GINKGO BILOBA PREVENTION TRIAL IN OLDER INDIVIDUALS

Release Date:  February 26, 1999

RFA:  AT-99-001

P.T.

National Center for Complementary and Alternative Medicine
National Institute on Aging

Letter of Intent Receipt Date:  April 21, 1999
Application Receipt Date:  May 21, 1999

PURPOSE

The National Center for Complementary and Alternative Medicine (NCCAM) and the
National Institute on Aging (NIA) invite applications for a two-arm,
double-blind, randomized, placebo-controlled multi-site trial to assess
whether an extract of the botanical product, Ginkgo biloba, prevents the
occurrence of dementia and/or cognitive decline in older individuals.  If
Ginkgo biloba extract is found effective, then thousands of individuals at
high risk of developing dementia will have an inexpensive and safe prevention
option.  However, if the extract is ineffective as a prevention agent, these
data will provide important information to the U.S. Public and allow for
informed decision making concerning continued use of the botanical.

HEALTHY PEOPLE 2000

The Public Health Service is committed to achieving the health promotion and
disease prevention objectives of "Healthy People 2000," an initiative for
setting national health policy and priorities.  Although Healthy People 2000
does not currently specify a complementary and alternative medicine objective,
this RFA involves priority areas within the Healthy People 2000 objectives,
such as the areas mental health and chronic disabling conditions.  Applicants
may obtain a copy of "Healthy People 2000" (Full Report:  Stock No.
017-001-00474-0 or Summary Report:  Stock No. 017-001-00473-1) through the
Superintendent of Documents, Government Printing Office, Washington, D.C.
20402-9325 (Telephone: 202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted only by domestic for- profit and not-for-profit
organizations, public and private organizations such as universities,
colleges, hospitals, laboratories, units of State or local governments,
Federally recognized Indian Tribal organizations, and eligible agencies of the
Federal government.  Applications may include foreign components, but foreign
organizations are not eligible to apply.  Applications from minority and women
investigators and persons with disabilities are encouraged.

MECHANISM OF SUPPORT

This RFA will use the cooperative agreement (U01) mechanism.  The cooperative
agreement is an assistance mechanism in which NIH will have substantial
involvement with the recipient during the performance of the planned activity. 
The nature of the NIH's involvement is described under the "Terms and
Conditions" of the award.  Primary responsibility for the planning, direction,
and execution of the proposed project will be that of the applicant/awardee.

The total project period for applications submitted in response to the present
RFA may not exceed seven years.  The anticipated award date is September 30,
1999.  This RFA is a one-time solicitation.  Future unsolicited competitive
continuation applications will compete with all other investigator-initiated
research applications and be evaluated for technical merit by an appropriate
peer-review group convened by NCCAM.

FUNDS AVAILABLE

Up to $15,000,000 (total cost) over the entire project period is available to
support this initiative.  It is expected that one award will be made. 
Although this program is provided for in the financial plans of the NCCAM,
awards made pursuant to this RFA will be contingent on the quality of
submissions and continued availability of funds for this purpose.

RESEARCH OBJECTIVES

A.  Background

Surveys indicate that one-third of all Americans over the age of 85 suffer
from some kind of dementia (Alzheimer's disease, vascular dementia or mixed
types), with about four million Americans currently suffering from Alzheimer's
disease alone (Evans et al., 1989).  Although dementia is rare in those less
than 60 years of age, incidence of dementia approximately doubles every five
years past the age of 65, with a yearly incidence rate of almost 12% being
reported in individuals 85 years or older (Bachman et al., 1993).  Dementia
often leads to long-term institutionalization of the victim, and financial and
emotion devastation of the family.  In 1993, it was estimated that the United
States spent as much as 100 billion dollars/year for the direct and indirect
costs of care for patients with Alzheimer's disease (Rice et al., 1993).  The
cost for all dementias together would run substantially higher.

There are large numbers of people in fear of developing dementia who are
self-medicating with Ginkgo biloba without clear, compelling evidence of
benefit.  U.S. sales for Ginkgo biloba have been estimated as high as $100
million per year (Landes, 1998).  Ginkgo biloba is used by people to improve
memory and/or cognitive function, as well as to treat Alzheimer's disease
specifically.  Ginkgo biloba has been approved by the German BFGA- Commission
E for use in primary degenerative dementia (including Alzheimer's), vascular
dementia and mixed forms (Blumenthal et al., 1998).

The preclinical scientific literature suggests that Ginkgo biloba can prevent
or delay the progression of dementia.  For instance, Ginkgo biloba has been
shown to sustain the function of the hippocampal mossy fiber system, reverse
age-related losses in neocortical or hippocampal alpha adrenergic and
serotonergic receptors, protect against ischemic neuronal death, inhibit PKC
activity, and increase hippocampal high- affinity uptake of choline (e.g.,
Barkats et al., 1995; Huguet and Tarrade, 1992; Klein et al., 1997;
Kristofikova and Klaschka, 1997; Rogue and Malviya, 1996).  Also Ginkgo biloba
has antioxidant, free radical-scavenging activities and anti-inflammatory
properties (e.g., Smith et al., 1996; Scholtyssek et al., 1997; Szabo et al.,
1997; Pitchumoni and Doraiswamy, 1998) and appears to increase
microcirculation through vasorelaxation ( e.g., Stucker et al., 1996 and
1997), all of which might prove beneficial in preventing the development of
dementia.

The efficacy of Ginkgo biloba extract for the treatment of dementia
(Alzheimer's disease specifically) was assessed in a recent meta-analysis by
Oken et al, 1998.  They identified four randomized controlled trials of Ginkgo
biloba extract that met rigorous methodological criteria.  The studies were
relatively small, ranging from 19-104 subjects per group; subject follow-up
varied from 12 to 26 weeks in duration.  The meta- analysis of these four
trials revealed an overall effect size of 41% (95% CI: 22%/61%) when comparing
Ginkgo biloba versus placebo in individuals with mild to moderate Alzheimer's
disease.  Evidence also suggests that Ginkgo biloba is moderately effective
for dementia other than Alzheimer's disease (Kanowski et al., 1996, Le Bars et
al., 1997) and that there are no serious side effects attributable to the
extract.

B.  Research Goals

This RFA invites applications for a prevention trial of Ginkgo biloba extract
to determine its effects on dementia and cognitive decline in the elderly. 
Also examined will be the safety, tolerability and acceptability of the
extract.  Research activities will be conducted by clinical investigators
skilled in multi-site clinical trials and knowledgeable about the diagnosis,
staging and clinical management of dementia.  The ultimate goals are to
determine the efficacy of Ginkgo biloba extract for preventing dementia and
cognitive decline in individuals at least 75 years of age and to extend
knowledge about the extract's utility for these conditions.

C.  Research Plan

1.  General

Although objectives of the RFA can be met through the initiation of a
full-scale, randomized, two-arm, double- blind, placebo-controlled, multi-site
prevention trial of Ginkgo biloba extract in individuals 75 years of age or
older, other designs will be considered if sufficiently justified.  A lower
age cutoff of 75 years is suggested as a balance between a reasonably high
incidence rate of dementia and the rates of co-morbidity and mortality.  While
it is expected that the trial will compare 240 mg/day of Ginkgo biloba extract
to a placebo control, other doses can be proposed if justified and adequately
supported by the literature (Note: an appropriate extract and matching placebo
control will be identified and supplied by the NCCAM).  Subjects should be on
protocol for a minimum of three years, with longer follow-up encouraged as
justified and budgeted by the applicants.

The study should consist of four phases:  1) an initial phase during which the
protocol is finalized (e.g., study procedure and Manual of Operations, data
collection manuals, data management, training, establishment of the Data and
Safety Monitoring Board, etc.) by the trial Steering Committee (see "Special
Requirement"); 2) a recruitment period; 3) a period of intervention and
follow-up; and 4) data analysis and dissemination.

2.  Outcomes

The primary outcome will be the onset of any type of dementia.  While the
diagnostic criteria for Alzheimer's disease should be based on the Diagnostic
and Statistical Manual of Mental Disorders, Fourth Edition and/or the National
Institute of Neurological Disorders and Stroke - Alzheimer's Disease and
Related Disorders Association criteria, applicants will need to identify and
justify their diagnostic schemes for specific categories of non-Alzheimer's
type dementia.  The secondary outcome will be change in cognitive function;
outcome measures should, as a minimum, include the Alzheimer's Disease
Assessment Scale-Cognitive Subscale, the Clinician's Interview-based
Impression of Change with Caregiver Input and the Mini-Mental State
Examination (MMSE) in accordance with Food and Drug Administration (FDA)
guidelines for Alzheimer's trials.  Plans for patient follow-up and choices of
additional outcome measures should be well-defined and clearly justified
including criteria for meaningful clinical improvement.  Additional outcome
measures could include, but are not limited to:

1) functional measure of activities of daily living;
2) general health status/quality-of-life indicators;
3) neuropsychological measures; and
4) health care utilization (e.g., increased or decreased use of other
medications or office visits; cost-effectiveness data).

3.  Inclusion/Exclusion Criteria

Subjects enrolled in the trial may have mild cognitive deficits as determined
by a Global Deterioration Scale score < 3, a Clinical Dementia Rating score<
0.5 and an MMSE > 24.  Any other cognitive problems would be reasons for
exclusion.  Subjects who have previously used Ginkgo biloba may be included in
the study.  Other inclusion and exclusion criteria (including preexisting
medical conditions and the use of counter-indicated drugs) should be
identified and justified by the applicant; in general, these criteria should
address exclusion of individuals who might be harmed by participation in the
trial, or who are likely to be poor compilers.  A database should be
maintained on all potentially eligible subjects who were identified but not
enrolled, including the reasons for their exclusion or refusal to participate.

4.  Compliance

Research designs that maximize patient compliance should be described and
justified in the application.  In this regard, it is suggested, but not
required, that applicants employ a one-month single-blind, placebo run-in
period.  Ideally, the serum blood levels of ginkgolides should be assessed in
all subjects.  However, budgetary restraints might require some type of random
sampling or banking of blood samples until a reliable, cost-effective assay
for ginkgolides becomes available; NCCAM plans future initiatives in this
regard.  In addition, periodic assessments of patient self-medication should
be made.

5.  Recruitment

For all proposed trial sites, applicants must demonstrate the ability to
recruit and randomize the required number of study participants, be able to
implement the various study procedures, and maintain high rates of follow-up
during the course of the trial.  It will be particularly important to minimize
the number of self-medicating patients.

6.  Sample Size and Power Calculations

To ensure acceptable statistical power, the clinical trial design should
include an adequate number of participants and should be of sufficient
duration to address the study questions of efficacy, safety, tolerability and
acceptability, as well as any other secondary research questions.  To this
end, biostatistics and clinical trial design expertise are essential during
the planning and design of the study.  Study size and duration will vary
according to specific study hypotheses, target population and endpoints; as
such, the study size and duration should reflect both the choice of outcome
measures and the predicted effect sizes.  The following items should be
considered in all sample size calculations; other assumptions used by the
applicant need to be identified and justified:

a.  The yearly incidence rate of dementia in individuals 75 years of age or
older is assumed to be 5%.

b.  The meta-analysis of Oken et al., 1998, suggested an overall effect size
of 0.4 when comparing Ginkgo biloba extract to placebo in patients diagnosed
with mild to moderate Alzheimer's disease (i.e., a treatment trial).  It can
be safely assumed that the effect size in a prevention trial will be
substantially less.

c.  Adjustments should be made for the high mortality rate seen in individuals
75 years of age or older, as well as for drop-outs.

d.  Sample size calculations should include the possibility of one interim
analysis of the data.  Given these parameters, it is understood that the
calculated sample size may underpower (or overpower) the study.  The
applicants should discuss ways they might directly assess the adequacy of
their sample size calculations (e.g., through internal or external pilot
studies) and make appropriate adjustments in recruitment and/or follow-up as
necessary.

SPECIAL REQUIREMENTS

A.  Steering Committee A Steering Committee will be established to serve as
the main governing body of the trial.  Trial sites will be required to accept
and implement the protocol and procedures approved by the Steering Committee. 
Descriptions of Committee membership, scheduling, responsibilities and
authority are listed under "TERMS AND CONDITIONS OF THE AWARD."

B.  Data and Safety Monitoring Board An independent Data and Safety Monitoring
Board will be appointed by the Director of NCCAM with input from the Awardee. 
Descriptions of Board membership, scheduling, responsibilities, and authority
are listed under "TERMS AND CONDITIONS OF THE AWARD."

C.  Minimum Requirements for Application Each application must include the
following elements; applications that fail to meet these requirements will be
considered unresponsive to the RFA and will not be reviewed:

1.  Investigators The application must name a single Principal Investigator
(PI) who will have scientific responsibility for the application as a whole,
including all consortium-related research activities.  The PI is required to
commit a minimum of 10% time to these administrative duties.  In addition, the
PI is the Senior Investigator (see below) from his or her Institution and will
be expected to commit 10% time to these scientific activities, bringing her or
his total commitment to 20% time (10% administrative and 10% scientific).  The
PI must have substantial experience in the treatment and management of
dementia and in the design, implementation and evaluation of clinical trials. 
Such experience must be documented in full.  Biographical sketches for all key
investigators must be provided.  In addition, applications must name a Senior
Investigator for each trial site in the consortium who will be responsible for
on-site clinical and scientific implementation, direction and management of
the trial protocol, as well as the coordination of requirements for any
adjunct studies of underlying mechanisms and surrogate markers.  Senior
Investigators are required to commit at least 10% time to this trial.  Senior
Investigators must have substantial experience in the treatment and management
of dementia and in the design, implementation and evaluation of clinical
trials.  The application should also name a Trial Manager (or Coordinator) who
is an individual with substantial technical/administrative experience in
managing patient enrollment, patient follow-up, and multi-source data
collection for clinical studies, such as an experienced nurse manager.  Each
trial site associated with the trial may also name a Trial Site Manager (or
Coordinator) if adequately justified.  The application can also include an
Administrative Manager to handle budgetary, IRB and sub-contract issues as
appropriate and justified.

2.  Trial Organization and Administration The trial group will be an
identifiable organizational unit formed by a consortium of cooperating
institutions.  Such a unit will involve the interaction of broad and diverse
elements.  Therefore, lines of authority and sanction by the appropriate
institutional officials must be clearly specified.  Specifically, applicant
must provide:  a clear, concise plan, in narrative and diagrammatic form, that
depicts the interrelationships among the members of the consortium, their
relevant experience/expertise, and the contribution of each to fulfillment of
the objectives of this RFA; an organizational chart of the consortium showing
the name, organization, and scientific discipline of the PI and of all key
scientific, technical and administrative personnel; and a mechanism for
selecting and replacing key professional or technical personnel.  Include a
description of the role, responsibility and authority of the PI, Senior
Investigators and Trial Manager.  The application must include a written
commitment to accept the participation and assistance of NCCAM staff in
accordance with the guidelines outlined under "Terms and Conditions of Award:
NCCAM Staff Responsibilities."  The application must also include a signed
letter from the PI and Senior Investigators that states:  a) their commitment
to this cooperative trial; b) their willingness to serve on the Steering
Committee and to adhere to the decisions reached by that Committee, including
following the finalized protocol and adjunct studies; and c) their commitment
that recruitment of patients for the Ginkgo biloba trial will take precedence
over any subsequent clinical trials started after the Ginkgo biloba trial is
awarded.

3.  Preliminary Studies Data that show the feasibility of the trial should be
presented; this should include prior examples of patient recruitment,
retention and follow-up.  Additional supporting data from other research
should be included so that the approach chosen is clearly justified. 
Conceptualization and planning must have progressed to a stage sufficient to
allow for an overall assessment of the likelihood of the trial's success.

4.  Patient Availability and Recruitment The applicant institution and each
institution participating in the trial must document:  their experience and
capacity to recruit and retain study participants; provide a description of
the population currently available for the proposed protocol; describe the
procedures for screening this population to identify eligible individuals, for
recruiting these individuals into the trial; and describe proposed mechanisms
for monitoring accrual performance and criteria for continued participation by
each participating institution.

5.  Data Coordination, Management and Quality Control Applicants should
document their previous experience and present:
a) a plan for randomization, data coordination, data collection and management
across trial sites;
b) the need for a Data Coordinating Center to interact with, and coordinate
among, multiple trial sites;
c) methods for monitoring the quality and consistency of the intervention and
outcome measures;
d) protocols for data collection, formatting and transmission to and from
individual trial sites; prototypes of data collection forms should be included
in an appendix;
e) a comprehensive set of procedures to assure data quality and also
procedures to assure confidentiality of subjects;
f) training programs to educate staff at trial sites about operating
procedures with the goal of maximizing efficiency of data operations;
g) data quality control systems;
h) an outline of the Manual of Operations in the appendix.  The Manual will be
finalized in conjunction with the Steering Committee ( see "Special
Requirements").

In addition, the applicants should provide evidence of their prior management
capability for the following:
a) to estimate appropriate and reasonable resources needed for the Ginkgo
biloba trial;
b) to manage resources efficiently during the research;
c) to adjust assigned resources to changing demands as the research work
progresses;
d) to keep NCCAM informed of changes of resource allocations; and e) to
subcontract with affiliated trial sites or other outside organizations.

D.  Adverse Events

All studies should have a structured adverse event determination, monitoring
and reporting system, including standardized forms and protocols for referring
and/or treating subjects experiencing adverse events.  The proposed schedule
for reporting adverse events to the DSMB, the NCCAM Program Officer and/or the
FDA should be described.

E.  Reporting and Publications

The PI will be required to submit semiannual progress reports to the NCCAM and
the DSMB.  These reports should include recruitment data, indices of quality
control, reports of significant side effects or morbidity (previously reported
to the DSMB, the NCCAM Program Officer and the FDA), and deviations from the
protocol.  Such reports are in addition to the annual awardee noncompeting
continuation progress report.  The Data Safety and Monitoring Board (see Terms
and Conditions of Award) may require additional information.  The PI also will
be requested to present both a mid-term and final report to the NCCAM Advisory
Council.

TERMS AND CONDITIONS OF THE AWARD

The following terms and conditions will be incorporated into the award
statement and provided to the Principal Investigator as well as to the
institutional officials at the time of the award.  These special Terms and
Conditions of Award are in addition to and not in lieu of otherwise applicable
OMB administrative guidelines, HHS grant administration regulations in 45 CFR
part 74 and 92, and other HHS, PHS and NIH grant administration policy
statements.

The administrative and funding instrument used shall be a cooperative
agreement (U01), an "assistance" mechanism (rather than an "acquisition"
mechanism) in which substantial NCCAM scientific and/or programmatic
involvement with the Awardee is anticipated during performance of the
activity.  Under the cooperative agreement, the purpose of the NCCAM is to
support and/or stimulate the recipient's activity by involvement in and
otherwise working jointly with the award recipient in a partner role, but it
is not to assume direction, prime responsibility, or a dominant role in the
activity.

Consistent with the above concept, the dominant role and prime responsibility
for the activity reside with the Awardee for the project as a whole, although
specific tasks and activities in carrying out the studies will be shared among
the Awardee, the NCCAM Program Officer and the NCCAM Clinical Trials
Coordinator.

Under the cooperative agreement, a relationship will exist between the
recipient of this award and the NCCAM, in which the performers of the
activities are responsible for the requirements and conditions described
below, and agree to accept program assistance from the NCCAM Program Officer.

A.  Awardee(s) Rights and Responsibilities. The Awardee(s) will retain custody
of and have primary rights to the data developed under these awards, subject
to Government rights of access consistent with current DHHS, PHS and NIH
policies.

The Awardee will have substantial and lead responsibilities in all tasks and
activities.  These include protocol development, data collection, quality
control, final data analysis, and assistance with preparation of publications. 
The Awardee agrees to work cooperatively with the NCCAM, and agrees to accept
guidance from the trial Steering Committee and to follow the Manual of
Operations approved by the Steering Committee.  At the time of award, the
Awardee will be requested to nominate prospective DSMB members to the Director
of NCCAM;  Other specific Awardee responsibilities are described below:

1.  Data Coordination and Management
The Awardee will be responsible for ensuring the provision of centralized data
management and coordination assistance for this trial.  Under the direction of
the Steering Committee, the Awardee will provide technical assistance and data
management services to the trial sites with respect to quality control,
uniformity of data collection, management of the collective data base, and
data analysis.

Each trial site will be responsible for providing the Awardee with all primary
study data for management, quality control and analysis, using procedures and
standards determined by the Steering Committee.  Specific analyses to be
performed by the Awardee will be directed by the Steering Committee.

2.  Quality Control and Data Assurance
The Awardee must follow procedures developed by the Steering Committee for the
prevention and/or identification of false or otherwise unreliable data and for
quality assurance of data collected by the trial sites.  The Awardee must
follow Steering Committee procedures for the assurance of data quality and
quality control in accordance with Steering Committee FDA and NCCAM
guidelines.

The Awardee is responsible for ensuring that all trial sites have routine
independent audits.  These audits should, at a minimum, include the auditing
of primary subject records over the course of the trial to verify conformance
with eligibility criteria, recruitment and outcome data, and adverse events,
as well as to monitor for non-compliance with protocol or regulatory
requirements, or possible alteration of data and other discrepancies that
become apparent.  In the event that the NCCAM determines that the Awardee
failed to comply with these guidelines, the accrual of new patients at the
sites shall be suspended immediately upon notice of the NCCAM determination. 
The suspension will remain in effect until the Awardee conducts the required
audit and the audit report or remedial action is accepted by the NCCAM.  In
the event that the audit identifies discrepancies or misconduct, these
findings must be reported the NCCAM Project Officer, the Awardee and the DSMB
within two weeks.  All accrual at the non-complying trial site(s) will be
suspended until remedial action is taken and accepted by the NCCAM.

The Awardee will be responsible for notifying any affected trial sites of the
suspension.  During the suspension period, no funds from this award may be
provided to the trial site(s) for new accruals, and no charges to the award
for new accruals will be permitted.  The NCCAM will also notify the PI's
institution that is the direct recipient of a cooperative agreement from the
NCCAM if it is necessary to suspend accrual at that institution or at a third
party institution supported under that institution's cooperative agreement.

3.  Protocol Closure
The Awardee, in consultation with the DSMB, shall establish and implement
mechanisms for interim monitoring of results and monitoring protocol progress. 
If the DSMB wishes to close accrual to a study prior to meeting the initially
established accrual goal, the interim results and other documentation should
be made available to NCCAM staff for review and concurrence prior to
implementation of the recommendation by the DSMB.  It is recommended that
statistical guidelines for early closure be presented as explicitly as
possible in the protocol in order to facilitate these decisions.

4.  Procedures in the Event of Scientific Misconduct If a duly authorized
governmental or institutional body issues a final determination that
scientific misconduct has occurred or if the Awardee determines that other
events have occurred which have significantly affected the quality or
integrity of the trial data or patient safety, the Awardee is responsible for
notifying the DSMB, the NCCAM, the collaborating investigators, the
appropriate Institutional Review Boards (IRBs), the FDA and other sponsors of
the affected work.

The Awardee is also responsible, if the events described above have occurred,
for ensuring that submitted but unpublished abstracts and manuscripts are
corrected, if possible.  If publication deadlines have passed or if abstracts
and/or manuscripts containing the affected data have already been published,
the Awardee is responsible, within 90 days after learning of the event(s)
significantly affecting the quality of the trial data or patient safety, for
submitting to NCCAM a re-analysis of the results deleting the false or
otherwise unreliable data, and disclosing within the text the reason(s) for
the reanalysis.  The Awardee must submit the reanalysis for publication.  In
addition, true copies of data files and other supporting documentation from
studies affected by scientific misconduct or other findings affecting the
quality or integrity of data or patient safety shall be made available to the
NCCAM in a timely manner upon request by the NCCAM Program Officer.  The NCCAM
reserves the right to reanalyze, to publish, or to distribute its analyses of
these data when it is in the interest of public health.  Prior to release,
publication or distribution of such analyses, the NCCAM will provide such
analyses to the awardee.

The Awardee must use its best efforts to notify all scientists, research
laboratories, and other organizations to which the awardee has sent research
materials affected by false or otherwise unreliable data.

5.  Reporting Requirements
Interim reports of the trial and adjunct studies shall appear in the minutes
of each Steering Committee meeting and shall include specific data on patient
accrual.  Quarterly accrual information must be provided by the Steering
Committee to NCCAM and the DSMB.  A system for providing such information in a
timely manner should be in place.  Participants must provide accrual data to
the Steering Committee in accordance with Steering Committee procedures.

All recipients of NCCAM support for clinical trials, including trial sites
responsible for coordinating and monitoring such trials, must promptly notify
the NCCAM, the FDA and any other sponsors of the trial of adverse events
(i.e., adverse drug reactions) according to directions provided in the adverse
event reporting section of the protocol.  The Awardee will notify all
institutions/investigators participating in this project, about the above
requirement and about the institutions'/investigators' responsibility to
report adverse events as specified in the protocol.

The Awardee will be required to submit semiannual progress reports to NCCAM. 
These reports should include recruitment data, indices of quality control, and
changes in the protocol.  Such reports are in addition to the annual awardee
noncompeting continuation progress report.  The DSMB may require additional
information.  The Awardee also will be requested to present a final oral
report to the NCCAM Advisory Council.

6.  Federally Mandated Regulatory Requirements
Each trial site participating in a consortium arrangement is required to meet
the DHHS/PHS regulations for the protection of human subjects and FDA
requirements for the conduct of research using investigational agents.  At a
minimum, these include:

a.  methods for assuring that each institution at which site investigators are
conducting clinical studies has a current, approved assurance on file (or will
obtain a single site assurance if appropriate) with the Office for Protection
from Research Risks (OPRR); that study protocols are reviewed and approved by
the responsible Institutional Review Board (IRB) prior to patient entry; that
active protocols are reviewed at least annually by the IRB; and that all
protocol amendments are approved by the IRB.

b.  methods for assuring or documenting that each patient, or patient's
parent/legal guardian, gives fully informed consent to participation in a
research protocol prior to the initiation of the experimental intervention. 
All informed consent documents must be available for review upon request by
the NCCAM or Steering Committee, or FDA or Industry sponsor, if applicable.

C.  NIH Staff Responsibilities

1.  Normal Stewardship

a) The NCCAM will name a Program Officer whose function will be to assist the
Principal Investigator and the Steering Committee in oversight of the trial. 
In addition, the NCCAM Program Officer will retain overall administrative
responsibility for the award and will be the contact point for all facets of
interactions with the Awardee concerning such issues.  The NCCAM Program
Officer will be assisted and advised by the NCCAM Clinical Trials Coordinator. 
In addition, ad hoc advisory committees may be formed as needed to
assist/advise the NCCAM Program Officer.

b) A change in the Principal Investigator, or in any key personnel identified
on the Notice of Award, must have the prior written approval of the NCCAM
Grants Management Specialist in consultation with the NCCAM Program Officer.

c) The NCCAM Program Officer and Clinical Trials Coordinator will assist with
the review and approval of adjunct protocols to ensure they are within the
scope of the grant and also for safety considerations, as required by Federal
regulations.

d) The NCCAM Program Officer and Clinical Trials Coordinator will review the
progress of each trial site through consideration of the annual reports, site
visits, patient logs, etc.  As required for these activities, the Program
Officer and Clinical Trials Coordinator will be assisted by other NCCAM staff
and contractors.  This review may include, but is not limited to, safety
issues, compliance with protocol, specifications, patient accrual, adherence
to uniform data collection procedures, data management and quality control,
and the timeliness of data reporting.  The NCCAM Program Officer is able to 
request additional data from investigators as needed on these issues.  Based
on this review, the NCCAM reserves the right to close the study the study (or
any individual trial site(s)) to accrual, or to terminate the study (or any
individual trial site(s)) for reasons including:
1) failure to implement the final collaborative protocol in a timely fashion;
2) substantive changes in the agreed-upon protocol to which the NCCAM does not
agree;
3) substantial shortfall in participant recruitment, follow-up, data
reporting, quality control, or other major breech of the protocol;
4) emergence of new information that diminishes the scientific importance of
the study question;
5) patient safety and regulatory concerns;
6) accrual goals met early and;
7) study results that are already conclusive.

e) The NCCAM Program Officer and Clinical Trials Coordinator will review all
DSMB reports.  As necessary, the NCCAM Program Officer will request advice of
the DSMB on study protocol and safety issues, data management, data quality,
data analysis, recruitment, retention and protocol adherence issues arising
over the course of study, and advisability of terminating the study.

f) The NCCAM will have access to and may periodically review all data
generated under this award.  The NCCAM Program Officer reserves the option, at
any point in the trial, to obtain an independent audit of a sample of primary
subject records for comparison with the trial's regular audit reports. 
Auditors so engaged will report directly to NCCAM and be reimbursed directly
by NCCAM, i.e., reimbursement will not be drawn from the award for the trial,
and costs of such audits will not be borne by the awardee institution(s).

2.  Substantial Additional Involvement
a) The Program Officer will have substantial scientific-programmatic
involvement including participation in database development, budget
monitoring, modification and finalization of the trial and any adjunct
protocols, quality control, data analysis and interpretation, preparation of
publications, and coordination and performance monitoring.  The prime
responsibility for these activities resides with the Awardee although specific
tasks and activities in overseeing the studies will be shared between the
awardee and the NCCAM Program Officer.

b) Certain organizational changes require the prior written approval of the
NCCAM Program Officer.  These changes include the addition or replacement of a
trial site that is associated with this study.

c) The NCCAM Program Officer and Clinical Trials Coordinator may contribute,
through review, comment, analysis, and/or co-authorship, to reporting results
of the study to interested scientific and lay organizations.  Co-authorship by
the NCCAM staff will be subject to approval in accordance with NIH policies
regarding staff authorship of publications resulting from extramural awards.

d) The NCCAM Program Officer has the authority to adjust funds provided to the
trial sites as appropriate for the level of participation in trial sites
activities, including (but not limited to) accrual.  This procedure can be
either prospective (i.e., reimbursement by the case) or retrospective
(financial adjustment at the time a non-competing continuation [Type 5] award
is made).

f) Product Acquisition - The NCCAM will be responsible for the identification,
acquisition and distribution of the Ginkgo biloba extract and a matching
placebo.  It is expected that the manufacturer will hold the Investigational
New Drug Application (IND) and be responsible for obtaining all Food and Drug
Administration (FDA) approvals.

D.  Collaborative Responsibilities

1.  Steering Committee

A Steering Committee will be established to serve as the main governing body
of the trial.  The Steering Committee will be composed of the NCCAM Program
Officer, the NCCAM Clinical Trials Coordinator, the cooperative agreement
Principal Investigator, the Trial Manager and up to five trial site Senior
Investigators (see below).  A plan should be provided for selecting Senior
Investigators to the Steering Committee; this should include their length of
term and plans for rotation among Senior Investigators, if appropriate.  Also
serving on the Committee will be an ex officio, non-voting Project Consultant
from the National Institute on Aging, who will provide scientific advice to
the Steering Committee, and, as appropriate, keep the Steering Committee
informed of related NIA activities.  Outside ad hoc consultants will be added
as appropriate and needed.

All major scientific decisions will be determined by the Steering Committee,
with the Principal Investigator, the Senior Investigators and the Trial
Manager having one vote each.  The NCCAM Program Officer and Clinical Trials
Coordinator will share one vote.  The first meeting will be convened by the
NCCAM within two months of the award.  The Committee will meet at least once
more during the first 12 months of the study and annually thereafter.  All
meetings will be held in the Bethesda, Maryland area.  At the first Committee
meeting, the Chairperson will be selected by the Steering Committee from
members other than the PI or NCCAM staff, or alternatively, from among experts
in the field who are not participating directly in the trial.  This Committee
will have primary responsibility for finalizing the trial protocol, and
approving the design and implementation of all adjunct studies, facilitating
the conduct and monitoring of the clinical trial and adjunct studies,
analyzing and interpreting study data, reporting study results, and setting
guidelines for authorships.  Each Steering Committee member (or their
surrogate) will be expected to participate in all other Steering Committee
activities, e.g., conference calls, special subcommittees as may be necessary,
etc.

The Steering Committee will be responsible for ensuring the provision of
centralized data collection, management and quality assurance.  Under the
direction of the Steering Committee, the NCCAM will provide technical
assistance, as available, to the trial sites with respect to quality control,
uniformity of data collection, management of the collective data base, and
data analysis.

Specific data analyses to be carried out will be determined by the Steering
Committee.  The results of those analyses will be delivered to the Steering
Committee as the group responsible for determining if further analyses should
be performed, how the results are interpreted, and how the findings should be
disseminated.  Applicants should include in their budget requests support for
on-site data collection and transmittal, as well as for centralized data
collection and management.

Each trial site will follow the procedures required by the final protocol
generated by the Steering Committee regarding study conduct and monitoring,
patient management, data collection, data management, data analysis and
quality control.  Trial sites will be required to accept and implement the
common protocol and procedures approved by the Steering Committee.

The Steering Committee will establish mechanisms for assessing performance of
the trial sites, including institutions participating in consortia
arrangements, with particular attention to accrual of adequate numbers of
eligible patients, timely submission and quality of required data and
conscientious observance of protocol requirements.  At a minimum, this will
include:
1) assessment of treatment administration and measurement of outcomes;
2) tracking and reporting of patient accrual and adherence to defined accrual
goals;
3) ongoing assessment of case eligibility and availability;
4) timely medical review and assessment of patient data;
5) rapid reporting of morbidity, and measures to ensure communication of this
information to all interested parties, including the FDA;
6) interim evaluation and consideration of measures of outcome as consistent
with patient safety and good clinical trials practice;
7) timely communication of study results to NCCAM, the scientific community
and the U.S. Public; and
8) an on-site quality-control and safety monitoring program.

The Steering Committee shall establish and follow policies and procedures for,
and conducting periodic review of, the performance and membership status of
each trial site.  This review should examine scientific contributions, patient
accrual, data accuracy and timeliness, protocol compliance, long-term patient
follow-up and audit results.  These procedures should be as simple as
appropriate in order to encourage maximum participation of physicians entering
patients and to avoid unnecessary expense.  This information will be made
available to the NCCAM in a timely fashion.

2.  Publication and Presentation of Study Findings Timely publication of major
findings is encouraged.  Publications and oral presentations of work performed
under this agreement will require appropriate acknowledgment of both the trial
sites and NCCAM support.  Analyses to be performed using the collective data
from all trial sites will be determined and directed by the Steering
Committee, as will policies for authorship on any subsequent publications. 
Trial sites wishing to perform analyses of local data will inform the Steering
Committee of any such analyses prior to initiation in order to avoid
duplication.  Review and approval by the Steering Committee will be required
for all analyses, including that of local data by individual trial sites,
prior to publication or presentation according to criteria that will be
developed by the Steering Committee. The Steering Committee may establish a
Publications Subcommittee to serve this function.

The Government, via the NCCAM Project Officer, will have access to data
generated under this Cooperative Agreement and may periodically review the
data and progress reports.  NCCAM Staff may use information obtained from the
data for the preparation of internal reports on the activities of the study. 
However, the Awardee will retain custody of and have primary rights to all
data developed under these awards.

3.  Investigational Drug Management

All trial sites are expected, in cooperation with the NCCAM, to comply with
all FDA monitoring and reporting requirements for investigational agents.

4.  Data and Safety Monitoring Board

An independent Data and Safety Monitoring Board will be appointed by the
Director of NCCAM, with input from the Awardee, and meet at least twice a
year.  DSMB meetings will be open only to designated NCCAM staff and other
individuals who have been approved to have access to unmasked data.  The DSMB
will be composed of experts in relevant medical, botanical, statistical and
bioethical fields who are not otherwise involved in the trial.  An NCCAM staff
member other than the designated trial Program Officer of Clinical Trials
Coordinator will serve as an ex-officio, non-voting members of this Board. 
The Board will oversee participant safety, evaluate results, monitor data
quality, adverse events and patient accrual, and provide operational and
policy advice to the Steering Committee and the Director of NCCAM regarding
the status of the study.  The DSMB will document progress in written reports
at least twice annually to the Director of NCCAM through the NCCAM Program
Officer, and will provide periodic supplementary reports to designated NIH
staff upon request.

The initial tasks of the DSMB are to review the entire protocol and informed
consent forms with regard to subject safety; identify needs for protocol
modification; review the Manual of Operations; and, after receipt of a
satisfactory protocol, recommend to the NCCAM initiation of expenditure of
project funds.  The DSMB will also identify the relevant data parameters to be
reported by the Awardee and the Steering Committee to the DSMB, and the format
of these data.  Subsequently, it must meet on a regular schedule (not less
than twice a year) over the course of study (with additional meetings as
needed) to:

1.  Review data (including masked data) relating to recruitment,
randomization, compliance, retention, protocol adherence, trial operating
procedures, form completion, intervention effects, auditing of primary subject
records, data management, quality control, and subject safety;
2.  Identify problems relating to safety over the course of the study;
3.  Identify needs for additional data relevant to safety issues and request
these data from the study investigators;
4.  Review unmasked outcome data as needed and appropriate over the course of
the trial;
5.  Propose appropriate analyses and periodically review developing data on
safety and endpoints;
6.  At each meeting, consider the rationale for continuation of the study,
with respect to progress of randomization, retention, protocol adherence, data
management, safety issues, and outcome data, if relevant, and make
recommendation to the Director of NCCAM for or against continuation of the
trial.
7.  Provide advice on issues regarding data discrepancies found by the data
auditing system or other sources.  If this advice is requested by the NCCAM
Program Officer, it should be provided in writing within two weeks of the date
of this request.
8.  Send the NCCAM Program Officer written reports following each DSMB
meeting, and additionally as needed, on all issues reviewed by the DSMB

At the time of award, the Awardee will be requested to nominate prospective
DSMB members to the Director of NCCAM.  The NCCAM reserves the right to
appoint additional members to the DSMB to include scientific expertise in
topic areas relevant to the trial such as biostatistics, ethics, or patient
advocacy.

The NCCAM Program Officer is charged with facilitating implementation of DSMB
recommendations by the NCCAM and with conveying DSMB recommendations and
requests to the Awardee.

The trial sites must comply with the approved policies and procedures of the
DSMB.

5. Arbitration
Any disagreement that may arise in scientific-programmatic matters between
award recipients and NCCAM may be brought to arbitration.  An arbitration
panel will be composed of three members--one selected by the Steering
Committee (with NCCAM member not voting) or by the individual awardees in the
event of an individual disagreement, a second member selected by NCCAM and the
third member selected by the two prior members.  This special arbitration
procedure in no way affects the awardee' right to appeal an adverse action
that is otherwise appealable in accordance with the PHS regulations at 42 CFR
part 50, Subpart D.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and
their subpopulations must be included in all NIH supported biomedical and
behavioral research projects involving human subjects, unless a clear and
compelling rationale and justification 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 was published in the Federal Register of March 28, 1994 (FR
59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No.
11, March 18, 1994, available on the web at: 
http://grants.nih.gov/grants/guide/notice-files/not94-100.html.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them. This
policy applies to all initial (Type 1) applications submitted for receipt
dates after October 1, 1998.  All investigators proposing research involving
human subjects should read the "NIH Policy and Guidelines" on the Inclusion of
Children as Participants in Research Involving Human Subjects that was
published in the NIH Guide for Grants and Contracts, March 6, 1998, and is
available at the following URL address: 
http://grants.nih.gov/grants/guide/notice-files/not98-024.html

However, the scientific goals of this RFA are focused on aging.  In describing
the plan to recruit human subjects, investigators may cite a focus on aging or
on aging-related aspects of disease as the justification for why children will
be excluded.  In this regard applicants may use Justification 1, the research
topic to be studied is irrelevant to children, from the policy announcement.

LETTER OF INTENT

Prospective applicants are asked to submit, by April 21, 1999, a letter of
intent that includes a descriptive title of the proposed research, the name,
address, and telephone number of the Principal Investigator, the identities of
other key personnel and participating institutions, and the number and title
(Ginkgo Biloba Prevention Trial in Older Individuals AT-99-001) of this RFA.

Although a letter of intent is not required, is not binding, and does not
enter into the review of subsequent applications, the information that it
contains allows NCCAM staff to estimate the potential review workload and to
avoid conflict of interest in the review.

Mail/Fax letters of intent to:

Richard L. Nahin, Ph.D., M.P.H.
Division of Extramural Research, Review and Training
National Center for Complementary and Alternative Medicine
Building 31, Room 5B-368
Bethesda, MD  20892-2182
FAX:  (301) 594-6757

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used in
applying for these grants.  Application kits are available at most
institutional offices of sponsored research; 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; and are available on the internet at
http://grants.nih.gov/grants/forms.htm.

Prior to writing the application, applicants should carefully read the
instructions provided with PHS 398 and this RFA.  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 two of the face page of the application form and the YES box
must be marked.

Submit a typewritten, signed original of the application, three 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, two additional complete, signed copies of the
application must be sent to:

Richard L. Nahin, Ph.D., M.P.H.
Division of Extramural Research, Review and Training
National Center for Complementary and Alternative Medicine
Building 31, Room 5B-36
Bethesda, MD  20892-2182

Applications must be received by May 21, 1999.  If an application is received
after the date, it will be returned to the applicant without review.  The
Center for Scientific Review (CSR) will not accept any application in response
to this RFA that is essentially the same as one currently pending initial
review, unless the applicant withdraws the pending application.  The CSR will
not accept any application that is essentially the same as one already
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 PHS 398 application instructions for the preparation of
revised applications, including an introduction addressing the previous
critique.

Preparation of the Application

The general instructions provided in PHS-398 must be used for the preparation
of applications except as modified under "Special Requirements" and as listed
below.  Because the "Terms and Conditions of Award" will be included in all
awards issued as a result of this RFA, it is critical that each applicant
provides specific plans for responding to the terms and conditions of award
and requirements stated in the RFA.  Plans must take into account NIH staff
involvement, as well as how all the responsibilities of Awardee will be
fulfilled.  The following items apply to all applications:

1.  General

All applicants should demonstrate their ability to manage a complex trial, and
provide a detailed patient recruitment plan, a detailed data management plan,
and sample size and power calculations.  In addition, it is important to
evaluate any side effects or complications of treatment.

2.  Trial Organization

The application should describe the organization of the study and how the
trial will be managed.  The application should identify the single applicant
organization that will be legally and financially responsible and accountable
for the use and disposition of funds awarded on the basis of this RFA to other
trial sites and institutions participating in the consortium, and show
availability of personnel and facilities capable of performing and supporting
the administrative functions necessary.

The application should provide a plan to assure the maintenance of close
cooperation and effective communication among members of the consortium.

The application should discuss the capability of the applicant organization
and each institution in an applicant consortium to participate and interact
effectively in cooperative, multi-center clinical trials.

The application should discuss the coordination of participating trial sites,
including proposed methods of blinding, communication, data transfer, and
trial oversight (e.g., how will recruitment goals of trial sites be
monitored).  A timetable for completion of the various stages of the trial
should be included.

3.  Research Design and Data Analysis
The applicant should describe the procedure for assignment of patients to
experimental conditions, as well as the procedures used to assure compliance
with, and standardized implementation of, the proposed protocol.  Applicants
should also discuss potential biases in the proposed research protocol and how
they will be addressed.  Clinical (including behavioral), laboratory and
physiological tests and protocols should be described briefly, with additional
detail provided in the appendix if needed.  Methods of randomization and
standardization across trial sites should be described and endpoints clearly
defined.  The specific criteria and procedures for unblinding should be
specified and justified in the application.

Applicants should discuss patient availability and recruitment.  Discuss the
characteristics of the population and the approaches proposed for recruitment,
retention and follow-up. Discuss plans for maintaining the cooperation of the
study population over the length of the trial, including compliance with the
assigned treatment, as well as plans for addressing any anticipated changes in
the composition of the study population over the course of the trial (e.g.,
different mortality rates in men versus women).  Data should be presented
supporting recruitment and retention estimates.

Describe the methods of data analysis, linking the analyses to the hypotheses
to be tested.  Include methods of data preparation and presentation, analytic
methods, and approaches to data synthesis.  Discuss how interim analyses will
be handled, as well as comparisons across subgroups.  Data analyses should
consider stratification by risk and protective factors when appropriate. 
Choice of these factors should be specified and justified in the application,
and incorporated into sample size calculations.

Applications should demonstrate the scientific expertise required to design,
conduct and analyze all proposed adjunct studies.  Such expertise may be
provided by a single scientist serving the entire consortium or more than one
such scientist depending upon the proposed adjunct studies.

4.  Women and Minority Subjects
Women and minority individuals should be included in the study population in
accordance with NIH requirements.  Specific recruitment targets for women and
minority subjects and plans for achieving these goals must be explicitly
stated in a separate section of the application.  Approximate percentages of
women and minority groups expected in the study sample and the basis for these
estimates must be provided.  Generally, representation of women and minorities
should occur in the study population in the same proportions as in the U.S.
population having the disease being studied.  It is recognized that this may
require oversampling.

5.  Budget
All costs required for the proposed trial and adjunct studies should be
included in the application and fully justified.  If the trial is designed for
more than a seven-year period, complete, justified budgets for the future
years also must be included.  The review of the application will evaluate the
entire project.  Budgeted costs should include the costs of clinical research
associated with the proposed protocol costs for patient recruitment and
follow-up, adjunct studies, data collection, management and quality control,
and independent on-site quality assurance audits.  Costs at participating
trial sites, exclusive of salary, should be calculated on a per patient-visit. 
Requested budgets should also include travel to the Bethesda, Maryland area
for two 1-2 day Steering Committee meetings during the first 12 months, and
annually thereafter for the Principal Investigator, the Trial Manager and up
to five trial site Senior Investigators.

NOTE:  A signed, completed face page (PHS 398, page A) should be provided for
each trial site, as well as for the applicant institution.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR and
responsiveness by the NCCAM.  Incomplete and/or non-responsive applications
will be returned to the applicant without further consideration.  Applications
that are complete and responsive to the RFA will be evaluated for scientific
and technical merit by an appropriate peer review group convened by the NCCAM
in accordance with the NIH peer review procedures.  As part of the initial
merit review, all applications will receive a written critique and undergo a
process in which only those applications deemed to have the highest scientific
merit, generally the top half of applications under review, will be discussed,
assigned a priority score, and receive a second level review by the National
Advisory Council for NCCAM.

Review Criteria

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  In
the written comments reviewers will be asked to discuss the following aspects
of the application in order to judge the likelihood that the proposed research
will have a substantial impact on the pursuit of these goals.  Each of these
criteria will be addressed and considered in assigning the overall score,
weighting them as appropriate for each application.   Note that the
application does not need to be strong in all categories to be judged likely
to have major scientific impact and thus deserve a high priority score.  For
example, an investigator may propose to carry out important work that by its
nature is not innovative but is essential to move a field forward.

(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

Reviewers will consider these criteria when assigning a single overall score
to each application.  In addition, reviewers will consider the following
issues, which are specific to this RFA:

o  Appropriateness of the proposed budget and duration in relation to the
proposed research.

o  Overall feasibility and the likelihood of achieving the clinical trial
goals and the potential for a successful trial.

o  Pilot phase experience including evidence of patient accession and
retention.

o  Adequacy of the statistical features of the study including sample size
projections and power estimates, methods of analysis, and the use of
sequential analyses of data.

o  Logistical aspects of the project including plans for patient recruitment,
quality control of data, proper randomization and masking procedures, data
collection, data management and reporting, and plans for defining access and
restriction to data.  If preliminary data are not available, the proposal
should include a pilot phase to validate these procedures.

o  Availability of suitable subjects for the clinical trial and the likelihood
of participation through to completion of the study.

o  Commitment of the consortium institutions and staff to a collaborative
protocol and to the success of the study.  The inclusion of letters of
agreement from collaborating investigators, countersigned by the appropriate
institutional official, is necessary.  These letters should state the
willingness of the investigators to work with the Steering Committee and NCCAM
staff, and to comply with the policies and procedures developed by the
Steering Committee concerning this trial.

o  Adequacy of the facilities including technical resources and space.

o  Appropriateness of both the consortium organization and administration and
that at each trial site.

o  Adequacy of methods for data collection and reporting from each consortium
institution.

o  Adequacy of ethical and human safety issues, including current
Institutional Review Board (IRB) human subjects approval(s).

o  Adequacy of plans to include subjects from both genders, and from minority
groups and subgroups as appropriate for the scientific goals of the proposed
research.  Plans for the recruitment and retention of subjects also will be
evaluated.

AWARD CRITERIA

The anticipated date of award is September 30, 1999

Award criteria are:
o  responsiveness to goals and objectives of RFA
o  priority score
o  availability of funds

Award of funds for the approved future years of the grant will require
submission of a noncompeting continuation application, PHS form 2590, to NCCAM
at least two months prior to the anniversary date of the award.  Failure to
supply the PHS form 2590 in a timely manner will impede release of outyear
funding.

Letter of Intent Due:        April 21, 1999
Application Receipt Date:    May 21, 1999
Review by Advisory Council:  September, 1999
Anticipated Award Date:      September 30, 1999

INQUIRIES

Inquiries concerning this RFA are encouraged.  The opportunity to clarify any
issues or questions from potential applicants is welcome.

Direct inquires regarding programmatic issues to:

Richard L. Nahin, Ph.D., M.P.H.
Division of Extramural Research, Review and Training
National Center for Complementary and Alternative Medicine
9000 Rockville Pike
Building 31, Room 5B-38
Bethesda, MD  20892-2182
Telephone:  (301) 496-4792
FAX:  (301) 594-6757
Email:  NahinR@OD.NIH.GOV

Neil S. Buckholtz, Ph.D.
Neuroscience and Neuropsychology of Aging Program
National Institute on Aging
7201 Wisconsin Avenue, Suite 3C307, MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-9350
FAX:  (301) 496-1494
Email:  Buckholn@exmur.nia.nih.gov

Direct inquiries regarding fiscal matters to:

Marie Willett*
Grants Operations Branch
National Heart, Lung and Blood Institute
6701 Rockledge Drive, Suite 7156, MSC 7926
Bethesda, MD 20892-7952
Telephone:  (301) 435-0144
FAX:  (301) 480-3310
Email:  WillettM@gwgate.nhlbi.nih.gov

* Note: NHLBI is the Grants Management Service Center for the NCCAM

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance Nos.
93.213 (NCCAM) and 93.866 (NIA).  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 Parts 52 and 45 CFR Part 74 [and Part
92 when applicable for State and Local governments].  This program is not
subject to the intergovernmental review requirements of Executive Order 12372
or Health Systems Agency review.

The PHS strongly encourages all grant and contract recipients to provide a
smoke-free workplace and promote the non-use of all tobacco products.  In
addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking
in certain facilities (or in some cases, any portion of a facility) in which
regular or routine education, library, day care, health care or early
childhood development services are provided to children.  This is consistent
with the PHS mission to protect and advance the physical and mental health of
the American people.


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