RFA. A small business may apply for development of all four botanical products or only one. For each botanical product, the small business must submit a separate application. Only one award will be made for each botanical product project; however, a small business may be awarded projects for more than one botanical product. Note: Applicants may submit investigator-initiated applications for development of botanical products in addition to the four mentioned in the RFA; however, only those applications for feverfew, valerian root, echinacea, and silymarin will be considered responsive to the RFA. Investigator- initiated SBIR/STTR applications will be subject to the standard receipt, review, and award processes described in the Omnibus Solicitation. They will compete for available funds with all other favorably recommended SBIR/STTR applications. MECHANISM OF SUPPORT B PHASE 1/PHASE 2 FAST TRACK This RFA is a one-time solicitation and will use the National Institutes of Health (NIH) Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) Phase I/Phase II Fast Track (R44/R42) award mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. Applications for Phase I/Phase II Fast Track grants should be prepared following the directions for Fast Track applications as described in the Omnibus Solicitation, which is available electronically at: http://grants.nih.gov/grants/funding/sbir.htm A limited number of paper copies of the Omnibus Solicitation are available from PHS SBIR/STTR Solicitation Office 13687 Baltimore Avenue Laurel, MD 20707-5096 Telephone: 301-206-9385 FAX: 301-206-9722 E mail: a2y@cu.nih.gov PROJECT PERIOD AND AMOUNT OF AWARD SBIR Phase I awards normally may not exceed $100,000 total costs (direct costs, indirect costs and negotiated fixed fee) for a period normally not to exceed 6 months and SBIR Phase II awards normally may not exceed $750,000 total costs for a period normally not to exceed two years. STTR Phase I awards normally may not exceed $100,000 total costs for a period of 1 year and STTR Phase II awards normally may not exceed $500,000 total costs for a period normally not to exceed two years. Because the length of time and cost of research involving development and evaluation of botanical products often exceeds that routinely awarded for SBIR/STTR grants, modifications of award durations and amounts will be allowed. The NCCAM will entertain well-justified Phase I/Phase II Fast Track applications for an SBIR/STTR award with Phase I projects up to one year and Phase II projects up to three years and a budget not to exceed a total cost of $500,000 [direct costs, indirect costs, and negotiated fixed fee] per year. PERFORMANCE OF WORK In addition, because these projects may involve multiple disciplines (e.g., horticulture, taxonomy, botany, pharmacognosy, chemistry) and several project sites (e.g., agricultural fields, laboratories), the NCCAM will entertain very well-justified Phase I/Phase II Fast Track applications for an SBIR award with greater than 33% contractual costs in Phase I and greater than 50% in Phase II when those costs are necessary to support development and evaluation of herbal products. Normally the total amount of all consultant costs and contractual costs may not exceed 33% or 50% of the total costs requested for Phase I and Phase II SBIR applications, respectively. Even larger budgets than indicated in PROJECT PERIOD AND AMOUNT OF AWARD could be considered if required to develop a Drug Master File and if appropriately justified in the application. FUNDS AVAILABLE It is expected that four awards (one each for feverfew, valerian root, echinacea, and silymarin) will be made in FY01. The number of awards will be dependent upon receipt of a sufficient number and diversity of applications with high scientific merit. Total costs (direct costs, indirect costs, and negotiated fixed fee) for all four awards in the first year will be up to $2,000,000. Total costs for all four awards over all years will be up to $6,000,000. Awards will be made for either SBIR or STTR grants from funds set aside for these programs. RESEARCH OBJECTIVES Background Definitive randomized, controlled, double-blinded trials investigating the efficacy of feverfew, valerian root, echinacea, and milk thistle for any medical condition have not been reported in the literature. Of the randomized controlled trials that have been done, it is difficult to adequately quantify the clinical effects of the herbs because study designs, outcome methodologies, subject characteristics, dosage, and phytochemical content of the various preparations differ. Given this background, it would be premature for the NCCAM to support large-scale Phase III trials or possibly even Phase II trials with these non-standardized botanical products. Feverfew as Treatment for Migraine Several small, short-term, double-blind, placebo-controlled, randomized clinical trials suggested feverfew (Tanacetum parthenium) to be effective in reducing the frequency of migraine attacks (Johnson 1985; Murphy 1988), the accompanying nausea and vomiting (Johnson 1985; Murphy 1988; Palevitch 1997), and pain intensity (Palevitch 1997). De Weerdt (1996), however, showed no differences in frequency of headache attacks. Each study used different formulations of feverfew, including capsules of freeze-dried, powdered leaves (harvested at one time only), capsules of air-dried powdered leaves (harvested throughout the year), and capsules containing an ethanol extract standardized using parthenolide. The mechanism of action of feverfew in migraine is not known. The plant is rich in sesquiterpene lactones, the principal one being parthenolide. A definitive chemical link between the etiology of migraine and parthenolide or any other of the feverfew constituents has still not been established. The lack of effectiveness of de Weerdt's study, for example, could be due to the absence of essential therapeutic components of the granulated feverfew leaves which were either not sufficiently extracted or perhaps degraded during the preparation. More research is needed, both on a larger scale and with various feverfew extracts, including parthenolide-rich and parthenolide-free preparations. First, a comprehensive profiling of feverfew leaf secondary compounds, examining both the whole leaf and extracts of a broad range of feverfew components, is warranted. Valerian Root for Insomnia There seems to be considerable evidence for the sleep-inducing effects of valerian (Lindahl 1989; Schmitz 1998; Klasser 1984; Gerhard 1996; Balderer 1985; Schultz 1994; Leathwood 1982), and it would appear to be a relatively safe substitute for drugs, such as benzodiazepines, to aid onset of sleep (Houghton 1999; Wagner 1998; Barrett 1999). In addition to valerian alone, other studies with preparations consisting of mixtures of valerian and hops have also shown significant improvement in sleep quality. Because of study limitations, however, it is difficult to adequately quantify the sleep- promoting effects of valerian. Nevertheless, valerian's sedative effect is relatively well established through animal experimentation (Barrett 1999), and the adverse effects profile appears favorable. Valerian is the common name given to a crude drug consisting of the underground organs of species of Valeriana. In Europe the drug is derived from Valeriana officinalis L., but other species are used as crude drugs in other parts of the world (Houghton 1999). Valerian's mechanism of action has not been fully elucidated (Klepser 1999). Valerian is a classical example of an herbal where the overall effect may be due to several types of constituents and modes of activity. The activity of any particular valerian preparation could be due to both the profile of the types and amounts of the constituents present. This underlines the importance of standardizing the preparation both qualitatively and quantitatively, not only in terms of one constituent (Houghton 1999). Since the chemical basis of the observed activities is still not fully known, more work needs to be carried out before a satisfactory standard can be formulated that relates to activity. Echinacea for Prevention/Treatment of Upper Respiratory Infections Few rigorous clinical trials have been performed to demonstrate the efficacy of echinacea as an immune stimulator, although this is a reason for its common use in the United States. A recent systematic review (Melchart 1994) identified 26 controlled trials testing 34 treatments. After consideration of the methodological quality of the trials, the authors were only able to identify one trial (Braunig 1992) that demonstrated clear efficacy and nine trials that demonstrated "indications of efficacy." In a followup article, Melchart (1995) identified 16 randomized trials claiming positive results of treatment (e.g., Dorn 1989, Reitz 1990, Zimmer 1985) and prevention (e.g., Schmidt 1990) of upper respiratory infections. Three of these trials used monopreparations (a species of echinacea alone) and several trials tested preparations that contained plant extracts, homeopathic dilutions, or echinacea as part of a herbal mixture. The authors concluded that while echinacea may be an efficacious immunomodulator, the evidence is still insufficient for clear therapeutic recommendations as to which preparation to use and which dose to employ. There are nine different echinacea plants, but only three are used for medicinal purposes: E. purpurea, E. pallidea, and E. angustifolia These three echinacea plants have been chemically characterized and found to contain the following compounds in varying quantities: polysaccharide, flavonoids, caffeic acid derivatives, essential oils, polyacetylenes, alkylamides, and miscellaneous chemicals (Bauer Wagner 1990). Extracts from the three echinacea species can not be clearly distinguished from each other in terms of their apparent beneficial activity (Dorn 1989). Without knowing a preparation's chemical composition, extrapolation of the results obtained with that preparation compared to others is impossible (Melchart 1995). Multiple chemicals apparently contribute to echinacea's mechanisms of action. To date, there is no universally agreed-on standardization procedure to ensure comparability among products. Given the unequal distribution of active constituents in the flowers, leaves, and roots of the three species, and variation by season, soil type, and climate, it is difficult to determine exactly what kind of standardization would be optimal (Reichling 1998). Also, the dose of echinacea depends on the type of echinacea used, as well as the preparation procedure (Blumenthal 1998). There are different guidelines for extracts, tablets, or capsules. Milk Thistle in the Treatment of Hepatic Diseases Silybum marianum (milk thistle) is currently the most well researched plant in the treatment of liver disease. Silymarin, which is found in the entire plant but is concentrated in the fruit and seeds, is an extract of milk thistle which contains the flavonoids silybinin, silydianan, and silichristin. Silybinin constitutes 60-90% of silymarin and is the component with the greatest degree of biological activity. Milk thistle extracts are usually standardized to contain 70-80% silybinin. Milk thistle is not water soluble and is typically administered as an encapsulated standardized extract. The use of silymarin in chronic liver disease was recently reviewed in the NIDDK/NCCAM symposium, Complementary and Alternative Medicine in Chronic Liver Disease (Seeff 1999 draft). The hepatoprotective properties of silybinin against a variety of hepatotoxins are established by experimental data. The mechanisms that provide silymarin's hepatoprotective effects are many and varied, and include antioxidation, anti-lipid peroxidation, enhanced detoxification, and protection against glutathione depletion. In contrast, the clinical benefits of silymarin therapy are difficult to establish. Conflicting data has emerged from randomized controlled studies in the treatment of chronic liver disease with differing results. No randomized trials have yet been performed in patients with chronic hepatitis C, although small pilot studies have shown a lowering of serum enzymes without accompanying loss of HCV RNA levels. It seems apparent that silymarin has a clearly positive effect on the liver with little to no accompanying side effects, and is therefore deserving of more rigorous clinical trials. The first challenge will be to identify a pure and standardized product and then to consider which form of liver disease is likely to benefit from rigorously developed and conducted treatment trials (NIH Symposium 1999). Significance Standardized formulations of botanical products have not occurred in either the US market or research arena. The development and use of standardized products in research will (1) allow for comparisons across studies using the same products, (2) allow for comparisons between known products, and (3) lead to subsequent, large randomized controlled clinical trials. A reliable and constant source for these products will assure the quality of study outcomes. Objectives The goal of each project is to characterize for each of the four herbs (feverfew, valerian root, echinacea, and milk thistle or silymarin) the standardized product(s) suitable for testing in NIH-sponsored research, including Phase II and Phase III trials. The objectives to achieve this goal are listed below and may be divided between Phases I and II of the SBIR/STTR project as justified by the applicant. Some may be developed as measurable goals for Phase I. After completion of Phase 2, the next step (using other funding sources) would be the production of these products at least in sufficient supply for clinical research. Successful applicants would be expected to participate in an annual meeting in the Washington, DC, metropolitan area with other grantees developing botanical products. It is anticipated that each grant application will include the following: - Review in detail the state of the knowledge on the use of the herb, differentiating between human clinical, animal, and in vitro data, in order to determine the appropriate botanical product(s) to develop and standardize; - Identify accurately the species for the selected herb (botanical description, including comparative descriptions of different species as needed); - Describe the macro- and microscopic physical characteristics; - Provide a standard, high-quality source of the raw material, describing how the plant is grown; where the material is gathered; how and when it is collected, dried and stored to maintain optimal constituent profile; and adulterations and contaminations (presence of insecticide, herbicide, and toxic contaminants); - Develop and document substantiated, qualitative and quantitative analytic methods for the analysis of crude materials; - Identify the constituent (chemical) profile [the HPLC or other profile need not be based on the purported active ingredients, but could serve as a marker or fingerprint (DNA or other) for active constituents]; markers may be defined as those constituents known to be present in the plant that are not necessarily the active constituent; - For each standardized botanical product, identify and describe the species and plant parts from which it is derived, how it is derived (or extracted), the form in which it is provided; - Assess bioavailability, pharmacology, and pharmacokinetics of selected constituents of the profile; - Conduct stability testing of the standardized formulation; - If more than one product for the same herb is developed, compare bioavailability among the different products; - Establish protocols for the production, under Good Manufacturing Practices (GMP), of standardized dosage forms; - Develop the capability to provide the standardized botanical product to NIH- sponsored pre-clinical and clinical trials; - Develop and maintain a Drug Master File at the Food and Drug Administration that will be freely available for cross-reference by researchers participating in clinical trails of the herb. NOTE: It is not the intent of this RFA for the applicant to isolate single active ingredients for drug development. Isolation of single active ingredients is appropriate for identification and standardization of optimal whole products. 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, by the receipt date listed at the beginning of this RFA, 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. The letter of intent is to be sent (fax, e:mail, or post) to Marguerite Evans, NCCAM, at the address listed under INQUIRIES. APPLICANT INFORMATION It is expected that applicants will have questions concerning the RFA. In order to clarify the issues and improve the quality of applications submitted in response to this RFA, a Question/Answer web site will be constructed and may be accessed through the NCCAM website: http://nccam.nih.gov/ APPLICATION PROCEDURES This RFA must be read in conjunction with the most current Omnibus Solicitation of the Public Health Service for Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) Grant Applications (http://grants.nih.gov/grants/funding/sbir.htm). An example of a sample SBIR Phase I application can be found on the internet at: http://www.nhlbi.nih.gov/funding/sbir/modelsbi.htm. All of the instructions within the Omnibus Solicitation apply except as noted otherwise in this RFA. Applications in response to this RFA are to be prepared as described in the Omnibus Solicitation for the SBIR/STTR Programs, which are available electronically at (http://grants.nih.gov/grants/funding/sbir.htm). Phase I/Phase II Fast Track applications must be prepared according to the Fast Track instructions in the Solicitation http://grants.nih.gov/grants/funding/sbirsttr1/6method.htm#6g. Applications are to be submitted on the applicable grant application forms as follows: PHASE I SBIR GRANT APPLICATION FORM (PHS 6246-1) and REMINDER SHEET http://grants.nih.gov/grants/funding/sbirsttr1/11instructions.htm PHASE II SBIR GRANT APPLICATION FORM (PHS 6246-2) http://grants.nih.gov/grants/funding/sbir2/index.htm OR PHASE I STTR GRANT APPLICATION FORM (PHS 6246-3) and REMINDER SHEET http://grants.nih.gov/grants/funding/sbirsttr1/11instructions.htm PHASE II STTR GRANT APPLICATION FORM (PHS 6246-4) http://grants.nih.gov/grants/funding/sttr2/index.html Phase I application forms are also located in the back pages of the Omnibus Solicitation. Applicants submitting under the SBIR/STTR Fast Track process must prepare and submit both a Phase I and Phase II application together for concurrent initial peer review and evaluation. Fast Track applications must specify clear, measurable goals for Phase I 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 application from consideration. The Phase II application must be a logical extension of the Phase I research and must include a concise Product Development Plan as described in Section VI, item G of Omnibus Solicitation. Projects may be presented for SBIR/STTR support at all stages of the botanical product development process. Projects will be evaluated on overall innovation and success potential of the research path proposed to botanical product characterization/development. PHASE I: Larger budgets (SBIR and STTR) and longer project period (SBIR) will be considered for Phase I if required for conduct of the research and appropriately justified in the application. Phase I milestones are determined by the applicant but must address some of the objectives outlined in the section RESEARCH OBJECTIVES of this RFA. PHASE II: As with Phase I, requests for larger budgets and longer project periods will be considered. Even larger budgets than indicated in PROJECT PERIOD AND AMOUNT OF AWARD could be considered if required to develop a Drug Master File and is appropriately justified in the application. The second phase of support will be contingent upon the NCCAM programmatic evaluation to ensure that investigators are accomplishing Phase I milestones and time lines presented in the original application. The project=s Phase II objectives should include the objectives outline in the RESEARCH OBJECTIVES section of this RFA that were not addressed in Phase I. In addition, in the Phase II application, applicants should develop a detailed plan for the release of data and the sharing of research materials in order to ensure that data and research materials generated under the SBIR/STTR grant are accessible to the research community for future studies. The adequacy of this plan will be reviewed as one of the criteria for award. Finally, applicants are reminded that the grantee institution is required to disclose each subject invention to the Federal Agency providing research funds within two months after the inventor has disclosed it in writing to grantee institution personnel responsible for the patent matters. NCCAM will monitor the patenting activity associated with these awards to determine to what extent the patenting of program-funded inventions has interfered with the timely dissemination of research data, results and materials. If the approach above is insufficient to ensure the timely sharing of data and materials, the NIH will consider invoking a determination of exceptional circumstances to restrict or eliminate the right of grantee parties to retain title to intellectual property under future grants. Applicants are encouraged to see the Federal Register Notice published on December 23, 1999, entitled, "PRINCIPLES FOR RECIPIENTS OF NIH RESEARCH GRANTS AND CONTRACTS ON OBTAINING AND DISEEMINATING BIOMEDICAL RESEARCH RESOURCES" (64 FR 72090) for an in-depth discussion of NIH principles and guidelines for sharing biomedical research resources. This Notice is also available at an NIH Internet site: http://www.ott.nih.gov/policy/rt_guide_final.html. All of the instructions within the Omnibus Solicitation apply with the following exceptions: - Receipt date; - Increased award amount and duration; - Additional award consideration. Applications will be accepted on or before November 14, 2000. If an application is received after the application receipt date, it will be returned to the applicant without review. The Center for Scientific Review 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. For purposes of identification and processing, the title and number of this RFA must be shown in item 2 on the face page of the SBIR/STTR Phase I applications and in item 1A of the face page of Phase II grant applications (e.g., RFA-00-003, Botanical Products Development: SBIR/STTR). The completed original application and one exact, signed 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) At the time of submission, mail one additional complete copy of the application to the following RFA program administrator: Dr. Richard L. Nahin Director, Division of Research, Training and Review 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 REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the NIH Center for Scientific Review and responsiveness by NCCAM. Incomplete or non- responsive applications will be returned to the applicant without further consideration. Applications will be reviewed for scientific and technical merit by a special emphasis panel convened by the National Center for Complementary and Alternative Medicine, 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 will be discussed and assigned a priority score. Scored applications will receive a secondary review by the NCCAM Advisory Council. REVIEW CRITERIA Review criteria are described in the Omnibus Solicitation. The Phase I application 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 study section to judge the application non-competitive. In addition, the adequacy of a plan for the release of data and the sharing of research materials will be reviewed as one of the criteria for award. AWARD CRITERIA The following will be considered when making funding decisions: quality of the proposed project as determined by peer review, program balance among research areas of the announcement, the availability of funds, and the commercialization status where the small business concern has received more than 15 Phase II awards in the prior five (5) fiscal years, if applicable (see this application requirement under "Prior SBIR Phase II Awards" found in the "Grant Application Preparation Instructions and Requirements" portion of the Omnibus Solicitation). ADVICE ON SUBMITTING APPLICATIONS Potential applicants are strongly encouraged to contact program staff for pre- application guidance and/or for more specific information on the research topics described in this RFA. They are also encouraged to read the advice and information on SBIR/STTR programs located on the Internet at: http://grants.nih.gov/grants/funding/sbirgrantsmanship.pdf INQUIRIES Written and telephone inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Inquiries regarding programmatic issues may be directed to: Marguerite Evans Division of Extramural Research, Training, and Review National Center for Complementary and Alternative Medicine National Institutes of Health Building 31, Room 5B58 Bethesda, MD 20892 Telephone: (301) 402-5860 FAX: (301) 402-4741 Email: evansm@od.nih.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,Room 7150, MSC 7926 6701 Rockledge Drive Bethesda, MD 20892-7926 Telephone: 301-435-0170 FAX: 301-480-3310 Email: sw52h@nih.gov * The NHLBI is the Grants Management Service Center for the NCCAM. Inquiries regarding review issues should be directed to: Dr. Richard L. Nahin Director, Division of Extramural Research, Training and Review 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.nih.gov 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 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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