NATIONAL COOPERATIVE DRUG DISCOVERY GROUPS

Release Date:  April 14, 1999

RFA:  CA-99-010 (see reissuance RFA-CA-05-001)

P.T.

National Cancer Institute

Letter of Intent Receipt Date:  June 16, 1999
Application Receipt Date:  July 14, 1999

This RFA is a reissuance of CA-95-020, which was published in the NIH Guide on
September 22, 1995.

PURPOSE

The Developmental Therapeutics Program, Division of Cancer Treatment and
Diagnosis, NCI, invites applications for the continuance of the National
Cooperative Drug Discovery Group (NCDDG) and National Cooperative Natural
Products Drug Discovery Group (NCNPDDG) Programs for the discovery of new and
more effective anticancer treatments.  For this Request for Applications (RFA),
the term NCDDG will apply, whether the products are from natural sources or of
synthetic or biological origin. Applications are sought from both recompeting
NCDDGs and NCNPDDGs as well as from new Groups.

It will support broad, innovative, multidisciplinary, multi-project approaches
to the discovery of new, rationally based or natural-source derived anticancer
treatments or strategies.  A multi-institutional, group approach involving
academic, nonprofit, and/or commercial/industrial institutions is envisioned
because the creative talents in the required scientific disciplines are rarely
available in a single institution.  Although not required, 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 therapies, although these latter activities are not within
the scope of this RFA.  Biological or molecular targets for drug discovery and
the sources and types of natural products to be investigated will be selected by
the applying Group.  Both mechanism of action and disease-oriented approaches are
being solicited.

Subsequent studies required for development of new treatments (e.g., formulation
development, large-scale production for clinical trials, or toxicology in support
of Investigational New Drug Applications, etc.) as well as the clinical trial
itself, are beyond the scope of this RFA.  However, a timely evaluation of
products is encouraged.  The development of analogs of established or well-
studied 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 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 Summary Report: Stock No.  017-001-00473-1) through the
Superintendent of Documents, Government Printing Office, Washington, DC
20402-9325 (telephone 202-512-1800) or at
http://www.crisny.org/health/us/health7.html.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic for-profit and non-profit
organizations, public and private, such as universities, colleges, hospitals,
laboratories, units of State and Local governments, and eligible agencies of the
Federal Government.  Although an NCDDG application may not be submitted by a
foreign institution or an intramural laboratory from the National Institutes of
Health, a foreign institution or an intramural laboratory may participate as a
Laboratory Program or Scientific Core in an NCDDG submitted by a domestic
institution.  All incumbent NCDDG/NCNPDDGs are eligible to apply.  Racial/ethnic
minority individuals, women, and persons with disabilities are encouraged to
participate.

MECHANISM OF SUPPORT

The administrative and funding instrument to be used for support of awards will
be a cooperative agreement (U19), an "assistance" mechanism (rather than an
"acquisition" mechanism) in which substantial NIH scientific and/or programmatic
involvement with the awardee is anticipated during performance of the activity. 
Under the cooperative agreement, the NCI's  role is to support and/or stimulate
the recipient's activity by working jointly with the award recipient as a
partner, but it is not to assume direction, prime responsibility, or a dominant
role in the activity.  Details of the responsibilities, relationships and
governance of the study to be funded under a cooperative agreement are discussed
later in this document under the section "Terms and Conditions of Award."

Assistance via cooperative agreement differs from the research project grant in
that the Government component (NCI) awarding the cooperative agreement
anticipates substantial programmatic involvement during performance of the award. 
This partnership relationship will facilitate technology transfer from
Government-owned data bases and use of appropriate NCI-derived 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.

An award will be made only to the Principal Investigator's (grantee) institution. 
All Group activities will be coordinated through an administrative core located
at the grantee institution.  Individual projects, called Programs, are funded as
consortium projects to the grantee institution if not located at the institution.

The total project period requested for applications submitted in response to the
present RFA may not exceed five years.  The earliest anticipated award date is
April 1, 2000. Because the nature and scope of the research proposed in response
to this RFA may vary, it is anticipated that the size of awards will vary.

The number of awards and the 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 the availability of funds for this purpose.

At this time, the NCI anticipates that there will be periodic recompetition of
this program.  However, if not, awardees may submit renewal grant applications
through the usual investigator-initiated grants program which will be reviewed
according to customary peer review procedures.

FUNDS AVAILABLE

The NCI has budgeted $12 million total costs (direct plus facilities and
administrative costs) for the first year of funding, subject to the availability
of funds.  It is expected that 12 - 14 awards will be made for periods up to five
years.  The number of awards and individual level of support is dependent on the
receipt of a sufficient number and diversity of applications with high scientific
merit.  Program balance and diversity of topics will be factors in selecting
applications for award.

Budget requests should be justified and commensurate with the needs of the
project.  Those in excess of $1.1 million total costs for the first year must be
carefully justified, and the projects must be highly meritorious.  Annual budgets
for years two to five should not exceed the first year budget plus a 3% yearly
increase.  Equipment needs, especially in future years, must be well justified.

RESEARCH OBJECTIVES

Background

Important new findings in molecular biology, cell biology  and related fields,
together with major technological advances, permit the design of highly selective
and specific approaches to discovery of new cancer therapies.  Harnessing these
exciting advances for development of more effective cancer therapy requires the
organization of outstanding scientists from diverse scientific disciplines within
the biological, chemical, and pharmacological sciences into highly synergistic
research teams without regard to institutional affiliation.  To realize this
objective as well as to utilize facilitating resources of NCI's drug development
program within these teams, the NCI acted on advice of a special subcommittee of
the Division of Cancer Treatment's Board of Scientific Counselors and established
the NCDDG program in 1982.  Since that time, Requests for Applications (RFAs)
were issued in July 1983, August 1984, October 1986, August 1987, August 1991,
March 1994, and September 1995.  National Cooperative Natural Products Drug
Discovery Groups were established through an RFA issued in September 1988 and
continued with issuances in October 1989, March 1994 and September 1995, in order
to enhance discovery of novel chemotypes from natural sources for subsequent
development as anticancer agents.  For additional information on the NCDDG
program, visit the web site: http://dtp.nci.nih.gov (under DTP Grants and
Contracts).

NCDDGs are peer-reviewed, multi-component, multidisciplinary  projects focused
on discovery of new approaches for treatment of cancer.  An NIH intramural
laboratory or a foreign institution may participate as a Laboratory Program or
a Scientific Core in an NCDDG submitted by a domestic institution.  NCDDGs are
funded as cooperative agreements which is a mechanism in which the NCI, through
its extramural staff, is an active partner in the Group.  NCI staff, represented
by a Project Coordinator appointed after award, provides advice and guidance in
the area of drug discovery and development and facilitates access to NCI
resources including repositories, chemical searches, and screens.  Resources for
advanced development including scale-up synthesis, pharmacology, toxicology,
Investigational New Drug Applications (INDAs) to the Food and Drug Administration
(FDA), and clinical trials support can be made available through the NCI
(Sausville, E.A, Working with the National Cancer Institute, from: Anticancer
Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval,
edited by: B. Teicher, Humana Press Inc., Totowa, NJ).  Additional information
can be obtained at the DTP web site: http://dtp.nci.nih.gov or the Cancer Therapy
Evaluation Program (CTEP) web site: http://ctep.info.nih.gov.  Extended
preclinical developmental support may be obtained though the Rapid Access to
Intervention Development (RAID) mechanism (http://dtp.nci.nih.gov) or through
private venture capital.

Objectives and Scope

The purpose of this RFA is to encourage the discovery of novel treatments or
strategies to improve the survival of cancer patients.  Groups should utilize
innovative approaches to drug discovery based on recent advances in tumor biology
and the molecular understanding of cancer.  Projects directed at targets and
regulatory pathways specifically altered in tumor cells are encouraged, whereas
approaches based solely on inhibition of cellular proliferation are discouraged. 
Specific approaches may encompass a wide range of topics such as gene therapies,
monoclonal antibodies, and vaccines; biological response modifiers; design of
agents to interfere with transcription factors, signal transduction, cell
adhesion factors, angiogenesis,  hormone or other receptors; and other novel
targets involved in the initiation and/or maintenance of the transformed state
and for which a strong rationale can be provided.  Development and use of new
chemical libraries, structural biology, or computer modeling of receptor targets
should be considered.  Non-mammalian models may be used if appropriate to the
goals of the project.  Applications related to treatment of AIDS-related
malignancies are encouraged.  It should be emphasized that approaches to
realization of the goals of this RFA are broad and limited only by the creativity
and scientific abilities of the applicants.

NCDDGs focused on the discovery and evaluation of new entities from natural
sources should emphasize novelty of the natural product sources and utilize 
molecular target-based screening assays.  Biosynthetic approaches are considered
within the scope of the RFA. The development or use of preclinical models based
on their ability to discriminate for antitumor activity and to test the rationale
for natural product selection and isolation is encouraged.

Programs for collection and screening of natural products extracts or existing
combinatorial libraries without strong rationales for material selection or
testing models, and projects designed to produce analogs of extensively studied
natural products or their derivatives are not responsive to this RFA.  Lead
optimization utilizing modern combinatorial chemistry technology is encouraged. 
If appropriate, Programs could include analysis of new and relevant procedures
to evaluate in vivo efficacy which will facilitate decisions regarding potential
clinical utility.  Approaches could include development of molecular end points
or non-invasive agent imaging for tumor and organ distribution analysis. 
Development and use of assays that can be applied to clinical evaluation
following completion of NCDDG-supported research are especially encouraged.

Funds for projects or cores which depend on the successful completion of other
activities, such as the availability of certain reagents or scale up synthesis,
may be included, but use of such phase-in funds will be restricted and released
only on specific written approval by the NCI.

Definitions:

AWARDEE: The institution to which the NCDDG (U19)is awarded.

BIOLOGICAL RESPONSE MODIFIER.  Agent that alters the relationship between the
tumor and its host by altering the host's response to the tumor cells.

CORE, ADMINISTRATIVE.  An  administrative unit located at the Principal
Investigator's institution that coordinates all Group activities.  It is
separately budgeted from the PI's Laboratory Program (if any) and budgets for
activities pertinent to the Group as a whole, such as travel for intra-Group
meetings.

CORE, SCIENTIFIC.  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. An NIH intramural laboratory may
participate as a Scientific Core.

CORE LEADER.  The director of a scientific core component who is responsible for
the conduct of that core.

DRUG.  In the context of this RFA, a term used broadly to encompass synthetic
agents, natural products  and biological products, as well as novel therapeutic
strategies and inventions designed to treat and cure cancer.  Strategies also
encompass creative methods to maximize antitumor selectivity.

GROUP.  See NCDDG below.

LABORATORY PROGRAM.  A research component headed by a Program Leader within an
NCDDG  with a separate, detailed research plan and budget.  An NIH intramural
laboratory may participate as a Laboratory Program.

NATIONAL COOPERATIVE DRUG DISCOVERY GROUP (NCDDG).  A unit consisting of a
Principal Investigator, Program Leaders, Core Leaders (if any), their respective
programs (at least three laboratory programs), and an NCI Coordinator (from the
NCI extramural staff, appointed after award) which functions as a unit with a
common goal: the conceptualization, invention, and evaluation of new entities and
strategies or rational selection, isolation, and evaluation of new entities from
natural sources for treatment and cure of cancer.  In this RFA, the terms NCDDG
and Group are used synonymously.

NATURAL PRODUCT: In the context of the NCDDG program, a term used broadly to
encompass any naturally occurring chemical or biological entity of non-human
origin selected and evaluated preclinically against cancer.

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

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

PRINCIPAL INVESTIGATOR: The scientist who is designated by the applicant
institution to direct the NCDDG.  The PI will assume responsibility and
accountability to the applicant institution and to the NCI for the performance
and proper conduct of the NCDDG in accordance with the terms and conditions
specified in this RFA. An NIH intramural scientist may not serve as a Principal
Investigator.

PROGRAM LEADER.  A senior scientist with proven independent research capabilities
who serves as director of one of the scientific Laboratory Programs of the Group
and is responsible for the scientific conduct of that program.  The Principal
Investigator of the Group may be a Program Leader. An NIH intramural scientist
may serve as a Program Leader.

SPECIAL REQUIREMENTS

A.  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 NCDDG requirements, criteria, and
NCI involvement.

B.  All proposed Groups must consist of at least three interrelated Laboratory
Programs.  While no maximum number of programs is stipulated, when an award
exceeds five programs the overall Group may become difficult to manage.  Groups
may also have Scientific Cores which provide essential services to two or more
Laboratory Programs, but a core cannot serve as one of the three required
Laboratory Programs.

C.  The Principal Investigator and each Program Leader must provide a signed
statement of acceptance of the participation of NCI staff during performance of
the award as outlined under "NCI Staff Responsibilities" below.

D.  A plan should be described for decision-making regarding identification and
evaluation of promising agents for development.  A plan should be provided for
developmental activities not supported by this RFA but required for introduction
of an agent into clinical trial.

E.  For projects involving natural products, a plan for lead optimization should
be included when appropriate.

F.  Pharmaceutical partners should include key personnel who have authority
within the company to allocate resources to ensure successful completion of the
proposed discovery and development efforts.

G.  PATENT COVERAGE:  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.

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, must be developed.  The signed agreement
must be submitted prior to award to Dr. George S. Johnson at the address provided
under INQUIRIES.

For  applications involving natural products, a formal statement of agreement
must be provided signed by authorized representatives of all institutions in the
Group, assuring that an equitable portion of royalties or profits arising from
drugs discovered, 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 the drug was
derived.  The signed document must be submitted prior to award to Dr. George S.
Johnson at the address provided under INQUIRIES.

A plan must be developed for disposition of natural products samples,
combinatorial libraries, etc., in conformance with TERMS AND CONDITIONS OF AWARD,
Item 1.C, listed below.  The signed document must be submitted prior to award to
Dr. George S. Johnson at the address provided under INQUIRIES.

The three documents listed above will be considered confidential and will not be
included with review material.  Awards will not be made until they are received
and approved by NCI.

H.  An NIH intramural scientist (IMS) may not serve as the Principal Investigator
of an NCDDG but may participate in a Group as a Program Leader, Scientific Core
Leader, collaborator, or consultant.  However, an IMS may not receive salary,
equipment, supplies, or other remuneration from this RFA.  The IMS must obtain
approval of his/her NIH Institute Scientific Director to allocate resources to
the project.  This letter must specify that no more than $500,000 direct costs
of intramural resources will be allocated to the project and provide assurance
that the conduct of the project will comply with the DHHS regulations for
research involving human subjects (if applicable)  and with the PHS policy of
vertebrate animal research. The participation of an intramural scientist is
independent of and unrelated to the role of the NCI Program Official and
Coordinator as described below in TERMS AND CONDITIONS OF AWARD. For NCDDG
applications which include NIH intramural components, the intramural resource
level will be accounted for in the total cost of the overall application.

TERMS AND CONDITIONS OF AWARD

The following terms and conditions will be incorporated into the award statement
and provided to the Principal Investigator as well as the institutional official
at the time of award.  Failure to abide by any of the Terms and Conditions 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 and Conditions of Award are in addition to and not in lieu
of otherwise applicable OMB administrative guidelines, DHHS Grant Administration
Regulations at 45 CFR parts 74 and 92, and other DHHS, 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 NIH scientific and/or programmatic involvement
with the awardee is anticipated during performance of the activity.  To qualify
as an NCDDG, the overall program must include a minimum of three laboratory
programs.  Under the cooperative agreement, the NIH 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 between the awardee and the
NCI Coordinator.

1.  Awardee Rights and Responsibilities

a.  The Principal Investigator will have primary authority and responsibility to
define objectives and approaches and to plan and  conduct the proposed research. 
She/he will assume responsibility  and accountability to the applicant
organization and to the NCI for performance and proper conduct of the research
supported in the NCDDG, including the NIH intramural component, if applicable,
in accordance with the TERMS AND CONDITIONS OF AWARD.

b.  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,
will be determined by the Principal Investigator who will be responsible for
scheduling the time and place (generally at one of the performance sites) and for
preparing concise proceedings or minutes (two or three pages) which will be
delivered to the members of the Group within 60 days of the meeting.  NCI
Coordinator or Program Official may not chair Group meetings.

c.  The Government, via the NCI Coordinator, will have access to data generated
under this cooperative agreement and may periodically review the data consistent
with current DHHS, PHS, and NIH policies.  However, the awardee will retain
primary custody of and have primary rights to data, and timely publication of
major findings by the Group members is encouraged.  Publication or oral
presentation of work done under this agreement will require appropriate
acknowledgment of NCI support, including the assigned cooperative agreement award
number.  Dissemination of information on synthetic or natural substances supplied
to the Group by NCI (e.g., for comparative testing purposes, as reference
material, etc.) will require clearance by NCI to assure conformity with existing
confidentiality agreements with suppliers.

d.  Ownership of natural product samples and combinatorial libraries acquired
during the course of the research rests with the Group.  Prior to award the Group
must 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.

e.  In order that samples be fully evaluated for anticancer potential 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 may
facilitate additional biological evaluation in NCI's contract-based screening
facilities or at an additional testing resource of mutual agreement to NCI and
the Group.

f.  The NCI recognizes that most countries retain interest in samples collected
within their domains.  All applicants who propose foreign collections of natural
products must provide a formal statement of agreement to NCI prior to award,
signed by authorized representatives of all Group member institutions, for
equitable return of a portion of any profits or royalties derived from NCDDG
discoveries to indigenous peoples, research collaborators, cooperating
institutions or Governmental entities in the countries of origin, as appropriate
to their contributions.

g.  Foreign trips for collection purposes must be itemized separately.  These
funds will be restricted by NCI and require prior approval for release.  Written
approval for release of funds will be granted only after appropriate clearance
documentation from the source country is provided.

2.  NCI Staff Responsibilities

NCI will participate as a member of the Group and will be represented by a
Coordinator.  The NCI Coordinator will be selected after award by the NCI Program
Official for the NCDDG Program from the extramural but not intramural staff. 
During performance of the award, NCI may provide appropriate assistance by
participating in the design of activities; advising in the selection of sources
for resources, staff, etc.; and advising in management and technical performance. 
In all cases, the role of NCI will be to assist and facilitate and not to direct
activities.

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.  However, the NCI Coordinator will not
conduct laboratory studies.

Upon recommendation of the NCI Coordinator, NCI may utilize its drug development
resources (http://www.dtp.nci.nih.gov) in support of Group research activities
when such resources may be required on an occasional basis.  The following is a
list of resources that may 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 a Group 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 these costs in their application.

These "Terms and Conditions of Award" require that the NCI Program Official
approve the following: changes in the Principal Investigator or Program Leaders;
reports intended for inclusion in Investigational New Drug Applications (INDAs)
and Clinical Brochures; redistribution, outside the NCDDG, of  biological and
chemical materials received from the Government; and dissemination of  research
findings resulting from the use of such materials.

3.  Collaborative Responsibilities

The following Collaborative Responsibilities are based on the premise that the
NCDDG is a unit consisting of a Principal Investigator, Program Leaders, Core
Leaders, and their respective programs, and an NCI Coordinator (appointed from
the NCI extramural staff after the award) which functions as a unit as specified
in this RFA.  Foreign institutions and NIH intramural laboratories may be
participants as Programs or Scientific Cores but not as the awardee institution,
and their scientists may not serve as the Principal Investigator.

a.  The principal end product of NCDDG activities will be the discovery of new
entities and strategies for development to clinical trial.  Subsequent
developmental work through private resources is encouraged.  Alternatively, the
Group may recommend that development be 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.

b.  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 shall be submitted promptly by
the Principal Investigator to the NCI Coordinator upon request.  Such reports
shall 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 disagreement that may arise on scientific/programmatic matters (within the
scope of the award, including the NIH intramural component), between the awardee
and the NCI may be brought to arbitration.  An arbitration panel will be composed
of three members: one Group designee, one NCI designee, and a third designee with
expertise in the relevant area chosen by the other two.  This special arbitration
procedure in no way affects 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 DHHS regulations at 45 CFR Part 16.

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 on the Inclusion of Women and Minorities as Subjects in Clinical
Research," which was published in the Federal Register of March 28, 1994 (59 FR
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 clear and compelling 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.

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

LETTER OF INTENT

Prospective applicants are asked to submit, by June 16, 1999, a letter of intent
that includes a descriptive title of the overall proposed research; the name,
address, telephone number, and institution of the Principal Investigator; names
of prospective Program Leaders, other key investigators, and their respective
participating institutions; title and Program Leader for each Group Program; and
the number and title of the RFA in response to which the application may be
submitted.

Although the letter of intent is not required, is not binding, and is not a
factor in the peer review of the application, the information it contains is
helpful in planning for the review of applications.  It allows NCI staff to
estimate the potential review workload and to avoid conflict of interest in the
review process.

The letter of intent is to be sent to Dr. George S. Johnson at the address listed
under INQUIRIES.

APPLICATION PROCEDURES

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

This RFA requires the submission of a single application.  Because of the multi-
disciplinary and likely multi-institutional nature of an NCDDG and the special
requirements in this RFA, additional written instructions regarding format, which
are incorporated by reference as if fully set forth herein, are available at
http://dtp.nci.nih.gov  (under DTP Grants and Contracts) or from Dr. George S.
Johnson (see INQUIRIES below).  Potential applicants are urged to obtain the
"Special Instructions to Applicants for Preparation of NCDDG Applications" to
avoid omitting essential information and to expedite review.  If required
information is not contained within the application, the application will be
returned without review.

On line 2 of the face page of the application form, the YES box must be marked,
the Number should be listed as RFA CA-99-010 and the Title must be given as
"National Cooperative Drug Discovery Groups"; personalized titles more fitting
for the application should be listed on line 1.

The RFA label available in the PHS 398 (rev. 4/98) application form 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 with the result that
it may not reach the review committee in time for review.

The following special instructions must be followed when NIH intramural
laboratories serve as a Laboratory Program or Scientific Core.  Application
procedures specified in the PHS 398 form must be followed. The Principal
Investigator of the NCDDG must incorporate into the application, in the usual
grant format, a full description of the project, including technical details and
methodology.  The budget pages should supply the time and effort for each
intramural program participant, but no other budget information should be
provided.  A letter of approval from the Scientific Director must be provided
which specifies that not more than $500,000 direct costs of intramural resources
will be allocated to the project, and provide assurance that the conduct of the
project will comply with the DHHS regulations for research involving human
subjects (if applicable) and with the PHS policy of vertebrate animal research.

The Principal Investigator must submit a signed, typewritten original 
application, including NIH intramural laboratory component, if applicable, the
Checklist, and three signed photocopies, in one package to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD  20817 (for express/courier service)

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

Ms.Toby Friedberg
Division of Extramural Activities
National Cancer Institute
6130 Executive Boulevard, Room 636 - MSC 7407
Bethesda, MD 20892-7407
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 496-3428

Applications must be received by July 14, 1999.  If an application is received
after that 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 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 documented ability of the investigators to meet the RESEARCH
OBJECTIVES of the RFA.  Although the technical merit of the proposed studies is
important, the likelihood of identifying a clinical trial candidate and the plan
for pre-clinical development activities beyond the scope of the RFA will be part
of the evaluation.

Review Method

Upon receipt, applications will be reviewed for completeness by CSR and
responsiveness by NCI.  Incomplete applications will be returned to the applicant
without further consideration.  If NCI staff finds 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 NCI in accordance with the review criteria stated below.  As part of the
initial merit review, all applicants will receive a written critique and may
undergo a process in which only those applications deemed to have the highest
scientific merit generally the top half of the applications will be discussed,
assigned a priority score, and receive a second level review by the National
Cancer Advisory Board (NCAB).

Review Criteria

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  Within
this framework the specific goal of this RFA is the discovery and pre-clinical
analysis of new agents to treat cancer.  The reviewers will address the following
criteria in assigning priority scores, weighting them as appropriate for each
application.  Individual Programs and Cores within the NCDDG ,as well as the
NCDDG as a whole, will be evaluated.  Note that each Program within the NCDDG
does not need to be strong in all categories as long as it contributes a
necessary function to the goals of the Group.

Review Criteria for NCDDG as a Whole

Significance.  Does the study address an important problem? If the aims of the
application are achieved, what is the likelihood of a new cancer therapy or
strategy for clinical evaluation?  Is the development plan adequate to bring the
agent to clinical trial?

Approach.  Are the conceptual framework, design, methods, and analyses adequately
developed, well-integrated, and appropriate?  Are the scientific disciplines
represented in Programs and Scientific Cores adequate to achieve Group
objectives?  Does the applicant acknowledge potential problem areas and consider
alternate tactics? Are targets and screens relevant to the neoplastic process? 
Are plans adequate for ensuring effective intra-Group communication and for
assuring Group cohesiveness?  Is the plan  to optimize lead structures, from both
synthetic and natural sources, adequate to ensure that the most efficacious drug
will result?  Are plans for decision-making regarding identification and pursuit
of lead candidates reasonable and appropriate?

Innovation.  Does the NCDDG employ novel concepts, approaches, or methods?  Are
the aims original and innovative?  Does the NCDDG challenge existing paradigms
or develop new methodologies or technologies?  Is the target under investigation
for drug discovery novel?  Will new paradigms for drug discovery emerge?

Investigators.  Are the Principal Investigator and Program/Core Leaders
appropriately trained and well suited to carry out this work?  Is the time
commitment for each sufficient to achieve goals?  Has the Principal Investigator
demonstrated leadership in development, implementation and management of
comprehensive research programs?

Environment.  Does the scientific environment in which the Programs will be done
contribute to the probability of success?  Do the proposed experiments take
advantage of unique features of the scientific expertise and foster effective
collaborations?  Is there evidence of institutional support and competence of the
applying Institution to serve as the Administrative Core for the Group?

Review Criteria for Programs

Significance: Does this study address an important problem?  If the aims 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?

Approach: Are the conceptual framework, design, methods, and analyses adequately
developed, well-integrated, and appropriate to the aims of the program?  Does the
applicant acknowledge potential problem areas and consider alternative tactics?

Innovation: Does the Program employ novel concepts, approaches or methods?  Are
the aims original and innovative?  Does the Program challenge existing paradigms
or develop new methodologies or technologies?

Investigators: Is the Program Leader appropriately trained and well suited to
carry out this work?  Is the work proposed appropriate to the experience level
of the project leader and other researchers (if any)?

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?

Review Criteria for Cores

The utility of the Core to the NCDDG.  Each Core must provide essential
facilities or services for two or more programs judged to have substantial merit.

The quality of the facilities or services provided by the Core.

The qualifications, experience, and commitment of the personnel involved in the
Core.

Additional Considerations.  Each application will be evaluated for the extent of
progress on prior award (RECOMPETING GROUPS) or preliminary results (NEW
APPLICANTS).  Groups will be evaluated  for extent of effectiveness of
cooperation with the NCI (RECOMPETING GROUPS) and adequacy of plans for
cooperation with the NCI (ALL APPLICANTS).

The review group will critically examine: the budget requested for each program,
core and overall NCDDG and will recommend an appropriate budget and period of
support for each approved application; adequacy of plans to include both genders,
children, and minorities and their subgroups as appropriate for the scientific
goals of the research and plans for recruitment and retention of subjects;
provisions for protection of human and animal subjects; and the safety of the
research environment.

AWARD CRITERIA

Applications recommended by the NCAB will be considered for award based on
scientific merit as reflected in the priority score; on programmatic priorities
and relevance; on program balance; and on funds available.  The following
schedule will be followed:

Schedule

Letter of Intent Receipt Date:  June 16,1999
Application Receipt Date:       July 14, 1999
NCAB Meeting Date:              January/February 2000
Earliest Award Date:            April 1, 2000

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged. The
opportunity to clarify any issues or questions from potential applicants is
welcome.

Direct inquiries regarding programmatic issues and for a copy of the "Special
Instructions to Applicants" on application format to:

George S. Johnson, Ph.D.
Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Boulevard, Suite 841, MSC 7456
Bethesda, MD  20892-7456
Rockville, MD  20852-7456 (for express/courier service)
Telephone:  (301) 496-8783
FAX: (301) 402-5200
Email: johnsong@exchange.nih gov

For specific information related to chemistry or structural biology contact Dr.
John Biesler, or related to natural products research contact Dr. Yali Hallock,
at the same address and telephone number.

Direct inquiries regarding fiscal matters to:

Ms. Priscilla Grant
Grants Administration Branch
National Cancer Institute
6120 Executive Boulevard, Room 243, MSC-7150
Bethesda, MD  20892-7150
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 496-7800, Ext. 245
FAX:  (301) 496-8601
Email:  pg38h@nih.gov

Direct inquiries regarding review issues to:

Ms. Toby Friedberg
Division of Extramural Activities
National Cancer Institute
6130 Executive Boulevard, Room 636, MSC 7407
Bethesda, MD  20892-7407
Rockville, MD 20852-7407 (for express/courier service)
Telephone:  (301) 496-3428
FAX:  (301) 402-0275
Email:  tf12w@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No. 
93.395, Cancer Treatment Research.  Awards are made under authorization of the
Sections 301 and 405 of the Public Health Service Act, as amended ( 42 USC 241
and 284) and administered under PHS grants policies and Federal Regulations 42
CFR Parts 52 and 45 CFR Parts 74 and 92. 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 all tobacco products. In
addition, Public Law 103-227, The Pro-Children Act of 1994, prohibits smoking in
certain facilities (or in some case, 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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