NATIONAL COOPERATIVE DRUG DISCOVERY RESEARCH ON OPPORTUNISTIC INFECTIONS

Release Date:  August 25, 1998

PA NUMBER:  PAR-98-101

P.T.

National Institute of Allergy and Infectious Diseases

Application Receipt Date:  November 19, 1998

PURPOSE

The National Institute of Allergy and Infectious Diseases (NIAID), National
Institutes of Health (NIH), invites multidisciplinary program project grant
applications to support projects with adequate preliminary data for serious
development of new therapies to treat AIDS-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 PA are human cytomegalovirus,
Mycobacterium tuberculosis, Mycobacterium avium, Cryptosporidium parvum and
the Microsporida.

NIH Support of Research on this Topic

Although this Program Announcement is being issued by NIAID, 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 Program Announcements 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, 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.  Foreign institutions are not eligible for program
project grant (P01) awards.  Racial/ethnic minority individuals, women, and
persons with disabilities are encouraged to apply as Principal Investigators.

MECHANISM OF SUPPORT

Program project grants (P01) support broadly based, multidisciplinary research
programs that have a well-defined, central research focus or objective.  An
important feature is that the interrelationships of the individual
scientifically meritorious projects will results in a greater contribution to
the overall program goals than if each project were pursued individually.  The
program project grant consists of a minimum of two interrelated individual
research projects that contribute to the program objective.  This type of
award also can provide support for certain common resources termed cores. 
Such resources should be utilized by two or more projects within the award. 
The total project period for P01 grants may not exceed five years.  At this
time, the NIAID is administratively limiting the duration of P01 grants to
four years; this administrative limitation may change in the future.  In
addition, P01 grant applications submitted in response to this PA may not
request in excess of $800,000 first-year total (direct and indirect) costs.

Responsibility for the planning, direction, and execution of the proposed
research will be solely that of the applicant.

Applicants for P01 grants must follow special application guidelines in the
NIAID Brochure entitled "Instructions for Applications For Multi-Project
Awards" (August 1997); this brochure is available via the World Wide Web at: 
http://www.niaid.nih.gov/ncn/grants/multibron.htm

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).

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.

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, 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.

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 to Grants and Contracts, Volume 19,
Number 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.

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 via the WWW. at:
http://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 the responsiveness of their proposed
project to the goals of this PA.

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) 435-0714,
email:  grantsinfo@nih.gov

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)

P01 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 (1) policies
that require pre-approval by the Institute before acceptance of Program Project
applications that request $500,000 or more in annual direct costs and (2) guidelines
for preparation of multi-project (including P01) research grant applications.

Potential applicants must contact the appropriate program staff listed in
INQUIRIES to initiate clearance processes for acceptance of their application
and to obtain guidelines for the preparation of P01 applications.

CONCURRENT SUBMISSION OF AN R01 AND A COMPONENT PROJECT OF A P01 APPLICATION. 
Current NIH policy permits a component research project of a multi-project P01
grant application to be concurrently submitted as a traditional individual
research project grant (R01) application.  If, following review, both the
multi-project P01 application and the R01 application are found to be in the
fundable range, the investigator must relinquish the R01 and will not have the
option to withdraw from the multi-project P01 grant.  This is an NIH policy
intended to preserve the scientific integrity of a multi-project grant, which
may be seriously compromised if a strong component project(s) is removed from
the program.  Investigators wishing to participate in a multi-project grant
must be aware of this policy before making a commitment to the Principal
Investigator and awarding institution.

SPECIAL INSTRUCTIONS FOR COMPLETION OF P01 APPLICATIONS IN RESPONSE TO THIS PA

The NIAID brochure, "INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS," 
(August 1997) presents specific instructions for sections of the PHS 398 (rev.
5/95) application form that should be completed differently than usual.  This
brochure is available via the WWW at: http://www.niaid.nih.gov/ncn/grants/
multibron.htm

P01 applications that are not received as a single package on a receipt date
or that do not conform to the instructions contained in PHS 398 (rev. 5/95)
Application Kit (as modified in, and superseded by, the NIAID BROCHURE
ENTITLED "INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS", August
1997) will be judged non-responsive and will be returned to the applicant.

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.  Upon receipt, applications will be reviewed for completeness by
the NIH Center for Scientific Review and for responsiveness to the goals of
the PA by NIAID staff.  Incomplete applications will be returned to the
applicant without further consideration.

P01 applications that are complete and responsive to this PA 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- 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.

Requests for the NIAID brochure "INSTRUCTIONS FOR ABBREVIATED APPLICATIONS FOR
MULTI-PROJECT AWARDS" as well as inquiries regarding programmatic (research
scope, eligibility and responsiveness) 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:  BL17u@nih.gov

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:  dt15g@nih.gov

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:  jane_unsworth@nih.gov

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.


Return to Volume Index

Return to NIH Guide Main Index


Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
  National Institutes of Health (NIH) - Home Page National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS)
  USA.gov - Government Made Easy


Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.