kristoff@GENBANK.BIO.NET (Dave Kristofferson) (11/06/90)
REQUEST FOR COOPERATIVE AGREEMENTS APPLICATIONS:
RFA: AI-91-01
RE-ISSUANCE OF RFA-87-AI-14 DATED 2/87
P.T. 34; K.W. 0740012, 1002008, 1002045
MOLECULARLY TARGETED APPROACHES TO ANTIVIRAL THERAPY
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Letter of Intent Receipt Date: November 28, 1990
Application Receipt Date: January 17, 1991
The National Institute of Allergy and Infectious Diseases (NIAID)
invites applications for research that applies an understanding of the
molecular biology of virus replication and pathogenesis to the
development of antiviral agents that are targeted to inhibit specific
viral functions. Therapeutic and prophylactic agents (other than
vaccines) that specifically inhibit virus replicative functions without
interfering with normal cellular processes are likely to provide
clinical benefit with minimal toxicity. Research on any virus that is a
human pathogen or that serves as a model for a human pathogen, except
for human immunodeficiency virus (HIV) and/or other retroviruses, is an
appropriate subject for a proposal. Research on HIV antiviral agents is
the subject of a separate initiative.
Successful applicant(s) funded under this Request for Applications (RFA)
will be supported through Cooperative Agreements. Cooperative
Agreements are awarded to both nonprofit and for-profit organizations
and institutions. This type of solicitation is utilized when it is
desired to encourage investigator-initiated research projects in areas
of special importance to the NIH and where substantial programmatic
involvement by staff is anticipated. This RFA solicitation represents a
single competition, with a specified deadline for receipt of
applications. There are no plans to reissue this RFA at any future
time. All applications received in response to the RFA will be reviewed
by the same NIAID Initial Review Group (IRG) and by the National
Advisory Allergy and Infectious Diseases Council. The deadline for the
receipt of applications in response to this RFA is January 17, 1991.
Applications should be prepared and submitted in accordance with the
aims and requirements as set forth in the remainder of this document.
I. BACKGROUND INFORMATION
The Division of Microbiology and Infectious Diseases (DMID), NIAID,
invites applications for Cooperative Agreements to support research
projects to develop molecularly targeted agents as inhibitors of virus
infection. Viral infections account for significant morbidity and
mortality, as well as economic loss, in the United States and the rest
of the world. NIAID continues to play a central role in the development
of vaccines and therapies for viral diseases. DMID has targeted the
control of infections caused by cytomegalovirus and other herpesviruses,
papillomaviruses, hepatitis viruses and respiratory viruses as a high
priority. (The Division of AIDS has responsibility for the control of
HIV and other retroviral infections). DMID sponsors programs for both
in vitro and animal model preclinical evaluation, as well as clinical
trials of promising experimental therapies. Since there is a desperate
public health need for effective, nontoxic agents for antiviral therapy,
NIAID would like to stimulate research on the design and discovery of
novel antiviral agents.
The search for effective therapeutic agents to combat these serious
infections was long delayed by the widely-held belief that the
intracellular nature of virus replication made the development of
clinically useful drugs improbable. More recently, as knowledge of the
molecular mechanisms of virus replication and pathogenesis has become
available, it is evident that there are both virus-coded and
virus-induced functions which may be specifically, or at least
selectively, inhibited. The efficacy of acyclovir at inhibition of
herpes simplex infection is a dramatic example and has resulted in
significant industrial support for the development of derivatives of
acyclovir and some other nucleosides. However, the detailed
understanding of the mechanisms of virus replication and the
three-dimensional structure of virions and virus proteins that is
rapidly accumulating should be exploited to investigate additional
innovative approaches to the design of molecularly targeted antivirals.
Infectious processes, which may provide vulnerable targets, include
virus adsorption and entry, the synthesis and processing of nucleic
acids and proteins, transport of macromolecules, assembly of progeny
virions, the identification of viral markers on infected cells, and the
spread of virus to uninfected cells. It may also be possible to target
latently infected cells.
Preliminary studies in this area have already been reported although the
majority of novel approaches have been directed at HIV. Advances in
crystallographic molecular modelling have led to the ability to predict
the tertiary structure of the active sites of viral particles and
enzymes and illustrate the interaction of these entities with known
inhibitors. This ability has already led to the design of novel
inhibitors for the HIV protease and rhinovirus adsorption and uncoating.
"Anti-sense" oligonucleotides complementary to important viral
regulatory or coding sequences inhibit virus replication in tissue
culture and may also be effective in vivo. Selective inhibition of
enzymes encoded by the viral genome, as well as cellular enzymes whose
synthesis is enhanced as a result of infection, has been achieved in
several instances. Molecular identification of the cellular receptors
for virus adsorption should permit the design of agents that block the
first stage of virus infection. Immunoliposomes have been developed on
the assumption that they may reduce drug toxicity by enabling specific
and selective delivery. These and other imaginative approaches to the
development of targeted antiviral therapies are made possible by the
recent explosion in our knowledge of the molecular details of virus
replication and pathogenesis.
II. RESEARCH GOALS AND SCOPE
The purpose of this RFA is to stimulate research in the development of
novel molecularly targeted approaches to antiviral therapy. This
includes strategies for both the design of novel specific agents and
development of methods for selective drug delivery. The strategies
proposed should involve a molecular rationale for anticipated antiviral
activity without significant concomitant cellular and/or organism
toxicity. The preparation and testing of derivatives of previously
identified nucleoside analogue antiviral agents does not constitute a
novel approach. However, investigators may propose to extend a
preliminary approach, such as those listed above in Section I, or apply
such an approach to a different system. Investigators will choose the
virus and system they prefer for these studies, but the selected virus
should either be a clinically important human pathogen or serve as a
model for a human viral pathogen. Possible choices include, but are not
limited to: hepatitis B, C, and D virus, papillomavirus,
cytomegalovirus, herpes simplex virus, varicella zoster virus, influenza
viruses, respiratory syncytial virus, parainfluenza, rotavirus,
coxsackievirus, and rhinovirus. The development of agents inhibitory to
HIV and other retroviruses is the focus of a separate RFA and,
therefore, proposals to target HIV will not be accepted in response to
this initiative.
III. MECHANISM OF SUPPORT
A. Award(s) will be made as Cooperative Agreements. These are
assistance relationships with substantial involvement of NIAID staff, as
outlined under Part IV, "Terms of Award". Universities, medical
colleges, hospitals, and laboratories or other public, private, or
for-profit institutions are eligible.
B. NIAID anticipates making ten to fifteen awards as a result of this
request. However, the number of awards to be made is dependent upon
receipt of a sufficient number of applications of high scientific merit
and upon the availability of funds. If appropriate, collaboration with
other investigators or institutions is encouraged. It is expected that
the initial year's awards for successful applications will average
$150,000 in direct costs, however, individual awards may be higher or
lower. Awards will be made for a project period of up to five years.
(When the applicant institution is outside the United States, awards
will be limited to three years.) The earliest possible award date is
July 1, 1991. It is the intent of DMID to fund a group of proposals
that will ensure that a variety of approaches and virus systems will be
investigated. The specific recommendations for proposals to receive
awards will be made by a staff committee. Committee members will be the
Director, DMID and the chiefs of the Antiviral Research Branch, the
Enteric Diseases Branch, the Respiratory Diseases Branch, and the
Sexually Transmitted Diseases Branch. Criteria will be technical
excellence and program balance. NIAID has no plans to reissue this
announcement.
IV. TERMS OF AWARD: AWARDEE RIGHTS AND RESPONSIBILITIES; NATURE OF
PARTICIPATION OF NIAID STAFF
Under the Cooperative Agreement, a partner relationship between the
recipient of the award and NIAID exists in which the applicant is
responsive to the requirements and conditions set forth in the RFA.
Specifically, the Principal Investigator defines the details for the
project within the guidelines of the RFA, retains primary responsibility
for the performance of the scientific activity, and agrees to accept
close assistance of NIAID staff in all aspects of scientific and
technical management of the project in accordance with the terms
mutually agreed upon prior to the award. The applicant must define the
research objectives and approaches in accord with his/her own interests
and perceptions of novel and exploitable molecular approaches to the
development of specific novel antiviral agents and must develop the
details of the research design following the guidance given in this RFA.
The awardee is to plan and conduct the research stipulated in the
application and to ensure that the results obtained are analyzed and
published in a timely manner. The data obtained will be the property of
the awardee.
Assistance via Cooperative Agreement differs from the traditional
research grant in that, in addition to the normal programmatic and
administrative stewardship responsibilities, the component awarding the
Cooperative Agreement anticipates substantial programmatic involvement
during performance of the project. The staff assistance mandated by the
cooperative agreement mechanism will permit NIAID staff to participate
in, but not direct, the research to ensure that important disease
targets are addressed. A member of the NIAID staff will serve as
Scientific Coordinator and will participate as a member of the research
team. The Scientific Coordinator will be the Chief, Antiviral Research
Branch, DMID. The Scientific Coordinator will interact closely with the
Principal Investigators and Co-investigators in the overall research
planning and in data analysis. During performance of the award the
NIAID Scientific Coordinator may provide appropriate assistance by
participating in the design of research group activities; advising in
the selection of sources or resources, replacement of staff;
coordinating or participating in collection and/or analysis of data; and
advising in management and technical performance. The Scientific
Coordinator may organize the further evaluation, both in vitro and in
animal models, of agents resulting from this research. However the role
of NIAID will be to facilitate and not to direct the activities.
Specifically, it is presently envisioned that the NIAID will be actively
engaged in the coordination of all components including assisting the
awardees in:
1. Collaborative participation in overall research planning and data
analysis. Specifically, the NIAID Scientific Coordinator may suggest
studies within the scope of the award's objectives and research
activities; may present to the investigators experimental findings from
published sources or from contract projects in support of these
suggestions; may participate in the design of experiments and may
participate in the analysis of results.
2. Provision of needed resources and information that may not be
otherwise available to the investigator. This may include the provision
of data from testing conducted in resource contract laboratories.
3. In the event that an awardee's research results in a procedure or a
product that requires testing of a nature beyond the awardee's
capabilities, the NIAID Scientific Coordinator may provide resources
available to the Institute for comprehensive preclinical efficacy
evaluations. DMID has facilities to evaluate compounds in vitro for
activity against panels of herpesviruses (HSV-1, HSV-2, CMV, VZV, and
EBV), respiratory viruses (influenza A, influenza B, parainfluenza,
respiratory syncytial virus, adenovirus, and measles), and hepatitis B.
Compounds are also evaluated for toxicity for stationary and
exponentially growing primary human fibroblasts and for activity against
multiple strains of each virus which include recent clinical isolates
and drug-resistant strains. DMID also supports animal models for most
of the above-listed viruses as well as human and rabbit
papillomaviruses. For example, the awardee may devise an agent that
inhibits the expression of cloned respiratory syncytial virus or
hepatitis B virus genes in vitro. The NIAID Scientific Coordinator can
arrange for the agent to receive more extensive in vitro testing as well
as evaluation in a cotton rat animal model for RSV infections or a
woodchuck model for hepatitis B infection. In addition, the awardee may
want NIAID to assist in the eventual clinical testing of the agent.
Alternatively, the awardee may pursue testing of his/her agent
independently.
4. Prior approval of changes of key personnel including the Principal
Investigator and co-investigators.
5. The NIAID Scientific Coordinator will organize an annual symposium
in Bethesda, Maryland, at which the principal investigators will discuss
their progress. This will facilitate overall program planning and
development, the evaluation of the feasibility of the attempted
approaches, and will promote productive interactions among the
successful applicants. The NIAID Scientific Coordinator will also
ensure the participation in this symposium of investigators from other
NIAID preclinical and clinical programs to provide the most relevant
antiviral expertise possible to facilitate planning for future research
and expedite the design and development of novel antiviral agents.
Funds for travel to this meeting should be included in the budget.
6. In addition to the annual symposium, the NIAID Scientific
Coordinator will interact informally with the principal investigators
through additional meetings, averaging once a year, at the Principal
Investigator's institution as well as by regular telephone and written
communication.
It is anticipated that decisions in all activities outlined above, as
well as changes in research direction, will be reached by consensus of
the Principal Investigator and the NIAID Scientific Coordinator. Such
changes may be occasioned by the emerging clinical importance of
different infections or the suitability of developed approaches for the
design of antiviral therapies for other infections. The manner of
reaching this consensus and the decision-making authority will rest with
the Principal Investigator. However, if a dispute should arise, the
decision of a three-member arbitration team will be binding. One member
of this team will be chosen by the Principal Investigator and the second
will be chosen by the NIAID Scientific Coordinator. These two members
of the arbitration team will select the third member.
Although the NIAID Scientific Coordinator may participate in discussions
on planning and evaluation, the recipients of these awards will be
responsible entirely for the design, conduct, and evaluation of their
proposed research. The NIAID Scientific Coordinator will not direct,
nor be liable for, the awardee's research activities. The awardee will
be responsible for publishing and disseminating the results of his/her
studies. In the event that collaborative studies with NIAID grantees,
awardees, or contractors, are undertaken (as described above), the NIAID
Scientific Coordinator may assist in the design of study protocols and
evaluation of data.
These special Terms of Award are in addition to, and not in lieu of,
otherwise applicable OMB administrative guidelines, HHS Grant
Administration Regulations at 45 CFR Part 74, and other HHS, PHS, and
NIH grant administration policy statements.
V. METHOD OF APPLICATION
A. LETTER OF INTENT
Prospective applicants are asked to submit, by November 28, 1990, a
short letter of intent that includes a descriptive title of the proposed
research, and the names and affiliation(s) of proposed key
investigators. The letter of intent is requested in order to provide an
indication of the number and scope of applications to be reviewed. The
letter of intent does not commit the sender to submit an application,
nor is it a requirement for submission of an application.
The letter of intent should be sent to:
Dr. Olivia Preble
Chief, Microbiology and Immunology Review Section
Program and Project Review Branch
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Westwood Building, Room 3A10
Bethesda, MD 20892
Telephone: (301) 496-8208
B. Format of Applications
1. Applications must be submitted on form PHS 398 (Rev. 10/88, 9/89),
the application form for research grants. Application kits are
available at most institutional business offices or may be obtained from
the Office of Grants Inquiries, Room 449, Westwood Building, Division of
Research Grants, NIH. The format and detail applicable to regular
research grant applications should be followed, and the requirements
specified under Review Criteria (VII.C.) must be fulfilled.
2. For purposes of identification and processing, mark "yes" in item 2
on the face page of the application and type in the words COOPERATIVE
AGREEMENT FOR MOLECULARLY TARGETED APPROACHES TO ANTIVIRAL THERAPY and
the RFA number AI-91-01.
The RFA label (found in the 10/88 revision of application form PHS 398)
must be affixed to the bottom of the face page of the original copy of
the application. Failure to use this label could result in delayed
processing of your application such that it will not reach the review
committee in time for review.
3. The research proposed should describe plans to accommodate the RFA
research program requirements and NIAID staff involvement. Note that
the applications will be judged by the stated review criteria (see
section VIII.C.).
C. Application Procedure
1. The completed original application and four (4) exact copies should
be sent or delivered to:
Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD 20892**
TWO (2) ADDITIONAL COPIES MUST BE SENT TO:
Dr. Olivia Preble
Chief, Microbiology and Immunology Review Section
Program and Project Review Branch
National Institute of Allergy and
Infectious Diseases
National Institutes of Health
Westwood Building, Room 3A10
Bethesda, MD 20892
Telephone: (301) 496-8208
VI. CONSEQUENCES OF LATE APPLICATIONS AND DUPLICATE SUBMISSIONS
To ensure their review, applications must be received by both the
Division of Research Grants (DRG) and Dr. Olivia Preble by January 17,
1991. Applications received after the above date will be returned
without review. If the application submitted in response to this RFA is
substantially similar to a research grant application already submitted
to the NIH for review, but has not yet been reviewed, the applicant will
be asked to withdraw either the pending application or the new one.
Simultaneous submission of identical applications will not be allowed,
nor will essentially identical applications be reviewed by different
review committees. Therefore, an application cannot be submitted in
response to this RFA that is essentially identical to one that has
already been reviewed. This does not preclude the submission of
substantial revisions of applications already reviewed, but such
applications must include an introduction addressing the previous
critique.
VII. REVIEW PROCEDURES AND CRITERIA
A. Assignment of Applications: Applications will be received by the NIH
DRG and assigned to NIAID.
B. Review Procedures: Applications will be reviewed by NIAID staff to
determine administrative and programmatic responsiveness to this RFA;
those judged to be non-responsive will be returned to the applicant
without review. Those applications considered responsive to the RFA may
be subjected to a triage review by an NIAID peer review group to
determine their scientific merit relative to the other applications in
response to the RFA. The NIH will withdraw from competition those
applications judged by the triage peer review group to be noncompetitive
for award and will notify the applicant principal investigator and the
institutional business official.
Those applications judged to be competitive for award will be reviewed
for scientific and technical merit by a Review Committee convened by the
Division of Extramural Activities, NIAID, during March 1991. The second
level of review will be provided by the National Advisory Allergy and
Infectious Diseases Council in May 1991.
C. Review Criteria:
The factors to be considered in scientific evaluation of the
applications are:
1. Originality and scientific merit of research approach, design, and
methodology as well as the potential scientific, technical, or medical
significance of the proposed research.
2. Research experience and competence of the Principal Investigator and
staff to conduct the proposed studies.
3. Adequacy of time (effort) that the Principal Investigator and staff
would devote to the proposed studies.
4. Adequacy of facilities.
5. Reasonableness of proposed costs.
The review criteria listed above will be those used by the initial
review group. In selecting applications for funding, while scientific
merit is of prime consideration, applications also will be evaluated for
programmatic relevance and importance.
VIII. FUTURE FUNDING
This is a one-time request for applications. NIAID has no plans to
reissue this announcement at any future date.
IX. INQUIRIES
Investigators seeking information relevant to this RFA should contact
Dr. Catherine Laughlin at the address below. Questions regarding review
procedures should be addressed to Dr. Preble, at the address given in
Section V.A.
Dr. Catherine Laughlin
Chief, Antiviral Research Branch
Division of Microbiology
and Infectious Diseases
National Institute of Allergy
and Infectious Diseases
Westwood Building, Room 753
Bethesda, MD 20892
Telephone: (301) 496-8285
This program is supported under authorization of the Public Health
Service Act, Sec. 301(c), Public Law 78-410; as amended. The catalog of
Federal Domestic Assistance citation is Sec. 93.856, Microbiology and
Infectious Diseases Research. Awards will be administered under PHS
grant policies and Federal Regulations 42 CFR Part 52 and 45 CFR Part
74. This program is not subject to the intergovernmental review
REQUEST FOR APPLICATIONS: RFA
RFA: HL-90-09-H
CARDIOVASCULAR DEVICE-CENTERED INFECTIONS
P.T. 34; K.W. 0715040, 0740035, 0715125
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE*
NATIONAL SCIENCE FOUNDATION
Letter of Intent Receipt Date: December 3, 1990
Application Receipt Date: January 14, 1991
PURPOSE
The Devices and Technology Branch (DTB), Division of Heart and
Vascular Diseases of the National Heart, Lung, and Blood
Institute (NHLBI), and the Section of Bioengineering and
Environmental Systems of the Engineering Directorate,
National Science Foundation (NSF), invite grant applications for
support of interdisciplinary research (Biomedical Sciences
and Bioengineering) on the mechanisms, prevention, and
treatment of infections developing in and around permanently
implanted cardiovascular devices in humans.
BACKGROUND
Foreign bodies have long been known to be infection-
potentiating, but mechanisms to explain this phenomenon are
not clearly defined. Infection in close proximity to a valve
(endocarditis) occurs in 1-4% of patients with
mechanical or bioprosthetic heart valves. One to 6% of
patients with prosthetic vascular grafts develop a graft-
associated infection. However, in patients with total
artificial hearts (TAHs) or ventricular assist devices (VADs)
implanted for periods longer than 3 months, the incidence of
infection has been reported as 25-100%. It is likely that
this high incidence stems in part from the existence of
external drive-lines which serve as portals of entry for
microorganisms despite all efforts at prevention. Some of
the newer VAD systems currently undergoing preclinical
testing will require no external drive-lines. This advance
is expected to reduce but not eliminate the risk of implant-
related infections in patients receiving these new devices.
Infection in patients with TAHs or VADs is commonly
associated with thromboembolism, and there is evidence that
these two complications are interrelated. Ultrastructural
studies of TAHs examined following autopsy in several human
subjects have demonstrated failure of tissue integration and
diffuse adhesive bacterial colonization of biomaterial
surfaces. At device retrieval, thrombotic material has been
observed, especially in the region of the valve struts and at
the connections between the device and the great vessels. In
addition, patients have suffered embolic stroke, and
thromboembolic material has been observed in other organs,
especially the kidney. These thrombi and emboli are
frequently infected. An association between thrombosis and
infection has long been observed in a number of clinical
conditions, which include implanted prosthetic heart valves
and prosthetic vascular grafts, and several mechanisms have
been proposed for this. A thrombus forms an ideal nidus for
bacteria to adhere and multiply in a nutrient environment.
Conversely, certain bacteria can induce activation and
aggregation of platelets or leukocytes, and activation of
factors in the coagulation and complement cascades, thus
favoring thrombosis. These mechanisms may result in a
vicious cycle between thrombosis and infection, each
increasing the likelihood of the other, especially in a
chronic setting. Proteins that mediate adhesion of certain
cells, such as platelets and endothelial cells, to one another
and to other surfaces include fibronectin, laminin,
vitronectin, von Willebrand factor, and certain collagen
types. The role of these and other proteins in bacterial
adhesion has not been fully defined. Finally, TAH
implantation has been associated with alterations in
complement and leukocyte functions, perhaps contributing to
the high risk of periprosthetic and intraprosthetic infection
in these patients.
OBJECTIVES AND SCOPE
This special grant program is for support of
interdisciplinary research approaches to the problem of
infections associated with implanted prosthetic
cardiovascular devices. Molecular, structural, and
computational biology approaches to the life and medical
sciences are encouraged: these may deal with the nature of
the interaction between bacterial surface components, the
biomaterial surface, and molecules mediating bacterial
adhesion, growth, and colonization on biomaterials. Other
approaches, especially employing the concepts and methods of
modern cell and molecular biology, are encouraged.
Applications should have a substantive content in
engineering. This may include the development of new
engineering techniques or the novel application of existing
ones. Research projects involving human subjects, animal
models, or other experimental approaches may be focused on:
(1) the etiology, pathogenesis, and natural history of
device-centered infections, including the relationship to
thromboembolism; (2) elucidation of possible predisposing
factors for their development; and/or (3) potential
approaches to improved prevention, monitoring, and treatment
of such infections.
In order for applicants to be responsive to this Request for
Applications (RFA), the
research should have a strong interdisciplinary component.
NSF support is contingent on a strong bioengineering
contribution. This may include mathematical modeling,
instrumentation, tissue engineering, or any novel engineering
technique that may help characterize or understand the
mechanisms. The routine use or modification of state-of-the-
art technology by itself will not qualify. In addition, the
investigative approach should include one or more of the
following areas: microbiology, immunology, infectious
diseases, cardiovascular diseases, molecular biology, cell
biology, pathology, and rheology.
Applications might include, but are not limited to, the
following:
o Investigation of mechanisms for monitoring, producing, or
enhancing the development of a biological (cellular or
acellular) layer on the inner and outer surfaces of a
circulatory support device with the object of inhibiting
device-centered infections; with available methods for gene
transfer and expression, attempt the alteration of the
functions of leukocytes, endothelial cells, or other cells
with the object of making them more resistant to infection.
o Examining the role of the bacterial cell surface
glycocalyx or other surface molecules in the specificity of
the adhesion of certain bacteria to certain polymers or
metals.
o Investigation of bacterial adhesion to cardiovascular
implants by delineating binding sites on the surface of
biomaterials for bacteria or for extracellular molecules
mediating bacterial adhesion; determine the specificity of
binding sites for specific types of bacteria or proteins;
investigate techniques for saturating these binding sites or
synthesizing new materials, which have fewer binding sites for
bacteria, or for molecules mediating their adhesion.
o Examination and defining the molecular basis of plasma and
extracellular matrix proteins in bacterial adhesion and
colonization on biomaterials. These proteins include
fibrinogen, fibronectin, laminin, vitronectin, von
Willebrand factor, and various collagen types.
o Investigating the relation between infection and
thrombosis by studying the basic mechanisms whereby certain
microorganisms activate blood coagulation, fibrinolysis, and
complement.
o Evaluating the changes in T- and B- lymphocytes,
macrophages, neutrophils, lymphokines, complement, and other
components of the immune system in response to interaction
between well-characterized biomaterials and blood or tissues
under controlled conditions; evaluate the role these
abnormalities may play in device-related infections.
o Examining the production and possible effect on
susceptibility to infection of oxygen-free radicals released
following contact of biomaterials with blood and other
tissues.
o Using in vitro, ex vivo, or in vivo models plus monitoring
and visualization, evaluation of the role of physical
properties (e.g., smoothness vs. roughness, porosity,
compliance, surface-free energy) or chemical composition of
various biomaterials, as elements influencing adhesion and
proliferation of microorganisms on a biomaterial or device
and in the development of an intraluminal and extraluminal
layer of host cells formed in response to device
implantation.
o Evaluation of the use of new monitoring techniques,
including in-vivo visualization, to characterize changes in
surface phenomena.
o Evaluation of mass transport and fluid mechanical factors
(e.g., shear stress, stasis, recirculation) in the adhesion,
colonization, and localization of bacteria on devices in
contact with blood.
Applicants are not required to include the above-mentioned
topics and are encouraged to consider other avenues of
investigation that have the potential of yielding
significant information regarding mechanisms of biomaterial-
centered infections. To be responsive to this RFA,
applications must describe experimental conditions that
simulate those encountered by implanted cardiovascular
devices. Attention should be given to appropriate
statistical design of the study. Although not a
requirement, the inclusion of NHLBI-DTB primary reference
materials (low-density polyethylene and silica-free
polydimethylsiloxane) in the research plan is encouraged.
Arrangements for procuring these materials may be made by
contacting Dr. Paul Didisheim at the address and phone number
listed at the end of this announcement. Also, if the
research involves infectivity or adhesiveness of specific
strains of microorganisms, these should be known to play
significant roles in device-related infections in man.
Engineering approaches proposed should have general
applicability.
In any studies involving human subjects, women and minority
individuals must be included in the study population;
otherwise a clear rationale for their exclusion must be
provided in the application. Minority institutions are
encouraged to apply, and other institutions are encouraged to
establish collaborative arrangements with minority
institutions.
EXCLUSIONS
Applications aimed primarily at examining the biological
problem of infections with non-cardiovascular implants (e.g.,
orthopedic, dental, eye, ear) will not be considered
responsive to this RFA.
This solicitation will not support large-scale clinical
trials. While interdisciplinary research is required, this
should not be in the form of a large number of projects which
would constitute a program project. Applicants may request
equipment; however, funds will not be provided to equip a
laboratory or for major, expensive items. Specifically,
funds will not be provided for the purchase of expensive
cardiovascular devices.
MECHANISM OF SUPPORT
The support mechanism for this program will be the
traditional, individual research grant as administered by the
NHLBI and NSF. A committee comprised of NHLBI and NSF staff
will determine which agency will fund the most highly rated
applications. Although approximately $1.0 million total
costs (direct plus indirect) for this program is included in
the financial requests for fiscal year 1991, award of grants
pursuant to this RFA is contingent upon receipt of funds for
this purpose. The hope is to award up to five grants under
this program. The specific amount to be funded, however,
will depend on the merit and scope of the applications
received and the availability of funds. Since a variety of
approaches would represent valid responses to this
announcement, it is anticipated that there will be a range of
costs among individual grants awarded. If collaborative
arrangements involve sub-contracts with other institutions,
the NHLBI Grants Operations Branch should be consulted
regarding procedures to be followed (tel: 301-496-7255).
Following initiation of the program, NHLBI and NSF will
jointly sponsor annual meetings to encourage exchange of
information among investigators who participate in this
program. In the budget for the grant application, applicants
should request ADDITIONAL TRAVEL FUNDS for a one-day meeting
each year, to be held in the Washington, D.C. area.
Applicants should also include a statement in their
applications indicating their willingness to participate in
these meetings. Applicants, who will plan and execute their
own research programs, are requested to furnish their own
estimates of the time required to achieve the objectives of
the proposed research project. Up to FIVE YEARS of support
may be requested.
At the end of the official award period, renewal applications
may be submitted through the regular grant programs of the
NIH or NSF. It is anticipated that support for the present
program will begin in July 1991. Administrative adjustments
in project period and/or amount of support may be required at
the time of the award.
All current policies and requirements that govern the
research grant programs of NIH and NSF will apply to grants
awarded under this RFA. Awards to foreign institutions will
be made only for research of very unusual merit, need and
promise, and in accordance with Public Health Service and NSF
policy governing such awards.
REVIEW PROCEDURES AND CRITERIA
Review Method: Upon receipt, applications will be reviewed
for their responsiveness to the objectives of this RFA by NIH
and NSF staffs. If an application is judged unresponsive,
the applicant will be contacted and given the opportunity to
withdraw the application, or have it considered for the
regular NIH or NSF grant programs. If an application
submitted in response to this RFA is substantially similar
to a research grant application already submitted to the NIH
or NSF for review, but has not yet been reviewed, the
applicant will be asked to withdraw either the pending
application or the new one. Simultaneous submission of
identical applications will not be allowed, nor will
essentially identical applications be reviewed by different
review committees. Therefore, an application cannot be
submitted in response to this RFA that is essentially
identical to one that has already been reviewed. This does
not preclude the submission of substantial revisions of
applications already reviewed, but such applications must
include an introduction addressing the previous critique.
Those applications that are judged to be responsive will be
reviewed for scientific and technical merit by an invited
review group convened by the Division of Extramural Affairs,
NHLBI. The review group will be composed of mostly
nonfederally employed reviewers with expertise that will
include the disciplines represented by the applications.
Applications will be reviewed in competition with each other
on a nation-wide basis. This RFA solicitation is a single
competition and has one specific deadline for receipt of
applications.
Review Criteria: The factors to be considered in the
evaluation of scientific and engineering merit of each
application will be similar to those used in the review of
traditional research project grant
applications, including:
o the novelty, originality and feasibility of the
approach and the merit of the experimental design
o clear indication of an interdisciplinary approach
encompassing a substantive and innovative bioengineering
component
o the competence of the principal investigator and
collaborators to accomplish the proposed research, and the
commitment and time they will devote to the project
o the suitability of the facilities to perform the
proposed research, including laboratories, instrumentation,
and data management systems
o the appropriateness of the requested budget for the
work proposed.
METHOD OF APPLICATION
Letter of intent: Prospective applicants are asked to submit
a letter of intent to apply to this RFA. This letter should
include the names of any participating institutions and all
investigators, together with a descriptive title. Such a
letter of intent is not binding and it will not enter into
the review of any application. Letters of intent are
requested solely for planning purposes. The NHLBI and NSF
Staff will not provide responses to such letters. Letters of
intent to apply to this RFA should be received no later than
December 3, 1990, and should be addressed to:
Dr. Charles L. Turbyfill
Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 553
NIH, Bethesda, MD 20892
Format for Applications: Submit applications on form PHS-398
(revised 10/88), the application form for the traditional NIH
research project grant. Copies of this form are available in
the applicant institution's office of sponsored research, or
may be obtained from the following:
Office of Grants Inquiries
Division of Research Grants
Westwood Building, Room 449
NIH, Bethesda, MD 20892
Use the conventional format for research project grant
applications and ensure that points identified in the section
above on "Review Procedures and Criteria" are fulfilled.
Applications that contain prior work supported by the NSF
must include a "Results from prior support" statement. To
identify the application as a response to this RFA, CHECK
"YES" on item 2 of page 1 of the application and enter the
title "Cardiovascular Device-Centered Infections", and enter
the RFA number HL-90-09-H in the space provided.
THE RFA LABEL FOUND IN THE FORM PHS-398 APPLICATION KIT MUST
BE AFFIXED TO THE BOTTOM OF THE FACE PAGE OF THE ORIGINAL
COMPLETED APPLICATION FORM PHS-398. FAILURE TO USE THIS
LABEL COULD RESULT IN DELAYED PROCESSING OF YOUR APPLICATION
SUCH THAT IT MAY NOT REACH THE REVIEW COMMITTEE IN TIME FOR
REVIEW.
Application Procedure: Send or deliver the completed, signed
application and four (4) complete photocopies of it to the
following, making sure that the original application with the
RFA label attached is on top:
Division of Research Grants
Westwood Building, Room 240
National Institutes of Health
Bethesda, MD 20892**
SEND TWO ADDITIONAL COPIES OF THE APPLICATION TO DR. CHARLES
TURBYFILL AT THE ADDRESS LISTED UNDER "LETTER OF INTENT". IT
IS IMPORTANT TO SEND THESE TWO COPIES AT THE SAME TIME AS THE
ORIGINAL AND FOUR COPIES ARE SENT TO THE DIVISION OF RESEARCH
GRANTS, OTHERWISE THE NHLBI CANNOT GUARANTEE THAT THE
APPLICATION WILL BE REVIEWED IN COMPETITION FOR THIS RFA.
Applications must be received by January 14, 1991. An
application not received by this date will be considered
ineligible
Timetable:
Letter of Intent December 3, 1990
Application Receipt Date January 14, 1991
Review by National Heart, Lung,
and Blood Advisory Council
and NSF Staff May 23-24, 1991
Anticipated Award Date July 1, 1991
Inquiries: Inquiries regarding this announcement may be
directed to the following:
Dr. Paul Didisheim Norman Caplan
Head, Biomaterials Program Section Head
Devices and Technology Branch Bioengineering and
Division of Heart and Vascular Environmental Systems
Diseases National Science Foundation
National Heart, Lung, and 1800 G Street
Blood Institute Washington, D.C. 20550
Federal Building, Room 312 Telephone: (202) 357-7955
7550 Wisconsin Avenue
Bethesda, MD 20892
Telephone: (301) 496-1586
*This program is described in the Catalog of Federal
Domestic Assistance number 93.837, Heart and Vascular
Diseases. Awards will be made under the authority of the
Public Health Services Act, Section 301 (42 USC 241) and
administered under PHS grant policies and Federal
regulations, most specifically 42 CFR Part 52 and 45 CFR Part
74. This program is not subject to the intergovernmental
review requirements of Executive Order 12372, or to Health
CLINICAL TRIAL PLANNING GRANT
FOR DIGESTIVE AND NUTRITIONAL DISEASES
RFA AVAILABLE: DK-91-02
P.T. 34; K.W. 0755015, 0715085, 0715135, 0710095
National Institute of Diabetes and Digestive and Kidney Diseases
Application Receipt Date: January 22, 1991
PURPOSE
The Division of Digestive Diseases and Nutrition of the National
Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invites
applications for Planning Grants (R21) to support the development of
single center or multicenter clinical trials in digestive and
nutritional diseases. Areas of particular importance include obesity,
inflammatory bowel disease, irritable bowel syndrome, helicobacter
pylori, primary biliary cirrhosis, and sclerosing cholangitis. It is
anticipated that three planning grant awards will be made.
BACKGROUND
Recent advances in basic biomedical research have provided new insights
into the pathogenesis of many nutritional and digestive diseases. These
advances have led to new possibilities for therapeutic intervention in
these diseases. New therapies or interventions are best evaluated in
prospective, randomized controlled clinical trials. However, the
planning, design, conduct, and analysis of clinical trials are
difficult. Each step in the process requires major commitment of effort
and time, financial support, and multidisciplinary expertise. As a
consequence, opportunities can be lost to identify and rigorously
evaluate important new therapeutic possibilities.
In the area of digestive diseases and nutrition there are several
diseases or conditions that warrant studies of new therapeutic
interventions. Digestive and nutritional diseases or conditions of
importance for which there are currently no satisfactory long-term
therapies include severe obesity, inflammatory bowel disease, irritable
bowel syndrome, primary biliary cirrhosis, and sclerosing cholangitis.
These are important conditions that affect many Americans and cause
considerable morbidity and mortality. Primary biliary cirrhosis, for
example, is an autoimmune disease of the liver that largely affects
women and leads slowly but inexorably to cirrhosis and death from liver
failure. Primary biliary cirrhosis is the leading single indication for
liver transplantation in adults. Despite these features, there is
currently no therapy of proven benefit for primary biliary cirrhosis.
In recent years, several small clinical trials in primary biliary
cirrhosis have reported some benefit of several agents including
ursodeoxycholic acid, chlorambucil, cyclosporine A, methotrexate,
prednisone, and colchicine. While results from several of these studies
have been promising, they have not been convincing enough to provide
firm guidance for therapy of patients with this important disease. It
is obvious, however, that one or several of these agents could be
adequately evaluated in a proper, large, multicenter randomized
controlled trial.
Clinical Trial Planning Grants have been designed to aid investigators
in designing clinical trials in important areas of digestive and
nutritional diseases. These Planning Grants will support the
development of a clinical trial research plan. This grant also provides
a means for early peer review of the rationale and need for the trial.
OBJECTIVES AND SCOPE
The overall goal of this Request for Applications (RFA) is to encourage
experienced clinical investigators in digestive and nutritional diseases
to undertake prospective, randomized, controlled, single-center or
multicenter trials in the treatment of digestive and nutritional
diseases.
The NIDDK Clinical Trial Planning Grant has been designed to help
support the extensive planning that should precede any well-designed
single-center or multicenter clinical trial. The grant provides a
mechanism for early peer review of the rationale and need for the trial
as well as support for the development of a detailed Manual of
Procedures. In addition, a limited number of patients can be recruited
to test the operational aspects of the trial.
It is expected that this Planning Grant RFA will be followed by a
program announcement within twelve months from the funding of grants in
response to this initial RFA, for applications to perform single-center
or multicenter clinical trials. Applications in response to this latter
announcement will be required to provide detailed information regarding
the rationale, experimental design, protocols and procedures, analytical
techniques, facilities and environment, adequacy of the proposed
administrative procedures, and collaborative arrangements for the trial.
A well documented Manual of Procedures will also need to be part of the
latter submission. The actual funding of a single-center or multicenter
clinical trial will be contingent on the excellence and feasibility of
the proposed trial, programmatic needs, and on the availability of
designated funds.
PREPARATION OF THE APPLICATION
General instructions for the preparation of applications contained in
Grant Application Form PHS 398 (Revised 10/88) are to be used in
preparing Planning Grant (R21) applications. Item 2 should state "RFA #
DK-91-02 Clinical Trial Planning Grant for Digestive and Nutritional
Diseases."
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. In such a case, a letter of agreement from either the GCRC
program director or principal investigator should be included with the
application.
ELIGIBILITY REQUIREMENTS
All applicants must be qualified nutritionists, gastroenterologists,
hepatologists, or surgeons, with the demonstrated ability to recruit
adequate numbers of patients. Applicants for a Planning Grant for a
multicenter clinical trial must have demonstrated expertise in the many
complex features of conducting a multicenter study. If participating
centers are proposed, they must have an adequate patient load and
demonstrate ability to adhere to clinical trial protocols and
procedures. All applicants are responsible for obtaining and
maintaining the appropriate Investigational New Drug Application from
the Food and Drug Administration and the appropriate assurance and
certification from their Institutional Review Boards on Human Subjects.
Only costs that are not usual costs for the normal care of patients
entered in the trial may be requested as research costs to the grant
application.
The NIH places special emphasis on the need for inclusion of minorities
and women in studies of diseases which disproportionately affect them
and also requires that applicants give added attention, where feasible
and appropriate, to their inclusion in other clinical studies. For
proposed population-based studies that include neither women nor
minorities, a clear rationale for not including them must be provided.
In attempting to include either group in a particular study, attention
must be paid to such issues as research design and sample size.
TERMS OF THE AWARD
Applications for single-center or multicenter clinical trial Planning
Grants should request up to 1 year duration and a maximum of $50,000 in
direct cost. Three Planning Grants may be awarded. Funding decisions
will be based in part on relative merit recommendation of the IRG and in
part on programmatic needs as determined by the National Diabetes and
Digestive and Kidney Diseases Advisory Council and by the staff of the
Division of Digestive Diseases and Nutrition. The award of applications
submitted in response to this RFA is contingent on the actual
availability of funds and receipt of applications deemed worthy of
support by the accepted NIH peer review process.
REVIEW PROCEDURES
All applications submitted in response to this RFA will be evaluated for
scientific and technical merit by an initial review group convened for
this purpose by the Division of Extramural Activities, NIDDK.
REVIEW CRITERIA
In evaluating a Clinical Trial Planning Grant Application, the Initial
Review Group (IRG) will consider the criteria outlined below. The
greatest weight will be given to Items I, IV and V.
I.Rationale
A. Clinical importance of the disease or condition being studied.
B. Rationale for therapy being applied.
C. Ethical considerations of treatment.
II.Experimental Design
A. Merit of the study design.
B. Appropriateness of intervention groups.
C. Plans to minimize bias through randomization, statification,
choice of controls, and masking of treatment or results.
D. Identification of appropriate primary and secondary outcomes for the tri
E. Recognition of possible problems inherent in the design and the
adequacy of plans for dealing with them.
III. Experimental Procedures and Plans for Patient Participation
A. Quality of plans (even if broadly described) for recruitment and
retention of patients, identification of eligibility and
exclusion criteria, and standardization and maintenance of quality
control among participating centers.
B. Patient protection, including informed consent and monitoring
data for safety and efficacy. Plans for early termination if it
becomes necessary.
C. Documentation of potential availability of patients at each of
the participating centers.
D. Plans for the preparation of a Manual of Procedures that must be
submitted with any future application for actual conduct of the
randomized controlled trials.
IV. Plans for Data Analysis
A. Rationale and validity of sample size.
B. General methods to be used for data analyses.
V. Planned Preliminary Studies
A. Suitability for providing the necessary supporting data.
B. Feasibility particularly in conducting preliminary studies.
C. Provisions not made for needed preliminary information.
VI. Investigators
A. Professional credentials of the organizers indicating experience
in such areas as:
1. The problem under study
2. Clinical trial administration
3. Methodology
4. Adequate and similar patient recruitment potential of
participants
5. The proposed procedures.
B. Professional credentials of the participating center
investigators in the clinical problem and in clinical trial
participation. Verification of the cooperating investigators and their
institutions should be included.
VII. Budget
The budget should be itemized on page 4 and justified on page 5 of the
application. The total direct cost budget may not exceed $50,000 and
may not exceed a 12-month period. Examples of typical use of these
funds include:
A. Travel expenses of personnel assisting in preparation of the Manual
of Procedures
B. Secretarial assistance
C. Consultant fees
D. Preliminary studies to refine trial procedures, document
recruitment
potential, etc.
E. Office supplies
F. Communication expenses.
METHOD OF APPLYING
The regular research grant application form PHS-398 (revised 10/88) must
be used. The RFA label available in the application kit must be affixed
to the bottom of the face page. Failure to use this label could result
in delayed processing of your application. There will be a single
receipt date of January 22, 1991. Applications received after that date
will be returned. Earliest possible funding will be December 1991.
Submit a signed, typewritten original of the application, including the
Checklist and four (4) signed, exact photocopies, in one package to:
DIVISION OF RESEARCH GRANTS
National Institutes of Health
Westwood Building, Room 240
Bethesda MD 20892**
IMPORTANT: At time of submission, two (2) additional copies of the
application should be sent under separate cover to:
CHIEF, REVIEW BRANCH
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Room 406, Westwood Building
Bethesda MD 20892
Applications must be received by January 22, 1991. If an application is
received after that date, it will not be accepted and will be returned.
Potential applicants should write or phone the individual listed below
for the full RFA document.
Tommie S. Tralka
Director, Clinical Trials Program
Division of Digestive Diseases and Nutrition
Westwood Bldg., Rm 3A-15
5333 Westbard Ave.
Bethesda, MD 20892
Telephone: (301) 496-9717
This program is described in the Catalog of Federal Domestic Assistance
No. 93,848, Digestive Diseases and Nutrition. Awards will be made under
the authority of the Public Health Service Act, Title III, Section 301
(Public Law 78-410, as amended; 42 USC 241) and administered under PHS
grant policies and Federal Regulations 42 CFR Part 52 and CFR Part 74.
This program is not subject to the intergovernmental review requirements