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) 435-0714, 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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