CRANBERRY: URINARY TRACT INFECTION AND OTHER CONDITIONS RELEASE DATE: February 21, 2003 RFA: AT-03-004 National Center for Complementary and Alternative Medicine (NCCAM) (http://nccam.nih.gov/) National Institute of Dental and Craniofacial Research (NIDCR) (http://www.nidr.nih.gov/) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (http://www.niddk.nih.gov/) Office of Dietary Supplements (ODS) (http://dietary-supplements.info.nih.gov/) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBERS: 93.213, 93.121, 93.849. LETTER OF INTENT RECEIPT DATE: April 22, 2003 APPLICATION RECEIPT DATE: May 20, 2003 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism(s) of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The purpose of this initiative is to support basic and clinical research on the role of cranberry (Vaccinium macrocarpon) in the prevention and treatment of urinary tract infections (UTI), other infections, and other conditions for which there is credible evidence of efficacy. For clinical trials, preference will be given to those that also test mechanistic hypotheses. This research may lead to definitive Phase III trials to determine the efficacy of cranberry in the prevention and/or treatment of UTI or other conditions. Products of primary interest are (1) cranberry juice cocktail and (2) encapsulated powders, and their matching placebos. RESEARCH OBJECTIVES Cranberry juice and to a lesser extent encapsulated powders have been used to prevent or treat UTI. Preliminary evidence supports efficacy but the research suffers from major limitations. Additional, but more limited, research of cranberry because of its inhibition of bacterial adhesion and antioxidant properties has been conducted for other infectious diseases and other conditions. The appropriate product, dose, duration of intervention, and mechanism(s) of action are unknown or not clearly elucidated. Finally, the nature and quality of previously studied cranberry products is not available in most of the published literature. This limitation led NCCAM to award a contract for the development, preparation, characterization, standardization, and maintenance of a supply of research-grade cranberry products and matching placebos for use in NIH-sponsored clinical trials on cranberry. These products will be available and are required for use by respondents to this RFA which seeks investigator-initiated basic and clinical research applications. Significance UTIs are a serious health problem affecting millions of people each year. Infections of the urinary tract are common - only respiratory infections occur more often. Each year, UTIs account for about seven million office visits and another one million emergency department visits, resulting in about 100,000 hospitalizations. One woman in five develops a UTI during her lifetime; UTIs in men are less common. Nearly 20% of women who have a UTI will have another, and 30% of those will have yet another. Most infections arise from one type of bacteria, Escherichia coli, which normally live in the colon. Usually, the most recent infection stems from a strain or type of bacteria that is different from the infection before it, indicating a separate infection. (Even when several UTIs in a row are due to E. coli, slight differences in the bacterial strains indicate distinct infections.) NIH-funded research suggests that one factor behind recurrent UTIs may be the ability of bacteria to attach to cells lining the urinary tract. Cranberry Use for UTI Traditionally UTIs are treated with antibacterial drugs, but these are expensive, can have side effects, and may promote the emergence of drug-resistant bacteria. Therefore, physicians suggest additional steps that patients can take on their own to avoid infection, including drinking cranberry juice (http://www.niddk.nih.gov/health/urolog/pubs/utiadult/utiadult.htm). Although cranberry juice is the form of cranberries most widely used, other cranberry products include cranberry powder in hard or soft gelatin capsules. Market share data reported for 1999 and 2001 rank cranberry as number 10 and 9, respectively, among top-selling herbal products in the U.S. in the mainstream retail market Efficacy of Cranberry for UTI The use of cranberry to prevent or treat UTI is common. The accumulating evidence from small, non-controlled and controlled clinical trials suggests that cranberry may relieve symptoms associated with UTI and may reduce the need for antibiotics. The findings from the preliminary research provide reasons to support the conduct of small- scale, focused clinical studies. In 1998 (updated 2001), the Cochrane Library conducted separate reviews of cranberry for the prevention and treatment of UTI. Each review used similar search strategies and selection criteria. These included all randomized or quasi-randomized controlled trials. Trials of at least one month and at least five days were included for prevention and treatment, respectively. For prevention, four trials met the inclusion criteria. For treatment, no trials meeting the inclusion criteria were found; only a few uncontrolled trials were found. The Cochrane Library concluded that there was no good quality or reliable evidence of the effectiveness of cranberry juice or other cranberry products for the prevention or treatment of UTI and that more research is needed. Three crossover studies (not included in either review) investigated the effect of cranberry on urine pH but did not attempt to assess activity in UTI. Two of these three studies demonstrated a decrease in pH whereas the third study did not demonstrate a decrease in pH. Several other studies not included in the Cochrane reviews reported apparently contradictory results. The first did not support the efficacy of cranberry in UTI in children with neurogenic bladder. The second was a study of adults with spinal cord injury that demonstrated a reduction in biofilm load, but the importance of this effect for frank UTI was not determined. A small study of urostomy patients also found equivocal results. Many of the clinical study reports available in the literature suffer from major limitations, as acknowledged in the Cochrane Library reviews. Many trials have not been controlled or randomized, and randomization procedures have not always been described. Crossover designs used in some studies may not be appropriate for studies of UTI. Other limitations include no blinding or failed blinding, lack of controlled diets or dietary assessment, use of convenience samples, and small numbers of subjects. Sample sizes have ranged from as few as 10 to as many as 192. Trials have been faulted for the large number of dropouts/withdrawals which may be indicative that cranberry juice is not acceptable over the longer periods. Intention-to-treat analyses were not often applied. Most studies have been conducted in older or elderly patients. Very few have been conducted in younger patients, with or without co-morbidities. Primary outcomes have differed from study to study and have often included urinary pH, as well as rate of bacteriuria, biofilm load, and urinary white and red blood cell counts, rather than UTI. Finally, the published articles do not describe the quality and character of the product. Mechanism of Action for UTI The mechanism of action of cranberry in treatment of UTI has not been clearly elucidated, but several potential hypotheses have been proposed. High levels of benzoic acid have been detected in cranberry juice, and until recently, it was suggested that the bacteriostatic effect of cranberry juice was due to acidification of the urine. Several studies, however, have cast doubt on this mechanism. Current belief is that the prevention of UTI is achieved by inhibiting adhesion of the infecting bacteria, E. coli, to uroepithelial cells. Bacterial adherence to these cells is a critical step in the development of infection. It is facilitated by fimbriae (proteinaceous fibers on the bacterial cell well). Fimbriae produce adhesins which attach to receptors on uroepithelial cells. It is hypothesized that cranberry constituents act by preventing adhesion. Thus, the causative bacteria are flushed, preventing their colonization of the urinary tract. In addition, there has been a report of the potential of cranberry juice to weaken attachment of E. coli to inert (nonliving) surfaces for control of biofilm formation on urinary catheters. Two components of cranberry juice have been shown to inhibit the adherence of E. coli to uroepithelial cells in vitro. The first is fructose which may not survive absorption and metabolism intact to reach the urinary bladder. The second is a group of polymeric proanthocyanidins; the chemical structures of three have been elucidated. Fructose inhibits the adherence of type-1 fimbriated E. coli and proanthocyanidins inhibit the adherence of P-fimbriated E. coli to uroepithelial cells. Cranberry for Other Infections and Conditions While much of the focus on the benefits of cranberry has been on UTI, cranberry could influence other conditions as well. Examples of other areas of cranberry research follow. These are for illustration only and are not meant to be exhaustive. Burger et al. reason that because cranberry has been shown to inhibit bacterial adhesion to uroepithelial cells, it may also be useful as antiadhesion therapy of Helicobacter pylori infections. In a number of small in vitro studies, the investigators demonstrated that a high- molecular-weight constituent of cranberry inhibits sialyllactose- specific adhesion of H. pylori to a human gastric cell line and mucus, and to human erythrocytes. Because of cranberry's purported antiadhesive properties, the effect of cranberry on the coaggregation of oral bacteria was tested. A high- molecular-weight nondialysable material was isolated from cranberry juice. Although the molecular structure of this material and its mechanism of action are not known, in vitro studies showed that coaggregation of pairs of bacteria was inhibited and pilot in vivo studies showed that coaggregation of a large number of different pairs was reversed. A small pilot study of individuals using a standard mouthwash which contained this high-molecular-weight constituent was conducted. Results showed a reduction in colony forming units in saliva. Cranberry extracts may inhibit the oxidative modification of low- density-lipoprotein (LDL) particles in a fashion similar to that of red wine and Concord grape juice as demonstrated in an in vitro study. In vivo studies to evaluate the potential of cranberry to improve LDL antioxidant capacity have not been conducted. Other areas of emerging preliminary data include the inhibition of breast cancer cells in animals, as well as the inhibition of certain strains of Haemophilus influenzae that is a common cause of ear and respiratory infections in children. Safety Cranberry taken orally in food amounts appears safe, although ingesting large amounts may result in diarrhea and other gastrointestinal symptoms. Safety of amounts greater than that consumed in foods is unknown. One study of cranberry tablets suggests caution for patients at risk for nephrolithiasis until safety of cranberry is confirmed. Currently, there is insufficient reliable information available to assess the interaction of cranberry with dietary supplements, medications, foods or laboratory tests. Cranberry Product The dose, duration of intervention, and product characteristics necessary for efficacy in prevention or treatment of UTI are unknown. While cranberry juice cocktail is the most studied product, concentrates and encapsulated powders have also been used. Some sources suggest six capsules of dried cranberry powder are equivalent to two fluid ounces cranberry juice cocktail. The chemical composition of the study agents, in general, has not been described in the published literature, nor has the equivalence of the active constituents or markers among cocktails, concentrates, and capsules/tablets been described. Therefore, comparison among study agents or trial results has not been possible. The single-strength cranberry juice is highly acidic and astringent which makes it unpalatable. Accordingly, the juice drink, i.e., cranberry juice cocktail, is a mixture of single-strength cranberry juice, sweetener, water, and vitamin C. Cocktails are sweetened with fructose or artificially sweetened. The percent of concentrate used in cocktails has ranged from about 25% to 80%, although cocktail with 33% pure juice is common. Cranberries contain about 88% water. Among the other organic constituents are flavonoids, anthocyanins, catechin, triterpenoids, beta-hydroxybutyric acid, citric, malic, glucuronic, quinic and benzoic acids, ellagic acid, and vitamin C. Quinic acid and the ratio of quinic acid to malic acid are reasonably constant and are used to calculate percentage of cranberry juice content in juice drinks and to assess cranberry juice authenticity. Although anthocyanins change and degrade with processing and storage, the anthocyanin profile is unique to cranberry, and its qualitative pattern is characteristic. Doses of the cocktails used in studies have ranged from 160 to 750 ml a day, usually in divided doses at meals. Intervention duration has also ranged from 5 days to 6 months (longer trials for prevention). The rationale behind the amount and concentration of cranberry juice given to participants and the duration of intervention is usually not indicated. Related NIH-Supported Cranberry Projects The NCCAM awarded a contract to support the preparation, characterization, standardization, and maintenance of a supply of research-grade cranberry products and matching placebos with concomitant quality control and quality assurance. See the Request for Proposals for more detail: http://nccam.nih.gov/research/ announcements/rfp/sow.pdf. These products will be used in NIH-supported basic and clinical research, which is responsive to this RFA, on the role of cranberry (Vaccinium macrocarpon) in the prevention and treatment of urinary tract infections (UTI), other infections, and other conditions for which there is credible evidence of efficacy. Products developed by the contractor will be (1) cranberry juice cocktail and (2) encapsulated powders, and their matching placebos. Potential Research Directions Although the objectives of this RFA are listed in the next section (Objectives of This Research Program), the published literature suggests that research directions might include, but not be limited to: o Study the effect of cranberry in prevention of UTI and as adjunct to antibiotics in the treatment of UTI; o Demonstrate whether cranberry reduces symptomatic UTI (primary endpoint being UTI; secondary endpoints being bacteriuria or pyuria); o When justified, conduct randomized controlled trials of longer durations in a variety of patients with recurrent UTI; o Determine the optimum amount of cranberry (dose-response), timing of ingestion, peak times to effect (temporal effect), variations in response; o Assess adherence to study dosage and frequency requirements and participant retention; o Assess the contribution of cranberry juice to increased fluid intake (concentrate vs. juice vs. other beverage) and the effect on UTI; o Collect data systematically on adverse effects; o Assess interactions with medications (such as antibiotics and H2 blockers), dietary supplements, foods, and laboratory tests; o Evaluate relationship of cranberry/cranberry constituents to bacterial adherence; o Evaluate relationship of cranberry/cranberry constituents and bacterial adherence to urinary pH; o Study the absorption and distribution of marker compounds and key constituents of cranberry, such as the proanthocyanidins, to determine whether they achieve tissue and body fluid concentrations needed to inhibit bacterial adherence and other relevant biological endpoints; o Investigate the antiadhesive property of cranberry/cranberry constituents on different strains of bacteria, as well as on various cellular substrates; o Confirm/identify active agent(s) and/or other biochemical properties; o Assess the equivalence of different cranberry products. Objectives of This Research Program Specifically, the objectives of this RFA are to: o Conduct laboratory studies to identify and test mechanisms that could explain the biological effects of cranberry/cranberry constituents; o Study the basic mechanism(s) by which the constituents of cranberry block supra- or subgingival biofilm formation associated with dental caries, periodontal diseases or oral mucosal infections. o Determine pharmacodynamics and pharmacokinetics of cranberry/cranberry constituents in animal models and/or human subjects; and o Conduct Phase I/II clinical studies to assess dose range effects, pharmacology, feasibility, safety, and biological efficacy of a cranberry products to justify subsequent, more definitive trials of their safety and efficacy. (A Phase II study may be of modest size, provided it explores a range of dosages and is adequately powered to detect a meaningful difference between groups or validate surrogate markers of disease or clinical endpoints.) (Phase III studies will be considered not responsive to this RFA). MECHANISM OF SUPPORT This RFA will use NIH R01 and R21 award mechanisms. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing-continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is December 1, 2003. Applications that are not funded in the competition described in this RFA may be resubmitted as NEW investigator-initiated applications using the standard receipt dates for NEW applications described in the instruction to the PHS 398 application. This RFA uses just-in-time concepts. It also uses the modular as well as the non-modular budgeting formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular format. Otherwise follow the instructions for non-modular research grant applications. FUNDS AVAILABLE The NIH intends to commit approximately $2.6 million in FY04 to fund five to 13 new and/or competitive continuation grants in response to this RFA. An R21 applicant may request a project period of up to two years with a combined budget for direct costs of up to $275,000 for the two-year period. An R01 applicant may request a project period of up to four years and a budget of no more than $500,000 direct costs per year. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the NCCAM, NIDCR, NIDDK, and ODS 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. Applicant institutions are strongly encouraged to discuss proposed projects with relevant NIH staff listed under INQUIRIES prior to submission. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign o Faith-based or community-based organizations INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Individuals with the skills, knowledge, and resources necessary to carry out the proposed research are invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. SPECIAL REQUIREMENTS This RFA seeks investigator-initiated basic and clinical research applications. There is no common protocol. However, special requirements are listed below. o All grantees responsive to this RFA will be required to use the research-grade cranberry product(s) developed by a contractor. Therefore, the grant applicant is not responsible for the cost of the cranberry product(s). Products developed by the contractor will be (1) cranberry juice cocktail and (2) encapsulated powders, and their matching placebos. The contractor will prepare, characterize, standardize, and maintain a supply of research-grade cranberry products and matching placebos with concomitant quality control and quality assurance. It will provide (e.g., label, package, store, inventory, and distribute) the standardized cranberry products to the NIH-sponsored grantees responsive to this RFA. The contractor will also provide the grantees with information about the proper dispensing, handling, and administration of the study agents. See the Request for Proposals for more detail: http://nccam.nih.gov/research/announcements/rfp/sow.pdf. The contractor has been asked to provide cranberry products in batches to the grantees. A one-year supply of cranberry juice cocktail will be delivered annually on or about June 1, 2004-2007. A two-year supply of the supplement will be delivered on or about June 1, 2004 and 2006. For application purposes, grant applicants may plan their own study timelines; however, they should indicate their willingness to be flexible if their study agents are not available at the time they had originally planned. The actual delivery dates and type and dose of products will be finalized in collaboration with the grantees, the contractor, and the NIH. o For only those applicants who intend to study single constituents isolated from the whole cranberry: Studies that aim solely to identify/test a single chemical constituent of cranberry will not be supported by NCCAM under this RFA. Studies in which single constituents are compared with the complex cranberry product are, however, appropriate. For application purposes, these applicants will be responsible for the chemical isolation, characterization, quality and supply of the product for their own project. After grant award, the NIH will negotiate with the contractor for the research-grade whole cranberry product to develop and provide the isolated constituent. If successful in this negotiation, grant awards will be revised. o All grantees are responsible for their own travel costs in about January 2004 (or earlier)to meet once in the Washington DC metropolitan area with the contractor providing the research-grade cranberry products and the NIH to determine study agent needs (agent type, dosing, quantities, labeling, packaging and delivery) and production/delivery schedules. In addition, the contractor will conduct monthly conference calls (from about December 2003 through September 2004) with the grantees and the NIH. o Grantees conducting clinical studies are expected to file applications for Investigational New Drugs (IND) with the Food and Drug Administration (FDA) after award (tentatively prior to April 2004). However, contact with the FDA regarding FDA requirements and need for an IND would be appropriate prior to submission of the grant application to the NIH. The contractor providing the research-grade cranberry products will be responsible for assisting the grantees by completing sections of the IND application. The contractor will provide the following sections of the IND applications (referencing the Drug Master File may be appropriate) to the grantees by January 1, 2004: (1) Investigator's Brochures for the cranberry products. (2) Chemistry, manufacturing, and control information on the cranberry products. (3) Pharmacology and toxicology data, if available. (4) Previous human experience, including a list of the countries where the products are in clinical testing or have been approved or marketed, if appropriate. The grantee will be responsible for all other sections. [NOTE: Under current regulations, any use in the United States of a drug product (e.g., well-characterized, therapeutic, biotechnology- derived products) not previously authorized for marketing in the United States first requires submission of an IND to the FDA. NIH grantees are required in the PHS 398 application to name the test article and state whether the 30-day interval between submission of applicant certification to the FDA and its response has elapsed or has been waived and/or whether use of the test article has been withheld or restricted by the FDA. However, for purposes of this RFA, grant applicants are not expected to submit IND applications until after the grant award.] o Grantees conducting clinical trials must enter into a Clinical Trial Agreement. Further information on NCCAM requirements for clinical trials are posted on the NCCAM website (http://nccam.nih.gov/research/policies/index.htm). Clinical trials will be conducted under Good Clinical Practice (GCP) conditions as defined in the FDA document "E6 Good Clinical Practice: Consolidated Guidance" (http://www.fda.gov/cder/guidance/959fnl.pdf). o Applications for studies comparing cranberry product to a non- cranberry product will not be considered responsive to this RFA and will be returned to the applicant without further consideration. o Phase III studies will be considered not responsive to this RFA and will be returned to the applicant without further consideration. o Applications requesting greater than $500,000 direct costs in any year will be considered not responsive to this RFA and will be returned to the applicant without further consideration. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues to: Marguerite Klein Program Officer Division Extramural Research and Training National Center for Complementary and Alternative Medicine Democracy 2, Suite 401 6707 Democracy Blvd. Bethesda, MD 20892 Telephone: (301) 402-5860 FAX: (301) 480-3621 Email: kleinm@mail.nih.gov Dennis F. Mangan, Ph.D. Division Basic and Translational Sciences National Institute of Dental and Craniofacial Research Building 45, Suite 18 Bethesda, MD 20892-6402 Telephone: (301) 594-2421 FAX: (301) 480-8318 Email: Dennis.Mangan@nih.gov Chris Mullins, Ph.D. Director of Basic Cell Biology Programs Division of Kidney, Urologic and Hematologic Diseases National Institute of Diabetes and Digestive and Kidney Diseases Democracy 2, Suite 637 6707 Democracy Blvd. Bethesda, MD 20892 Telephone: (301) 451-4902 FAX: (301) 480-3510 Email: mullinsc@extra.niddk.nih.gov Joseph M. Betz, Ph.D. Director, Dietary Supplements Methods and Reference Materials Program Office of Dietary Supplements 6100 Executive Blvd., Room 3B01 Bethesda, MD 20892 Telephone: (301) 435-2920 FAX: (301) 480-1845 Email: betzj@od.nih.gov o Direct your questions about peer review issues to: Dr. Martin Goldrosen Director, Office of Scientific Review National Center for Complementary and Alternative Medicine Democracy 2, Suite 401 6707 Democracy Blvd. Bethesda, MD 20892-5475 Telephone: (301) 594-2014 FAX: (301) 480-2419 Email: goldrosm@mail.nih.gov o Direct your questions about financial or grants management matters to: Victoria Carper Grants Management Officer National Center for Complementary and Alternative Medicine Democracy 2, Suite 401 6707 Democracy Blvd. Bethesda, MD 20892-5475 Telephone: (301) 594-9102 FAX: (301) 480-1552 Email: vp8g@nih.gov Mary Daley Chief, Grants Management Officer National Institute of Dental and Craniofacial Research 45 Center Drive, MSC 6402 Bldg. 45, Room 4AN-44B Bethesda, MD 20892-6402 Telephone: (301) 594-4808 FAX: (301) 480-3562 Email: md74u@nih.gov Donna Huggins Supervisory Grants Management Specialist Grants Management Branch, DEA National Institute of Diabetes and Digestive and Kidney Diseases Democracy 2, Suite 711, MSC 5456 6707 Democracy Blvd. Bethesda, MD 20892-5456 Telephone: (301) 594-8848 FAX: (301) 480-3504 Email: Hugginsd@extra.niddk.nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel, consultants, collaborators o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: Marguerite Klein Program Officer Division Extramural Research and Training National Center for Complementary and Alternative Medicine Democracy 2, Suite 401 6707 Democracy Blvd. Bethesda, MD 20892 Telephone: (301) 402-5860 FAX: (301) 480-3621 Email: kleinm@mail.nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. SUPPLEMENTAL INSTRUCTIONS: All instructions for the PHS 398 (rev. 5/2001) must be followed, with these exceptions which apply to the R21 exploratory/developmental grant only: o Research Plan: Items a – d of the Research Plan (Specific Aims, Background and Significance, Preliminary Studies, and Research Design and Methods) may not exceed a total of 15 pages. No preliminary data is required but may be included if it is available. o Appendix: Use the instructions for the appendix detailed in the PHS 398 except that no more than five manuscripts accepted for publication may be included. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html includes step- by-step guidance for preparing modular grants. Additional information on modular grants is available at http://grants.nih.gov/grants/funding/modular/modular.htm. For the R21 grant application, you may request direct costs in $25,000 modules, up to a total direct cost of $275,000 for the combined two- year award period. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist and appendices, and three signed, photocopies (including appendices), in one package to: Center For Scientific Review National Institutes Of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to: Dr. Martin Goldrosen Director, Office of Scientific Review National Center for Complementary and Alternative Medicine Democracy 2, Suite 401 6707 Democracy Blvd. Bethesda, MD 20892-5475 Telephone: (301) 594-2014 FAX: (301) 480-2419 Email: goldrosm@mail.nih.gov APPLICATION PROCESSING: Applications must be received on or before the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within eight weeks. 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. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA, it is to be prepared as a NEW application. That is the application for the RFA must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes. While the investigator may still benefit from the previous review, the RFA application is not to state explicitly how. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness and responsiveness by the NCCAM. Incomplete applications will be returned to the applicant without further consideration. 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: o Receive a written critique o 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 and assigned a priority score o Receive a second level review by the National Advisory Council for Complementary and Alternative Medicine, NCCAM. REVIEW CRITERIA The R21 exploratory/developmental grant is a mechanism for exploring the feasibility, as well as the development, of research projects and for generation of preliminary data. 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 grants are intended to serve as a basis for planning and strengthening future research project grant applications(R01). It is important to note that, while originality (innovation) of approach and potential significance of the proposed research are major considerations in evaluation of R21 grant applications, the applicant is responsible for presenting the background literature that provides some basis for the approach and for developing a rigorous research plan. Because the research plan is limited to 15 pages, an exploratory/developmental grant application need not have as much background material or preliminary information as one might normally expect in an R01 application. Accordingly, reviewers will focus their evaluation on the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or from investigator-generated data. Preliminary data are not required but should be presented if available. 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 your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application's overall score, weighting them as appropriate for each application. Your 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. 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? 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? 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? 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)? 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? PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below). INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below). CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. ADDITIONAL CONSIDERATIONS o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: April 22, 2002 Application Receipt Date: May 20, 2003 Peer Review Date: September-October, 2003 Council Review: November, 2003 Earliest Anticipated Start Date: December 1, 2003 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. REQUIRED FEDERAL CITATIONS HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: 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). INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub- populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at http://grants. nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH- defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy 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 is available at http://grants.nih.gov/grants/funding/children/children.htm. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide the official NIH identifier(s)for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. 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. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. 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 RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm. The ODS was mandated by Congress in 1994 and established with the Office of the Director, NIH. The Dietary Supplement Health and Education Act (SHEA) [Public Law 103-417, Section 3.a] amended the Federal Food, Drug, and Cosmetic Act "to establish standards with respect to dietary supplements." This law authorized the establishment of the ODS. The PHS strongly encourages all grant recipients to provide a smoke- free workplace and discourage the 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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