CENTERS FOR DIETARY SUPPLEMENTS RESEARCH: BOTANICALS

Release Date:  March 8, 1999  

RFA: OD-99-007

P.T.

Office of Dietary Supplements
Fogarty International Center
National Cancer Institute
National Center for Complementary and Alternative Medicine
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 Dental and Craniofacial Research
National Institute of Environmental and Health Sciences
National Institute of Mental Health
Office on Research of Women's Health

Letter of Intent Receipt Date: April 13, 1999
Application Receipt Date: May 13, 1999

PURPOSE

The Office of Dietary Supplements (ODS), Fogarty International Center (FIC),
National Cancer Institute (NCI), National Center for Complementary and
Alternative Medicine (NCCAM), 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 Dental and Craniofacial Research (NIDCR), National Institute of
Environmental and Health Sciences (NIEHS), National Institute of Mental Health
(NIMH), and the Office on Research of Women's Health (ORWH) invite
applications 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 develop systematic evaluation of the
safety and efficacy of botanicals.  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, and 4) conduct both pre-clinical and clinical
evaluations of botanicals.  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.  Each NIH RFA addresses one or more of 22
Health Promotion and Disease Prevention priority areas. These areas can be
found via the World Wide Web at http://www.crisny.org/health/us/health7.html

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.  The Principal Investigator (PI)
must be located in a public or private non-profit institution, government or
governmental agency of the United States.  Racial/ethnic minority individuals,
women, and persons with disabilities are encouraged to apply as principal
investigators. Questions about eligibility may be addressed to the program
contacts listed under INQUIRIES.

To be considered, applicant organizations must have a PI 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 such as multiple, simultaneous
research project grants (R01), program project grants (P01), center grants, or
multi-site clinical investigations. The PI should have demonstrated ability to
oversee and conduct planning activities, provide direction to the Center,
ensure an interdisciplinary research emphasis, and build a career development
program.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) specialized center
grant (P50) 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 resources and shared facilities aimed at supporting the range
of proposed research.  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 NIH Grants Policy Statement (Oct 98).

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, interdisciplinary, and
synergistic.  Research supported through this mechanism must reflect in clear
ways interdependence of components of the research program that would not
occur simply from the mere collection of the individual components. Taken as a
whole, a 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, 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 indirect 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 costs
(direct and indirect 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 30, 1999. 
Note: Indirect costs refer to facilities and administration.

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
the 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 00, a RFA may be reissued 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 adults 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 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) 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 identify potential
health benefits and also address concerns about safety, Congressional
appropriations for fiscal year 1999 (FY 99) included additional funds for the
Office of Dietary Supplements to "expand its efforts and develop a botanical
research center initiative with major research institutions across the
nation."

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 are comprised of many diverse compounds rather than a
single active pharmacological agent.  In many instances the active
ingredient(s) is not known.  Further, 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, 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 emphasis is to assess 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 to 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 though
genetic engineering could be explored.

o  The third area of emphasis is to identify active constituent(s) in
botanical ingredients and explore their mechanism(s) of action.  Both of these
efforts will place botanical research on a more scientific 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 to incorporate human studies 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/nutraceuticals (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 would be substantial.  Further, any apparent health benefits
or risks of botanicals might be attributed to confounding by other lifestyle
factors.  This RFA would support 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.  Phase III studies are beyond the scope of
this RFA.  Phase I and Phase II studies are within the scope of this
initiative, 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.

Several NIH Institutes have joined with the ODS to support this initiative.
Examples of topics of interest to specific Institutes are:

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. 
Specifically, the Institute supports and coordinates extramural projects
conducted by universities, hospitals, research foundations, and businesses
throughout this country and abroad through research grants and cooperative
agreements; supports education and training in fundamental sciences and
clinical disciplines for participation in basic and clinical research programs
and treatment programs relating to cancer; supports a national network of
cancer centers; collects and disseminates information on cancer; and conducts
research in its own intramural laboratories and clinics.

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 mechanisms of
action of their putative anticarcinogenic effects. These effects may include
altering gene expression, suppressing proliferation, inducing differentiation
and or encouraging apoptosis.  Even less is known about interactions among the
various botanical constituents and with other components of the diet. There
are also important issues related to quality assurance, clinical
applicability, pharmacology, dose, precautions, contraindications, and adverse
reactions that need to be considered.

Expansion of ongoing research is needed to provide a better understanding of
the potential impact of various constituents of botanicals on human cancer
prevention, including information on dietary exposure, metabolism, and
mechanisms of action.  Natural botanical substances may provide novel
approaches in cancer prevention by increasing the intake of biologically
active compounds found in natural botanical materials that are consumed in the
normal daily diet.  Such information should aid in refining dietary guidance
on the amounts and types of botanicals and in the identification and
development of naturally-occurring chemopreventive agents that have the
potential to reduce cancer risk.

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, etc.) or side effects of conventional
therapies (e.g. nausea, vomiting, neuropathy, mucositis).

The NATIONAL CENTER FOR COMPLEMENTARY AND ALTERNATIVE MEDICINE (NCCAM)
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.  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 vivo and in vitro; 2) development
of methods for the cultivation and extraction of standardized natural products
to meet the Good Manufacturing Practice (GMP) requirements of the FDA
Investigational New Drug (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 for chemical
and biological identification of active ingredients in botanicals; 5)
development and validation of methods to examine the bioavailability of
botanical products; 6) development and validation of animal and in vitro
models to study botanical interventions

The NATIONAL HEART, LUNG, AND BLOOD INSTITUTE (NHLBI) supports research and
training in the prevention, diagnosis, and treatment of diseases of the heart,
blood vessels, lung, blood, and sleep disorders.  The 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. A particular interest of NHLBI is
to advance our understanding of the biomedical effects of botanicals at the
molecular level through the modern methods and approaches of molecular
medicine. It is desirable that strategies would 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 botanicals 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 botanicals and affect the various
diseases of the heart, blood vessels, lung, blood, and sleep disorders

As an example, atherosclerosis underlies most coronary heart disease, a major
cause of death (500,000 per year) and disability, as well as much peripheral
vascular disease, many cases of stroke and several other diseases, all are
under the purview of NHLBI. Atherosclerosis is a multifactorial process with a
complex and incompletely understood etiology.  An interdisciplinary approach
integrating basic sciences with the clinical aspects of the disease is
required to study this disorder.  Many systemic factors associated with
atherosclerosis have been identified.  However, information is needed to
understand how dietary supplements, including those containing botanical
ingredients, might influence risk factors and interact with vascular cells. 
One high priority area in this regard involves the complex interactions and
effects of botanicals in cases of insulin resistance, dyslipidemia,
hypertension, and central obesity as they influence coronary heart disease.
Furthermore, botanicals 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 of
botanicals which need further investigation.

Research of interest to the NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
(NIGMS) would include: 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 & burn injury,
sepsis, shock, multiple organ failure, and anesthesiology; 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 research in three major areas, reflected in the three extramural
operating divisions of the Institute.  The Institute is particularly
interested in supporting research opportunities yielding fundamental,
innovative, significant contributions to human health through basic and
clinical studies.  To that end studies are encouraged on prevention and
treatment of diabetes; other endocrine and metabolic diseases; digestive
diseases and nutritional disorders; and kidney, urologic and hematologic
diseases.  Current trans-NIDDK interests focus on diabetes and its
complications, nutrition in disease prevention and health promotion,
prevention of obesity and its co-morbid conditions, AIDS-related research, and
gene therapy of human disease.  Examples of more specific special emphasis
areas include research initiatives on cytokines in the pathogenesis of
disease, developmental biology and disease pathogenesis, developmental biology
and organ regeneration, and prevention and treatment of hepatitis C and other
liver diseases.

NIDDK encourages collaborative efforts between natural product scientists, and
basic and clinical scientists in its program areas. 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 basic mechanisms underlying
treatment. Particular emphases should 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. Specific examples
would include projects focusing on efficacy and safety of flavones and flavo-
ligins in the treatment of hepatitis and cirrhosis. 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 (NIA) 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 DENTAL AND CRANIOFACIAL RESEARCH (NIDCR) supports
basic and clinical research as well as research training leading to
contributions to improvement in human health and prevention of disease.
Studies are encouraged that involve the etiology, pathogenesis, treatment and
prevention of inherited diseases, infectious diseases, neoplastic diseases and
chronic disabling diseases such as neurogenic and autoimmune diseases as well
as chronic pain conditions.  The Institute also supports research aimed at
developing biomimetic approaches to design and development of materials used
in the repair and replacement of craniofacial, oral and dental tissues. 
Examples of research of interest within the parameters of the current
initiative include, but are not limited to, the development and testing of
botanicals used in the prevention and/or treatment of:  1) oral infections
such as dental caries or periodontal diseases (e.g., plant derived
antibodies); 2) oral and pharyngeal cancer as well as precancerous conditions;
3) oral and craniofacial pain conditions (e.g., those of the mouth and/or
temporomandibular joint); 4) autoimmune diseases such as Sjogren's syndrome as
well as autoimmune related inflammation of the temporomandibular joint; 5)
oral manifestations of HIV/AIDS including oral candidiasis; 6) apthous ulcers
and oral herpes; 7) specific craniofacial, oral or dental conditions (e.g.,
cleft lip and palate).  In addition, the Institute is interested in supporting
research that leads to the development and testing of botanicals involved in
the prevention and/or treatment of systemic diseases and conditions that may
influence craniofacial, oral or dental conditions (e.g., diabetes).  The
Institute also encourages research involving botanicals leading to the
development of biopolymers for use as scaffolds for cell growth and delivery.

The OFFICE ON RESEARCH OF 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 safety and effectiveness, including
assessment of underlying processes 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.

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 or resources 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 develop thorough and systematic
approaches to evaluate the safety and efficacy of botanicals, particularly
those included as ingredients in dietary supplements (see ODS operating
definition of dietary supplements in Definitions section).

SPECIAL REQUIREMENTS

This section provides descriptions of required and optional elements of the
grant application.  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) an
Administrative and Planning Core, which will provide coordination, research
planning, logistical, and technical support; 2) a Research Projects Component
providing for the implementation of R01-like research projects; 3) a Pilot
Research Projects Component providing for the implementation of pilot studies,
feasibility or preliminary research projects. 4) In addition, the Center grant
may include one or more Research Resource Cores shared by Center investigators
(e.g., animal colonies, analytical chemistry laboratories, statistical
services, clinical research facilities).

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 program'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 research space,
cost sharing of resources, or other way to be proposed by the applicant.

(3) Center Director

Each applicant institution shall name a Center Director who will be the key
figure in the scientific administration and management of the Center grant.
The Director should be an experienced researcher with demonstrated leadership
appropriate to the coordination of the Center.  A minimum of 25 percent (10%
minimum administrative and 15% minimum research) effort on activities directly
supported by the Center's funding is required of the Director.  The Director
must be a PI on one but not more than two research projects.

(4) Research Projects Component

The Research Projects Component consists of 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 studies
relevant to two of them.  Similarly, the application need not address all of
the topical areas identified by the participating Offices, Institutes and
Centers (ICs).  At least one of these topics should be addressed, however.
Applicants are encouraged, but not required, to develop research programs that
cut across traditional IC-specific mandates.

Applications must propose at least three to six research projects. The
research projects should be of a scope similar to the traditional NIH research
grant (R01).  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 these submitted projects must
be judged meritorious by the peer-review panel for the application to meet the
minimal requirements of a P50 Center.  Further, the Center Director's research
project must receive a fundable score.  Failure to meet these requirements
will remove the application from funding consideration.

At least one of the approved 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 principal investigators are required to commit at least 15%
time to these projects.

The research must be oriented toward the most critically needed areas of
botanicals research. The projects should show evidence of an interdisciplinary
focus. Thus, an explanation of how the projects fit together across
disciplines to promote synergy and syntheses should be included.

Research 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 on the www:
https://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 an award will be made to one
institution only; that institution is expected to demonstrate the full
institutional commitment noted in item 2 above.

(5) Pilot Research Projects Component

Applicants may propose support for pilot or feasibility research projects that
will facilitate the development of 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 Projects should take maximum advantage of the new
research opportunities created through the Center. It is not expected or
required that feasibility projects will be identified by the time of
submission.  However, the Center application should include an institutional
review process for pilot or feasibility projects. The review process might
involve the Advisory Committee (see section 8 below) in selecting pilot
projects during the subsequent years of the grant. 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.

Collaborative or Associated Projects (Optional):  Applicants are encouraged
but not required to apply for other sources of support for additional research
projects relevant to this initiative.  Projects that would benefit from access
to the Center's core facilities are encouraged.

(6) Cores

A core is defined as a resource shared by multiple investigators that should
enhance research productivity and increase the functional capacity of the
Center.  Subproject utilization of these cores is essential and needs to be
specified in the application.  At a minimum, the Center is required to have an
administrative and planning core that is responsible for the day to day
administrative details as well as program coordination and ongoing evaluation
of the Center.  Also falling within the administrative core would be the
Career Development Program and the Advisory Committee (items 7-8 below).

Centers are encouraged but not required to develop a research resource core. 
Examples 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 cores (i.e., Center use of
existing facilities) are acceptable with adequate justification.

(a) Administrative and Planning Core

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
Director, the principal investigators of the research projects, 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.

Research Resource Core (optional)

The Center may establish one or more research resource cores to provide and
administer shared research resources (e.g., herbaria, animal colonies,
analytical chemistry laboratories, statistical services, survey research
samples, clinical research facilities such as NIH sponsored General Clinical
Nutrition Research Units).

(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, the criteria for eligibility and for selection
of candidates, and describe the selection process. The candidates may be
advanced graduate students, post-doctoral researchers or junior faculty. Also,
the application should indicate potential mentors who are already in place at
the proposed Center, briefly describe their research programs, and describe
complementary activities that contribute to the interdisciplinary environment
for career development (e.g., existing training grants, other career
development mechanisms and relevant programs).  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, enrichment
of desirable constituents in plants through genetic engineering).  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.

(8) 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 the meeting 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 can not 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 may
review pilot studies not included in the original grant application.  The AC
shall have representation from the 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.

(9) Annual Meeting of Center

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.

(10) 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. An initial FDA
contact is listed under INQUIRIES.  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," which have been 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 on the Web:
https://grants.nih.gov/grants/guide/notice-files/not94-100.html.

Investigators also may obtain copies of the policy from the program staff
listed under INQUIRIES. Program staff may also provide additional relevant
information concerning the policy.

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 to exclude them. See NIH
Guide to Grants and Contracts, March 6, 1998 or
https://grants.nih.gov/grants/guide/notice-files/not98-024.html

LETTER OF INTENT

Prospective applicants are asked to submit, by April 13, 1999, a letter of
intent that includes a descriptive title of the proposed research, the name,
address, telephone and telefax number of the Principal Investigator; the
identities of other key personnel (including research project PIs,
collaborators, and 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 is to be sent to:

Christine A. Swanson, Ph.D.
Office of Dietary Supplements
National Institutes of Health
Building 31, Room 1B25
Bethesda, MD  20892
FAX:  (301) 480-1845

APPLICATION PROCEDURES

The research grant application form PHS 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:
[email protected]; and may also be obtain on the Web
https://grants.nih.gov/grants/forms.htm

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 Projects Component, Career Development), as well as each research
project and each core facility. This  composite budget should be in tabular
format, with each budget year being listed in a separate column and each
Center activity, core or subproject 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 subproject listed in the composite budget. These pages
should be clearly labeled as to which Center activity, subproject or core they
address.

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.

Research Projects and Core Facilities:
Applicants may use up to 25 pages to describe all required Center activities
(e.g., the Advisory Committee, Pilot Research Projects Component, Career
Development Program, the Administrative and Planning Core and the Center's
overall goals and objectives).  Up to 25 pages may be used to describe each of
the research projects and each core facility (excluding the Administrative and
Planning Core); this page limit does not include bibliographies.  Descriptions
of the research projects and the core facilities should follow the PHS 398
format, section 9 (Research Plan).  In addition, each project should provide a
detailed description of core utilization and each core 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.

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 copies of the application to:

Christine A. Swanson, Ph.D.
Office of Dietary Supplements
National Institutes of Health
Building 31, Room 1B25
Bethesda, MD 20892

It is important to send these copies at the same time that the original and
four copies are sent to the Center for Scientific Review (CSR).

Applications must be received by May 13, 1999.  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 subprojects 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 subproject 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 awarding
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.

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 CSR 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 plans 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 Research Project Component - Each subproject 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 principal investigator 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 subproject 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., cores).

Each subproject 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 unit

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 and
his/her ability to devote 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 program, and the appropriateness of
resources and policies for the administration of a Center

9.  The proposed organization and activities of the Advisory Committee will be
evaluated, including the process to prioritize pilot/feasibility research
proposals and the process to chose 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 and Feasibility 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 projects on a consistent basis

12.  The appropriateness of the budget for the proposed program and its
individual components will be 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:  April 13, 1999
Application Receipt Date:       May 13, 1999
Peer Review Date:               June/July 1999
Council Review:                 August/September 1999
Anticipated Award Date:         September 1999

AWARD CRITERIA

Applications recommended by the NIH Initial Review Group 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.

Direct General inquiries to:

Christine A. Swanson, Ph.D.
Office of Dietary Supplements
National Institutes of Health
Building 31, Room 1B25
Bethesda, MD  20892
Telephone: (301) 435-2920
FAX:  (301) 480-1845
Email:  [email protected]

Direct inquiries regarding specific programmatic issues to the staff of the
appropriate Institute/Center:

Dr. Joshua Rosenthal
Biodiversity Program
Fogarty International Center
31 Center Drive MSC 2220
Bethesda, MD  20892-2220
Telephone:  (301) 496-2516
FAX:  (301) 402-2056
Email:  [email protected]

Winfred Malone, Ph.D., MPH
Division of Cancer Prevention
National Cancer Institute
Executive Plaza North, Suite 200
Bethesda, MD  20892
Telephone:  (301) 496-8563
FAX:  (301) 402-0553
Email:  [email protected]

Dr. Richard Nahin
National Center for Complementary and Alternative Medicine
Building 31, Room 5B-38
Bethesda, MD  20892-2182
Telephone:  (301) 435-5042
FAX:  (301) 402-4741 or (301) 594-6757
Email:  [email protected]

Dr. Momtaz Wassef
Vascular Research Program
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 8112
Bethesda, MD  20892-7212
Telephone:  (301) 435-0422
FAX:  (301) 480-1864
Email:  [email protected]

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:  [email protected]

Michael Ken May, Ph.D.
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AN-18J
Bethesda, MD  20892-6600
Telephone:  (301) 594-8884
FAX:  (301) 480-8300
Email:  [email protected]

Pamela E. Starke-Reed, Ph.D.
Office of Nutrition
National Institute on Aging
7201 Wisconsin Avenue, Room 2C231
Bethesda, MD  20892-9205
Telephone:  (301) 496-6402
FAX:  (301) 402-0010
Email:  [email protected]

Jag H. Khalsa, Ph.D.
Center on AIDS and Other Medical Consequences of Drug Abuse
National Institute on Drug Abuse
6001 Executive Building, Room 5190, MSC 9593
Bethesda, MD  20892-9593
Telephone:  (301) 443-1801
FAX:  (301) 594-6566
Email:  [email protected]

Dr. Norman Braveman
Assistant Director for Program Development
National Institute of Dental and Craniofacial Research
Natcher Building, 4AN-24B
Bethesda, MD  20892
Telephone:  (301) 594-2089
FAX:  (301) 480-8318
Email:  [email protected]

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:  [email protected]

Matthew Rudorfer, MD
Adult and Geriatric Treatment and Preventive Interventions Branch
National Institute of Mental Health
6001 Executive Boulevard
Rockville, MD  20892-9669
Telephone:  (301) 443-1185
FAX:  (301) 594-6784
Email:  [email protected]

Dr. Marietta Anthony
Director of Research Programs
Office on Research of Women's Health
1 Center Drive
Bethesda, MD  20892
Telephone:  (301) 402-1770
FAX:  (301) 402-1798
Email:  [email protected]

Inquiries regarding fiscal matters may be directed to:

Suzanne White
Grants Operations
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7150
Bethesda, MD  20892-7926
Telephone:  (301) 435-0171
FAX:  (301) 480-3310
Email:  [email protected]

Inquiries regarding FDA issues may be directed to:

Freddie Ann Hoffman, M.D.
Office of Health Affairs
Food and Drug Administration
Telephone:  (301) 827-6630 or - 6606
FAX:  (301) 443-2446
Email:  [email protected]

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.
93.399 (NCI), 93.213 (NCCAM), 93.937 (NHLBI), 93.821, 93.859, 93.862 (NIGMS),
93.847, 93.848, 93.849 (NIDDK), 93.866 (NIA), 93.279 (NIDA), 93.121 (NIDCR),
93.113 and 93.115 (NIEHS), and 93.242 (NIMH).  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 and 285) 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  
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' or some substances that may be termed 'nutraceuticals', may
also be dietary supplements if they fall within the statutory definitions of
DSHEA.

Functional food: any modified food or food ingredients that may provide a
health benefit beyond the traditional nutrients it contains.

Nutraceutical: any substance that may be considered a food or part of a food
and provides medical or health benefits, including the prevention and
treatment of disease.

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, meal replacements,
or conventional foods are not dietary supplements as defined in DSHEA, and
thus are outside the scope of the research interests of the ODS.

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
regulatory dossier for marketing authorization.

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