Full Text PAR-97-056
 
INTEGRATED PRECLINICAL/CLINICAL AIDS VACCINE DEVELOPMENT
 
NIH Guide, Volume 26, Number 13, April 25, 1997
 
PA NUMBER:  PAR-97-056
 
P.T.34

Keywords: 
  AIDS 
  Vaccine 

 
National Institute of Allergy and Infectious Diseases
 
Application Receipt Dates: July 30, 1997, July 30, 1998, July 30,
1999
 
PURPOSE
 
The National Institute of Allergy and Infectious Diseases (NIAID)
gives special consideration for funding to scientifically meritorious
applications in response to Program Announcements (PAs), including
award of grants beyond our regular percentile and priority score
paylines.  NIAID PAs identify current areas of ongoing research
emphasis for NIAID.
 
The Division of AIDS (DAIDS), NIAID invites applications for research
and development efforts directed toward obtaining a safe and
efficacious vaccine to protect against HIV-1 infection or AIDS.  The
aim of this program, Integrated Preclinical/Clinical AIDS Vaccine
Development, is to encourage the process of laboratory-to-clinic
development, evaluation, and refinement of vaccine concepts. This PA
expands upon the current National Cooperative Vaccine Development
Groups (NCVDG) program to include limited human clinical trials.
Applicants may apply for support for preclinical/basic research aimed
at creation of vaccines and testing in animal models, vaccine lot
production and toxicology testing, and limited clinical studies in
humans. The information obtained in human studies can then be used to
refine the vaccine approach, or advance the product further in human
trials.
 
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,
"Integrated Preclinical/Clinical AIDS Vaccine Development", is
related to the priority areas of HIV Infection and Immunization, and
Infectious Diseases. 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) through the Superintendent
of Documents, Government Printing Office, Washington, DC 20402-0325
(telephone 202-512-1800).
 
ELIGIBILITY
 
Applications may be submitted by domestic non-profit and for-profit
organizations, public and private organizations such as universities,
colleges, hospitals, laboratories, units of state and local
governments, and eligible agencies of the federal government. While
foreign organizations are not eligible to apply as the principal
institution, foreign components may apply as sub-projects; however,
these components will receive no support for indirect costs.
Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as principal investigators.
 
MECHANISM OF SUPPORT
 
The administrative and funding mechanism will be the program project
grant (P01). Program project grants support broadly-based,
multidisciplinary research programs that have a well-defined, central
research focus or objective. An important feature is that the
interrelationships of the individual scientifically meritorious
projects will result in a greater contribution to the overall program
goals than if each project were pursued individually. The program
project grant consists of a minimum of three (3) interrelated
individual research projects that contribute to the program
objective. This type of award can also provide support for certain
shared  resources termed cores which provide funds for tasks common
to 2 or more projects within the award. NIH limits the time period
for P01 grants to 5 years. In addition, P01 grant applications
submitted in response to this PA may not request in excess of $1
million first-year total (direct plus indirect) costs.
 
Responsibility for the planning, direction, and execution of the
proposed research will be solely that of the applicant under this
type of award.
 
RESEARCH OBJECTIVES
 
Background
 
NIAID has a history of strongly supporting efforts to obtain a safe
and efficacious vaccine against AIDS. The complexity of vaccine
research requires the contributions and collaboration of
investigators from fields which typically do not need to interact
significantly. In 1986, the National Cooperative Vaccine Development
Groups (NCVDG) were conceived to foster the necessary collaborative
efforts between immunologists, molecular biologists, and
primatologists to ultimately develop an AIDS vaccine. A primary
objective of the program was to facilitate the progression of HIV
vaccines from basic research through to preclinical evaluation in
non-human primates. A variety of vaccine strategies for both SIV and
HIV have been evaluated through this mechanism, with participation
from academic institutions and industry.
 
The intent of this PA is to continue the work of the NCVDG and also
to expand it to include small-scale human clinical trials.
 
Research Objectives and Scope
 
As stated above, the overall goal of this program announcement is to
support multidisciplinary research that will lead to a protective
AIDS vaccine. To that end, research responsive to this PA will
describe studies to move preclinical research through to testing in
animal models and humans. Applications can include preclinical
research, vaccine production, and in vivo testing in their
application. Preclinical research alone, without clear, feasible, and
realistic plans to progress to testing in animals and humans within
the period of award, will not be considered responsive to this PA.
Applications that describe only production and in vivo testing will
be acceptable, as will testing only, if the applicant provides
sufficient evidence that the product is indeed ready for production
and/or trial. An iterative process of development, production and
testing of candidate vaccines is the goal of this program.
 
Studies responsive to this program announcement can include, but are
not limited to, vaccine delivery and vector systems, methods of
enhancing specific immune responses, dissection of viral and host
contributions to immunity and combinations of these. Research
directed toward optimization of existing vaccine concepts is also
encouraged.
 
The participation of the private sector is strongly encouraged
because of its unique infrastructure and capital resources which make
it especially appropriate for collaboration in these types of
studies. For example, a pharmaceutical or biotechnology interest
might compose a subproject of an application to provide production
capabilities when a preclinical concept is ready to be tested and
sufficient vaccine product is necessary for the studies.
 
Applicants with viable vaccine concepts may apply for support of the
preclinical research necessary to realize the concept, and ultimately
produce and test a product. One or more subproject components of the
application can be involved in this preclinical development phase for
which funds will be used for the extensive immunologic
characterization of the proposed vaccine. Applicants must delineate
discreet goals, milestones, and criteria that will be used by the
investigators to evaluate progress toward a testable vaccine. If
preclinical evaluation of the concept shows that further studies are
not warranted, funding for those latter phases of the project will
not be released.
 
Applicants may also request funds for production of clinical grade
(manufactured under Food and Drug Administration (FDA)-Good
Laboratory Practices (GLP) guidelines) vaccine and subsequent in vivo
testing. Applicants seeking to move from preclinical research to lot
production must detail the goals, milestones, and criteria, which
will be reviewed by the Scientific Peer Review Group (SPRG), to
justify the release of funds for this purpose. Those investigators
who are not requesting support for preclinical research and are
applying for lot production and in vivo testing only, must present
sufficient preclinical data to justify that the vaccine concept is
ready for production and animal or human trials. Applicants seeking
to move from preclinical development to production during the period
of award must document successful completion of the goals and
milestones for the preclinical evaluation of the vaccine strategy to
show that vaccine efficacy is a reasonable expectation. The
application must contain all regulatory guidelines that the applicant
is proposing to complete which will need to be satisfied before the
release of funds.
 
Applicants may apply to study their vaccine concept in small, focused
human studies. Since these studies will require the filing of an IND
application with the FDA, certain regulatory requirements must be met
prior to the release of funds to initiate this part of the study.
Additionally, information that may be useful in improving or refining
the vaccine may arise during these clinical studies. The applicant
should address how the results of the clinical evaluations will be
used to either improve the vaccine concept or advance it to a
traditional phase I trial.
 
Investigators are encouraged to discuss clinical evaluation of their
candidate vaccines by the NIAID-supported AIDS Vaccine Evaluation
Group (AVEG) with NIAID Program Staff and with the Executive Group of
AVEG. For clinical trials, NIAID Program Staff can arrange for review
of data by the AIDS Vaccine Data and Safety Monitoring Board which
reviews data for AVEG trials. Funds available under this PA are for
small-scale clinical studies . Investigators interested in pursuing
NIAID support for large-scale human vaccine trials should contact the
AVEG (see below for contact information).
 
Applications requesting support for small-scale human clinical
studies must address: design of the clinical trial, plan for
recruitment, enrollment, education and follow-up of clinical
subjects, including attention to the possibility of social harms and
discrimination arising from vaccine-induced positive screening tests
that may be interpreted incorrectly as HIV infection, plus
documentation of compliance with all applicable federal (FDA), state
and local laws and regulations governing clinical research. The
completeness and feasibility of these plans will be reviewed by the
SPRG. If an application proposes preclinical development or
evaluation of a vaccine concept and/or vaccine production, and
subsequent limited human studies , the applicant must describe
milestones and criteria that will be used to approve the transition.
These criteria must be clearly stated in the application, approved by
the SPRG, and attained during the study before funds will be released
for the next phase of the project.
 
SPECIAL REQUIREMENTS
 
All awardees are strongly encouraged to attend the NIAID-sponsored
annual meeting on AIDS vaccine development and may include a request
for travel funds for this purpose.
 
Patent Coverage
 
Since applications may involve several institutions, including the
private sector, complex patent situations may arise. To avoid delays
in the implementation of new vaccines for HIV related to intellectual
property issues, each multi-project group is requested to provide a
plan as part of the application, detailing 1) the approach, agreed to
by all parties, to be used for obtaining patent coverage and for
licensing, where appropriate, and, 2) the procedures to be followed
for the resolution of legal problems that potentially may develop.
Attention is drawn to the reporting requirements of 35 U.S.C. Parts
200-212 and 37 CFR Part 401 or FAR 55.227-11. Instructions were also
published in the NIH GUIDE FOR GRANTS AND CONTRACTS, Vol. 19, No. 23,
June 22, 1990. Note that non-profit organizations (including
universities) and small business firms retain the rights to any
patent resulting from Government grants or cooperative agreements.
 
It is also noted that a Presidential memorandum of February 18, 1983
extended to all business concerns, regardless of size, the first
option to the ownership of rights to inventions as provided in P.L.
96-517. As a result of this memorandum, the relationships among
industrial organizations and other participants are simplified, since
all Group members can now be full partners in the research and in any
inventions resulting therefrom. The specific patenting arrangements
among the institutions may vary and could include joint patent
ownership, exclusive licensing arrangements, etc. Applicants are
encouraged to develop an arrangement that is most suitable for the
Group's particular circumstances.
 
The patent agreement among the institutions comprising the Group,
signed and dated by the organizational officials authorized to enter
into patent arrangements for each Group member and member
institution, must be delivered prior to submission of the application
to Dr. Steven Bende, at the address listed under INQUIRIES. A copy of
the patent agreement should also be submitted with the application.
If the Group wishes to place all inventions and discoveries resulting
from these studies within the public domain, a letter to that effect
must be submitted to Dr. Bende in lieu of the patent agreement . The
letter must be co-signed by the Principal Investigator, each of the
Project Leaders, and each of the business officials representing the
respective institutions.
 
Federal regulation clause 37-CFR-401 and HHS Inventions regulations
at 45 CFR Parts 6 and 8 require that NIH be informed of inventions
and licensing occurring under NIH funded research. Invention and
licensing reports must be submitted to the Extramural Invention
Reports Office at 301 435 1986.
 
For Awards Including a Clinical Component
 
For awards including vaccine pilot lot production, release of funds
for this purpose will be contingent on successful accomplishment of
milestones and criteria proposed by the applicant. These criteria
must include compliance with all applicable laws and regulations,
shall be stated in the grant application, and reviewed by the SPRG.
Production facilities for clinical material must meet FDA standards
for Good Laboratory Practices, and clinical trials must be initiated
and conducted via a US IND application.
 
Release of funds for clinical research will be contingent on
successful accomplishment of milestones and criteria for preclinical
evaluation of the product and plans for its production and
availability of funds. These criteria must include compliance with
all applicable laws and regulations, shall be stated in the grant
application, and reviewed by the SPRG. If an awardee group
anticipates successful achievement of its milestones and applies to
move from preclinical to clinical research during the period of
award, funds to accommodate the potentially more costly clinical
study should be budgeted into the application.
 
The Principal Investigator is responsible for:
 
1.  assuming responsibility for developing protocols and monitoring
study performance, participant recruitment and follow-up, interim
data and safety monitoring. All proposed protocols will be submitted
by the Principal Investigator to the NIAID Program Officer (Dr.
Steven Bende, address below) for review for safety issues by the
DAIDS Prevention Sciences Review Committee. There will be additional
reporting requirements to inform DAIDS/NIAID of recruitment,
retention, and adverse events;
 
2.  establishing procedures to comply with FDA regulations for
studies involving investigational agents or devices and to comply
with the requirements of 45 CFR Part 46 for the protection of human
subjects. Terms of award for any human clinical trial component will
be developed to ensure volunteer safety and monitoring of compliance
with regulations and Good Clinical Practices. NIAID staff will
provide guidance and technical advice on meeting FDA requirements for
investigational substances.
 
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 and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research. This policy results from the
NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43).
 
All investigators proposing research involving human subjects should
read the "NIH Guidelines For Inclusion of Women and Minorities as
Subjects in Clinical Research," which have been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513), and the NIH
Guide For Grants And Contracts of March 18, 1994, Volume 23, Number
11.
 
APPLICATION PROCEDURES
 
Applications are to be submitted on the grant application for PHS 398
(rev. 5/95).  Application 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: asknih@odrockm1.nih.gov.  The title
and number of the PA must be typed in section 2.
 
The application receipt dates for this program announcement are: July
30, 1997, July 30, 1998, and July 30, 1999.
 
The completed, signed original and three legible, single-sided copies
of the application must be sent or delivered to:
 
DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817-7710 (for express/courier service)
 
At the time of submission, two additional exact copies of the grant
application and all five sets of any appendix material must be sent
to Dr. Dianne Tingley at the address listed under INQUIRIES.
 
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, Vol.
25, No. 14, May 3, 1996, and became effective June 1, 1996. NIAID has
(1) policies that require pre-approval by the Institute before
acceptance of Program Project applications and applications that
request $500,000 or more in annual direct costs and (2) guidelines
for preparation of multi-project (including P01) research grant
applications.
 
Potential applicants must contact the appropriate program staff
listed under INQUIRIES to initiate clearance processes for acceptance
of their applications and to obtain guidelines for the preparation of
P01 applications.  Applicants are strongly encouraged to contact
program staff early in project development with any questions
regarding their proposed project(s).
 
Current NIH policy permits a component research project of a
multi-project P01 grant application to be concurrently submitted as a
traditional individual research project (R01) application.  If,
following review, both the multi-project P01 application and the R01
application are found to be in the fundable range, the investigator
must relinquish the R01 and will not have the option to withdraw from
the multi-project P01 grant. This is an NIH policy intended to
preserve the scientific integrity of a multi-project grant, which may
be seriously compromised if a strong component project(s) is removed
from the program. Investigators wishing to participate in a
multi-project grant must be aware of this policy before making a
commitment to the Principal Investigator and awarding institution.
 
Research Plan Page Limits. Sections a - d of the research plan are
limited to 25 pages for: (1) the overview of the proposed program;
(2) each research project; and (3) each core.
 
Applicants from institutions that have a General Clinical Research
Centers (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the Center as a resource for
conducting the proposed clinical research. If so, a letter of
agreement from the GCRC Program Director must be included in the
application material.
 
REVIEW CONSIDERATIONS
 
Review Procedures
 
Upon receipt, applications will be reviewed for completeness by the
NIH Division of Research Grants. 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.
 
Review Criteria
 
For preclinical evaluation of vaccine concepts/strategies reviewers
will consider:
 
A.  The overall scientific and technical merit of the proposed
vaccine study with regard to impact on the AIDS epidemic.
 
B.  Appropriateness and adequacy of the experimental approach and the
methodology proposed to carry out the research, specifically
including the feasibility of the applicant's plans, and the
availability of necessary facilities to conduct the research. In
addition, the goals and milestones to be met for progression through
to production and in vivo trial will be reviewed for adequacy,
feasibility, and likelihood of attainment during the period of the
grant.
 
For production of clinical grade vaccine product, reviewers will
consider:
 
A.  Appropriateness of the scientific rationale for advancing to the
vaccine production stage. To obtain funds for optional vaccine
production, milestones and criteria to be attained in order to merit
that funding must be proposed in the application. The SPRG will judge
the suitability of such criteria. If satisfactory proof that these
criteria and milestones have already been met is supplied, funds to
produce vaccine product will be released at the time of grant award.
 
B.  Completeness and feasibility of the plan to produce the vaccine.
This includes adherence to any and all federal (FDA), state, and
local regulations for the production of clinical grade material.
 
For optional clinical studies, reviewers will consider:
 
A.  Scientific, technical, and clinical significance and originality
of the proposed research.
 
B.  The completeness of plans for the design of the clinical trial,
plan for recruitment, enrollment, education and follow-up of clinical
subjects, including attention to the possibility of social harms and
discrimination arising from vaccine-induced positive screening tests
that may be interpreted incorrectly as HIV infection, and other harms
such as true HIV infection as the result of vaccination, and
compliance with all applicable Federal, State and local laws and
regulations governing clinical research will be reviewed by the SPRG.
Criteria and milestones to be met to permit release of funds and
progression of the study to the clinical phase will be evaluated by
the SPRG as well.
 
For all applications:
 
C.  Leadership and research experience of the Principal Investigator
and key staff in the areas of proposed research. For optional
clinical-grade vaccine production, the track record and facilities of
the proposed producer. For optional clinical trials research, the
leadership, scientific ability and administrative competence of the
applicant for the development, implementation and management of pilot
clinical trials, and for effective interaction with designated NIAID
staff.
 
D.  Adequacy of the proposed means for protecting against adverse
effects of the research upon humans, animals or the environment,
where such are involved.
 
E.  Justification of the usefulness of the core facilities to the
various research projects, including the administrative core, if
applicable. Each core unit must provide essential facilities or
service for two or more approved individual projects.
 
F.  A sound 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.
 
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.   For
applications assigned to the NIAID, preference will be given to
applications that propose to pursue the complete iterative process of
laboratory-to-clinic development, evaluation, and refinement of
vaccine concepts.
 
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:
 
Dr. Steven Bende
Division of AIDS
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 2A29
Bethesda, MD  20892-7620
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 435-3756
FAX:  (301) 402-3684
Email:  sb22k@nih.gov
 
Direct inquiries regarding review issues to:
 
Dr. Dianne Tingley
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4C07
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:
 
Laura Eisenman
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4B23
Bethesda, MD  20892-7610
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 402-5541
FAX:  (301) 480-3780
Email:  le55d@nih.gov
 
Direct inquiries regarding the AVEG to:
 
Barbara Savarese, RN
Division of AIDS
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 2A36
Bethesda, MD  20892-7620
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 435-3750
FAX:  (301) 402-3684
Email:  bs30g@nih.gov
 
AUTHORITY AND REGULATIONS
 
This program is described in the Catalog of Federal Domestic
Assistance Nos. 93.855, 93.856.  Awards are 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 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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