Full Text AI-93-021

STRATEGIC PROGRAM FOR INNOVATIVE RESEARCH ON AIDS TREATMENT

NIH GUIDE, Volume 22, Number 29, August 13, 1993

RFA:  AI-93-021

P.T.


Keywords: 


National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  September 23, 1993
Application Receipt Date:  December 22, 1993

PURPOSE

The NIAID invites applications for the establishment of Strategic
Program for Innovative Research on AIDS Treatment (SPIRAT).

This Request for Applications (RFA) will support innovative,
integrated preclinical and clinical research to validate clinical
therapeutic concepts for the treatment of HIV-1 infection.  A SPIRAT
can focus its therapeutic research activities on viral gene(s) or
cellular factors required for HIV expression, novel immunotherapeutic
approaches, or other approaches with the potential for effective
therapy.  Studies supported by this RFA may have a greater conceptual
risk than currently exercised for treating HIV-infected individuals,
but also a greater potential for effective, long-term therapeutic
returns.  The SPIRAT Program thus complements existing, more
conservative preclinical and clinical programs for the treatment of
HIV infection, managed by the Division of AIDS/NIAID (National
Cooperative Drug Discovery Groups for the Treatment of HIV Infection
(NCDDG-HIV), AIDS Clinical Trial Groups (ACTG), DAIDS Treatment
Research Initiative (DATRI), Community Program for Clinical Research
on AIDS (CPCRA)).  The development of drugs and treatment for
opportunistic infections are the subject of other NIAID sponsored
programs and are not responsive to this RFA.

Each SPIRAT will form an interdependent collaborative enterprise
between preclinical and clinical scientists in the conceptualization
and proof of concept of an identified therapeutic strategy.  This
will entail iterative research and information exchange between
preclinical and clinical studies in order to maximally refine and
improve upon the therapeutic concept.  The Group must, therefore,
possess the expertise necessary to (1) evaluate the proposed strategy
in preclinical systems, and (2) conduct pilot clinical study(ies) in
HIV-infected individuals (and uninfected volunteers, as appropriate)
using the proposed therapeutic approach.  Information gained from
pilot clinical studies will be 'cycled' between preclinical and
clinical studies to further refine/revise the therapeutic approach.
A SPIRAT should be dedicated to the expedited transition of
ground-breaking research from advanced preclinical findings to
applied clinical mode in HIV-infected individuals.  A SPIRAT is
encouraged to include investigators from academic, non-profit, and
commercial (pharmaceutical, chemical, or biotechnological companies)
organizations.

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,
Strategic Program for Innovative Research on AIDS Treatment (SPIRAT),
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 "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, private and public, such as universities, colleges,
hospitals, laboratories, units of State and local governments, and
eligible agencies of the Federal government.  Applications from
minority individuals and women are encouraged.

MECHANISM OF SUPPORT

Awards will be made as Cooperative Agreements (U19s).  The
Cooperative Agreement is an assistance mechanism in which substantial
NIAID programmatic involvement with the recipient during the
performance of the planned activity is anticipated. The nature of
NIAID staff participation is described under SPECIAL REQUIREMENTS -
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 projects conducted by at least three independent
laboratories.  For the purpose of this RFA, two (or more) projects
within a single company will not be considered independent.
Similarly, two (or more) projects within the same academic department
will not be considered independent.  This limitation on the number of
independent projects from the same academic or private sector
organization is intended to increase the diversity and multi
disciplinary expertise available to the Group from other than the
parent institution or organization.  While no maximum number of
projects is stipulated, it has been observed that when a multi
disciplinary grant or award exceeds six component projects the
program becomes less coordinated and more difficult to manage.

This RFA is a one-time solicitation.  If by the end of the third year
of the award, the NIAID has not announced its intent to re-issue the
RFA, incumbents should contact NIAID program staff and consider
submitting investigator-initiated (R01) applications which will
compete with all investigator-initiated applications and be reviewed
according to the customary peer review procedures.  All policies and
requirements that govern the grant program of the U.S. Public Health
Service (PHS), and the National Institutes of Health (NIH) apply.

FUNDS AVAILABLE

The NIAID has set aside $6.0 million total costs for the first year
of funding.  This level of support is dependent on the receipt of a
sufficient number and diversity of applications of high scientific
merit.  Five to eight awards are anticipated for project periods up
to four years.  However, recommended support beyond the second year
of each SPIRAT is subject to determination by an external ad hoc
review committee, convened by the NIAID, that stated goals
(milestones) have been sufficiently met.  Specifically, the committee
will evaluate: accomplishment in executing the proposed studies as
outlined in the research proposal; preclinical achievements including
quality and substance of findings; transition of such studies to
clinical research; and initiation of a clinical pilot study.  The
committee's recommendation resulting from the second year review will
be used by NIAID staff to determine if funding should continue beyond
two years for the full term of the award.

Because the nature and scope of the research proposed in response to
this RFA may vary, it is anticipated that the size of individual
awards will vary also.  Awards are subject to a first year limit of
$1.3 million in total costs (direct plus indirect costs).  Budget
requests should be carefully justified and commensurate with the
complexity of the project.  Although this program is provided for in
the financial plans of the NIAID, awards pursuant to this RFA are
contingent upon the availability of funds for this purpose.
Applications in excess of $1.3 million total cost will be returned
without review, unless a waiver has been granted by the SPIRAT
Program Director, Dr. Nava Sarver (address listed INQUIRIES).

RESEARCH OBJECTIVES

Background

The NIAID and the PHS are currently supporting comprehensive
extramural and intramural projects for (2) the study of the etiology,
natural history, and demographics of AIDS; (2) determining means of
diminishing the risk of infection; (3) screening of high risk
individuals; (4) developing prophylactic vaccines; (5) developing
therapies to treat those with all stages of HIV disease; and (6)
developing therapies that may be useful chemopreventive or
prophylactic agents. Notwithstanding these efforts, effective,
long-term therapies are lacking, and the number of HIV-infected
individuals and AIDS cases is increasing. As of March 31, 1993,
289,320 cases of AIDS had been reported in the U.S. by the Centers
for Disease Control (CDC) and more than 182,275 of these patients (63
percent) had died.  Recent estimates indicate that 1,000,000 to
1,200,000 individuals in the U.S. may already be infected with HIV.
The World Health Organization projection of worldwide HIV infection
is placed at 30 to 40 million individuals by the year 2000.

Advances in the understanding of the biology and pathogenesis of HIV
disease have been made; nonetheless, the disease, which is associated
with severe immune dysfunction, remains an intransigent infection
with usually fatal consequences.  Presently, no treatment that can
eradicate or curb HIV infection for extended periods exists.
Moreover, FDA approved therapies for HIV infection are associated
with toxic side effects and emergence of HIV drug-resistant variants
(generally within six to twelve months of treatment), which precludes
their long term use.  Given the precedence of reverse transcriptase
and protease drug resistant variants, it is expected that resistance
to inhibitors directed against other viral targets is likely to
occur.  The search for more effective and innovative therapies that
may be less susceptible to the emergence of resistant HIV variants,
is one of the highest priorities of the NIAID.

In recent years, the scientific information base on HIV has expanded
and the number of technological breakthroughs has increased
significantly; however, application of developments to clinical and
preventive activities has not been commensurate with this expansion.
There is a need to apply these research advances to clinical research
studies, an effort that requires interdependent research activities
between preclinical and clinical investigators in the planning and
implementation of studies whose ultimate goal is an effective
clinical therapy for HIV+ individuals. Significant scientific and
clinical expertise exists throughout the country.  A concerted effort
to mobilize this expertise through SPIRAT can accelerate advances in
the management and ultimately the effective treatment of the disease.

The SPIRAT Program is specifically designed to support refinement and
proof of concept of innovative molecular intervention and
immunotherapy strategies for the treatment of HIV infection. This
program complements and balances present efforts pursued under
existing NIAID programs, including the AIDS Clinical Trial Groups
(ACTG), the Division of AIDS Treatment Research Initiative (DATRI),
and the National Cooperative Drug Discovery Groups for the Treatment
of HIV Infection (NCDDG-HIV).

Research Goals and Objectives of the SPIRAT Program

A.  The principal goals of this RFA are to (1) interface between
innovative, advanced preclinical research of sound scientific
rationale and clinical proof of concept of an identified HIV
therapeutic strategy; and (2) implement pilot clinical studies of a
therapeutic strategy in HIV-infected individuals.  In line with this
objective, the SPIRAT Program will support projects with a common
thematic goal for which advanced preclinical data exist.  These
efforts are to be implemented through a concerted, interdependent
Group effort by components comprising the SPIRAT Group.  A SPIRAT can
focus its preclinical and clinical research activities on strategies
directed against a viral gene or cellular component(s) required for
HIV expression, novel cell based immunotherapeutic approaches, or
other pioneering approaches.

B.  Applicants for SPIRAT funding are expected to have an identified
strategy based on creative, solid scientific rationale and supported
by advanced preclinical data which is proposed for pilot clinical
evaluation.  Therapeutic strategies that require studies in humans as
well as preclinical studies to refine the clinical approach are
appropriate for funding under the SPIRAT Program.  Each SPIRAT will
have a well-defined central research focus consistent with the
research objectives of the Program as stated in the RFA. The
following approaches are provided as examples and are not intended to
be inclusive or restrictive:

o  Strategies that target HIV gene expression via interference with
HIV cis-acting elements, viral regulatory elements, viral structural
components, or cellular factors required for HIV expression;

o  Strategies that interrupt/prevent steps involved in HIV/cell
interaction, entry, biochemical processes, virus (or viral
components) transport between cellular compartments, assembly,
release, maturation;

o  Intracellular delivery of antagonists to curb critical events in
HIV life cycle, such as transdominant suppressors, decoys,
competitors, catalytic RNA, using viral vectors or other delivery
strategies (gene therapy)

o  Innovative exploitation of the humoral and cellular mechanisms of
the immune system for a targeted anti-HIV attack;

o  Immune system reconstitution, capitalizing on new advances in
restoring immune functions;

o  Direct DNA transduction ('naked' DNA injection) to augment immune
response(s) via intracellular expression of HIV immunogen(s);

o  Strategies that target non T cell compartment(s) which may play an
essential role in cell free virus transport, cell cell transmission,
and general dissemination of HIV in the body;

o  Strategies that prevent the onset of HIV related neurologic
dysfunction, or counteract  the neurological damage seen in patients
with AIDS related dementia;

o  Novel therapeutic interventions that are not affected by emergence
of drug resistant HIV variants, or are insensitive to factors
affecting the emergence of drug resistance;

C.  Applications should address advanced preclinical refinements of
the proposed strategy, evaluation and demonstration of therapeutic or
immune benefit in laboratory animals, if applicable, and
implementation of pilot clinical studies in HIV infected individuals.
The cyclic flow of information between preclinical and clinical
phases is critical for maximal refinement and optimization of the
proposed clinical modality, clinical evaluation of the therapeutic
concept, and ultimately, accelerate transition to clinical treatment.

Projects or cores with proposed animal models must be integrated
into, and required to attain, the Group's objectives.  Funds awarded
for evaluation in animal models will be withheld (not awarded) until
the therapeutic strategy is available for animal efficacy studies.
Funds awarded for pilot clinical studies will similarly be withheld
(not awarded) until the therapeutic strategy is available for
clinical studies.  Due to budgetary limitations, primate animal
models should not be requested in the original application unless
they constitute an integral component of the proposal. Requests for
assistance in evaluation studies in primate animals may also be
directed to the NIAID for consideration in conducting such studies in
its primate model resources.  The availability of these models will
depend on the nature of the therapeutic approach.  In all other
cases, should the need for such models become evident during the
course of studies under this cooperative agreement, the Principal
Investigator may submit a competitive supplement request for the
support of primate animal models.  Funding of competitive supplements
will be from set aside funds allocated to future RFAs for this
initiative, and is not guaranteed. Consideration for funding will
also depend on the competitive merit and justification of the
competitive supplement relative to all other competing applications
submitted in response to the RFA.

D.  Studies required for the IND targeted preclinical development
(formulation, toxicology) of proposed treatments are generally beyond
the scope of this RFA, but such development through private venture
capital is encouraged. Alternatively, a Group may request that the
NIH assist in these developmental tasks using existing NIH/NIAID
contract resources.  The NIAID has several programs for clinical
evaluation of therapies for HIV/AIDS.  These include the AIDS
Clinical Treatment Units (ACTUs) large phase I and Phase II clinical
studies, and DATRI.  It is envisioned that extended clinical studies
of treatments developed by a SPIRAT group can be accommodated under
the clinical trial mechanisms available through Division of AIDS.
Queries about these programs may be directed to Dr. Nava Sarver, at
the address listed under INQUIRIES.

E.  The Group's objectives and goals should be relevant to and
compatible with the NIAID Program's missions and directions as stated
in this RFA. Applicants should describe their plans to accommodate
the stated SPIRAT Program requirements, criteria, and NIAID
involvement.

F.  Applications on the discovery/development/evaluation of anti HIV
drugs or on treatment of opportunistic pathogens associated with AIDS
are the subject of other NIAID programs and are excluded from this
RFA.
 G.  Relevance to other NIAID programs:  This RFA will support
innovative, integrated preclinical and clinical studies to validate
therapeutic concepts for HIV-1 infection.  Other DAIDS/NIAID
initiatives involving only preclinical studies for novel intervention
strategies address (1) preclinical immune reconstitution, focusing on
the basic biology hematopoietic bone marrow and alternative stem
cells and genetic modification for future use immune restoration in
vivo; (2) preclinical refinement and optimization of gene therapy
strategies (including vectors, transcriptional cassettes, anti viral
genes) for HIV-1; and (3) early preclinical discovery of new drugs
and therapeutic approaches for the treatment of HIV infection
(NCDDG-HIV).  SPIRAT applicants must ensure that no overlap exists
between the specific aims proposed under this RFA and those proposed
under any of the three initiatives referenced above, if applicable.

SPIRAT applicants from an institution receiving government funds
under General Clinical Research Center (GCRC), Center for AIDS
Research (CFAR), AIDS Clinical Trial Unit (ACTU), AIDS Vaccine
Evaluation Unit (AVEU), DATRI, and CPCRA programs, should describe
how these programs are integrated with the proposed studies, and
ensure that no scientific and budget overlap exists with the SPIRAT
proposal.

Definitions

ADMINISTRATIVE CORE.  An administrative facility that provides
central operations and support for the overall management of the
cooperative agreement and services shared by the Group as a whole.
The Administrative Core should have a budget separate from that of
the Principal Investigator's research project, but should be
administered by the Principal Investigator's organization.  The
Administrative Core will have in its budget for each year travel
costs for:  (1) two required meetings of individual members of the
Group; (2) one meeting of representative of all Groups in the SPIRAT
Program; and (3) travel expenses for the Scientific Advisory Panel
(see below).  The Administrative Core will be responsible for
allocating required travel expenses to appropriate members of the
Group.  Only SPIRAT related travel will be supported under this RFA;
travel funds to other domestic or foreign meetings is not provided
under this RFA.  (For additional details of required travel see
SPECIAL REQUIREMENTS Terms and Conditions of Award:  C. Awardee's
Rights and Responsibilities.)

ARBITRATION PANEL.  An NIAID-convened ad hoc panel that is formed to
review scientific or programmatic activity that is impeding progress
within a Group. It will be composed of a "Group" designee, one NIAID
designee, and a third designee with expertise in the relevant area
and chosen by the other two. The Arbitration Panel may help resolve
both scientific and programmatic issues that develop during the
course of work that restrict progress.

COOPERATIVE AGREEMENT.  An assistance mechanism in which substantial
NIAID programmatic involvement is anticipated with the recipient
organization during the performance of the planned activity.

CORE COMPONENT.  Laboratory facilities for equipment and services
that are shared by two or more projects of the SPIRAT.  Examples of
core components are:  biochemical, cell based, virological, and
immunological studies; animal model studies; pharmacology/toxicology
studies; scale-up synthesis of the therapeutic agent.  The core can
be defined as a facility laboratory with established techniques and
assays which performs a service function resulting in an economy of
effort and savings in the overall costs of the Group.  The core unit
is to be described with the same detail as the research projects to
enable evaluation of its scientific merit.  (See details for
preparation of the budgets under PREPARATION AND ORGANIZATION OF THE
APPLICATION).

CORE LEADER.  The leader of one of the Scientific or Administrative
Cores of the SPIRAT.

GROUP.  see SPIRAT, below.

INVENTION.  An innovative therapeutic approach that is or may be
patentable under Title 35 of the United States Code.

STRATEGIC PROGRAM FOR INNOVATIVE RESEARCH ON AIDS TREATMENT (SPIRAT).
In this RFA the terms Strategic Program for Innovative Tesearch on
AIDS Treatment (SPIRAT) and "Group" are synonymous.  Each Group may
consist of a number of scientific investigators from academic and/or
non profit research institutions as well as scientists from
commercial organizations, performing research on interdependent
projects whose central focus is development of effective clinical
therapy for HIV-infected individuals.  A CORE component cannot be
used toward fulfillment of the three research projects requirement.

NIAID SPIRAT PROGRAM DIRECTOR.  A Senior Scientist of the NIAID
extramural staff who coordinates NIAID's participation in the SPIRAT
Program, oversees the entire SPIRAT Program, maintains the overall
scientific balance in the SPIRAT Program commensurate with new
research and therapeutic findings and emerging research
opportunities, and who ensures that the SPIRAT Program is consistent
with the Division of AIDS and NIAID missions and goals.

NIAID SCIENTIFIC COORDINATORS.  Scientists of the extramural staff of
the Division of AIDS, NIAID, who function as peers with the Principal
Investigators and Project Leaders and who facilitate the partnership
relationship between NIAID and each Group.  Two Scientific
Coordinators from the Division of AIDS one from the Basic Research
and Development Program, and one from the Clinical Research Program
will be assigned to each Group by the SPIRAT Program Director.  The
Scientific Coordinators are the immediate contact persons to the
Group.

PRINCIPAL INVESTIGATOR.  The person who assembles the SPIRAT, who is
responsible for the performance of the Group as a whole and for that
of each of the Project Leaders, and who is responsible for submitting
the single application in response to this RFA.  The Principal
Investigator will coordinate Group activities scientifically and
administratively and should preferably be project leader of one of
the Research Projects of the Group.  The awardee (Principal
Investigator's) institution establishes and operates the Central
Operations Office that funds Group members and is legally and
fiscally accountable for the disposition of funds awarded.

PROJECT LEADER.  The leader of one of the scientific research
projects of the SPIRAT, who is responsible for the scientific conduct
of that project.

RESEARCH PROJECT.  A discrete, specified, circumscribed project that
must relate to the overall theme of the SPIRAT.

SCIENTIFIC ADVISORY PANEL.  A panel, comprised of two to three peers
from the scientific community, whose mission is to provide the
Principal Investigator with a comprehensive review of the Group's
activities and progress, consult on future goals and strategies, and
recommend alternative directions, as appropriate.   Selection and
appointment of the Panel is the responsibility of the Principal
Investigator.

SPECIAL REQUIREMENTS

Terms and Conditions of Award

NOTE:  Failure to abide by any of the Terms of Award pertaining to
awardee responsibilities stipulated in this Section may result in
withholding of funds by the NIAID until compliance with the Terms is
restored.

A.  Working Relationships Within a Cooperative Agreement

Under the Cooperative Agreement, a partner relationship exists
between the recipient of the award and NIAID.  The participation of
the Government through the NIAID extramural staff is intended to
promote and facilitate a concerted effort by all members of the
SPIRAT Program by providing appropriate scientific input and analysis
of experimental data, by coordinating efforts among Groups, by
providing access to appropriate data bases, by providing ancillary
testing and other resources (such as reagents, samples or
experimental animals) available under existing Government contracts
and, as appropriate, by making available to Groups biological
materials for testing.  The interaction of academic and non-profit
research institutions with commercial organizations and the
Government is strongly encouraged and is expected to favor
expeditious clinical development of innovative HIV/AIDS therapies.

B.  Patent Coverage

As the discovery of innovative, effective clinical therapies for
HIV/AIDS is the goal of this effort, and since active involvement by
private sector laboratories is facilitated by the existence of
adequate patent coverage, it is essential that applicants provide
plans to assure such coverage. Since several institutions may be
involved, complex patent situations may arise.  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.  In addition each Group
must provide a detailed description of the procedures to be followed
for the resolution of legal problems which 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 contracts, 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 their
own particular circumstances.

The proposed patent plan among the institutions comprising the Group
must be submitted with the application.  This patent agreement,
signed and dated by the organizational officials authorized to enter
into patent arrangements for each Group member and member
institution, must be delivered two weeks prior to submission of the
application to Dr. Nava Sarver, Targeted Drug Discovery Section,
Developmental Therapeutics Branch, Division of AIDS, NIAID, Solar
Building Room 2C-11, 6003 Executive Boulevard, Bethesda, MD  20892.
(For express mail or courier services, the address is Rockville, MD
20852.)

NOTE:  Should the Group wish 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 two weeks prior to submission of the application.  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 37CFR401 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 Extramural Invention Reports
office, Office of Extramural Research, Building 31, Room 5B41, NIH,
9000 Rockville Pike, Bethesda, Maryland 20892.

C.  Awardee Rights and Responsibilities and Nature of NIAID
Participation

The applying Group must define its objectives and strategies in
accord with its own interests and perceptions of novel and
exploitable approaches to implementation of effective, innovative
HIV/AIDS therapy, and must develop the details of the research design
following the guidance given in this RFA.  It is the primary
responsibility of the Principal Investigator to clearly state the
objectives and approaches of the Group, to plan and conduct the
research stipulated in the proposal, and to ensure that the results
obtained are analyzed and published in a timely manner.  The data
obtained will be the property of the awardee.  Specifically, the
Principal Investigator defines the details for the project within the
guidelines of the RFA, retains primary responsibility for the
performance of the scientific activity, and agrees to accept
assistance in coordination, cooperation, and participation of NIAID
staff in all aspects of scientific and technical management of the
project in accordance with the terms formally and mutually agreed
upon prior to the award.  The responsibility for the planning,
direction, and execution of the proposed project will be solely that
of the applicant.

1.  Meetings

a.  Two mandatory Group meetings.  The Principal Investigator and
Project Leaders of the Group, and one or both of the NIAID Scientific
Coordinators, will meet twice per year to review progress, plan and
design research activities, and establish priorities within the
Group.  The Principal Investigator will be responsible for scheduling
the time and place (generally at one of the performance sites),
notifying the NIAID at least 30 days prior to the meeting date, and
preparing concise proceedings or minutes which will be delivered to
the members of the group within thirty days of the meeting.  The
agenda for this meeting will be determined by agreement between the
Principal Investigator and the NIAID Scientific Coordinator.  NIAID
staff will not chair Group meetings.

b.  One mandatory meeting will be held annually (SPIRAT Program
annual meeting) at a site designated by the NIAID (usually the
Washington DC vicinity) during which the Principal Investigators and
Project Leaders of all the Groups will present significant findings
and progress in symposium format.  The NIAID SPIRAT Program Director
will consult with the Groups' key personnel in formulating the
overall agenda and in identifying key topics for discussion, with
specific focus on inter Group interaction and sharing information of
general importance to the implementation of clinical studies.  It is
expected that NIH staff, members of established committees and
advisory boards, and others active in the clinical application of
innovative therapies for HIV/AIDS will also be invited.

Applicants should include requests for travel funds specifically for
and restricted to the above meetings when they prepare their budgets.
Funds to cover operating costs of the SPIRAT Program annual meeting
may be contributed by one or more Groups; NIAID will provide
administrative supplements for this purpose, as needed.

c.  Informal meetings.  A critical determinant of Group success will
be the degree of communication among its members.  Thus, in addition
to the three meetings listed above, two additional meetings which may
be necessary for coordination of Group activities may be scheduled,
and funds should be requested in the budget, with justification.
Regular telephone and written communication will be important and are
encouraged.

NOTE:  This RFA will support only SPIRAT-related travel as specified
above; no additional travel funds will be provided to attend other
domestic or foreign scientific meetings under this RFA.

2.  Principal Investigator responsibilities

The Principal Investigator will be responsible for the timely
submission of all abstracts, manuscripts and reviews (co)authored by
members of the Group and supported in part or in total under this
Agreement.  The Principal Investigator and Project Leaders are
requested to submit manuscripts to the Scientific Coordinator within
three weeks of acceptance for publication so that an up-to-date
summary of program accomplishments can be maintained.

3.  Annual Progress Report

An annual progress report should be submitted, which should include a
complete and cumulative list of all  publications (abstracts,
manuscripts, reviews) (co)authored by Group members and supported in
part or in total under this Agreement.

Each Progress Report should also include a brief section outlining
intra Group interactions which have augmented activities, citing
specific occurrences (e.g., construct X was made under Project 1 and
transferred to Project 2 for clinical evaluation).  Inter-Group
collaboration with other SPIRAT should be specified, where
applicable. Interaction with the Scientific Coordinator and the NIAID
during the reporting period should be described.

The Progress Report should routinely include basic information.
Please refer to PHS 2590 (noncompeting continuation application form)
which describes the basic information required by NIH for preparation
of the progress report.

4.  Publications and oral presentations

Publications or oral presentations of work done under this Agreement
is the responsibility of the Principal Investigator and appropriate
Project Leaders and will require appropriate acknowledgement of NIAID
support.

5.  Acknowledgement of published work

All published (abstracts, peer reviewed manuscripts, reviews) and
oral presentations of work supported in part or in total by the
SPIRAT cooperative agreement must be acknowledged as part of the
presentation and will include the mechanism, cooperative agreement
number and Institute, e.g., "This work was supported in whole (or in
part) by the SPIRAT Program, cooperative agreement number
U19-AI-12345, NIAID".

6.  Rights to data

While the NIAID Scientific Coordinator has a right of access to the
data (see NIAID staff responsibilities below) the applicant will
retain custody of and rights to the data.  Timely publication of
major findings is encouraged.

The applicant institution and the Principal Investigator will be
responsible for the Group's application.  The award will be made to
the applicant institution on behalf of the Group as a whole and not
to individual research projects within the Group.  The applicant
institution will provide a Central Operations Office for the Group,
will be responsible for the performance of the entire Group, and will
be accountable for the funds awarded.

7.  Group's scientific advisory panel

Each Group will designate a Scientific Advisory Panel of two to three
investigators within six months of funding.  The Panel members will
attend one or more of the Group's meetings (see above).  The
Scientific Coordinator(s) will participate in all meetings of the
Panel.  The Panel will review the Groups's activities and will advise
the Principal Investigator on the Group's progress, including the
timeliness of progress in individual projects relative to original
projections; progress relative to Group's objectives and needs;
continued relevance of a given project to Group's goals; continued
coordination of Group's objectives with the objectives of the SPIRAT
Program; and recommendations for new directions, as appropriate. The
Panel will provide the Principal Investigator with a comprehensive
written review of the Group's activity in each year of funding, as
specified under Definitions:  SCIENTIFIC ADVISORY PANEL.  A copy of
the Panel's report will be submitted to the NIAID as a supplement to
the annual progress report, or within 30 days of the report,
whichever is earlier.

A Scientific Advisory Panel is required of all Groups.  Members of
the Panel will not be affiliated with any of the institutions
comprising the Group.  The composition of the designated Panel will
be provided to the NIAID within six months of funding.  Funds to
cover expenses incurred by the Panel should be included in the
Administrative Core component of the application and will be
restricted solely for this purpose.

D.  NIAID Staff Responsibilities:  Nature of NIAID Participation

Assistance via a Cooperative Agreement differs from the traditional
research grant in that, in addition to the normal programmatic and
administrative stewardship responsibilities, the awarding component
(NIAID) anticipates substantial programmatic involvement during
performance of the research program.  NIAID shall work with each
Group and shall be represented by two NIAID Scientific Coordinators,
both members of the professional staff of the Division of AIDS:  one
coordinator will be from the Basic Research and Development Program
(primarily of the Developmental Therapeutics Branch), and one
coordinator will be from the Clinical Research Program (primarily of
the Medical Branch).

During performance of the award, the NIAID SPIRAT Program Director
(Dr. Sarver, Chief, Targeted Drug Discovery Section, Developmental
Therapeutics Branch) and the Scientific Coordinators will provide
appropriate assistance, advice, and guidance by: participating in the
design of Group activities; advising in the selection of sources or
resources; coordinating or participating in collection and/or
analysis of data; advising in management and technical performance;
or participating in the preparation of publications. However, the
role of NIAID will be to promote and facilitate and not to direct the
activities.  It is anticipated that decisions in all activities will
be reached by consensus of the Group and that NIAID staff will
provide input to this process.  The manner of reaching this consensus
and the final decision-making authority will rest with the Principal
Investigator.

1.  NIAID Participation in Design of Group Activities, Development of
Research Protocols and Evaluation of Results

a.  The NIAID Scientific Coordinators, like other Group members, 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, but not in the execution,
of experiments agreed to by the Group; and may participate in the
analysis and publication of results.

b.  The NIAID Scientific Coordinators may assist the Group or other
individual members in research planning, particularly with respect
to:

i.  provision of needed resources and information that otherwise may
not be available to the Group (e.g., reference compounds for
standardization of test systems or as analytical standards);

ii.  provision of data from testing conducted in resource contract
laboratories when the occasional need arises in Groups whose main
research activities do not require these resources on a regular basis
(e.g., biochemical, cell based assay, and animal model studies).  On
occasion, and under mutual agreements, NIAID will arrange for limited
preclinical evaluations at other SPIRAT sites.  The requesting Group
is expected to provide sufficient material for such testing.  Groups
whose experimental approach involves studies that require testing in
animals on a regular basis must budget for costs to be paid from
award funding.

iii.  provision of information concerning work being conducted in
other NIAID supported extramural projects, in order to reduce or
prevent duplication of efforts.

iv.  A SPIRAT may also request that further evaluation of the
therapeutic strategy under a larger phase I clinical trial be
conducted under other clinical programs sponsored by the NIAID.  A
SPIRAT will be supported by strong commitment by their home
institution to the organization and conduct of these programs.

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.

2.  NIAID Participation in Collection and Analysis of Data,
Procedures for Submission of Results to NIAID, and Preparation of
Group Findings for Presentation and Publication

In addition to the special reports and stipulations described below,
reporting requirements will be identical to those currently in
existence for awardee of traditional NIH research project grants.

1.  The principal end product of SPIRAT activities will be the
development of an innovative, effective clinical therapy for
HIV/AIDS.  Transitional preclinical and clinical development through
private resources is encouraged.  Alternatively, the Group may
recommend that further clinical studies be sponsored by NIAID (see
item 2, below). In this case, it will be necessary for the Principal
Investigator, appropriate Project Leaders and the NIAID Scientific
Coordinators to collaborate in the analysis, summary preparation, and
subsequent presentation of data to the Division of AIDS and other
NIAID staff and NIAID advisory committees, such as the AIDS Clinical
Drug Development Committee (ACDDC), DATRI Executive Group, or AIDS
Research Advisory Committee (ARAC).

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

3.  The NIAID, via the SPIRAT Program Director or the Scientific
Coordinator, will have access to data generated under this
Cooperative Agreement. Information obtained from the data may be used
by the Scientific Coordinator for the preparation of internal reports
on the Group's activities.

E.  Arbitration Process

Inasmuch as certain activities require approval by NIAID staff during
performance of this Cooperative Agreement specifically, reports
intended for inclusion in INDA's and Clinical Brochures,
redistribution of materials received from the Government, and
dissemination of research findings resulting from the use of these
materials NIAID will establish an arbitration process to resolve any
differences of opinion between the awardee and NIAID, on scientific
and programmatic matters.  An arbitration panel, composed of one
Group designee, one NIAID designee, and a third designee with
expertise in the relevant area and chosen by the other two, will be
formed to review any scientific or programmatic issue that is
significantly restricting progress.  These special arbitration
procedures in no way affect the awardee's right to appeal an adverse
action in accordance with PHS regulations at 42 CFR Part 50, Subpart
D, and HHS regulations at 45 CFR Part 16.

The special Terms and Conditions of Award: Nature of NIAID
Participation described in this Section are in addition to, and not
in lieu of, otherwise applicable OMB administrative guidelines, HHS
grant administration regulations at 45 CFR Parts 74 and 92, and other
HHS, PHS, and NIH grant administration policies.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements will be required to include minorities and
women in study populations so that research findings can be of
benefit to all persons at risk of the disease, disorder or condition
under study; special emphasis should be placed on the need for
inclusion of minorities and women in studies of diseases, disorders
and conditions which apply to males and females of all ages.  If
women or minorities are excluded or inadequately represented in
clinical research, particularly in proposed population-based studies,
a clear and compelling rationale should be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group, and related to the
prevalence of the condition (e.g. HIV infection) in the catchment
area.  Gender and racial/ethnic issues should be addressed in
developing a research design and sample size appropriate for the
scientific objectives of the study.  This information should be
included in the form PHS 398 in sections 1-4 of the Research Plan AND
summarized in Section 5, Human Subjects.  Applicants/offerors are
urged to assess carefully the feasibility of including the broadest
possible representation of minority groups.  However, NIH recognizes
that it may not be feasible or appropriate in all research projects
to include representation of the full array of United States
racial/ethnic minority populations (i.e., Native Americans (including
American Indians or Alaskan Natives), Asian/Pacific Islanders,
Blacks, Hispanics).  The rationale for studies on single minority
population groups should be provided.

For the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology,
prevention (and preventive strategies), diagnosis, or treatment of
disease, disorders or conditions, including but not limited to
clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded from the
clinical research requirements.  However, every effort should be made
to include human tissues from women and racial/ethnic minorities when
it is important to apply the results of the study broadly, and this
should be addressed by applicants.  If the required information is
not contained within the application, the application will be
returned.

NOTE:  Peer reviewers will address specifically whether the research
plan in the application conforms to these policies.  If the
representation of women or minorities in a study design is inadequate
to answer the scientific questions(s) addressed and the justification
for the selected study population is inadequate, it will be
considered a scientific weakness or deficiency in the study design
and will be reflected in assigning the priority score to the
application.

All applications for clinical research submitted to NIH are required
to address these policies.  NIH funding components will not award
grants or cooperative agreements that do not comply with these
policies.

Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research
Resources are encouraged to respond to this RFA and should identify
the GCRC as a resource for conducting the proposed research.  If so,
a letter of agreement from either the GCRC program director or
Principal Investigator could be included with the application.

LETTER OF INTENT

Prospective applicants are asked to submit, by September 23, 1993, a
letter of intent (maximum of three pages) that includes a descriptive
title of the overall proposed research; the name, address, telephone
number, and institution of the Principal Investigator; names of
prospective Project Leaders, other key investigators, and their
respective institutions; title, project leader, and institution for
each component research project, and the number and title of this 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 NIAID 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. Dianne Tingley at the
address listed under INQUIRIES.

APPLICATION PROCEDURES

This RFA requires the submission of a single application for the
proposed SPIRAT.  Because of the multi institutional nature of a
SPIRAT and the special requirements in this RFA, additional
instructions regarding format are contained in the Special
Instructions for Preparing the Group Application, which are available
from the program contacts listed under INQUIRIES.

The individual research projects comprising the SPIRAT are subjects
to the same format and page limitations as for a research grant
application The research grant application form PHS 398 (rev. 9/91)
is to be used in applying for these cooperative agreements.  These
forms are available at most institutional offices of sponsored
research and may be obtained from the Office of Grants Information,
Division of Research Grants, National Institutes of Health, 5333
Westbard Avenue, Room 449, Bethesda, MD 20892, telephone
301/710-0267.

The special requirements of this RFA also necessitate certain
modification.  The Introductory Section should apply to the proposed
SPIRAT as a whole with respect to goals, objectives, and overall
research plan.  The Introductory Section, not to exceed three pages,
should contain any additional information about the proposed
Principal Investigator or his/her institution as evidence of
capability to carry out the scientific and administrative duties
required in this RFA and the functions of the Central Operations
Office.

Refer to the Special Instructions for Preparing the Group
Application, for additional instructions how to prepare and assemble
the Groups's application.

The RFA label available in the PHS 398 (rev. 9/91) 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 such that it may not reach the review committee in time
for review.  In addition, to assure the identification of your
application with this RFA the "YES" box must be marked in item 2a of
the face page of the application form and the title and number of
this RFA typed.  Applications that are not received as a single
package from the Principal Investigator and that do not conform to
the instructions contained in PHS 398 (rev. 9/91) application kit
will be judged non-responsive and will be returned to the applicant.

Submit a signed, typewritten original of the application, including
the Checklist, and three signed, 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, also submit two exact copies of the
application directly to:

Dr. Dianne Tingley
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C-16
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-0818

Applications must be received by December 22, 1993.  If an
application is received after that date, it will be
returned to the applicant without review.  If the application
submitted in response to this RFA is substantially similar to a grant
application already submitted to the NIH for review, but has not yet
been reviewed, the applicant will be asked to withdraw either the
pending application or the new one.  Simultaneous submission of
identical applications will not be allowed, nor will essentially
identical applications be reviewed by different review committees.
Therefore, an application cannot be submitted in response to this RFA
that is essentially identical to one that has already been reviewed.
This does not preclude the submission of substantial revisions of
applications already reviewed, but such applications must include an
introduction addressing the previous critique.

REVIEW CONSIDERATIONS

A.  Review procedures

Applications will be reviewed by the Division of Research Grants for
completeness and by NIAID staff to determine administrative and
programmatic responsiveness to this RFA; those judged to be
incomplete or non-responsive will be returned to the applicant
without review.

Applications with first year total costs (direct and indirect) in
excess of $1.3 million will be returned without review unless the
applicant has received a written waiver from the NIAID to exceed this
amount (see FUNDS AVAILABLE, above).  Those applications that are
complete and responsive may be subjected to a triage by an NIAID peer
review group to determine their competitiveness relative to the other
applications received in response to this RFA.  The NIAID will remove
from further competition those applications judged to be
noncompetitive for award and will notify the applicant (Principal
Investigator) and responsible institutional official.

Those applications judged to be competitive for award will be further
reviewed for scientific and technical merit by a Review Committee
convened by the Scientific Review Program, Division of Extramural
Activities, NIAID.  Second level of review will be provided by the
National Advisory Allergy and Infectious Diseases Council.  In the
event of multiple highly qualified applications, final funding
recommendations will be based on highest Program priorities.  Review
date, Council meeting date, and earliest award date are stated under
Schedule, below.

B.  Review Criteria

The application must be directed towards the attainment of the stated
programmatic goals (see RESEARCH OBJECTIVES).  The following factors
are the criteria to be used by peer review groups in the scientific
and technical review of these applications:

o  The scientific merit of the program as a whole, as well as that of
each individual project, and the originality and uniqueness of the
proposed preclinical and clinical activities.  Each project must be
supportable on its own merit;

o  The significance of the overall program goals and the development
of a well-defined central research focus, in relation to the research
objectives of the SPIRAT Program;

o  The cohesiveness, multidisciplinary and multifaceted scope of the
program and the coordination and interdependence of the individual
projects and core(s); plans for effective intra-Group communication
and for assuring cohesiveness within the Group as a whole;

o  Demonstration of experience in the planning, design, and conduct
of clinical research with a small number (6 to 10) of HIV-infected
individuals (inpatient and outpatient).  Relevant prior experience
should be noted.  The plan for clinical data management and adverse
event reporting (AER) should be described;

o  The likelihood that innovative preclinical therapeutic strategies
will be refined and pilot clinical research implemented within two
years of award date;

o  The justification for, and usefulness to the various research
projects of the core facilities. The relationship of each core to the
central focus of the overall program.  Each core unit must provide
essential facilities or service for two or more approved individual
research projects;

o  The leadership, scientific ability, and administrative competence
of the Principal Investigator for the development, implementation,
and management of a comprehensive preclinical and clinical research
program; and the Principal Investigator's commitment to devote
substantial time and effort to the program;

o  The qualifications, experience, and commitment of the
investigators responsible for the individual research projects or
core(s) (Project Leaders) and their contribution to the program,
including their ability to devote adequate time and effort to the
Group.  It is anticipated that, due to the complexity and time
required to maintain a well-coordinated and productive research
effort, a minimum 20 percent (time) effort by the Principal
Investigator and each Project Leader should be devoted to the study,
unless there are compelling arguments to the contrary;

o  Research training, experience and accomplishments of other
participating investigators and support personnel in the Group in the
research areas outlined in the RFA;

o  The academic, clinical, and physical environment in which the
research will be conducted, including the adequacy of space,
equipment, animal facilities, biohazard containment facilities;
access to HIV/AIDS patient care; and the potential for interaction
with active scientists from other departments and/or institutions in
relevant disciplines including infectious diseases, virology,
molecular biology, immunology, gene therapy, hematology.  The
availability of a GCRC (General Clinical Research Center) should be
noted. The responsible IRB (Institutional Review Board) should be
identified;

o  Documented commitment of Institutions represented by Group
members; documented capability of Principal Investigator's
Institution to serve as the Central Operations Office for the Group;

o  Soundness of the  institutional administrative and organizational
structure that facilitates attainment of the objective(s) of the
program, including fiscal responsibility and management capability to
assist the PI and staff in following PHS policy;

o  Description of the laboratory capabilities in immunology and
virology with particular emphasis on ability to detect changes in
parameters related to HIV infection.  Pharmacological capabilities
should also be described, when relevant;

o  Arrangements for internal quality control of on-going research,
allocation of funds, day-to-day management, contractual agreements,
and mechanism for selecting and replacing key professional or
technical personnel, if required, on an interim or permanent basis;

o  Management for the ethical and hazardous aspects of the
project(s);

o  Appropriate representation of women and minorities in study
design;

o  Commitment to accept the assistance of NIAID staff in accordance
with the guidelines outlined under Terms of Award;

o  Reasonableness of cost.

AWARD CRITERIA

Award criteria will be based on scientific merit as reflected in the
priority score; on programmatic priorities and relevance; on the
overall diversity and balance of proposed therapeutic modalities; and
on funds available.

INQUIRIES

The opportunity to clarify issues or questions about the RFA from
potential applicants are welcome.  Please send the letter of intent
and direct inquiries regarding the RFA and programmatic issues to:

Nava Sarver, Ph.D.
Division of AIDS
National Institute of Allergy and Infectious Diseases
Solar Building, Room 2C-11
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-8197
FAX:  (301) 402-3211

Direct inquiries regarding application preparation and review to:

Dr. Dianne Tingley
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C-16
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-0818
FAX:  (301) 402-2638

Direct inquiries regarding fiscal matters to:

Ms. Jane Unsworth
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B-22
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-7075
FAX:  (301 480-3780

Schedule

Letter of Intent Receipt Date:  September 23, 1993
Application Receipt Date:       December 22, 1993

Scientific Review Date:         February/March 1994
Council Meeting Date:           June 17-19, 1994
Earliest Award Date:            August 1, 1994

AUTHORITY AND REGULATIONS

This program is described in the catalog of Federal Domestic
Assistance, 93.856 Microbiology and Infectious Diseases Research and
93.855 Immunology, Allergy and Transplantation 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 PHS grants policies and Federal
Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.  This program
is not subject to the intergovernmental review requirements of
Executive Order 122372 or Health Systems Agency review.

.

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