CENTERS FOR DIETARY SUPPLEMENT RESEARCH: BOTANICALS Release Date: December 21, 1999 RFA: OD-00-004 Office of Dietary Supplements National Center for Complementary and Alternative Medicine Fogarty International Center National Cancer Institute National Heart, Lung, and Blood Institute National Institute of General Medical Sciences National Institute of Diabetes and Digestive and Kidney Diseases National Institute on Aging National Institute on Drug Abuse National Institute of Environmental and Health Sciences Office of Research on Women’s Health Applicant Information Meeting: January 28, 2000 Letter of Intent Receipt Date: March 25, 2000 Application Receipt Date: April 25, 2000 PURPOSE The Office of Dietary Supplements (ODS), National Center for Complementary and Alternative Medicine (NCCAM), Fogarty International Center (FIC), National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI), National Institute of General Medical Sciences (NIGMS), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute on Aging (NIA), National Institute on Drug Abuse (NIDA), National Institute of Environmental and Health Sciences (NIEHS), and the Office of Research on Women’s Health invite proposals to establish Specialized Research Centers to investigate the biological effects of botanicals including, but not limited to, botanicals available as dietary supplements. The creation of such Centers is needed to advance the quality and quantity of scientific information on botanicals and to promote further research in this area. The major goal of this Request for Applications (RFA) is to foster interdisciplinary research in order to promote the scientific study of botanicals, particularly those available as dietary supplements. Further, this RFA is intended to explore more fully the potential role of botanical dietary supplements as a significant part of the efforts of the United States to improve health care. Applications in response to this RFA are encouraged to propose research projects ranging from basic research to those involving clinical applications. It is anticipated that a fully integrated Center eventually will have the capacity to 1) identify, characterize and authenticate botanicals, 2) assess the bioavailability and bioactivity of botanical ingredients, 3) identify active constituents in botanicals, explore their mechanism(s) of action, 4) conduct both pre- clinical and clinical evaluations of botanicals, and 5) serve as a primary information resource for the public. Note: Phase III clinical trials are beyond the scope of this RFA. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of Healthy People 2000 , a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of Healthy People 2000 at http://odphp.osophs.dhhs.gov/pubs/hp2000. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and 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. Foreign organizations may participate if they are components of domestic U.S. organizations or via contractual or consortium agreements with domestic U.S. organizations. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as the Center Director. The Center Director is also the Principal Investigator (PI) for this grant application. Questions about eligibility may be addressed to the program contacts listed in the INQUIRIES section. To be considered, applicant organizations must identify a Center Director who is a recognized leader in scientific research with a demonstrated history of research funding and scientific productivity, as well as demonstrated experience in the administration of complex research projects grants, center grants, or multi-site clinical investigations. The Center Director should have demonstrated ability to oversee and conduct planning activities, provide administrative and scientific direction to the Center, ensure an interdisciplinary research emphasis, and build a career development program. MECHANISM OF SUPPORT This RFA will use the NIH specialized center grant (P50) award mechanism. This mechanism supports the full range of research and development from basic to clinical and intervention studies, as well as health services, policy, and surveillance research. These grants differ from traditional program project grants in that they are more complex and flexible in terms of the activities that can be supported. In addition to support for interdisciplinary research projects, support may be provided for career development research activities, a limited number of pilot research projects, and specialized core resources and shared facilities aimed at supporting the range of proposed research. A Specialized Center of Research must contain both clinical and basic science research studies. The PI will be responsible for the planning, direction, and execution of the proposed program. Awards will be administered under NIH grants policy as stated in the most recent NIH Grants Policy Statement. A P50 award provides support for a broad interdisciplinary research program consisting of related research endeavors and associated core infrastructure to ensure their effective and synergistic functioning. The activities included in the supported research must be thematically integrated and interdisciplinary. Research supported through this mechanism must reflect in clear ways the interdependence of components of the research program that would not occur simply from a mere collection of the individual components. Taken as a whole, the Center is expected to enable a level of achievement that exceeds that expected on the basis of the sum of its parts. Further, the Center is encouraged to address a range of research questions, from basic to clinical applications, around a central theme of the Center. Center support should be essential to the achievement of the work that is proposed. The Center is expected to attract established and promising investigators into natural products and botanicals research and to provide opportunities for research experience, career development, and mentoring. FUNDS AVAILABLE It is estimated that $1,500,000 total costs (direct and facilities and administrative (F&A) costs combined) are available in the first year of the program. It is anticipated that one award will be made. Applicants may request up to $1,500,000 in annual total cost (direct and F&A costs combined). Annual increases are limited to three percent. The total project period for an application may not exceed five years. The anticipated award date for applications is September 29, 2000. Funding in response to this RFA is dependent upon the receipt of a sufficient number of applications of high scientific merit and upon the anticipated availability of funds for this purpose. Depending on NIH priorities and budget at the end of the five-year award period, a RFA may be reissued to continue this Centers program. If the RFA is not reissued, then grantees must compete for support through other research grant mechanisms (e.g., R01, P01). Depending on NIH priorities and budget for FY 2001, another RFA may be issued to increase the number of Centers. Applications will be assigned to the National Center for Complementary and Alternative Medicine (NCCAM) for administrative purposes. RESEARCH OBJECTIVES Background A recent survey conducted by the Food and Drug Administration (FDA) Center for Food Safety and Applied Nutrition indicates that 16 million Americans use dietary supplements containing botanical ingredients, supporting an industry that is growing at 20 percent per year. The reasons for the increased popularity of botanicals are not fully understood. Many people believe that botanicals will maintain or improve health, preventing the onset of a variety of chronic diseases and health problems associated with aging. Many believe that botanicals, particularly herbal remedies, are both therapeutically effective and free of any side effects commonly associated with prescription medications. Self-medication with botanical products is sometimes viewed as allowing individual control over primary health care. Finally, some consumers are under the mistaken impression that dietary supplements containing botanical ingredients have been approved for use by the FDA following the same rigorous testing and evaluation required for drugs. For centuries, a number of botanicals have been used with purported and demonstrated efficacy. The active ingredients in a number of life- saving drugs in current use were isolated originally from plants. In Germany, where many herbal remedies as phytomedicines are regulated and prescribed as drugs, botanicals are an integral component of primary health care. There are respected scientific monographs (e.g., United States Pharmacopia, German Commission E, European Scientific Cooperative on Phytotherapy, WHO Monograph on Selected Medicinal Plants) covering a number of botanicals. Nonetheless, health practitioners and consumers in the U.S. currently do not have adequate knowledge to evaluate critically the health effects of the majority of botanical products in the market place. To evaluate systematically the efficacy and safety of botanicals, particularly botanicals available as dietary supplements, innovative approaches are needed. The classical drug development model may be inappropriate. Botanicals used in folk and traditional medicine and products available commercially as dietary supplements usually contain many diverse compounds rather than a single active pharmacological agent. In many instances, the active ingredient(s) is not known. Furthermore, drugs tend to have specific targets while many botanicals appear to have biological effects that may derive from multiple activities. Areas of Emphasis Four areas of research are emphasized: 1) identification and characterization of botanical ingredients, 2) assessment of the bioavailability and bioactivity of botanical ingredients, 3) identification of active constituents and elucidation of their mechanisms of action, and 4) investigation of potential health effects of botanicals. The formation of multidisciplinary teams to perform the research of this initiative is viewed as essential. For example, collaborations among botanists, natural products chemists, pharmacologists, pharmacognosists, and clinical investigators would be appropriate. o The first area of emphasis is the identification and characterization of botanical ingredients. Methods of identification of botanical species could include, but are not limited to, classical plant taxonomy and chemical characterization. In addition to using state-of-the-art methods of chemical analysis, applicants are encouraged to develop novel approaches for plant identification. For example, a DNA-based taxonomy system utilizing genetic fingerprints could be explored. o The second area of emphasis is the assessment of the bioavailability and bioactivity of botanical ingredients. This RFA will be supportive of research to identify the determinants of bioavailability (i.e., absorption, utilization, excretion) of botanical constituents (e.g., marker compounds or active ingredients). Questions such as the following would be appropriate: How does the final physical form of the botanical (e.g., powder, extract, isolate) affect bioavailability? Is bioavailability likely to be affected if the botanical is taken with food, alcohol, other botanicals, prescription or over-the-counter medications. Potential interaction of botanicals with medications commonly used by older adults is of particular interest since the use of prescription medications is relatively common in this population. The RFA will support the development of in vitro and in vivo methods to assess bioavailability. This includes development and validation of feasible methods to evaluate bioavailability in clinical studies (e.g., measurement of the concentration of the test material or relevant metabolites in blood). This RFA will support research to examine bioactivity of botanical constituents. Biological functions of interest include, but are not limited to, the following: immune response, hormonal action, neurochemistry as it relates to cognitive function, muscle function as it relates to strength or physical performance, regulation of energy metabolism, antioxidant activity, age-related repair of DNA, and cell cycle regulation. The RFA is supportive of efforts to develop rapid and reliable screening tests to assess bioactivity. The use of genomics to develop mechanism-based bioassays directed towards assessing potential therapeutic efficacy or safety is encouraged. Bioactivity is sometimes described in quantitative terms related to specific activity. The bioactivity of botanicals may be enhanced or diminished by a variety of factors. Efforts to modify the bioactivity of botanicals could be explored. o The third area of emphasis is the identification of the active constituent(s) in botanical ingredients and the exploration of their mechanism(s) of action. Both of these efforts will place research on botanical supplements on a more scientifically valid footing. As mentioned in the Background section, many botanicals may have multiple effects. Sorting out mechanisms of action at a molecular or cellular level will require new approaches akin to sorting out other complex interacting systems. This RFA supports the development of methods for analyzing complex actions of multi-component mixtures. o The fourth area of emphasis is the incorporation of human studies in the research plan, in order to document the health effects of botanicals. Observational epidemiological studies (e.g., retrospective case-control or prospective cohorts) have provided useful leads to identify relations between dietary constituents and health. Numerous epidemiological studies of select botanicals including functional foods (e.g., green tea, soy, garlic) have been conducted to evaluate their relation to health. However, dietary supplements containing botanical ingredients are not uniformly standardized and exposure misclassification (i.e., measurement error) could be substantial. Further, any apparent health benefits or risks of botanicals might be attributed to confounding by other lifestyle factors. This RFA encourages the development of innovative approaches to epidemiological studies of dietary supplements containing botanical ingredients. This RFA encourages the identification and evaluation of botanicals with high potential for therapeutic benefit. While Phase III studies are beyond the scope of this RFA, Phase I and Phase II studies are certainly within its scope, particularly if existing clinical facilities are available at the awarding institution or can be identified at other collaborating institutions. Phase I and Phase II studies shall be conducted with an Investigational New Drug (IND) from the FDA. Issues that are relevant to these studies include criteria for the evaluation of safety, determination of appropriate dose, and justification of relevant measures of biochemical/physiologic change or selection of intermediate endpoints for Phase II studies. While careful chemical characterization and identification of chemical constituents of botanicals is encouraged, efficacy testing of isolated constituents is not. This RFA is not intended to result in the development of new drugs. Several NIH Institutes have joined with the ODS to support this initiative. Examples of topics of interest to specific Institutes are: The NATIONAL CENTER FOR COMPLEMENTARY AND ALTERNATIVE MEDICINE conducts and supports basic and applied research, research training and other programs to identify, investigate and validate complementary and alternative medical treatments, diagnostic and prevention modalities, disciplines and systems (P.L.105-277). In order to meet this mandate, NCCAM supports research and training programs that increase knowledge of botanical products of possible use to the U.S. public. NCCAM has a particular interest in botanical products having potential immunomodulatory or anti-cancer activity. Examples of research topics include, but are not limited to 1) development and validation of methods to test the clinical applications of botanicals both in vitro and in vivo, 2) development of methods for the cultivation and extraction of standardized natural products to meet the Good Manufacturing Practice (GMP) requirements of the FDA IND process, 3) development of simple biological assays that can be used to monitor the levels of constituents of interest in simple whole extracts, 4) development and validation of methods to examine the bioavailability of botanical products, 5) development and validation of animal and in vitro models to study botanical interventions, 6) examination of botanical/drug, botanical/botanical and botanical/supplement (e.g., vitamins, minerals) interactions. The FOGARTY INTERNATIONAL CENTER (FIC) is dedicated to promoting international health through collaborative research and training in the biomedical sciences. FIC is interested in international collaborative research in field, laboratory and/or clinical settings on botanicals that are widely used in developing countries to promote health, prevent or treat diseases. This may include 1) taxonomy, cultivation, and chemical standardization of botanicals toward production of sustainable high quality materials, 2) study of mechanisms of action and bioavailability, 3) identification of toxicity or other potentially ill health affects associated with their use, 4) analysis of potential interactions with pharmaceuticals used for similar diseases or with minerals that may be found in foods. The NATIONAL CANCER INSTITUTE (NCI) coordinates the National Cancer Program, which conducts and supports research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer, rehabilitation from cancer, and the continuing care of cancer patients and families of cancer patients. A large number of naturally occurring nutritive and non-nutritive constituents present in botanicals has been shown to inhibit carcinogenesis in animals when fed in purified form and at pharmacological levels. Little information is available on the dietary intake of non-nutrient constituents of botanicals, the metabolism of botanical constituents in humans, and the potential mechanisms of action for their anticarcinogenic effects, such as altering gene expression, suppressing proliferation, inducing differentiation and or encouraging apoptosis. Even less is known about interactions among the various botanical constituents and other components of the diet. Important issues related to quality assurance, clinical applicability, pharmacology, dose, precautions, contraindications, and adverse reactions should be considered. Research is also needed to provide a better understanding of the potential impact of botanicals or various constituents of botanicals on the treatment of precancerous conditions or early stage cancerous lesions. Research is also sought that examines the potential use of botanicals for the treatment of the sequelae of cancer (e.g. pain, anorexia) or side effects of conventional therapies (e.g. nausea, vomiting, neuropathy, mucositis). Such information should provide novel approaches in cancer prevention and aid in refining dietary guidance. The NATIONAL HEART, LUNG, AND BLOOD INSTITUTE (NHLBI) fosters and supports an integrated and coordinated program of basic research, clinical investigations and trials, observational studies, and demonstration and education projects related to the causes of, prevention, diagnosis, and treatment of heart, blood vessels, lung, blood diseases and sleep disorders supported by research grants and contracts. An area of interest to NHLBI is to advance our understanding of the biomedical effects of dietary supplements (including botanicals) at the molecular level through the modern methods and approaches of molecular medicine. It is desirable that strategies be aimed at understanding the molecular basis of how botanicals affect diseases of the heart, lung, and blood, and at studying how the structure and activity of living cells are controlled by active components of the dietary supplements under investigation. In addition to human studies, the advent of genetically altered animals provides a new avenue to explore the integrative metabolic and local aspects of risk factors that promote interactions with dietary supplements and affect the various diseases of the heart, blood vessels, lung, blood, and sleep disorders. As an example, atherosclerosis underlies most coronary heart disease, peripheral vascular disease, stroke and several other diseases. Many systemic factors associated with atherosclerosis have been identified. However, information is needed to understand how botanicals, might influence risk factors and interact with vascular cells. In this regard, the interactions and effects of supplements on insulin resistance, dyslipidemia, hypertension, and central obesity are areas of interest. Furthermore, dietary supplements may contain active compounds that may influence blood vessel spasms, contraction or dilation of the wall, all play important roles in the pathophysiology of the cardiovascular diseases. In addition, effects on the coagulation cascade and various proteins and factors of thrombosis are important targets for some of the observed clinical manifestations which need further investigation. Research of interest to the NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES includes: 1) development of broadly applicable methods for the taxonomic identification of botanical materials and the characterization of their chemical constituents, 2) development of plant genetic markers as well as development of chemical markers of botanical material potency, 3) elucidation of the pathways and regulation of secondary metabolite biosynthesis, and the development of methods to enhance the production of selected metabolites, 4) studies on the relationship between chemical structure and biological activity, 5) methods for analyzing and modeling the effects of multi-component mixtures of potentially low concentration or low-affinity ligands acting synergistically upon multiple pharmacological targets, 6) studies into the mechanisms of action or toxicity of botanicals, 7) studies of botanical supplement/drug interactions and the mechanistic basis thereof, including studies of the effect of botanicals on drug- metabolizing enzymes and studies relating to the bioavailability of botanical constituents, 8) studies on the potential impact of pre-admission botanical supplement usage in the areas of NIGMS clinical responsibility, i.e., trauma and burn injury, sepsis, shock, multiple organ failure, and anesthesiology, and 9) studies of botanical materials having potential efficacy in wound healing, or having anesthetic or analgesic effects. The NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES (NIDDK) encourages collaborative efforts between natural product scientists, and basic and clinical scientists in its three major program areas: diabetes, endocrinology and metabolism, digestive diseases and nutrition, and kidney, urology and hematology. Thus, research efforts leading to promising new treatments and to elucidation of mechanisms of action underlying treatment would be welcomed. Specific examples of research projects appropriate for inclusion in applications responsive to this initiative include, but are not limited to, studies on: 1) efficacy and safety of botanicals in the treatment of obesity and diabetes, complications, and basic mechanisms underlying treatment. Additional emphases could be placed on compounds or isolated active ingredients in botanicals which lower weight, decrease fat mass, decrease appetite or increase energy expenditure. This initiative also would be supportive of studies to evaluate the use of botanicals as part of standard behavioral weight loss treatment programs that include diet and exercise. 2) herbal-based remedies applied to the intestinal tract. Studies focusing on the efficacy and safety of treatment and on the underlying mechanisms focusing on organ integrity and function of the stomach and intestine would be appropriate. Specific examples would include work on effects of botanicals on peptic ulcers, maintenance of epithelial lining, studies of diarrheal diseases, irritable bowel syndrome and intestinal motility. 3) treatment and underlying mechanisms relevant to liver and gall bladder diseases and to botanicals with promising hepato-regenerative potential. Additional studies should focus on the potential role of botanicals in the treatment and prevention of hepatotoxity. 4) mechanisms underlying the effects of botanicals in the treatment of benign prostatic hyperplasia. Studies would be encouraged on interactions between relevant botanicals and regulation of hormonal action and metabolism, immune function, anti-congestive actions, and muscle function. The NATIONAL INSTITUTE ON AGING would be interested in proposals to assess the potential anti-aging effects of botanicals. Various approaches and models could be used, including invertebrates and vertebrates. A high priority would be given to proposals to examine the effects of botanicals on longevity and the incidence of specific age-related pathology. In addition, the effects of botanicals on aging in specific systems ranging from molecular to physiological levels of organization would be important to investigate. Priorities within this systems approach would be as follows: 1) age-related damage and repair to nuclear and mitochondrial DNA in various organs, 2) gene expression as it relates to stress responses, 3) oxidative stress as it relates to item 1 as well as to the integrity of proteins and cellular membranes, 4) glycation, 5) immune function, 6) vascular stiffness and plaque formation, 7) bone metabolism, 8) neuroanatomy and neurophysiology particularly as it relates to motor and cognitive function. Proposals examining the effects of botanicals on other age-related parameters would also be considered, but the approach should relate to fundamental processes of aging and be linked to a specific mechanistic hypothesis. The NATIONAL INSTITUTE ON DRUG ABUSE (NIDA) supports more than 85 percent of the world’s research on health aspects of drug abuse and addiction. It also supports research on infections including HIV/AIDS and associated medical and health consequences in drug users. It is not known if botanicals (e.g., medicinal plants, herbal products) alter the course of drug addiction or drug taking behavior or if they can be used to treat drug addiction. NIDA would be interested in proposals focused on drug users with or without HIV/AIDS to determine: 1) if botanicals or their active chemical constituents alter the synthesis, release/uptake, metabolism or receptor binding of neurotransmitters thought to be related to drug addiction, 2) the interactions between botanicals and therapeutic agents used for the treatment of drug addiction, 3) the nature, extent and purpose of use of botanicals (excluding sources of illicit drugs) by addicts. The NATIONAL INSTITUTE OF ENVIRONMENTAL AND HEALTH SCIENCES (NIEHS) mission is to develop knowledge that will permit the better management of risks associated with body exposures to or processing of environmental factors or agents. Within this mission, the NIEHS supports research investigating the effects of chemical, physical and biological environmental agents on human health and well-being. NIEHS is presently interested in encouraging research on the potential health effects, either positive or negative, of self-administered botanical dietary supplements. This specifically includes research pursuing the systematic evaluation of the safety and efficacy of botanicals, including the elucidation of their mechanisms of action. Such knowledge is essential to ascertaining whether dietary botanical products diminish or amplify an individual"s sensitivity to toxicant exposure or the bioavailability of stored toxicants in the resident body burden mass of the individual. The modulating effects of botanicals on the expression of genetic susceptibilities to environmental diseases is poorly understood. The NIEHS will support projects that will expand our knowledge in these areas. The OFFICE OF RESEARCH ON WOMEN’s HEALTH (ORWH) advises the NIH Director and staff on matters relating to research on women=s health, strengthens and enhances research related to diseases, disorders, and conditions that affect women, ensures that research conducted and supported by NIH adequately addresses issues regarding women=s health, ensures that women are appropriately represented in biomedical and biobehavioral research studies supported by the NIH, develops opportunities for and supports recruitment, retention, re-entry, and advancement of women in biomedical careers, and supports research on women=s health issues. ORWH is interested in the biologic and molecular bases for sex differences in kinetics and dynamics of botanicals, specifically their active principles. A high priority would be given to proposals that examine the biological effects of botanicals on 1) reproductive health encompassing both pregnancy and non-pregnancy issues, including menopause, 2) kidney and urologic health and diseases, 3) gastrointestinal health and diseases, 4) biologic and molecular bases for sex differences in pharmacokinetics, pharmacodynamics, and pharmacogenetics, 5) multidisciplinary, basic and clinical research in women=s health in such areas as cardiovascular diseases, musculoskeletal injuries, disorders and diseases, and neuroendocrine function, 6) behavioral and cultural influences on disease risk and lifestyle changes, 7) mental health, including depression, anxiety and eating disorders. Types of Research This initiative in intended to stimulate and support both basic and clinical research on botanicals. Assessment of efficacy and safety, including assessment of underlying processes is encouraged. For this RFA, however, botanicals should not be thought of simply as sources of phytochemicals to be studied. A broader perspective, ranging from plant cultivation to effects on human health, is encouraged. While this research initiative is not principally concerned with the dissemination of information to the health practitioner and consumer, it encourages efforts to explore methods for disseminating information. The research must be oriented toward the most critically needed areas of botanicals research. The RFA encourages the identification and evaluation of botanicals with high potential for therapeutic benefit, particularly if the botanicals under consideration have not received significant research attention by the NIH. Applicants are also encouraged to propose work in thematic areas that will add both breadth and depth to the research program on botanicals currently supported by the ODS and participating ICs. This research initiative is inherently interdisciplinary, and should serve to facilitate and stimulate interdisciplinary projects. In that spirit, a variety of quantitative, qualitative, experimental, interview and observational research methods are appropriate. Research Projects (item 4 below) or Research Resource Core Components (item 6b below) involving animal models may be included but should not dominate the research program. The overall, dominant thrust of the Center and its research is to foster interdisciplinary collaborations in order to promote rigorous scientific study of botanicals and to develop rational and novel approaches to evaluate their efficacy and safety, particularly botanicals included as ingredients in dietary supplements (see ODS operating definition of dietary supplements in Definitions section). SPECIAL REQUIREMENTS This section provides descriptions of required elements of the grant proposal. Applications that fail to meet required elements will be considered unresponsive to the RFA and will not be reviewed. 1. Overview The Specialized Center Grant for this RFA minimally consists of 1) Administrative and Planning Core Components, which will provide coordination, research planning, logistical, and technical support, 2) Research Project Components which are individual R01-like research projects, 3) a Pilot Research Program providing for the implementation of pilot studies, feasibility or preliminary research projects, and 4) Research Resource Core Components to provide infrastructure and enhance the activities of the Research Projects. A Center should be an identifiable organizational unit formed by a single institution or a consortium of cooperating institutions. Such a Center will involve the interaction of broad and diverse organizations or units. Therefore, lines of authority by the appropriate institutional officials must be clearly specified. 2. Institutional Commitment An institution receiving this award should incorporate the Center highly within its institutional priorities. The institution should demonstrate a strong commitment to the Center’s stability and success. The applications must provide a plan that addresses how the institutional commitment will be established and sustained, how it will maintain accountability for promoting scientific progress, and how the Center research effort will be given a high priority within the institution relative to other research efforts. This institutional commitment may be in the form of commitments to recruit scientists, provision of discretionary resources to the Center Director, faculty appointments for Center investigators, assignments of additional research space, cost sharing of resources, or other ways to be proposed by the applicant. 3. Center Director Each applicant institution shall name a Center Director as the Principal Investigator (PI) who will be the key figure in the administration and management of the Center grant. The Center Director should be an experienced researcher with demonstrated leadership appropriate to the coordination of the Center. A minimum of 25 percent (15% minimum administrative and 10% minimum research) effort on activities directly supported by the Center’s funding is required of the Director. The Director must also be a Project Leader on one, but not more than two, R01-like research projects within the Center. Note: The Center Director is the only PI for this grant application. R01-like projects (see Research Project Components) will be headed by Research Project Leaders. A Research Project Leader is equivalent to a PI on a standard NIH R01 grant application. Research Cores (see Research Resource Core Components) will be headed by Core Leaders. (4) Research Project Components The Research Project Components are individual research studies funded through the Center. While an application need not address all four Areas of Emphasis described in the RESEARCH OBJECTIVES section, it should include research studies relevant to at least two of them. The applicant also should consider topical areas identified by the participating Offices, Institutes and Centers (ICs) described in the RESEARCH OBJECTIVES section. Applicants are encouraged, but not required, to develop research programs that cut across traditional IC- specific mandates. Applications must propose at least three, but no more than four, research studies. The research projects must show evidence of an interdisciplinary focus. Thus, an explanation of how the projects fit together across disciplines to promote synergy must be included. The Research Projects should be of a scope similar to the traditional NIH (R01) research grant. Each of these projects must request at least three, but not more than five, years of support. Research Projects may be phased in and out over the life of the Center grant. At least three of the submitted research projects, including that of the Center Director, must be judged meritorious by the peer-review panel for the application to meet the minimal requirements of a P50 Center. Failure to meet these requirements will remove the application from funding consideration. At least one of the recommended research projects must be a basic (mechanistic) study and one must be a clinical study other than a Phase III trial. Applications that do not meet this basic requirement will be ineligible for funding. Epidemiological studies and population surveys that can be completed in five years are permissible. With the exception of the Center Director, research project leaders are required to commit at least 15% time to these projects. Research project components involving Phase I and II clinical trials must include provisions for 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 Notice 98-084 located at: http://grants.nih.gov/grants/guide/notice-files/index.html.) Funds should be budgeted for these activities. The data and safety monitoring activities should not duplicate internal review and monitoring systems that are already in place at the institution. Collaborative arrangements within the Center, within the parent institution, and with other institutions are encouraged. Collaborations with scientists outside the immediate Center should be documented with appropriate letters of commitment as applicable. Collaborations with other institutions, including foreign institutions, may involve subcontracting arrangements but the award will be made to one institution only (i.e., the institution of the Center Director). (5) Pilot Research Program Applicants are encouraged to develop a Pilot Research Program that will generate the preliminary data sufficient to provide the basis for applications for independent research through conventional granting mechanisms (e.g., R01, P01) or improve the prospects for the Research Projects described above. Pilot studies should take maximum advantage of the new research opportunities created through the Center. Pilot or feasibility projects should not be presented at the time of submission. However, the Center application should include a description of the process that will be used to evaluate and select pilot or feasibility projects. In selecting projects, the Advisory Committee (see section 9 below) should be involved in the review process. Pilot research studies are typically limited to a period of one to two years. No more than $100,000 (direct costs) per year may be devoted to pilot research projects. This is not a per project maximum, but rather an aggregated maximum of all pilot research projects. NIH staff must be notified before the start of each pilot project, such that animal care and use and human subject assurances, and Advisory Committee approval can be verified. (6) Center Cores Components A Core is defined as resources shared by multiple investigators. Cores should enhance research productivity and increase the functional capacity of the Center. Research Project utilization of these Cores is essential and needs to be specified in the application. The Center is required to have Administrative and Planning Core and a Research Resource Core. (a) Administrative and Planning Core Components This core is responsible for the day-to-day administrative details as well as program coordination and ongoing evaluation of the Center. Components falling within the Administrative and Planning Core would be the Pilot Research Program (item 5 above), a Career Development Program and the Advisory Committee (items 7 and 9 below). This core manages the overall activities of the Center and should include a specified Center Director and a discrete administrative structure. The Center’s Administrative and Planning Core should accomplish the following: o Coordinate and integrate the Center’s activities o Plan and review the utilization of funds, including funds for research projects o Advise the Center Director on the activities of the Center While the final administrative structure of the Center will be left up to the discretion of the applicant institution, experience demonstrates that effective development of Center programs requires interaction among the Center Director, Research Project Leaders, Research Resource Core Leaders, appropriate institutional administrative personnel, and the staff of NIH. Like other interdisciplinary grant programs, the success of the Center depends on the involvement of scientific and professional personnel representing a variety of disciplines who must be willing to collaborate and cooperate with each other in order to facilitate the development of new knowledge. Moreover, it is important that a person with institutional management expertise and experience be involved directly with the fiscal aspects of the application and grant. (b) Research Resource Core Components Centers are required to develop Research Resource Core components. The Core is defined as shared research resources that enhance productivity or in other ways benefit investigators working to accomplish the common research goals of the Center. Examples of core components include data management cores, biostatistical cores, and laboratory-based cores. These resources should not duplicate resources already available to Center investigators. However, fee-for-service core components (i.e., Center use of existing facilities) are acceptable with adequate justification. The Center must establish two or more Research Resource Core components to provide shared research resources (e.g., herbaria, animal colonies, botany or plant science facilities, analytical chemistry laboratories, statistical services, survey research services, clinical research facilities such as NIH-sponsored General Clinical Nutrition Research Units). Note: One of the Research Core components must provide expertise in botany. (7) Career Development The Center shall demonstrate a strong commitment to career development, with a plan included as part of the application. This may include new investigators or established investigators who wish to change research directions. Recruitment must include qualified women and minorities. To this end, each applicant should propose a clear policy and plan for recruitment of career development candidates. The application should state the number of career development positions proposed, as well as the criteria for eligibility and for selection of candidates, and should describe the selection process. The candidates may be advanced graduate students, post-doctoral researchers or junior faculty. Also, the application should identify potential mentors who are already in place at the proposed Center and briefly describe their research programs. The application should include a description of complementary activities that contribute to the interdisciplinary environment for career development (e.g., existing training grants, other career development mechanisms, and other relevant activities such seminar series). Mentoring to enhance junior researchers or other researchers skills should be conducted within the context of the Center’s research proposal. Funds for training stipends may only be used for research directly supported by the Center grant. Researchers receiving mentoring may be paid a salary as long as it is received in conjunction with conducting research directly related to the Center’s proposal. Graduate training at the chemistry/biology interface is particularly relevant to botanical research center activities (e.g., molecular methods for plant identification, preservation of genetic stocks). Few universities in the U.S. currently offer graduate training in pharmacognosy. The RFA is generally supportive of applications from institutions that offer training in this discipline. Training to develop researchers with broad knowledge of key dietary supplement topics (e.g., legislation, regulation, activities of regulatory authorities both domestic and foreign, identification of reliable sources of survey data and research findings, U.S and global market activity) is also encouraged. (8) Consumer Information and Education The use of botanical products as dietary supplements is becoming increasingly popular among consumers in the U.S. With this increased popularity comes the need to ensure access to research findings so those consumers can make informed decisions about using botanicals for palliative, preventive and curative measures. In addition, consumers need to know when botanicals are contraindicated because of botanical- drug interactions. As such, it is expected that the Centers will serve as primary information sources for the public and provide user friendly access to information on botanicals. (9) Advisory Committee The Center shall establish an Advisory Committee (AC) to provide oversight and assist the Center Director in making scientific and administrative decisions related to the Center. The AC should be appointed by the Director, members would serve on a rotating basis. The AC shall not be chaired by the Director who will serve in an ex-officio capacity only. The AC should meet at least twice a year and minutes of meetings should be kept. These minutes shall be made available to NIH staff upon request. The AC should consist of at least nine individuals familiar with the Center"s research activities. The AC members may be employees of the grantee institution or other participating institutions, but cannot be participating directly in this RFA. At least one member must be from outside the Center. The AC shall include a pharmacognosist or ethnobotanist, toxicologist, and biostatistician. The AC will have oversight authority over the R01-type research projects submitted in the grant application but will not have the authority to review and modify proposals already approved by NIH. The AC shall have representation from the health care practitioner and lay communities. Members SHOULD NOT be identified until after an award is made. However, the process by which members will be chosen should be specified. In addition to evaluating and prioritizing projects submitted by the Center or, if applicable, consortium investigators, the AC should periodically review Center operations to ensure that Center resources, especially Core resources are used for the most scientifically worthy projects. The AC may perform other duties deemed appropriate by the applicant institution such as decisions concerning the Career Development Program and the Pilot Research Program. Support for the AC should be explicitly budgeted and justified. (10) Annual Meeting of Center Directors The Center Director and selected project investigators shall participate in one meeting per year in the Washington, DC metropolitan area or another mutually convenient location. Funds should be included in the proposed budgets to support attendance at this annual meeting. The purpose of the meeting is to meet with NIH staff to share scientific information, assess scientific progress, discuss problems, identify new research opportunities, and review research priorities. (11) Investigational New Drug (IND) Applications It is the sole responsibility of the applicant to obtain all necessary clearances from the Food and Drug Administration as required. In addition, applicants are strongly encouraged to consult their local Institutional Review Boards (IRB) concerning IND status and the IRB approval process. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. Information is also available 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: 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 policy. LETTER OF INTENT Prospective applicants are asked to submit, by March 25, 2000, a letter of intent that includes a descriptive title of the proposed research, the name, address, telephone and fax number of the Principal Investigator, the identities of other key personnel (including Research Project and Research Core Component Leaders, collaborators, consultants) and participating institutions, and the number and title of this RFA. Although a letter of intent is not required or binding and does not enter into the review of applications, the information that it contains allows NIH staff to estimate the potential review workload, identify appropriate reviewers and avoid conflicts of interest in the review. The letter of intent should be sent to: Christine A. Swanson, Ph.D. Office of Dietary Supplements National Institutes of Health 31 Center Drive, Rm. 1B29-2086 Bethesda, MD 20892-2086 FAX: (301) 480-1845 APPLICANT INFORMATION MEETING In order to improve the quality of applications submitted in response to this RFA, as well as to give potential applicants the opportunity to clarify any issues or questions concerning the RFA, an Applicant Information Meeting (AIM) will be held. At the meeting, potential applicants will have the opportunity to discuss application concepts and outlines of proposed applications with NIH staff. The meeting will be held at, or in close proximity to the NIH on Friday, January 28, 2000. Although a registration fee is not associated with this meeting, attendee travel to the workshop and all other travel costs are the responsibility of the attendee. For additional information regarding the AIM as well as registration materials, call (301) 435-2920. A summary of the presentations and issues discussed at the meeting will be made available through the ODS website about one week after the meeting. Hard copies will be available for those applicants without web access. APPLICATION PROCEDURES The research grant application form PHS Form 398 (rev. 4/98) is to be used in applying for this grant. 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. The application is also available at: http://grants.nih.gov/grants/funding/phs398/phs398.html. Prior to writing the application, applicants should carefully read the instructions provided with Form PHS 398 and this RFA. The total page limitation of the application, as specified in the instructions of the Form PHS 398, does not apply to this RFA. Instead, the following stipulations apply: Table of Contents: Disregard the Table of Contents page from PHS 398 and, instead, write a Table of Contents appropriate to this Center grant application. The Table of Contents should list all items for which funding is sought, in addition to each specific activity required of the Center as outlined under SPECIAL REQUIREMENTS section. Specifically list the locations of the checklist and the various supporting documents, including bibliographic sketches and other support pages. Each page of the application should be numbered consecutively. This numbering should be reflected in the Table of Contents. Budget: For preparation of the budget, the applicant should present a composite budget for all years of support. This composite budget should include the direct costs for each required Center activity (e.g., Advisory Committee, Pilot Research Program, Career Development), as well as each individual Research Project and each Research Resource Core component. This composite budget should be in tabular format, with each budget year being listed in a separate column and each Center activity, Core or Research Project component being listed in a separate row. Budget Form pages 4 and 5 of PHS Form 398 should be completed for each Center activity, Core or Research Project component listed in the composite budget. These pages should be clearly labeled as to which Center activity, Research Project or Core component they address. In addition, the utilization relationships between the Research Projects and Research Resource Core components should be represented in a table of direct costs, with the columns being the Research Projects and the rows being the Research Resource Core components. Biographical Sketches: Bibliographic sketches and other support pages are required for all proposed Center personnel and for all investigators associated with the research projects and cores. These pages should be in alphabetical order following the budget pages and should not be duplicated in the descriptions of individual component projects and cores. Cores and Research Projects: Applicants may use up to 25 pages to describe the following group of Center activities: the Center"s overall goals and objectives, the Administrative and Planning Core components including administrative and planning activities, the Advisory Committee, Career Development Program, and Pilot Research Project Program. Up to 25 pages may be used to describe each Research Resource Core Component. Pages not used for one component may not be used to extend the page limit of other core components. Up to 25 pages may be used to describe each of the R01-like Research Projects, this page limit does not include bibliographies. Descriptions of the individual R01-like Research Projects and the Research Resource Core component facilities should follow the PHS 398 format, section 9 (Research Plan). In addition, each Research Project should provide a detailed description of Research Resource Core utilization and each Research Resource Core component should document its contributions to Center Research Projects. Each of the six points listed under Human Subjects in the PHS 398 application must be addressed for those studies involving human subjects. Although not required at the time of the application, Institutional Review Board and Institutional Animal Care and Use Committee approval must be obtained for each project listed, if appropriate, within 60 days of submission. The RFA label available in the PHS 398 application package must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA number must be typed on the label as well. The sample RFA label is available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. Submit a typewritten, signed original of the application, four signed photocopies, and the completed checklist in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, SUITE 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the time of submission, send one additional copy of the application to: Christine A. Swanson, Ph.D. Office of Dietary Supplements National Institutes of Health 31 Center Drive, Rm. 1B29-2086 Bethesda, MD 20892-2086 It is important to send this copy at the same time that the original and four copies are sent to the Center for Scientific Review (CSR). Applications must be received by April 25, 2000. If an application is received after the date, it will be returned to the applicant without review. The CSR will not accept any application that is essentially the same as one previously reviewed. This does not preclude the submission of a substantial revision of an application already reviewed, but such an application must follow the guidance in the Form PHS 398 application instructions for preparation of revised applications, including an introduction addressing the previous critique. Individual Research Projects from the P50 Center application may be simultaneously submitted to the CSR as investigator-initiated applications (e.g., R01), this fact must be clearly documented in the Center application under "pending support". If, following review, both the Center application and the R01 application are found to be in the fundable range, the research project investigator must relinquish the R01 and will not have the option to withdraw from the Center grant. This is an NIH policy intended to preserve the scientific integrity of a multi-project grant, which may be seriously compromised if a strong component project(s) is removed from the program. Investigators wishing to participate in a multi-project grant must be aware of this policy before making a commitment to the Principal Investigator and applicant institution. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and for responsiveness by the participating NIH entities. Incomplete and/or unresponsive applications will be returned to the applicant without further consideration. In some cases, individual research projects that are incomplete or unresponsive will be withdrawn from the review process while the remainder of the application goes through peer review. 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 NIH peer review procedures. 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 applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate National Advisory Council or Board. Review Criteria All applications submitted in response to this RFA will be reviewed according to the following review criteria. Reviewers will consider these criteria when assigning a single overall score to each application. This single score should reflect their judgement that the proposed Center will have a substantial impact on the pursuit of its goals. Major factors to be considered in evaluation of applications will include: 1. The Center (a) How the proposed Center combines basic and clinical research to achieve scientific goals and develop a research theme. (b) Evidence of synergy of components. To aid in these determinations, reviewers may look at the quality of provisions for the sharing of resources, procedures for formal and informal planning, and review process for developmental or pilot work in order to determine if the application reflects a depth and breadth of expertise and experience not normally present in an individual research project grant. (c) The involvement of different scientific disciplines or subdisciplines in the Center"s activities and the demonstration of substantial interaction among scientists from different disciplines or subdisciplines and different perspectives. (d) Identification of a physical location for the Center that assures necessary activities can occur. (e) Demonstration of an effective relationship among consortium institutions, including documentation of current relationships, as well as the functions, commitments and contributions each consortium member will bring to the proposed Center. 2. Scientific merit of the R01-like Research Projects Each proposed Research Project will be reviewed according to the explicitly stated set of five review criteria recently adopted by the NIH: (a) Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? (b) Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? (c) Innovation: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (d) Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the Research Project Leader and other researchers (if any)? (e) Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? Each Research Project will receive a priority score. The score reflects not only the feasibility of the project and the adequacy of the experimental design, but also the relevance to the overall goals of the Center and the appropriate utilization of Center resources (e.g., Research Resource Core components). Applicants are cautioned against including a Research Project(s) that lacks scientific merit or is not integrated with the overall Center proposal. Each Research Project also will be reviewed for 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 also will be evaluated. In addition, the adequacy of the proposed protection for humans, animals or the environment will be evaluated to the extent they may be adversely affected by the project proposed in the application. 3. Scientific merit of combining the component parts into a Center. 4. Technical merit and justification of each Core component. 5. Adequacy of facilities to perform the proposed research, including laboratory and clinical facilities, instrumentation, and data management systems, when needed. 6. Qualifications, experience and commitment of the Center Director (PI) and his/her ability and intention to devote sufficient time and effort to provide effective leadership. 7. Scientific and administrative structure, including internal and external procedures for monitoring and evaluating the proposed research and for providing ongoing quality control and scientific review. 8. Institutional commitment to the Center, and the appropriateness of resources and policies for the administration of a Center. 9. The proposed organization and activities of the Advisory Committee, including the process to prioritize pilot/feasibility research proposals and the process to choose Committee members after an award is made. 10. Career Development Program, including adequacy of the process for selecting candidates for career development and plans for seeking out minority and women candidates, and adequacy of the individuals available to serve as possible mentors of career development candidates. 11. Pilot Research Program, including adequacy of the proposed process for continuously reviewing and funding projects for their quality, innovation and potential impact, and potential of the program to generate innovative, high-quality research projects on a consistent basis. 12. The appropriateness of the budget for the proposed program and its individual components, considered independently of the factors indicated above. A single numerical priority score will be assigned to the application as a whole. Although primary emphasis will be placed on scientific merit and innovation, significant consideration will be given to administrative structure, multidisciplinary interactions, potential for impacting on the disease/condition in question, and institutional commitment. Schedule: Letter of Intent Receipt Date: March 25, 2000 Application Receipt Date: April 25, 2000 Peer Review Date: June/July 2000 Council Review: September 2000 Anticipated Award Date: September 2000 AWARD CRITERIA Applications recommended by the NIH Special Emphasis Panel and by the appropriate National Advisory Council or Board will be considered for award based on: 1) scientific and technical merit as determined by peer review, 2) program relevance and balance, 3) availability of funds, and 4) responsiveness to the goals and objectives of the RFA. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. (a) Direct GENERAL INQUIRIES to: Christine A. Swanson, Ph.D. Office of Dietary Supplements National Institutes of Health 31 Center Drive, 1B29-2086 Bethesda, MD 20892-2086 Telephone: (301) 435-2920 FAX: (301) 480-1845 Email: SwansonC@od.nih.gov (b) Direct inquiries regarding specific PROGRAMMATIC ISSUES to the staff of the appropriate Institute/Center: Neal B. West, Ph.D. Program Officer National Center for Complementary and Alternative Medicine Building 31, 5B58 Bethesda, MD 20892-2182 Telephone: (301) 402-5867 FAX: (301) 402-4741 Email: westn@OD.NIH.GOV Joshua Rosenthal, Ph.D. Program Director Fogarty International Center National Institutes of Health Bldg 31, Rm B2C39 Bethesda, MD 20892-2220 Telephone: 301-496-1653 FAX: (301) 402-2056 Email: joshua_rosenthal@nih.gov Carolyn K. Clifford, Ph.D. Acting Chief, Nutritional Science Research Group Division of Cancer Prevention National Cancer Institute EPN 212 Bethesda, MD 20892 Telephone: (301) 496-8573 FAX: (301) 402-0553 Email: cc77v@nih.gov Momtaz Wassef, Ph.D. Leader, Atherosclerosis Research Group Vascular Research Program Division of Heart and Vascular Disease National Heart, Lung, and Blood Institute Two Rockledge Center 6701 Rockledge Drive, Suite 10193 Bethesda, MD 20892-7956 Telephone: (301) 435-0550 FAX: (301) 480-2858 Email: Wassefm@nih.gov Peter C. Preusch, Ph.D. Pharmacology, Physiology and Biological Chemistry Division National Institute of General Medical Sciences 45 Center Drive, MSC 6200 Bethesda, MD 20892-6200 Telephone: (301) 594-5938 FAX: (301) 480-2802 Email: preuschp@nigms.nih.gov Michael Ken May, Ph.D. Director, Nutrient Metabolism Program Division of Digestive Diseases and Nutrition National Institute of Diabetes and Digestive and Kidney Diseases, NIH Natcher Bldg., 45 Center Drive Room 6AN-18J Bethesda, MD 20892-6600 Tel: (301) 594-8884 FAX: (301) 480-8300 Email: mm102i@nih.gov Pamela E. Starke-Reed, Ph.D. Director, NIA Office of Nutrition National Institute on Aging, NIH 7201 Wisconsin Avenue Gateway Building/2C231 Bethesda, MD 20892-9205 Telephone: (301) 496 6402 FAX: (301) 402-0010 Email: PS39P@NIH.GOV Jag H. Khalsa, Ph.D. Health Scientist Administrator Center on AIDS & Other Medical Consequences of Drug Abuse (CAMCODA) National Institute on Drug Abuse, NIH 6001 Executive Building, Rm 5190, MSC 9593 Bethesda, MD 20892-9593 Telephone: (301) 443-1801 FAX: (301) 594-6566 Email: jk98p@nih.gov Michael McClure, Ph.D. Division of Extramural Research and Training National Institute of Environmental and Health Sciences, NIH 111 T.W. Alexander Drive Building 401, Room 3417 Research Triangle Park, NC 27709 Telephone: (919) 541-5327 FAX: (919) 541-5064 Email: mm461n@nih.gov Kay Anderson, Ph.D. Research Program Director Office of Research on Women’s Health 1 Center Drive, Room 201 Bethesda, MD 20892-0161 Telephone: (301) 402-1770 FAX: (301) 402-1798 Email: Andersok1@od.nih.gov (c) Inquiries regarding FISCAL MATTERS may be directed to: Suzanne White* Grants Management Specialist NHLBI Grants Operations, NIH Two Rockledge Center 6701 Rockledge Drive, Room 7150 Bethesda MD 20892-7926 Telephone: (301) 435-0171 Fax: (301) 480-3310 E-mail: sw52h@nih.gov *Note: NHLBI is the grants management service center for NCCAM. AUTHORITY AND REGULATIONS The Office of Dietary Supplements (ODS) was mandated by Congress in 1994 and established within the Office of the Director, National Institutes of Health (NIH). The Dietary Supplement Health and Education Act (DSHEA) [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. This program is described in the Catalog of Federal Domestic Assistance Nos. 93.213 (NCCAM), 93.399 (NCI), 93.937 (NHLBI), 93.821, 93.859, 93.862 (NIGMS), 93.847, 93.848, 93.849 (NIDDK), 93.866 (NIA), 93.279 (NIDA), 93.113, 93.866 (NIEHS). The NIH Revitalization Act of 1993 provided legislative language to mandate the ORWH. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410), as amended by Public Law 99-158, 42 USC 241, 285 and 287b) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The 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. Definitions: See ODS document: Merging Quality Science with Supplement Research: A Strategic Plan for The Office of Dietary Supplements at http://dietary-supplements.info.nih.gov Dietary Supplements: In the United States, dietary supplements have been defined by the Dietary Supplement Health and Education Act (DSHEA) [Public Law 103-417, Section 3.(a), October 1994] to include a product (other than tobacco) intended to supplement the diet that bears or contains one or more of the following dietary ingredients: (A) a vitamin, (B) a mineral, (C) an herb or other botanical, (D) an amino acid, (E) a dietary substance for use by man to supplement the diet by increasing the total dietary intake, or (F) a concentrate, metabolite, constituent, extract, or combination of any ingredient described in clause (A), (B), (C), (D), or (E) is not represented for use as a conventional food or as a sole item of a meal of the diet, and is labeled as a dietary supplement. Ingredients or chemical constituents derived from items that may be termed functional foods , may also be dietary supplements if they fall within the statutory definitions of DSHEA. Functional food: any food or modified food that may provide a health benefit beyond the traditional nutrients it contains. Botanical Ingredients: all plant-derived materials whether fresh, preserved, or dried full plants, plant parts, plant species mixtures, plant extracts, and compounds found in such materials. Items that are commonly termed herbs or herbal products, regardless of whether they meet the dictionary definition of herb or that are comprised of parts, extracts, or preparations of woody plants will be included as botanical ingredients. Herb: A flowering plant whose stem above ground does not become woody. ODS Operating Definition of a Dietary Supplement: Following DSHEA, a dietary supplement is viewed by the ODS as any substance that is consumed in addition to the regular diet that is, in addition to meals, snacks, and beverages- and follows the methods of delivery clauses outlined in the Act. Food items, in any physical form (such as a liquid or a powder intended to be added to a liquid) that are intended to be a sole source of nutrition or meal replacements are not dietary supplements as defined in DSHEA. Phytomedicine: A medicinal product which contains as active ingredients exclusively plant materials and/or standardized herbal medicinal products or preparations thereof. These products contain identified chemically defined substances or groups of substances of plant origin which are known to contribute to the therapeutic activity of the preparation when presented in a suitable dosage form. A phytomedicine as defined by the European Union Commission E is a drug, differing from other pharmaceutical products only in terms of its origin and composition. Clinical Trials: Definitions taken from Spilker, B. Guide to Clinical Trials. Philadelphia: Lippincott-Raven Publishers, 1996. Also see http://www.fda.gov/cder/guidance/iche8.htm. FDA draft guideline entitled General Considerations for Clinical Trials."" Phase I. Initial safety trials on a new medicine , usually conducted in healthy volunteers. An attempt is made to establish the dose range tolerated by volunteers for single and for multiple doses. Phase I trials are sometimes conducted in severely ill patients (e.g., in the field of cancer) or in less ill patients when pharmacokinetic issues are addressed. Pharmacokinetic trials are usually considered Phase I trials regardless of when they are conducted during a medicine’s development. Phase IIa. Pilot clinical trials to evaluate efficacy (and safety) in patients with the disease or condition to be treated, diagnosed, or prevented. Objectives may focus on dose-response, type of patient, frequency of dosing, or numerous other characteristics of safety and efficacy. Phase IIb. Well-controlled trials to evaluate efficacy (and safety) in patients with the disease or condition to be treated, diagnosed, or prevented. These clinical trials usually represent the most rigorous demonstration of a medicine’s efficacy. Sometimes referred to as pivotal trials. Phase IIIa. Trials conducted after efficacy of the medicine is demonstrated, but prior to regulatory submission of a New Drug Application (NDA) or other dossier. These clinical trials are conducted in populations for which the medicine is eventually intended. Phase IIIa clinical trials generate additional data on both safety and efficacy in relatively large numbers of patients in both controlled and uncontrolled trials. Clinical trials are also conducted in special groups of patients (e.g., renal failure patients), or under special conditions dictated by the nature of the medicine and disease. Phase IIIb. Clinical trials conducted after regulatory submission of an NDA or other dossier, but prior to the medicine’s approval and launch. These trials may supplement earlier trials, complete earlier trials, or may be directed toward new types of trials (e.g., quality of life, marketing) or further evaluations. This is the period between submission and approval of a regulator dossier for marketing authorization.

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