Full Text CA-94-007

NATIONAL COOPERATIVE NATURAL PRODUCTS DRUG DISCOVERY GROUPS

NIH GUIDE, Volume 23, Number 21, June 3, 1994

RFA:  CA-94-007

P.T. 34

Keywords: 
  Cancer/Carcinogenesis 
  Chemotherapeutic Agents 
  Biomedical Research, Multidiscipl 
  Natural Products 


National Cancer Institute

Letter of Intent Receipt Date:  July 15, 1994
Application Receipt Date:  September 20, 1994

PURPOSE

The Developmental Therapeutics Program, Division of Cancer Treatment,
National Cancer Institute (NCI) invites applications for the
continuance of National Cooperative Natural Products Drug Discovery
Groups (NCNPDDGs) for the discovery of new effective anticancer
treatments from natural sources.  Applications are sought from both
re-competing NCNPDDGs and new applicant groups.

This Request for Applications (RFA) will support innovative,
multi-disciplinary approaches to the discovery of new anticancer
agents derived from natural sources.  Each Group will be assembled by
a Principal Investigator (PI) to form a multidisciplinary and
multi-institutional consortium of skills needed to execute
successfully the conceptualization, development, and preclinical
investigation of the new, rationally based drug candidates.  A
multi-institutional approach involving academic, nonprofit, and/or
commercial/industrial institutions is envisaged because the existence
of all of the creative talents in the required scientific disciplines
will rarely be available in a single institution.  The biological or
molecular cancer targets for drug discovery and the sources and types
of natural products to be investigated will be selected by the
applicant groups.  Although NCNPDDG awards will not support clinical
trials, timely evaluation of drug candidates discovered by this
mechanism is encouraged.

The present RFA is a reissuance of 89-CA-17 issued on September 14,
1989, with the same goals.  The RESEARCH OBJECTIVES of the RFA
require that an NCNPDDG has the capacity within itself to conceive,
create and evaluate new approaches to discovery of natural products
based drug candidates and to recommend the best candidates for
development towards clinical trials.  Subsequent studies required for
development of new treatments to clinical trial (e.g., formulation
development, classical toxicology, etc.) are beyond the scope of this
RFA.  Within this context, scientific approaches to the achievement
of the RFA goals are broad, and are limited only by the creativity
and the capability of the applicant group.  The development of
analogues of well-studied classes of anticancer agents is not
responsive to this RFA.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000",
A PHS-led national activity for setting priority areas.  This RFA,
National Cooperative Natural Products Drug Discovery Groups, is
related to the priority area of cancer.  Potential applicants may
obtain a copy of "Healthy People 2000" (Full Report: Stock No.
017-001-00474-0) or "Healthy People 2000" (Summary Report:  Stock No.
017-001-00473-1) through the Superintendent of Documents, Government
Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic for-profit and non-profit
organizations, public and private, such as universities, hospitals,
laboratories, research institutes, units of State and local
governments, and eligible units of the Federal government.
Applications from women and minority investigators are encouraged.

MECHANISM OF SUPPORT

The administrative and funding instrument to be used for this program
will be a cooperative agreement (U19), an assistance mechanism in
which substantial NCI scientific and/or programmatic involvement with
the awardee is anticipated during performance of the activity.  Under
the cooperative agreement, the NCI purpose is to support and/or
stimulate the recipients 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.  Details of the responsibilities and the
relationships of the awardee and the Government during the course of
a cooperative agreement are found later in this document under the
section "Terms and Conditions of Award."

The awardee will be responsible for the planning, direction, and
execution of the proposed project, and interrelated activities.  All
applications must consist of at least three interrelated laboratory
programs.  While no maximum number of programs is stipulated, it has
been observed that awards containing more than five or six components
are more difficult to manage.

The partnership relationship will facilitate technology transfer from
Government owned data-bases and the use of appropriate NCI resources
to enhance the efficiency and effectiveness of a Group's efforts.
The nature of NCI staff participation is described below under "Terms
and Conditions of Award."  There is no intent, real or implied, for
NCI staff to direct Group activities or to limit the freedom of
investigators.  A Group is expected to consist of a single consortium
of multidisciplinary and/or multi-institutional Laboratory Programs
from academic, non-profit, or commercial organizations.  The
interaction of academic and non-profit research institutions with
commercial (including industrial) organizations and Government will
favor the efficient invention of new agents for cancer.  The active
participation of industry is encouraged because it will allow this
segment of the scientific community to contribute its considerable
intellectual and material resources.  Further, the interaction of
academic and non-profit research institutions with industry and
Government will facilitate subsequent development and marketing of
new drugs, although these latter activities are not within the scope
of this RFA.

Each award will be made only to the Principal Investigator's
institution.  All Group activities will be coordinated through a
Administrative Core located at the Principal Investigator's
institution.

The total project period for applications submitted in response to
the present RFA may not exceed five years.  The earliest anticipated
award date is April 1, 1995.

Because the nature and scope of the research proposed in response to
this RFA may vary, it is anticipated that the size of awards may vary
also.

Awards and level of support depend on receipt of a sufficient number
of applications of high scientific merit.  Although this program is
provided for in the  financial plans of the NCI, awards pursuant to
this RFA are contingent upon continuing availability of funds for
this purpose.

At this time, the NCI anticipates that there will be a renewed
competition of this program.  If the NCI does not continue the
program, awardees may submit grant applications through the usual
investigator-initiated grants mechanisms.

FUNDS AVAILABLE

The NCI has set aside approximately $4,000,000 in total costs for the
initial year's funding.  This level of support is dependent on the
receipt of a sufficient number and diversity of applications of high
scientific merit.  Five to seven awards, which will include both new
awards and competing continuation awards, are anticipated for project
periods up to five years.

Awards are subject to a first year limit of $900,000 total costs
(direct plus indirect costs).  Applications in excess of $900,000
first year total costs will be returned without review.

RESEARCH OBJECTIVES

A.  Background

The search for better cancer treatments is a dynamic process
dependent on the availability of new agents and strategies coupled
with the development and use of more predictive models.  Recent
advances in modern biomedical research provide unprecedented
opportunities for the discovery of novel and highly sophisticated
cancer treatments.  Exploitation of these exciting leads for
development of more effective cancer therapy requires the
organization of outstanding scientists from diverse scientific
disciplines within the biological, chemical, biochemical, and
pharmacological sciences into highly synergistic research teams
regardless of institutional affiliation.  To realize this objective
as well as to utilize facilitating resources of the NCI's drug
development program within these teams, the NCI established the
National Cooperative Drug Discovery Group (NCDDG) program as a result
of Request for Applications (RFAs) issued in July 1983 and August
1984 for the exploitation of mechanistically based differences
between normal and cancer cells.  October 1986 reissuances
established groups focused on exploitation of specific and unique
characteristics of lung and colorectal cancers.  The NCDDG approach
to modern drug discovery was broadened further in August 1987 by RFAs
inviting applications for the creation and evaluation of both general
mechanism of action based and specific disease-oriented anticancer
treatments as well as for the development of innovative preclinical
models for determining antitumor selectivity.  National Cooperative
Natural Products Drug Discovery Groups were invited by RFAs in
September 1988 and October 1989 in order to enhance discovery of
novel drug chemotypes for subsequent development as anticancer
agents.  A combined RFA was issued in August 1991 for general
mechanism of action and specific disease-oriented research.

NCNPDDGs are peer-reviewed projects funded through a cooperative
mechanism in which the NCI, through its extramural staff, is an
active partner in the group.  NCI staff, represented by an NCI
Coordinator, provide advice and guidance in the area of drug
discovery and development and facilitate access to NCI resources
including repositories, chemical searches, and screens. Resources for
advanced development including scale-up isolation and/or synthesis,
pharmaceutical development, toxicology and filing of Investigational
New Drug Applications (INDs) can be made available through the NCI
Decision Network process (M.R. Grever, S.A.  Schepartz, and B.A.
Chabner, Seminars in Oncology, Vol 19, No. 6 (December), 1992; pp
622-638) or through collaborating industrial partners, or through
private venture capital.

The present RFA is for the discovery of new therapies for cancer from
the universe of natural substances, historically a fruitful source of
agents effective against a wide variety of human diseases.  This RFA
is a reissuance of the 1988-1989 RFAs for National Cooperative
Natural Products Drug Discovery Groups.  A companion RFA (CA-94-008)
is being issued for National Cooperative Drug Discovery Groups
(NCDDGs) based on mechanistic/disease oriented approaches to
discovery of new therapies.

B.  Objectives and Scope

The goals of this RFA are to encourage the discovery and evaluation
of new entities from natural sources for the treatment of cancer.
Programs should utilize, to the extent possible, novel and innovative
approaches to drug discovery based on recent advances in tumor
biology and the molecular understanding of cancer.  Programs
appropriate to fulfillment of Group objectives could include, but are
not limited to: discovery of natural products that selectively
inhibit specific tumor types; products that may affect oncogene
expression in tumors, signalling pathways for tumor growth, or the
actions of hormones or growth factors on proliferation.  Approaches
to targets specifically present in tumor cells are encouraged.
Applications that emphasize targets related to breast cancer and
prostatic cancer, which are currently high priority research areas
for the NCI, are encouraged but this RFA is in no way limited to
these diseases.

1.  The goals of the NATURAL PRODUCTS DRUG DISCOVERY GROUP PROGRAM
are:

a.  The search for, discovery, and isolation from natural sources of
novel agents to treat cancer effectively and their evaluation in
appropriately developed and/or selected preclinical models.

b.  The development or use of preclinical models based on their
ability to discriminate for antitumor activity and their ability to
test the rationale for natural product selection and isolation.

c.  The optimization of leads sufficient to recommend viable
candidate compounds for development  to clinical trial.

d.  The design of preclinical studies that will facilitate subsequent
clinical evaluation and correlation of preclinical and clinical data
for validation of concept.

2.  Applications for funding as an NCNPDDG should stress creative
approaches to the discovery of effective anticancer therapies and
should emphasize the following:

a.  Objectives of the proposed NCNPDDG.

b.  Research approaches to the realization of objectives and the
provision of comprehensive information (including citations) in
support of the rationale(s) for the proposed approaches.

c.  Specific pertinence to cancer treatment.

d.  The scientific and technical areas of expertise (Program Leaders)
required to attain Group objectives.

Approaches to realization of the goals of this RFA are broad and
limited only by the creativity and ability of the applying Group.
Projects for random collection and screening of natural products
without strong rationales for material selection or testing models
and projects designed to produce analogues or derivatives of well
known antitumor natural products are not responsive to this RFA.
Applications should stress novelty of approach and strong rationale
both in terms of the cancer target and the natural products to be
evaluated.

Each group is envisioned as containing a number of Laboratory
Programs (minimum of three) whose cooperative activities may, for
example, include: (1) implementation of strategies to support the
selection and acquisition of natural sources of NOVEL agents; (2)
preparation of crude materials for testing; (3) development and use
of discriminating biological assays to select crude materials for
further study; (4) utilization of biological assays and
physical/chemical methods leading to the efficient isolation,
purification and structure elucidation of antitumor selective
moieties; (5) development of methods and models for secondary
evaluation of lead compounds, both in vitro and in vivo to enable
discrimination among leads and facilitate selection of compounds; (6)
optimization of selected leads to facilitate selection of and
priorities for the development of new agents to clinical trial.

A cohesive NCNPDDG should include all of the Laboratory Programs
needed to attain Group objectives.  Since it is unlikely that all of
the required laboratory capabilities will be found in any single
institution, it is probable that most proposed Groups will be
multi-institutional as well as multidisciplinary in nature.  The
specialized research competencies required could include scientists
(e.g., ecologists, botanists, chemists, molecular biologists, and
others) who have not been working primarily in cancer research.  The
participation of highly creative scientists from any scientific
discipline appropriate to the Group objectives is encouraged.  Group
efforts must be focused on clear, cancer-relevant goals to which all
Laboratory Programs must relate.

The desired end product of the funded applications is the discovery
of new drugs from novel approaches to cancer treatment and sufficient
secondary evaluation and optimization of these agents to enable the
Group to recommend candidate compounds for advanced preclinical
development.

3.  Funds for laboratory programs or cores that depend on the
successful completion of other parts of the group's activities will
be restricted and released only on specific approval of the NCI
Program Director or NCI Coordinator.  Examples of such restricted
funds might be for scale up re-collections, isolations, or syntheses,
use of advanced models for secondary evaluation, studies of mechanism
of action of lead compounds, and lead optimization studies.

4.  Studies required for development of new agents to clinical trial
(e.g., formulation development, classical toxicology, etc.) are
beyond the scope of this RFA.  However, such development is
encouraged through the NCI Decision Network process or through
industrial collaborations or venture capital.

5.  The Group's objectives and goals should be relevant to and
compatible with the NCI's mission in cancer treatment as stated in
this RFA.  Applicants should describe their plans to accommodate the
stated NCNPDDG requirements, criteria, and NCI involvement.

C.  Definitions

ADMINISTRATIVE CORE - An administrative unit located at the Principal
Investigator's institution that coordinates all Group activities. It
is separately budgeted from the P.I.'s laboratory program (if any)
and budgets for activities pertinent to the Group as a whole.

CORE LEADER - The director of  a core component, if any, of the
NCNPDDG, who is responsible for the conduct of that core.

GROUP -  see NATIONAL COOPERATIVE NATURAL PRODUCTS DRUG DISCOVERY
GROUP

LABORATORY PROGRAM - A research component within the NCNPDDG with a
separate, detailed research plan and budget.

NATIONAL COOPERATIVE NATURAL PRODUCTS DRUG DISCOVERY GROUP (NCNPDDG;
Group) - A number of Laboratory Programs representing diverse
scientific disciplines and usually multiple organizations which
consist of a Principal Investigator, Program Leaders, Core Leaders
(if any) and the NCI coordinator which function as a unit with a
common goal: the rational selection, isolation, and evaluation of new
entities from natural sources for treatment of cancer.  In this RFA
the terms National Cooperative Natural Products Drug Discovery Group,
NCNPDDG, and Group are used synonymously.

NATURAL PRODUCT - In the context of the NCNPDDG program, a term used
broadly to encompass any naturally occurring chemical or biological
entity of non-human origin selected and evaluated preclinically
against cancer.  This, of course, excludes materials which are
synthesized de novo by the investigator and also excludes
semi-synthetic derivatives of known antitumor agents.

NCI COORDINATOR - A  scientist from the NCI extramural staff,
appointed by the NCI Program Director after award, who participates
as a member of the Group, interacts scientifically with the Group,
and facilitates the role of NCI as partner in the NCNPDDG.  The NCI
Program Director may also serve as the NCI coordinator for a Group.

NCI PROGRAM DIRECTOR - The senior staff member of the Grants and
Contracts Operations Branch, Developmental Therapeutics Program,
Division of Cancer Treatment, who provides leadership and guidance
for the overall NCNPDDG program within the NCI, maintains overall
scientific balance in the NCNPDDG program, and ensures that the
NCNPDDG program is consistent with the NCI mission for treatment
research.

PROGRAM LEADER - The director of one of the Laboratory Programs of
the NCNPDDG, who is responsible for the scientific conduct of that
program.  The Principal Investigator may also  be one of the Program
Leaders.

SCIENTIFIC CORE  - A separately budgeted scientific service component
which provides essential facilities or services to two or more of the
proposed Laboratory Programs.  Core components typically use
established procedures or protocols rather than generating new
research.

SPECIAL REQUIREMENTS

1.  Since the discovery of new and improved anticancer treatments is
the objective of this effort and active involvement by industrial
laboratories is facilitated by the existence of adequate patent
coverage, it is essential that applicants provide plans to assure
such coverage.  The situation could be complicated since multiple
institutions are likely to be involved.  Each applicant Group must,
therefore, provide a detailed description of the approach to be used
for obtaining patent coverage and for licensing where appropriate, in
particular where the invention may involve investigators from more
than one institution.  Procedures must be described for resolution of
legal problems should they arise.  Your attention is drawn to P.L.
96-517 as amended by P.L. 98-620 and 37 CFR Part 401.  Instructions
were also published in the NIH GUIDE FOR GRANTS AND CONTRACTS, Vol.
19, No. 23, June 22, 1990.  The proposed patent plan among the
institutions comprising the Group must be included as part of the
application.  A formal patent agreement signed and dated by the
organizational official authorized to enter into patent arrangements
for each Group member and member institution must be on file at the
Division of Extramural Activities, NCI prior to peer review.

Note: A formal statement of Patent Agreement among all Group members
and their institutions as well as a detailed description of
procedures to be followed for resolution of legal problems which may
develop, signed and dated by the organizational official authorized
to enter into patent arrangements for each Group member and member
institution is preferred with the application.  If this signed
agreement is not included in the application, it must be submitted to
the Scientific Review Administrator prior to peer review.

2.  Provide from the Principal Investigator and from each Program
Leader a signed statement of acceptance of the provisions outlined
under "NCI Staff Responsibilities" listed below.

3.  A formal statement of agreement is desired with the application,
signed by authorized representatives of all the institutions in the
Group, assuring that an equitable portion of royalties or profits
arising from drugs discovered by the NCNPDDG, if any, will be
returned to indigenous peoples, research collaborators, research
institutions, or Governmental entities as appropriate, in the country
of origin of the natural product sample from which said drug was
derived.  If this signed agreement is not included in the
application, it must be submitted to the Scientific Review
Administrator prior to peer review.

4.  Provide a plan for the development of agents discovered in the
Group that are considered to be worthy of development towards
clinical trials, even though clinical trials and certain advanced
preclinical studies (as described above) are not supported under this
mechanism.

5.  Must have obtained and followed the special instructions for
preparation of applications as described under "Letter of Intent"

The following terms and conditions will be incorporated into the
award statement and provided to the Principal Investigator(s) as well
as the institutional official at the time of award.

A. Terms and Conditions of Award

NOTE:  Non-compliance with any of the Terms of Award pertaining to
awardee responsibilities stipulated in this Section may result in a
reduction of funding, withholding of support, suspension,or
termination of the award.

These special Terms of Award are in addition to, and not in lieu of,
otherwise applicable OMB administrative guidelines, HHS Grant
Administration Regulations at 45 CFR Part 74 and 92, and other HHS,
PHS, and NIH grant administration policy statements.

The administrative and funding instrument used for this program is a
cooperative agreement (U19), an "assistance" mechanism (rather than
an "acquisition" mechanism) in which substantial NCI scientific
and/or programmatic involvement with the awardee is anticipated
during performance of the activity.  Under the cooperative agreement,
the NCI purpose 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 this concept, the dominant role and prime responsibility for the
activity resides 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(s) and the NCI coordinator.

1.  Awardee Rights and Responsibilities

It is the primary responsibility of the Principal Investigator to
state clearly the objectives of the Group, to direct the research
stipulated in the proposal and to ensure that the results obtained
are published in a timely manner.  The Group must define its
objectives and its approaches to attain these objectives in accord
with its own interests and perceptions of novel and exploitable
approaches to the discovery of effective anticancer treatment and
must develop the details of the research design following the
guidance given in this RFA.  It is anticipated that decisions in all
activities will be reached by consensus of the Group under the
leadership of the Principal Investigator and that the NCI Coordinator
will have the opportunity to offer input to this process.

The Principal Investigator, Program Leaders, and NCI Coordinator will
meet periodically to review progress, plan and design research
activities, and establish priorities.  The frequency of meetings (not
fewer than two per year and preferably three or four) will be
determined by the Principal Investigator who will be responsible for
scheduling the time and place (generally at one of the performance
sites or at the NCI).  The application should also include plans for
scheduling Group meetings, notifying Group members, including NCI,
and documenting and disseminating Group meeting proceedings.  NCI
staff may not chair Group meetings.  NCI experience with the Drug
Discovery Group Program has shown that frequency of meetings and
communications within the Group is strongly correlated to Group
success in achieving its goals.  Therefore, additional informal
meetings among all participants as well as regular telephone and
written communication will be important.

a.  The principal end product of NCNPDDG activities will be the
discovery of new agents for development to clinical trial.
Subsequent developmental work through private resources is
encouraged.  Applicants should provide a plan for development of
agents beyond the stage of selection of candidate agents that is the
terminal objective of the NCNPDDG funded research.

NOTE:  It is understood that the Government supports studies in the
interest of promoting the transition of effective, innovative,
therapies to the clinic and that identified therapies that have been
derived via Government support mechanisms will be offered to the
public at reasonable costs.

b.  The Government, via the NCI Coordinator, will have access to data
generated under this Cooperative Agreement and may periodically
review the data.  However, the awardee will retain rights to the data
under these awards subject to Government rights and access consistent
with HHS, PHS, and NIH policies. Timely publication of major findings
by the Group members is encouraged.  Publications or oral
presentation of work done under this agreement will require
appropriate acknowledgement of NCI support.  Dissemination of
information on synthetic or natural substances supplied to the Group
by NCI (e.g., for comparative testing purposes, as reference
materials, etc.) will require clearance by NCI to assure conformity
to existing confidentiality agreements with suppliers.

c.  The ownership of natural product samples acquired during the
course of the research rests with the Group.  The Group should
formulate a policy for final disposition of the samples and ownership
rights in the event that the samples are transferred to other parties
who make discoveries using them.  In order that the samples be fully
evaluated for potential for anticancer activity and anti-AIDS
activity after the Group has concluded its evaluation but before the
samples are transferred to other parties for evaluation in other
therapeutic areas, it is requested that the Group provide lists of
completed samples to the NCI Coordinator, who will arrange for review
of these lists by NCI staff involved in the Developmental
Therapeutics Program's screening for anticancer and anti-AIDS
activity.  Should selected samples be of interest to the NCI, the
Group is requested to provide these to the NCI for evaluation before
release of samples for other purposes.

d.  The NCI recognizes that most countries, and in particular
developing countries, retain interests in samples collected in their
domains.  All applicants who propose foreign collections of natural
products must provide a plan, signed by all Group members, for
equitable return of a portion of any profits or royalties derived
from NCNPDDG discoveries to indigenous peoples, research
collaborators, cooperating institutions, or Governmental entities in
the countries of origin, as appropriate to their contributions.

e.  In order to facilitate Group activities the Principal
Investigator shall prepare minutes of Group meetings within two weeks
after each meeting and distribute copies to all Program Leaders and
the NCI Coordinator.  Such minutes will include a listing of action
items to be carried out by each of the Group members.

2.  NCI Staff Responsibilities

NCI shall participate as a member of the Group and will be
represented by a Coordinator.  The NCI Coordinator will be selected
from the scientific staff that manages extramural programs but not
from the NCI intramural staff.  During performance of the award, NCI
staff may provide appropriate assistance, advice, and guidance by
participating in the design of activities; advising in the selection
of sources for resources, staff, etc.; advising or participating in
management and/or technical performance; and participating in the
preparation of publications.  In all cases, the role of NCI will be
to assist and facilitate and not to direct activities. The dominant
role and prime responsibilities for the activity resides with the
awardee(s) for the project as a whole.

The NCI Coordinator, as well as any other Group member, may assist in
research planning; may suggest studies within the scope of the
Group's objectives and research activities; may present to the Group
experimental findings from published sources or from contract
projects in support of these suggestions; may participate in the
design of experiments agreed to by the Group; and may participate in
the analysis of results. The NCI Program Director or Coordinator will
not conduct Laboratory Programs.

Upon recommendation of the NCI Coordinator, NCI may utilize its drug
development resources in support of Group research activities when
such resources may be required on an occasional basis.  The following
is a list of some resources that might be supplied if they become
desirable during performance, are not anticipated as a continuing
need, and are readily available:

a.  Reference compounds for standardization of test systems, as
analytical standards, and for related purposes.

b.  Needed resources such as test materials and information that may
not otherwise be available to the Group.

c.  Data from testing conducted in resource contract laboratories.

d.  Laboratory testing capacity, whenever appropriate and possible,
in the current contract based preclinical therapy-related laboratory
testing program.  The Group is expected to provide sufficient test
material for such testing.

e.  Searches of computer files of materials, chemical structures and
biological activity, if requests for such searches are sufficiently
focused to avoid excessive costs.  Information given to an NCNPDDG
will be restricted by any standard confidentiality agreements between
the Government and suppliers of test materials to the Government.

f.  Experimental animals and cultured cells, if available, to Groups
whose main research activities do not require these materials on a
regular basis.  Groups whose experimental approach involves studies
that require animals on a regular basis must budget for costs in
their application.

g.  Computer processing and statistical evaluation if costs are not
excessive.

These "Terms and Conditions of Award" require that the NCI Program
Director approve the following: changes in the Principal Investigator
or Program Leaders; reports intended for inclusion in INDAs and
Clinical Brochures; redistribution, outside the NCNPDDG, of
biological and chemical materials received from the Government;
dissemination of research findings resulting from the use of such
materials; and release of funds restricted for use in specific
circumstances or contingencies.

3.  Collaborative Responsibilities

The Group (Principal Investigator, Program Leaders, and NCI
Coordinator) may recommend that development be co-sponsored or fully
sponsored by NCI.  In the latter case, it will be necessary for the
Principal Investigator and NCI Coordinator to cooperate in the
analysis, summarization, preparation, and presentation of data to the
appropriate NCI staff through the Decision Network process.
Co-development with the NCI is encouraged as part of the Government's
assistance in the Cooperative agreement process.

NCI will retain the option to cross-file or independently file an
application for investigational clinical trial (e.g., an
Investigational New Drug Application (INDA) to the United States Food
and Drug Administration) of any invention resulting from these NCI
supported Cooperative Agreements.  Reports of data generated by the
Group or any of its members required for inclusion in INDAs and
Clinical Brochures and for cross-filing purposes will be submitted by
the Principal Investigator to the NCI Coordinator upon request.  Such
reports will include background information, methods, results, and
conclusions.  They will be subject to approval and revision by NCI
and may be augmented with test results from other Government
sponsored projects prior to submission to the appropriate regulatory
agency.

4.  Arbitration

Any disagreements arising on scientific/programmatic matters will be
arbitrated by a panel composed of one Group designee, one NCI
designee, and a third designee with expertise in the relevant area
chosen by the other two.  These special arbitration procedures in no
way affect the awardee's right to appeal an adverse action that is
otherwise appealable in accordance with PHS regulations at 42 CFR
Part 50, Subpart D, and HHS regulations at 45 CFR Part 16.

STUDY POPULATIONS

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 is provided that inclusion is
inappropriate with respect to the health of the subjects or the
purpose of the research. This new policy results from the NIH
Revitalization Act of 1993 (Section 492B of Public Law 103-43) and
supersedes and strengthens the previous policies (Concerning the
Inclusion of Women in Study Populations) which have been in effect
since 1990. The new policy contains some new provisions that are
substantially different from the 1990 policies.

All investigators proposing research involving human subjects should
read the "NIH Guidelines on the Inclusion of Women and Minorities as
Subjects in Clinical Research," which was reprinted in the Federal
Register of March 28, 1994 (59 FR 14508-14513) to correct typesetting
errors in the earlier publication, and reprinted in the NIH GUIDE FOR
GRANTS AND CONTRACTS of March 18, 1994, Volume 23, Number 11.

Investigators may obtain copies from these sources or from the
program staff or contact person listed below.  Program staff may also
provide additional relevant information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by July 15, 1994, a short
letter of intent that includes a descriptive title of the proposed
research, the name, address, and telephone number of the Principal
Investigator, names of other key personnel, the participating
institutions, and the number and title of the RFA to which the
application may be submitted.  Although a letter of intent is not
required, is not binding, and does not enter into the review of
subsequent applications, it is requested in order to provide an
indication of the number and scope of applications to be reviewed.

The letter of intent is to be sent directly to:

Matthew Suffness, Ph.D.
Division of Cancer Treatment
National Cancer Institute
Executive Plaza North, Suite 832
Bethesda, MD  20892
Telephone:  (301) 496-8783
FAX:  (301) 480-4883 or (301) 496-8333

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 9/91) is to be used
in applying.  These forms are available at most institutional offices
of sponsored research; from the Office of Grants Information,
Division of Research Grants, National Institutes of Health, Westwood
Building Room 449, Bethesda, MD 20892, telephone (301) 435-0714.

The RFA label available in the application form PHS-398 must be
affixed to the bottom of the face page.  Failure to use this label
could result in delayed processing of the application such that it
may not reach the review committee in time for review. In addition
the RFA title and number must be typed on line 2a of the face page of
the application and the YES box must be marked.

This RFA requires the submission of a single application for the
proposed NATIONAL COOPERATIVE NATURAL PRODUCTS DRUG DISCOVERY GROUP.
Because of the multi-institutional nature of an NCNPDDG and the
special requirements in this RFA, additional suggestions regarding
format and some modifications are necessary to provide a
comprehensive yet readily reviewable application.  These are found in
the "Special Instructions to Applicants," which must be obtained from
the Program Director listed under INQUIRIES.

Submit a signed, typewritten original of the application, including a
single Checklist, and three signed, exact single sided photocopies in
one package to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892*

At the time of submission, two additional copies of the application
must be sent to:

Ms. Toby Friedberg
Division of Extramural Activities
National Cancer Institute
Executive Plaza North, Room 636
6130 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-3428

The deadline for receipt of applications is  September 20, 1994.
Applications received after this date will be considered as not
responsive to this RFA and will be returned without review.  The
Division of Research Grants (DRG) 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 DRG will not accept any application that is
essentially the same as one that has been reviewed.  This does not
preclude the submission of a substantial revision of an application
already reviewed, but such an application must include an
introduction addressing the previous critique.

REVIEW CONSIDERATIONS

General Considerations

All applications will be judged on the basis of the scientific merit
of the proposed project and the documented ability of the
investigators to meet the Research Objectives of the RFA.  Although
the technical merit of the proposed studies is important, it will not
be the sole criterion for evaluation of applications.  Other
considerations such as the likelihood of identifying candidate
compounds for a clinical trials, will be part of the evaluation
criteria.

Review Method

Upon receipt, applications will be reviewed for completeness by the
DRG and for responsiveness by the NCI.  Incomplete applications will
be returned to the applicant without further consideration.  If NCI
staff find that the application is not responsive to the RFA, it will
be returned 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 Division of Extramural Activities, NCI
in accordance with the review criteria stated below.  As part of the
initial merit review, a process (triage) may be used by the initial
review group in which applications will be determined to be
competitive or non-competitive based on their scientific merit
relative to other applications received in response to the RFA.
Applications judged to be competitive will be discussed and assigned
a priority score.  Applications determined to be non-competitive will
be withdrawn from further consideration and the principal
investigator and the official signing for the applicant institution
will be promptly notified.

Each Laboratory Program will be evaluated on its relevance to the
Group's objectives well as its individual scientific merit.

Review Criteria

Applicants are encouraged to submit and describe their own ideas
about how best to meet the goals of the cooperative study and are
expected to address issues identified under SPECIAL REQUIREMENTS of
the RFA.

1.  Extent to which application addresses the goals and objectives of
the RFA (see RESEARCH OBJECTIVES section) and the probability of
discovery of novel agents for treatment of cancer.

2.  Scientific merit and originality of proposed research.

3.  Adequacy of Group composition relative to proposed objectives in
drug discovery; adequacy of justification for all programs and cores.

4.  Technical merit of proposed methods for selecting and obtaining
natural products and for their evaluation.

5.  Adequacy of the scientific disciplines and specific competencies
represented by the Principal Investigator and Program Leaders;
scientific skills, research experience, competence, commitment, and
time availability of Principal Investigator, Program Leaders, and
other key personnel.

6.  Extent of progress on prior award (RECOMPETING GROUPS only) or
preliminary results (NEW APPLICANTS).

7.  Extent and effectiveness of cooperation with the NCI (recompeting
Groups) and adequacy of plans for cooperation with the NCI in the
event of an award (All applicants).

8.  Administrative experience and competence of Principal
Investigator in the development, implementation, and management of
comprehensive research programs.

9.  Adequacy of plans for effective intra-Group communication and for
assuring Group cohesiveness.

10.  Adequacy and availability of existing physical facilities and
resources of the Principal Investigator and Program Leaders.

11.  Evidence of availability and competence of the applying
institution to serve as the Administrative Core for the Group.

The review group will critically examine the submitted budget and
will recommend an appropriate budget and period of support for each
approved application.

AWARD CRITERIA

Applications recommended by the National Cancer Advisory Board (NCAB)
will be considered for award based on: scientific merit as reflected
in the priority score; programmatic priorities including breast and
prostate cancer research; programmatic balance including balance
between types of natural products to be studied, and types of assays
and cancer targets; and availability of funds.

Letter of Intent Receipt Date:  July 15, 1994
Application Receipt Date:       September 20, 1994
Scientific Review Date:         January/February 1995
NCAB Meeting Date:              May 31-June 2, 1995
Earliest Award Date:            July 1, 1995

INQUIRIES

Written, telephone, and FAX inquiries about this RFA are encouraged.
The opportunity to clarify questions from potential applicants is
welcomed.

Direct inquiries regarding programmatic issues, requests for the
Special Instructions, and address the letter of intent to:

Matthew Suffness, Ph.D.
Division of Cancer Treatment
National Cancer Institute
Executive Plaza North, Room 832
Bethesda, MD  20892
Telephone:  (301) 496-8783
FAX:  (301) 480-4883 or (301) 496-8333

Direct questions on budgets and grants regulations to:

Barbara A. Fisher
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Suite 242
Bethesda, MD  20892
Telephone:  (301) 496-7800 Ext. 229

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance number 93.395, Cancer Treatment Research.  Awards are made
under the authority 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 HHS grants policies.  This program is not
subject to the intergovernmental review requirements of Executive
Order 12372 or Health Systems Agency review.

The Public Health Service strongly encourages all grant recipients to
provide a smoke free workplace and promote the non-use of tobacco
products.  This is consistent with the PHS mission to protect and
advance the physical and mental health of the American people.

.

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