NATIONAL COOPERATIVE DRUG DISCOVERY RESEARCH ON OPPORTUNISTIC INFECTIONS

Release Date:  August 25, 1998

PA NUMBER:  PA-98-100

P.T.

National Institute of Allergy and Infectious Diseases
National Cancer Institute

Application Receipt Date:  November 19, 1998

PURPOSE

The National Institute of Allergy and Infectious Diseases (NIAID) and the
National Cancer Institute (NCI) invite investigator-initiated research project
grant applications to support projects with adequate preliminary data for
serious development of new therapies to treat AIDS- and cancer-associated
opportunistic infections.  Studies may include research on identified targets
for rational design of inhibitors or projects with chemically identified
candidate compounds with suitable efficacy and selectivity for exploration as
candidate drugs.  Applications that include collaborations with the private
sector (e.g., pharmaceutical, chemical or biotechnological companies) are
strongly encouraged.

The opportunistic pathogens emphasized in this program announcement (PA) are
human cytomegalovirus, Mycobacterium tuberculosis, Mycobacterium avium,
Cryptosporidium parvum, systemic candidiasis, Aspergillus, and the
Microsporida.

NIH Support of Research on this Topic

Although this PA is being issued by NIAID and NCI, other components of NIH
listed below also have an interest in and support research on the topics
covered.  Applicants may wish to contact Program Staff for each of these NIH
components to find out about other funding opportunities.

The National Institute for Dental Research
The National Health, Lung and Blood Institute

Applications submitted in response to PA are assigned according to established
PHS referral guidelines.  When the subject of an application is of interest to
more than one component of NIH, dual assignments are made.

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 PA, National Cooperative Drug
Discovery Research for Opportunistic Infections, is related to the priority
area of human 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).

ELIGIBILITY

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 governments, and eligible
agencies of the Federal government.  Racial/ethnic minority individuals,
women, and persons with disabilities are encouraged to apply as Principal
Investigators.

MECHANISM OF SUPPORT

Traditional research project grant (R01) applications may be submitted in
response to this program announcement.  Applications for R01 grants may
request up to five years of support.  Responsibility for the planning,
direction, and execution of the proposed research will be solely that of the
applicant.

RESEARCH OBJECTIVES

Background

Although HIV is the primary cause of the progressive immunological
deterioration seen in AIDS, the opportunistic infections (OIs) remain the most
important complications of HIV infection, resulting in profound morbidity and
mortality.  Patients who have experienced one OI are at great risk of
developing a second.  The pathologic consequences associated with OIs in AIDS
are debilitating retinitis (cytomegalovirus), tuberculosis (Mycobacterium
tuberculosis), disseminated nontuberculosis mycobacterial disease (M. avium),
and protracted diarrhea (Cryptosporidium parvum, Enterocytozoon bieneusi). 
Individuals immunocompromised by HIV or chemotherapy for malignancies are at
risk for additional opportunistic infections such as aspergillosis and
systemic candidiasis.

The clinical management of OIs in immunocompromised patients remains
difficult.  Available drugs to treat opportunistic infections (including
tuberculosis) do not exhibit adequate potency to completely eradicate
infecting organisms, and prolonged HIV-mediated immunosuppression requires
prolonged treatment schedules and prophylaxis regimens against recurrence of
infections.  Toxicity and adverse side effects of therapeutic agents,
long-term drug use leading to patient intolerance or drug resistance, frequent
relapses, drug-drug interactions, and/or lack of standard treatments for newly
emerging OIs (e.g., C. parvum, E. bieneusi) complicate the management of OIs
in AIDS patients.  New ideas and novel approaches are urgently needed to
overcome the lack of therapeutic options available to people with AIDS- and
cancer-associated OIs.

Research Objectives and Scope

The objective of this PA is to encourage biological, chemical/biochemical, or
pharmacological studies directed toward development of candidate drugs that
are lethal to the pathogen with minimal toxicity for the host.

The research scope emphasizes studies on the following opportunistic
pathogens: human cytomegalovirus (HCMV), Mycobacterium tuberculosis,
Mycobacterium avium, Cryptosporidium parvum, systemic candidiasis,
Aspergillus, and the Microsporida. Example areas of research include, but are
not limited to:

*  expression of confirmed drug targets; modeling and synthesis of inhibitors;
efficacy evaluations in vitro and in vivo; toxicity testing and preliminary
pharmacokinetics.

*  evaluation of known gene products expressed during infection for targeted
intervention; comparison of synthesized or known therapeutics on organisms
growing intracellularly or at the site of infection; selection and production
of candidate therapeutic agents for animal efficacy and toxicity testing.

*  molecular modeling using available crystalline proteins; selection and
synthesis of ligands; evaluation of molecular interactions and microbiological
effects; radiolabelling to track molecular and cellular transition of
candidate compounds.

*  further preclinical development to examine the clinical candidacy of a
selected compound or immune-based therapy including synthesis research,
biological efficacy testing in animal systems, bioavailability estimations,
interactions with anti-retroviral agents, toxicology evaluations, and
mechanism of action studies.

*  exploration of natural products as a source of novel, active agents through
bioassay-guided fractionation of extracts of plant, animal, and/or microbe
origin using specific, confirmed targets identified above.  (Investigators may
have access to the NCI natural products repository of plant and marine
organism extracts, subject to the signing of a Material Transfer Agreement
protecting the rights of all parties. More information may be obtained from
NCI program staff listed under INQUIRIES below.)

SPECIAL REQUIREMENTS

Patent Coverage

Because active involvement by the private sector is encouraged, it is
essential that applicants provide plans to ensure such coverage.  Since
several institutions may be involved in collaborative projects, complex patent
situations may arise.  Where applicable, 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 more suitable for their own particular
circumstances.

The patent agreement among the collaborating institutions, signed and dated by
the organizational official 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 institutions.

Applicants proposing to access the Natural Products Repository of the NCI must
obtain and execute the Natural Products Repository Material Transfer Agreement
in advance of submitting a grant application.  This agreement is available at
http://dtp.nci.nih.gov/branches/npb/agreements.html or by contacting NCI (see
INQUIRIES).

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.

TERMS AND CONDITIONS OF AWARD

Integration into the on-going program of the National Cooperative Drug
Discovery Groups for the Treatment of Opportunistic Infections (NCDDG-OI) is
anticipated.  Principal Investigators and project leaders will be expected to
attend an annual NCDDG-OI meeting to review progress and share information
among awardees.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and
their sub-populations must be included in all NIH supported biomedical and
behavioral research projects involving human subjects, unless a clear,
compelling rationale, and justification are 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", 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, which is available at:
https://grants.nih.gov/grants/guide/notice-files/not94-100.html

NIH POLICY AND GUIDELINES ON THE INCLUSION OF CHILDREN AS PARTICIPANTS IN
RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them. 
This policy applies to all initial (Type 1) applications submitted for receipt
dates after October 1, 1998.

All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjects" that was published in the NIH Guide for
Grants and Contracts, March 6, 1998, and which is available at the following
URL address:  http://www.nih.gov/grants/guide/notice-files/not98-024.html

APPLICATION PROCEDURES

Applicants are strongly encouraged to contact program staff early in project
development with any questions regarding their proposed project.

Applications are to be submitted on the grant application form PHS 398 (rev.
5/95) and will be accepted on the application deadline as indicated at the
beginning of this PA.  Applications kits are available at most institutional
offices of sponsored research and may be obtained from the Division of
Extramural Outreach and Information, National Institutes of Health, 6701
Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 710-0267,
email:  [email protected]

For purposes of identification and processing, item 2 on the face page of the
application must be marked YES.  The PA number and the PA title must also be
typed in section 2.

The completed, signed original and five legible, single-sided copies of the
application must be sent or delivered to:

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

ALL APPLICANTS REQUESTING $500,000 OR MORE IN ANNUAL DIRECT COSTS.  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 PA.  The Policy Update was published in the
NIH Guide for Grants and Contracts, March 20, 1998, and is available at:
http://www.nih.gov/grants/guide/notice-files/not98-030.html.  NIAID has a policy
that requires pre-approval by the Institute before acceptance of applications
that request $500,000 or more in annual direct costs.

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 research.  If
so, a letter of agreement from the GCRC Program Director must be included in
the application material.

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established PHS referral
guidelines.  Applications will be reviewed for completeness by the NIH Center
for Scientific Review (CSR).  Incomplete applications will be returned to the
applicant without further consideration.  Applications that are complete will
be evaluated for scientific and technical merit by an appropriate peer review
group convened by the NIAID.

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.

Review Criteria

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  The
specific goal of this PA is to support projects with adequate preliminary data
for serious development of new therapies to treat AIDS- and cancer-associated 
opportunistic infections.  The reviewers will comment on the following aspects
of the application in their written critiques in order to judge the likelihood
that the proposed research will have a substantial impact on the pursuit of
these goals.  Each of these criteria will be addressed and considered by the
reviewers in assigning the overall score weighting them as appropriate for
each application.  Note that the application does not need to be strong in all
categories to be judged likely to have a major scientific impact and thus
deserve a high priority score.  For example, an investigator may propose to
carry out important work that by its nature is not innovative but is essential
to move a field forward.

1.  Significance.  Does this study address an important problem? If the aims
of the application are achieved, how will scientific knowledge be advanced? 
What will be the effect of these studies on the concepts or methods that drive
this field?

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

3.  Innovation.  Does the project employ novel concepts, approaches or method? 
Are the aims original and innovative?  Does the project challenge existing
paradigms or develop new methodologies or technologies?

4.  Investigator.  Is the investigator appropriately trained and well suited
to carry out this work?  Is the work proposed appropriate to the experience
level of the principal investigator and other researchers (if any)?

5.  Environment.  Does the scientific environment in which the work will be
done contribute to the probability of success?  Do the proposed experiments
take advantage of unique features of the scientific environment or employ
useful collaborative arrangements?  Is there evidence of institutional
support?

The initial review group will also examine: the appropriateness of proposed
project budget and duration; the adequacy of plans to include both genders and
minorities and their subgroups, and children as appropriate for the scientific
goals of the research and plans for the recruitment and retention of subjects;
the provisions for the protection of human and animal subjects; and the safety
of the research environment.

AWARD CRITERIA

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 program announcement, and
availability of funds.

INQUIRIES

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

Inquiries regarding programmatic issues may be directed 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:  [email protected]

Mary K. Wolpert, Ph.D.
Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Boulevard, Room 841
Bethesda, MD  20892-7456
Telephone:  (301) 496-8783
FAX:  (301)  402-5200
Email:  [email protected]

Inquiries regarding Repository issues may be directed to:

Gordon Cragg, Ph.D.
Natural Products Branch
National Cancer Institute, NCI-FCRDC
Fairview Center, Suite 206
P.O. Box B
Frederick, MD  21702-1201
Telephone:  (301) 846-5387
FAX:  (301) 846-6178
Email:  [email protected]

Direct inquiries regarding review issues 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:  [email protected]

Direct inquiries regarding fiscal matters to:

Ms. Jane W. Unsworth
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4B25 - MSC 7610
Bethesda, MD  20892-7610
Telephone:  (301) 402-6824
FAX:  (301) 480-3780
Email:  [email protected]

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance Nos.
93.856 and 93.855.  This program is supported under authorization of the
Public Health Service Act, Sec. 301 (c), Public Law 78-410, as amended. 
Awards will be administered under PHS grants policies and Federal Regulations
42 CFR Part 52 and 45 CFR Part 74.  This program is not subject to the
intergovernmental review requirements of Executive Order 12372 or Health
Systems review.

The Public Health Service 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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