Full Text PAR-97-080
NIH GUIDE, Volume 26, Number 24, July 25, 1997
PA NUMBER:  PAR-97-080
P.T. 34


National Institute of Allergy and Infectious Diseases
National Institute of Mental Health
Application Receipt Date:  November 12
The Division of AIDS (DAIDS), National Institute of Allergy and
Infectious Diseases (NIAID), invites applications for the discovery,
preclinical evaluation, development, and/or pilot clinical study of
novel agents and strategies to suppress HIV replication, interfere
with disease progression, and ameliorate the consequences of
infection. The National Institute of Mental Health invites
applications to identify and treat the nervous system complications
of HIV infection that result in CNS dysfunction.  The Integrated
Preclinical/Clinical Program (IPCP) described in this Program
Announcement (PA) combines applications for the National Cooperative
Drug Discovery Groups for the Treatment of HIV Infection (NCDDG-HIV),
which supports preclinical discovery of new therapeutics;
applications from collaborative Groups seeking to transition from
preclinical to clinical studies during the award period; and
applications for the Strategic Program for Innovative Research on
AIDS Treatment (SPIRAT), which supports pilot clinical studies of
novel treatments.  By combining these into a single PA, the IPCP will
provide a continuous spectrum of research opportunities to Groups
interested in the discovery and development of new therapies for HIV
infection.  This PA is designed for multi-disciplinary preclinical
and clinical research Groups, each consisting of a minimum of three
interrelated projects, in which the participation of the private
sector is strongly encouraged.  Responsive applications will involve
creative and original therapeutic research that emphasizes diverse
facets of HIV infection.  Excluded from this PA are targets and
approaches already under extensive investigation by academia and the
pharmaceutical sector, non-targeted random screening of potential
inhibitors, and research on AIDS-associated opportunistic pathogens
and malignancies.
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 PA,
Novel HIV Therapies: Integrated Preclinical/Clinical Program, is
related to the priority area of HIV infection.  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).
Applications may be submitted by domestic for-profit and non-profit
organizations, public and private institutions such as universities,
colleges, hospitals, units of state and local governments, and
eligible agencies of the federal government.  While foreign
organizations are not eligible to apply as the principal institution,
foreign components may apply as a research project or core.  However,
these components will not receive support for indirect costs.
Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators
The administrative and funding mechanism will be the program project
grant (P01).  Program project grants support broadly-based,
multidisciplinary research programs that have a well-defined, central
research focus or objective.  An important feature is that the
interrelationships of the individual scientifically meritorious
projects will result in a greater contribution to the overall program
goals than if each project were pursued individually.  The program
project grant consists of a minimum of three interrelated individual
research projects that contribute to the program objective.  This
type of award can also provide support for certain shared  resources
termed cores that provide funds for tasks common to two or more
projects within the award.  To increase the diversity and
multi-faceted expertise in any Group, each project will be from a
different academic department (if  from the same  institution) and/or
from a different company.  Responsibility for the planning,
direction, and execution of the proposed research will be that of the
Research groups supported by the IPCP include: (1) Groups focusing
exclusively on preclinical discovery and development of novel
therapeutic entities and strategies; and (2) Groups positioned to
implement a proposed pilot clinical study during the award period.
The suggested maximum budget for a Group engaged in preclinical
research is $675,000 total (direct plus indirect) cost for the first
year; larger budgets must be strongly justified.  The maximum budget
for a Group actively engaged in clinical studies is $1.4 million
total (direct plus indirect) cost for the first year.  Groups
proposing a clinical phase during the award period should submit a
complete budget for both the preclinical and clinical portions of the
study using the preclinical and clinical limits set above.
It is noted that the level of support for clinical research under
this PA may well be insufficient to provide all the funds necessary
to conduct the proposed clinical study.  Prospective Groups should,
therefore, develop plans to use existing infrastructure and
organizational support to complement the award [including NIH
sponsored General Clinical Research Centers (GCRC) and Centers for
AIDS Research (CFAR)].  The total project period for any Group is
four years.  Awards pursuant to this PA are contingent upon the
availability of funds for this purpose.
Research advances in recent years have yielded a wealth of
information on HIV molecular biology, the pathogenesis of HIV
disease, and the impact of disease progression on immune function.
Concomitantly, seminal technological advances have been realized.
Together, these advances offer exciting opportunities to develop and
translate new therapeutic concepts to clinical application and
complement current FDA approved therapies. To assist in assembling
the diverse scientific expertise and ancillary resources needed to
translate basic discoveries to applied entities, this PA is designed
to support multi-disciplinary preclinical and clinical research
Groups.  The objective of the Integrated Preclinical/Clinical Program
is thus two-fold: (1) to maintain a strong and diverse base in
preclinical discovery and development of new therapeutics; and (2)
to support the translation of innovative treatment concepts from
preclinical studies to pilot clinical proof-of-concept studies. The
NIMH will consider co-support of NIAID-supported applications when a
component of the research is directed toward understanding and
treating the nervous system disease.
Scope of Research
As stated above, the ultimate goal of this PA is the discovery,
development, and exploratory clinical evaluation of new and effective
therapeutic approaches for the treatment of HIV disease and
prevention of HIV sexual transmission.  Such research is expected to
yield long term therapeutic returns as well as identify and open new
research directions.  In line with this objective, the PA will
support diverse and creative strategies of sound scientific rationale
that are new or under-studied and provide a continuous spectrum of
research opportunities from preclinical to pilot clinical studies.
This comprehensive effort will be conducted by interdisciplinary
research Groups.
Examples of preclinical and clinical research supported under the
IPCP include:
1.  development of under-explored/new antiviral therapies that target
viral and host proteins known to be critic
2.  development of entities and strategies that target cells and
tissues implicated in virus sequestration;
3.  development of entities or strategies to render the immune
'environment of HIV-1 infected individuals receptive to
reconstitution by hematopoietic stem cells or lymphoid cells/tissue;
4.  translation of innovative therapeutic and immunotherapeutic
strategies to multi-dimensional treatment regimens that address the
many facets of HIV disease;
5.  identification of molecular and cellular mechanisms underlying
HIV-associated CNS dysfunction and development of targeted
6.  identification and development of effective inhibitors of sexual
The involvement of the private sector is strongly encouraged because
of this sector's unique infrastructure and capital resources,
allowing rapid mobilization for the development of lead therapeutics.
Preclinical Research
The preclinical portion of the IPCP supports the discovery and
development of a specific therapeutic approach or strategy in a
concerted manner with obvious contribution by and need for each
project and core to the overall Group objective and development plan.
A successful preclinical Group should develop a new therapeutic
strategy that can subsequently be translated to clinical evaluation.
Preclinical Groups seeking to transition from preclinical to clinical
research during the award period must detail the goals and milestones
by which they will reach this point.  These goals and milestones
should include plans and timetable to obtain the required
institutional and government approvals (IRB, FDA, RAC).  These goals
and milestones will be reviewed by the Scientific Peer Review Group
(SPRG) and will subsequently be used to determine the successful
completion of the preclinical development phase.  Release of funds
for clinical research will be contingent upon the documented
successful completion of the proposed and peer-reviewed goals and
Clinical Studies
The clinical portion of the IPCP supports interdependent, iterative
clinical/laboratory research designed to evaluate and optimize a
clinical therapeutic approach.  Relative to the preclinical portion
of the IPCP, human subjects concerns and regulatory issues
substantially increase under the clinical phase.  These safety and
clinical proof-of-concept studies of innovative therapeutic
strategies may involve greater scientific risk than that practiced in
larger clinical trials.  A successful Group will develop and optimize
a therapeutic strategy to a point at which it can be determined
whether the strategy merits further clinical evaluation.
The clinical study application must be based on a strategy in an
advanced stage of preclinical development that is suitable for
evaluation in a small number (6-12) of patients.  The application
should include (1) a detailed plan of the iterative clinical and
laboratory research to be conducted to optimize the proposed
strategy; (2) a timetable to be followed; (3) plans for the clinical
studies including the clinical protocol; and (4) institutional and
government approvals (IRB, FDA, RAC).
All awardees are strongly encouraged to attend a scientific
conference  of  IPCP investigators, organized by NIAID and held every
12-18 months in the Washington DC vicinity.  Applicants should
include requests for travel funds in the original applications
specific for and restricted to the above meetings. No additional
travel funds will be provided to attend other domestic or foreign
Patent Coverage
Since an application may include several institutions, including the
private sector, complex patent situations may arise.  To avoid delays
related to intellectual property issues in implementing new therapies
for HIV, each multi-project Group is required to provide a plan as
part of the application, detailing (1) the approach, agreed to by all
parties, to be used for obtaining patent coverage and for licensing,
where appropriate; and (2) the procedures to be followed for the
resolution of  legal problems that potentially may develop.
Attention is drawn to the reporting requirements of 35 U.S.C. Parts
200-212 and 37 CFR Part 401 or FAR 55.227-11.  Instructions were also
published in the NIH GUIDE FOR GRANTS AND CONTRACTS, Vol. 19, No. 23,
June 22, 1990.  Note that non-profit organizations (including
universities) and small business firms retain the rights to any
patent resulting from Government  grants or cooperative agreements.
It is also noted that a Presidential memorandum of February 18, 1983
extended to all business concerns, regardless of size, the first
option to the ownership of rights to inventions as provided in P.L.
96-517.  As a result of this memorandum, the relationships among
industrial organizations and other participants are simplified, since
all Group members can now be full partners in the research and in any
inventions resulting therefrom.  The specific patenting arrangements
among the institutions may vary and could include joint patent
ownership, exclusive licensing arrangements, etc.  Applicants are
encouraged to develop an arrangement that is most suitable for the
Group's particular circumstances.
The patent agreement among the institutions comprising the Group,
signed and dated by the organizational officials authorized to enter
into patent arrangements for each Group member and member
institution, must be submitted with the application, and a copy
submitted to Dr. Nava Sarver (address under INQUIRIES). If the Group
wishes to place all inventions and discoveries resulting from these
studies within the public domain, a letter to that effect must be
submitted to Dr. Sarver in lieu of the patent agreement .  The letter
must be co-signed by the Principal Investigator, each of the Project
Leaders, and each of the business officials representing the
respective institutions.
Federal regulation clause 37-CFR-401 and HHS Inventions regulations
at 45 CFR Parts 6 and 8 require that NIH be informed of inventions
and licensing occurring under NIH funded research.  Invention and
licensing reports must be submitted to the Extramural Invention
Reports Office at (301) 435-1986.
For awards including clinical studies
Groups seeking to transition from preclinical to clinical studies
during the award period must include a long-range development plan
that details the preclinical, transitional, and clinical phases of
the proposed studies and a budget appropriate to each phase.  Funds
to accommodate the potentially more costly clinical study should be
budgeted in the application. The Group must articulate a set of
objectives and milestones to be completed prior to the transition to
clinical research and include the clinical site and clinical
investigators to be involved.  For purposes of peer review, the
application must include a clinical protocol  based on research
findings available at the time of submission (although it is
understood that the protocol may change as work progresses).   All
the above components - the development plan,  objectives and
milestones, clinical site and clinical investigators -  will be
essential elements of the initial review by the SPRG.  The NIAID
(NIMH) will review requests to transition to clinical research and
will use outside expertise to review the revised clinical protocol
and budget and to assist in determining whether the Group requesting
transition is positioned to proceed to clinical studies.
Release of funds for clinical research will be contingent on
successful accomplishment of milestones and criteria stated in the
original application, reviewed and approved by the SPRG, and include
compliance with all applicable laws and regulations. To initiate
clinical studies, an awardee must have IRB, FDA and RAC (if
applicable) approvals.  Funds for clinical studies will be withheld
until the required approvals are obtained and copies provided to
NIAID (Dr. Nava Sarver, address under INQUIRIES).  Additional details
for applications including a clinical component are listed under
'Special requirements', below.
The Principal Investigator is responsible for:
1.  assuming responsibility for developing protocols and monitoring
study performance, participant recruitment and follow-up, interim
data and safety monitoring. All proposed protocols will be submitted
by the Principal Investigator to the NIAID (Dr. Nava Sarver, address
below) for review for safety issues by the DAIDS Clinical Science
Review Committee (CSRC). The Principal Investigator will be
responsible for reporting recruitment, retention, and adverse events
2.  establishing procedures to comply with FDA regulations for
studies involving investigational agents and strategies and to comply
with the requirements of 45 CFR Part 46 for the protection of human
subjects. Terms of award for any human clinical trial component will
be developed to ensure volunteer safety and monitoring of compliance
with regulations and Good Clinical Practices. NIAID staff will
provide guidance and technical advice on meeting FDA requirements for
investigational substances.
It is the policy of the NIH that women and members of minority groups
and their sub-populations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research. This policy results from the
NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43).
All investigators proposing research involving human subjects should
read the "NIH Guidelines For Inclusion of Women and Minorities as
Subjects in Clinical Research," which have been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513), and the NIH
Guide for Grants and Contracts, Vol. 23, No. 11., March 18, 1994.
Applications are to be submitted on the grant application form PHS
398 (rev. 5/95) and will be accepted on the application deadlines of
November 12, 1997, November 1998, and November 1999.  Applications
kits 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
301/710-0267, email:  ASKNIH@odrockm1.od.nih.gov.  Applications may
also be obtained electronically via the WWW
For purposes of identification and processing of the application,
mark "YES" in item 2 on the face page and enter the PA number
PAR-97-080 and the title "Novel HIV Therapies: Integrated
Preclinical/Clinical Program".
The signed, completed, typewritten original of the application (plus
the Checklist) and three single-sided copies must be sent to:
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)
At the same time, two single-sided copies of the application and five
sets of appendices must be sent to Dr. Dianne Tingley at the address
listed under INQUIRIES.
NIH Policy Update on Acceptance for Review of Unsolicited
Applications that Request More Than $500,000 Direct Cost for Any One
Year applies to applications in response to this PA. The Policy
Update was published in the NIH Guide for Grants and Contracts, Vol.
25, No. 14, May 3, 1996, and became effective June 1, 1996.  NIAID
has policies that require pre-approval by the Institute before
acceptance of Program Project applications and applications that
request $500,000 or more in annual direct costs and guidelines for
preparation of multi-project (including P01) research grant
applications outlined in the NIAID Multiproject Instructions
Brochure.  Potential applicants must contact Dr. Sarver, at the
address listed under INQUIRIES, to initiate clearance processes for
acceptance of their applications and to obtain guidelines for the
preparation of P01 applications.  The NIAID Multiproject Instructions
Brochure is also available via the WWW
APPLICATION. Current NIH policy permits a component research project
of a multi-project P01 grant application to be concurrently submitted
as a traditional individual research project (R01) application. If,
following review, both the multi-project P01 application and the R01
application are found to be in the fundable range, the investigator
must relinquish the R01 and will not have the option to withdraw from
the multi-project P01 grant. This is an NIH policy intended to
preserve the scientific integrity of a multi-project grant, which may
be seriously compromised if a strong component project(s) is removed
from the program. Investigators wishing to participate in a
multi-project grant must be aware of this policy before making a
commitment to the Principal Investigator and awarding institution.
Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the Center as a resource for
conducting the proposed clinical research. If so, a letter of
agreement from the GCRC Program Director must be included in the
application material.
Upon receipt, applications will be reviewed for completeness by the
Division of Research Grants.  Incomplete applications will be
returned to the applicant without further consideration.
Applications will be evaluated for scientific and technical merit by
an NIAID ad hoc peer review Group convened in accordance with
standard NIH review procedures.  As part of the initial merit review,
all applications will receive a written review and may undergo a
process in which only those applications deemed to have the highest
scientific merit will be assigned a priority score and receive a
second level review by the NIAID Council.  Applications determined to
be non-competitive will be withdrawn from further consideration, and
the Principal Investigator and the official signing for the applicant
organization will be notified.
Review criteria are based on the objectives and goals of the IPCP.
The SPRG will evaluate applications for impact, approach, and
feasibility using the standard NIH review criteria , and additional
review criteria specific to this initiative and specific to either
preclinical or clinical studies, as follows:
IMPACT:  The extent to which the project, if successfully completed,
will make an original and important contribution to biomedical
science.  Specifically:
A.  The scientific, technical or medical significance, and
originality of the project.
B.  The likelihood that, if successfully executed, this  research
will open a new direction in the treatment of HIV infection ( e.g.,
the innovativeness and uniqueness of the proposed strategy),
demonstrate a capacity to be reduced to clinical practice, or merit
evaluation in clinical studies for safety and proof-of-concept.
C.  For previously funded preclinical Groups (NCDDG-HIV): evidence of
significant progress in the previous award (e.g. design, formulation,
or development of therapeutic entities/strategies that merit clinical
D.  For previously funded clinical (SPIRAT) Groups: demonstrate that
the concept proposed is new,  substantially improved, or represents a
new direction from that evaluated in the preceding funding period.
APPROACH:  the extent to which the conceptual framework, design
(including selection of appropriate subject populations or animal
models), methods, and analyses are properly developed, well
integrated, and appropriate to the objectives of the project.
A.  appropriateness and adequacy of the experimental approach, the
development plan, and the methodology proposed to carry out the
research, including laboratory capabilities (preclinical and/or
clinical) in immunology, virology, and cell biology; assays to detect
changes in parameters related to HIV infection based on
state-of-the-art methods.
B.  scientific and technical merit of the approach as a whole, and
the relationship and contribution of each project and core to the
central focus of the overall program.
C.  cohesiveness, multi-disciplinary and multifaceted scope of the
program and the coordination and interdependence of the individual
projects and core(s); plans for effective intra-Group communication.
D.  For Groups focusing on preclinical research: choice of the
therapeutic target or strategy, its contribution to the diversity of
potential therapeutics, and the likelihood that the target/strategy
can be developed during the award period.
E.  For Groups proposing clinical research:  adequacy and validity of
the proposed milestones for determining the readiness of the Group to
transition to clinical research (if applicable); iterative nature of
clinical/laboratory research plan to develop and optimize the
proposed treatment strategy;  protocol design (clinical and
scientific), short and long term development plans, and contingency
plans addressing the specific objectives set forth in the therapeutic
strategy; and provisions to obtain the required institutional and
regulatory approvals (IRB, FDA, RAC) to conduct the clinical study.
FEASIBILITY:  the likelihood that the proposed work can be
accomplished by the investigators, given their documented experience
and expertise, past progress, preliminary data, requested and
available resources, institutional commitment, and (if appropriate)
documented access to special reagents or technologies and adequate
plans for the recruitment and retention of subjects.  Specifically:
A.  leadership, scientific ability, and administrative competence of
the PI for the development and management of a comprehensive research
B.  qualifications and experience of each Project Leader (PL) or Core
Leader in relation to his/her proposed contribution to the program.
C.  the PI's and PLs' commitment to devote substantial time and
effort to the program.  [Due to the complexity and time required to
maintain a well-coordinated and productive research effort, a minimum
20% (time) commitment by the PI and PLs is strongly suggested unless
there are compelling arguments to the contrary.]
D.  the academic, clinical, and physical environment in which the
research will be conducted; the potential for interaction with
scientists from other departments and/or institutions in relevant
E.  For Groups proposing clinical research: experience of the PI and
PLs in the planning, design, and conduct of small clinical studies in
HIV-infected patients;  availability of a General Clinical Research
(GCRC), Center for AIDS Research (CFAR), or other additional source
of institutional support and/or statistical support;  the
infrastructure required for the conduct of safe and efficient
clinical research;  and short and long range plans that will result
in the successful implementation of clinical studies during the award
Funding decisions will be made on the basis of scientific and
technical merit as determined by peer review,  appropriate balance of
the preclinical and early clinical studies portfolios, overall
programmatic balance and relevance to the control of public health
problems, and availability of funds.
Application Receipt Date:  Nov 12, 1997
Scientific Review Date:    Feb/Mar 1998
Earliest Date of Award:    Jun/Jul 1998
Written and telephone inquiries concerning this PA are strongly
encouraged.  The opportunity to clarify any issues or questions from
potential applicants is welcomed.
Inquiries regarding programmatic issues may be directed to:
Nava Sarver, Ph.D.
NIAID, Division of AIDS
Chief, Targeted Interventions Branch
Solar Building, Room 2C01
Bethesda, MD  20892-7620
TELEPHONE:  301-496-8197
FAX:  301-402-3211
E-mail:  ns18p@nih.gov
Programmatic issues specific to CNS-related applications may be
directed to:
Dianne Rausch, Ph.D.
NIMH, Office on AIDS
5600 Fishers Lane, Room 10-75
Rockville, MD 20857
TELEPHONE;  301-443-6100
FAX:  301-443-9719
E-mail:  dr89b@nih.gov
Inquiries regarding review may be directed to:
Dianne Tingley, Ph.D.
NIAID, Division of  Extramural Activities
Scientific Review Program
Solar Building, Room 4C07
Bethesda, MD  20892-7610
TELEPHONE:  301-496-2550
FAX:  301-402-2638
E-mail: dt15g@nih.gov
Inquiries regarding fiscal matters may be directed to:
Mollie Shea
NIAID, Division of Extramural Activities
Grants Management Branch
Solar Building, Room 4B26
Bethesda, MD  20892-7610
TELEPHONE:  301-402-6576
FAX:  301-480-3780
E-mail:  ms256g@nih.gov
Diana S. Trunnell
Assistant Chief, Grants Management Branch
Parklawn Bldg, Room 7C-08
5600 Fishers Lane
Rockville, MD 20857
TELEPHONE:  301-443-2805
FAX:  301-443-6885
E-mail: diana_trunnell@nih.gov
This program is described in the Catalog of Federal Domestic
Assistance, No. 93.856 - Microbiology and Infectious Diseases
Research.  Awards are made under authorization of the Public Health
Service Act, Title IV, Part A (Public Law 78-410, as amended by
Public Law 99-158, 42 USC 241 and 285) and administered under PHS
grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74.
This program is not subject to the intergovernmental review
requirements of Executive Order 12372 or Health Systems Agency
The PHS strongly encourages all grant and contract recipients to
provide a smoke-free work place and promote the non-use of all
tobacco products.  In addition, Public Law 103-227, the Pro-Children
Act of 1994, prohibits smoking in certain facilities (or in some
cases, any portion of a facility) in which regular or routing
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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