Full Text PA-96-069
NIH GUIDE, Volume 25, Number 27, August 9, 1996
PA NUMBER:  PA-96-069
P.T. 34

  Infectious Diseases/Agents 
  Clinical Medicine, General 
  Diagnosis, Medical 
  Disease Prevention+ 

National Institute of Allergy and Infectious Diseases
Letter of Intent Receipt Dates:  September 16, 1996; August 1, 1997;
August 2, 1998
Application Receipt Dates:  October 25, 1996; September 1, 1997;
September 1, 1998
The National Institute of Allergy and Infectious Diseases (NIAID)
gives special consideration for funding to scientifically meritorious
applications that propose research that would meet the objectives and
program priorities that have been described in a Program
Announcement.  Program Announcements identify areas of ongoing
research emphasis for the NIAID.  The Opportunistic Infection
Research Branch (OIRB) of the Therapeutics Research Program in the
Division of AIDS (DAIDS), NIAID, invites applications for
Collaborations for Advanced Strategies in Opportunistic Infections
The purpose of this Program Announcement (PA) is to expand the
clinical knowledge of opportunistic infections in people with AIDS by
expediting the translation of promising innovative preclinical
findings into clinical research applications.  This PA announces the
interest of the NIAID in supporting focused collaborative research
between preclinical and clinical scientists to test, refine, and
improve diagnostic, pathogenic, or therapeutic concepts leading to
innovative approaches for the prevention and management of
opportunistic infections (OIs) in individuals infected with HIV.
This type of  collaborative research would be dedicated to the
expedited development and use of advanced preclinical findings into
clinical applications.
The opportunistic pathogens emphasized in this PA are Mycobacterium
avium, Cryptosporidium parvum, and cytomegalovirus.
Because the NIAID would like to fund more research in this area, the
NIAID announces the intent to give special funding consideration to
applications for integrated, multidisciplinary, translational
research activities that use molecular or cellular approaches to:
o  develop and clinically validate innovative methods for detection
of opportunistic infection;
o  elucidate the mechanisms of the human host-pathogen relationship
in opportunistic infections;
o  develop innovative approaches to measure response to treatment in
HIV-infected individuals; and/or
o  develop innovative strategies for the prevention or treatment of
opportunistic infection.
Research projects that principally encompass preclinical laboratory
research are not within the area of interest of this PA, but may be
within the areas of programmatic emphasis described in PA-96-068,
"Innovative Drug Discovery Research in AIDS Opportunistic
Infections," published in the NIH Guide, Vol 25, No. 26, August 2,
Applications that include collaborations with the private sector
(e.g., pharmaceutical, chemical, or biotechnological companies) are
strongly encouraged.
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,
Collaborations for Advanced Strategies in Opportunistic Infections
(CASOI), 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 20402-0325 (telephone 202/512-1800).
Applications may be submitted by domestic and foreign, for-profit and
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State and local
government, and eligible agencies of the Federal government.
Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators.
A request for up to five years of support in an application for a
~traditional~ research project grant (R01) will be considered if the
proposed research would help meet the objectives of this PA.
At this time, the NIAID has not determined whether or how this
solicitation will be continued beyond the three annual receipt dates
of this PA.
Prior approval by NIAID program staff must be obtained before
submitting an application that requests direct costs of $500,000 or
more for any budgetary year (see APPLICATION PROCEDURES).
HIV-infected persons experience progressive immunological
deterioration and are subject to life-threatening disease caused by a
variety of viruses, fungi, bacteria, and protozoa that, in the normal
human host, are either nonpathogenic or cause only minor, limited
infection.  Such opportunistic infections (OIs) are a clinical
hallmark of advanced HIV disease and are the primary cause of the
morbidity and mortality associated with AIDS.
Progress in the prevention, detection, and management of OIs is
essential to improve the health status and quality of life of HIV-
infected persons.  Advances in this area, though, are limited by
incomplete knowledge of the pathogenesis and clinical course during
HIV infection, as well as inadequate knowledge about the HIV-induced
immune defects that render infected persons unable to prevent or
overcome diseases caused by these organisms.  Therapeutic
interventions are limited by inadequate information about the
molecular or antigenic targets upon which the rational design of new
therapies could be based.  Finally, methods for diagnosis and
treatment assessment are limited, complex, and expensive, which
hinders the assessment and measurement of treatment responses in
patients with several OIs.
Advancing this knowledge base requires the collaboration of several
disciplines such as clinical investigation, microbiology, immunology,
molecular biology, pharmacology, and others.  A coordinated
multidisciplinary effort involving laboratory-based scientists and
clinical investigators exploring focused questions should facilitate
rapid advancement and lead to the development of innovative
approaches to the diagnosis and treatment of these OIs.  Such
approaches may have a more than average risk-to-benefit ratio, but
are likely to have greater potential for effective, long-term
therapeutic returns.  The Division of AIDS/NIAID supports a range of
preclinical and clinical research in opportunistic infections: the
National Cooperative Drug Discovery Group for the Treatment of
Opportunistic Infections In AIDS, research project grants, screening
contracts, animal model contracts, the AIDS Clinical Trials Group,
and the Terry Beirn Community Program for Clinical Research in AIDS.
While scientific exchange occurs among these disciplines and groups,
funding opportunities for prospective multidisciplinary research are
infrequent.  The intent of this PA is to encourage research that
bridges the gap between preclinical and clinical scientists,
encouraging clinically focused collaborative research and allowing
refinement and proof-of-concept of innovative strategies leading to
effective clinical applications.
Research Objectives and Scope
This PA announces the interest of the NIAID in encouraging and
supporting the advanced preclinical research and clinical proof-of-
concept strategies needed to more effectively combat the
opportunistic infections caused by human cytomegalovirus,
Mycobacterium avium, or Cryptosporidium parvum.  This PA encourages
laboratory-based scientists and clinical investigators
collaboratively to design and propose multi-component research that
has a common thematic goal for which advanced preclinical data exist.
This will entail iterative research and information exchange between
preclinical and clinical studies in order to refine and improve
matters such as the following:
o  molecular approaches to readily detect critical opportunistic
infections in humans,
o  identification of human host factors contributing to infection
(e.g., defects in immune response), and
o  methods of assessing response to treatment.
If appropriate to the research aims of the applicant group, projects
may include the implementation of proof-of-concept clinical trials of
innovative therapeutic strategies.  It is envisioned that feedback
from the patient care setting will validate hypotheses of pathogen-
host relationships, direct refinement of quantitative assessment
methodologies needed for advancement of care, or foster design of
improved therapeutic strategies.
Areas of special interest include, but are not limited to:
A.  Elucidation of immune responses to the infection occurring in
HIV-infected individuals, such as specific humoral and cellular
responses, and identification of features of immune dysregulation,
such as cytokine abnormalities, humoral factors, and effector cell
defects that promote infection.
B.  Elucidation of pathogenic mechanisms of the organism in HIV-
infected individuals, and identification of molecular targets that
can be exploited in innovative therapeutic approaches.
C.  Clinical evaluation of methods for early detection of infection
and quantitative assessment of response to therapy in inaccessible
infections (e.g., quantitative PCR, surrogate markers).
D.  Evaluation of innovative therapeutic strategies (e.g., immune-
based therapies, gene-based approaches) and preliminary clinical
testing, with modifications as necessary based on clinical research
Applicants are encouraged to focus on one infectious organism and to
link several research objectives from basic research laboratories,
clinical centers, and the private sector.  All proposed studies
should carefully consider the ultimate potential for clinical
application.  Examples of the types of projects to study the
pathogens emphasized by this PA include, but are not limited to, the
o  Characterization of organism/infected cell interactions at various
stages of HIV immunodeficiency for one of the targeted infections.
o  Evaluation of the role of cytokines and immune effector cells in
the pathogenesis of infection caused by Cryptosporidium parvum in
o  Advanced testing of convenient methods to quantify total parasite
burden of Cryptosporidium parvum (in contrast to methods relying on
cyst quantitation in stool samples).
o  Evaluation of drug delivery and distribution to intestinal and
extra-intestinal sites for the treatment of Cryptosporidium parvum
disease in HIV-infected persons.
o  Identification of immunological correlates of human CMV viral
proliferation; development and testing of diagnostic or immunologic
markers to facilitate identification of patients at high risk of CMV
disease or to provide improved quantitative indicators of response to
o  Characterization of M. avium pathogenic mechanisms and associated
control of gene expression in individuals with HIV-infection;
identification of potential targets for innovative therapeutic
approaches (e.g., gene-based therapies); evaluation of novel delivery
systems to intracellular sites.
o  Identification of M. avium-specific defects in the response of
HIV-infected hosts (e.g. T-cell and macrophage function, T cell-
macrophage interaction); and identification of M. avium antigens
associated with protective immune responses.
A.  Terms and Conditions of Award
The following terms and conditions will be incorporated into the
Notice of Grant Award and provided to the Principal Investigator as
well as the institutional official at the time of award.  These terms
and conditions are a reiteration of and in addition to, and not in
lieu of, otherwise applicable OMB administrative guidelines, HHS
grant administration regulations at 45 CFR Parts 74 and 92 [Part 92
is applicable when State and local Governments are eligible to
apply], and other HHS, PHS, and NIH grant administration policies.
All clinical trials involving human subjects must be reviewed and
approved by the Clinical Science Review Committee, DAIDS, NIAID prior
to implementation. Clinical and laboratory leadership will be
expected to attend an annual meeting with NIAID program staff in
Bethesda, MD to review progress and share information among awardees.
B.  Patent Coverage
Because the development and availability of innovative, effective
strategies for the clinical management of OIs is the principal goal
of this PA, and because active involvement by the private sector is
facilitated by the existence of adequate patent coverage, it is
essential that applicants provide plans to ensure such coverage.
Since several institutions may be involved in this collaborative
research, complex patent situations may arise.  Each applicant must
therefore provide a detailed description of (1) 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; 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 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 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 patent agreement among the collaborating institutions, signed and
dated by the organizational officials authorized to enter into patent
arrangements for each investigator and institution, must be delivered
to Dr. Barbara Laughon prior to an award at the address listed under
INQUIRIES.  A copy of the proposed patent agreement may be submitted
with the application.  If the collaborators 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.
Laughon in lieu of the patent agreement prior to award.  The letter
must be co-signed by the Principal Investigator, each investigator,
and each of the business officials representing the respective
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 Division of Extramural
Invention and Technology Resources, Office of Extramural Research,
NIH, 6701 Rockledge Drive, Room 3188, Bethesda, MD 20892.
C.  Federally Mandated Regulatory Requirements
The CASOI must be in compliance with all Federal regulations and NIH
policies that apply to the conduct of research involving human
subjects.  These include, but are not limited to, Title 21 CFR 50,
56, 312, and Title 45 CFR 46.  The CASOI must be able to demonstrate
that: (1) each institution conducting CASOI trials has a current,
approved Assurance Number on file with the NIH Office for Protection
from Research Risks (OPRR); (2) each protocol and informed consent is
approved by the responsible Institutional Review Board (IRB) prior to
subject entry; (3) each investigator has supplied a completed
(including curriculum vitae) FDA 1572 to Division of AIDS for each
protocol conducted at each site; and (4) each subject (or legal
representative) gives written informed consent prior to entry on
study.  The CASOI must assure timely reporting of all serious and
unexpected toxicities and adverse experiences to the IND sponsor with
concurrent notification to the NIAID Scientific Coordinator if the
IND sponsor is other than Division of AIDS.
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 new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations), which
have been in effect since 1990. The new policy contains some
provisions that are substantially different from the 1990 policies.
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 printed in
the NIH Guide for Grants and Contracts, Volume 23, Number 11, March
18, 1994.  Investigators also may obtain copies of the policy from
the program staff listed under INQUIRIES.  Program staff may also
provide additional relevant information concerning the policy.
Prospective applicants are asked to submit a letter of intent that
includes a descriptive title of the overall proposed research, the
name, address and telephone number of the Principal Investigator, and
the number and title of this PA.  The annual receipt dates for the
letter of intent are shown at the top of this PA.  Although the
letter of intent is not required, is not binding, does not commit the
sender to submit an application, and does not enter into the review
of subsequent applications, the information that it contains allows
DRG and NIAID staff to estimate the potential review workload and to
avoid conflict of interest in the review.  The letter of intent is to
be sent to Dr. Dianne Tingley at the address listed under INQUIRIES.
Applicants are strongly encouraged to call NIAID program staff with
any questions regarding whether or not their proposed project is
within the scope of the programmatic area of emphasis described in
this PA.
Applications are to be submitted on the grant application form PHS
398 (rev. 5/95).  Applications kits are available at most
institutional offices of sponsored research and through the NIH web
site (http://www.nih.gov).  If the application kit cannot be obtained
from either of those sources, contact ASKNIH, Office of Extramural
Outreach and Information Resources, National Institutes of Health,
6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone
301/435-0714, email:  ASKNIH@odrockm1.od.nih.gov.
Because of the relatively broad and potentially complex nature of
research encouraged, applications that include consortium/contractual
arrangements should fully explain the programmatic research, fiscal,
and administrative arrangements in section (h) of the research plan.
The description of consortium arrangements should follow the outline
in "Guidelines for Establishing and Operating Consortium Grants,
January 1989," available from the individuals listed under INQUIRIES.
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 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.  Applicants from an institution receiving
government funds under 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, if applicable, and ensure that no
scientific and budget overlap exists with the proposed project.
The National Institute of Dental Research (NIDR) also has an interest
in the basic biology, biochemistry, pathophysiology, diagnosis,
prevention and treatment of opportunistic pathogens; in particular,
how these organisms interact with host tissues and defense mechanisms
in the oral cavity.  Applications that are of mutual interest to
NIAID and NIDR are likely to be given a secondary assignment to NIDR
in accordance with the NIH referral guidelines.
The 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 Program
Announcement.  The Policy update was published in the NIH Guide, Vol.
25, No. 14, May 3, 1996, and is effective June 1, 1996.
An application that proposes research within the programmatic areas
described by this PA must be identified by "YES" and the number and
title of this program announcement in section 2 of the face page of
the application.  This will facilitate the assignment of the
application by the Referral Office.  However, the fundamental factor
upon which the assignment will be based is the content of the
proposed research.
The completed original and four legible, single-sided copies of the
application and four sets of the appendices must be sent or delivered
BETHESDA, MD  20892-7710
BETHESDA, MD  20817-7710 (for express/courier service)
At the same time, one complete copy of the application and appendices
must be sent or delivered to:
Dianne Tingley, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C07
6003 Executive Boulevard
Bethesda, MD  20892-7610
Rockville, MD  20852 (for express/courier service)
Review Procedures
Upon receipt, applications will be reviewed for completeness by the
NIH Division of Research Grants (DRG).  Incomplete applications will
be returned to the applicant without further consideration.
Applications that are complete will be assigned, based on the content
of the proposed research, the PHS Referral Guidelines, and the
elaboration of those guidelines set forth by this PA.  Applications
for research topics that are not within the areas described by this
PA will be assigned and reviewed according to standard procedures.
Applications that propose research that is within the scope described
by this PA will be assigned to a peer review group convened by DRG
and NIAID.  Each application will be evaluated for scientific and
technical merit by in accordance with the review criteria for
research project grant applications.  These criteria and an
elaboration of the meaning thereof in the context if this area of
interest are stated below.
As part of the initial merit review, all applications will receive a
written critique and undergo a process in which only those
applications deemed to have the highest scientific merit, generally
the top half of the applications under review, will be discussed,
assigned a priority score, and receive a second level review by the
appropriate national advisory council.  The assignment for funding
consideration and the second level of review for applications that
propose research within the areas of emphasis described by this PA
will be the National Institute of Allergy and Infectious Diseases.
Review Criteria
o  scientific, technical, or medical significance and originality of
the proposed research, specifically including relevance of study
objectives to advancing the prevention, diagnosis, or treatment of
opportunistic infections in HIV infected persons and the likelihood
that innovative and potentially practical strategies will be
identified during the course of the proposed project;
o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research, specifically
including assessment of the clinical and basic components in terms of
the incorporation of state-of-the-art approaches and methodologies of
the proposed project towards the attainment of the stated
programmatic goals; cohesiveness, multi-disciplinary and multifaceted
scope of the application and the coordination and interdependence of
all proposed components to the common theme;
o  qualifications and research experience of the Principal
Investigator and collaborators, particularly, but not exclusively, in
the area of the proposed research, as well as the leadership, and
administrative competence of the Principal Investigator for the
development, implementation, and management of the research program,
and the Principal Investigator's commitment to devote sufficient time
and effort to the project; and the qualifications, experience, and
commitment of all other investigators, including their ability to
devote adequate time and effort to the project;
o  availability of the resources necessary to perform the research,
particularly the soundness of the administrative and organizational
structure that facilitates attainment of the project objectives,
including the administrative planning and leadership capability to
provide for internal quality control of on-going research, allocation
of funds, day-to-day management, internal communications and
cooperation among the investigators involved in the project.
o  appropriateness of the proposed budget and duration in relation to
the proposed research;
o  adequacy of plans to include both genders and minorities and their
subgroups as appropriate for the scientific goals of the research.
Plans for the recruitment and retention of subjects will also be
The initial review group will also examine the provisions for the
protection of human and animal subjects and the safety of the
research environment.
Concerns expressed by the initial review group about any of these
factors may influence the recommendation of the National Advisory
Allergy and Infectious Diseases Council.
Applications will compete for available funds with all other
favorably recommended applications.  The following will be considered
when making funding decisions:  quality of the proposed project as
determined by peer review, program balance among research areas of
the announcement, and availability of funds.  The National Institute
of Allergy and Infectious Diseases gives special consideration for
funding to scientifically meritorious applications that propose
research in the areas of programatic emphasis described in PAs issued
by the NIAID.
Written and telephone inquiries are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.
Direct inquiries regarding programmatic issues to:
Barbara Laughon, Ph.D.
Division of AIDS
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 2C26 - MSC 7620
Bethesda, MD  20892-7620
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 402-2304
FAX:  (301) 402-3171
Email:  barbara_laughon@nih.gov
Direct inquiries regarding fiscal and administrative matters to:
Ms. Jane Unsworth
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4B22 - MSC 7610
Bethesda, MD  20892-7610
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 402-6824
FAX:  (301) 480-3780
Email:  jane_unsworth@nih.gov
Direct inquiries regarding application preparation and review, the
letter of intent and ONE copy of the completed application to:
Dianne Tingley, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4C07 - MSC 7610
Bethesda, MD  20892-7610
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 496-2550
FAX:  (301) 402-2638
Email:  dt15g@nih.gov
This program is described in the Catalog of Federal Domestic
Assistance No. 93.855, Immunology, Allergic and Immunological
Diseases Research, and 93.856, Microbiology and Infectious Diseases
Research.  Grants are awarded under the authority of the Public
Health Service Act, Section 301 (42 USC 241) and administered under
PHS grants policies and Federal Regulations, most specifically at 42
CFR Part 52 and 45 CFR Part 74.  This program is not subject to the
intergovernmental review requirements of the Executive Order 12372 or
Health Systems Agency review.
The PHS strongly encourages all grant and contract recipients to
provide a smoke-free workplace and promote the non-use of all tobacco
products.  In addition, Public Law 103-227, the Pro-Children Act of
1994, prohibits smoking in certain facilities (or in some cases, any
portion of a facility) in which regular or routine education,
library, day care, health care or early childhood development
services are provided to children.  This is consistent with the PHS
mission to protect and advance the physical and mental health of the
American people.

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