SEPSIS AND CAP: PARTNERSHIPS FOR DIAGNOSTICS DEVELOPMENT
RELEASE DATE: August 9, 2004
RFA Number: RFA-AI-04-043
EXPIRATION DATE: December 15, 2004
Department of Health and Human Services (DHHS)
PARTICIPATING ORGANIZATION:
National Institutes of Health (NIH)
(http://www.nih.gov/)
COMPONENT OF PARTICIPATING ORGANIZATION:
National Institute of Allergy and Infectious Diseases (NIAID)
(http://www.niaid.nih.gov)
CATALOGUE OF FEDERAL DOMESTIC ASSISTANCE NUMBERS:
No. 93.855, Immunology, Allergy, and Transplantation Research
No. 93.856, Microbiology and Infectious Diseases Research
LETTER OF INTENT RECEIPT DATE: November 15, 2004
APPLICATION RECEIPT DATE: December 14, 2004
THIS RFA CONTAINS THE FOLLOWING INFORMATION
o Purpose of this RFA
o Research Objectives
o Mechanism of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations
PURPOSE OF THIS RFA
Research of the National Institute of Allergy and Infectious Diseases
(NIAID), National Institutes of Health, strives to understand, treat and
ultimately prevent the myriad of infectious, immunologic, and allergic
diseases that threaten millions of human lives. The NIAID supports
extramural research to control and prevent diseases caused by virtually all
infectious organisms. Studies to evaluate these organisms involve basic
biomedical research in areas of microbial physiology and antigenic structure;
applied research, including the development of diagnostic tests; and clinical
trials to evaluate experimental drugs and vaccines.
This Partnership Program will support the development and testing of
diagnostic products for selected human infectious diseases of public health
importance. A key component of the Partnership initiatives is the development
of appropriate partnerships among government, academia, and the
biotechnology, chemical or pharmaceutical industries.
Investment by industry in new diagnostics for the control of a number of
infectious diseases of public health importance remains limited. This
initiative seeks to stimulate industry participation in decreasing the
medical impact of important targeted diseases.
This RFA is specifically focused on:
1) Development of diagnostics for early detection of the common causes of
sepsis and bacteremia or candidemia; and
2) Development of diagnostics for early detection of pathogens that commonly
cause community acquired pneumonia (CAP)
Partnerships
A key component of this initiative is the development of appropriate
partnerships between the government and industry. For the purpose of this
RFA, "industry" is defined as large and small, domestic or foreign,
pharmaceutical, biotechnology, bioengineering, and chemical companies. Since
academic organizations are often the source of new discoveries and leads for
candidate products, this RFA can also support a partnership between industry
and a collaborator(s) as necessary from academic or non-profit research
organizations. The involvement of an academic or non-profit research
organization is NOT a requirement; therefore, industry does not need a
collaborator to submit an application to this program.
All projects must demonstrate substantive involvement by the industry
partner. For the purpose of this RFA, "substantive involvement" is defined
as the commitment of any one or more of the following resources: funds;
personnel; or in-kind contributions of materials and/or reagents including,
but not limited to, chemical libraries, GMP chemical synthesis or recombinant
protein production, provision of animal or other laboratory models, and
assays, subcontracts, data management resources or regulatory support. The
Principal Investigator of the project may be affiliated with either industry
or academic organizations (if academia is part of a partnership with
industry). See information under Eligible Institutions below.
The Partnership Program is intended to support all phases of development of a
candidate product or platform technology including, but not limited to, pre-
clinical stages, pilot lot production, regulatory requirements, and where
appropriate, limited clinical evaluation. NIAID recognizes that the inherent
nature and demands of the product development process may require funding
large, complex grants with interdependent specific aims. Furthermore, some
aspects of the product development process (e.g., production of GLP and cGMP
product) are inherently not innovative. Recognizing that product development
is often an iterative and sequential process, and that steps early in the
process may not be successful and may need to be modified or reworked, NIAID
staff, through the cooperative agreement terms, will be actively involved in
evaluating the milestones of awardees and determining whether additional
investment in the development is warranted.
RESEARCH OBJECTIVES
Background
NIAID Partnership Programs: In late 2000, the NIAID convened a panel of
experts to discuss the role and nature of NIAID/industry collaborations in
antimicrobial drug development for public health needs and to learn how NIAID
could better facilitate and engage industry and academia in these endeavors
("Summit on Drug Development for Infectious Diseases."). One of the panel’s
recommendations was a continued pursuit of innovative opportunities to form
partnerships with the private sector for the control of a number of
infectious diseases with public health importance. A report of this meeting
is available at http://www.niaid.nih.gov/dmid/drug/. Since 2002, NIAID has
identified a diverse set of priority areas for partnership solicitations that
have included Partnerships for Novel Therapeutic, Diagnostic and Vector
Control Strategies in Infectious Diseases (PAR-02-026,
http://grants.nih.gov/grants/guide/pa-files/PAR-02-026.html), Partnerships:
Hepatitis B and Vector Borne Diseases Control (RFA-AI-03-003,
http://grants.nih.gov/grants/guide/rfa-files/RFA-AI-03-003.html) and
Partnerships for Vaccine and Diagnostic Development (RFA-AI-03-028),
http://grants.nih.gov/grants/guide/rfa-files/RFA-AI-03-028.html).
Diagnostics: Prompt and accurate diagnosis is key to effective disease
management and contributes significantly to positive outcomes in many
aggressive and life threatening illnesses. However, little attention is
placed on the diagnostic step relative to other components of patient
management in the health care system. Despite the importance of diagnosis in
the subsequent course of disease, less than four percent of health care
dollars is devoted to diagnostics.
The global in vitro diagnostic market is currently estimated to be worth
$23.4 billion, and is projected to increase to $28.5 billion by 2005. The
molecular biology diagnostics market for infectious diseases accounts for
approximately $5.627 billion, or close to 29% percent of the total medical
diagnostic market. Additional investment in diagnostics has the potential to
reduce patient care costs. For example, in 2000 sepsis accounted for a total
ICU expenditure of $7.6 billion in Europe and $16.7 billion in the United
States. Annual health care costs associated with CAP are estimated to be $23
billion in the United States. Improved detection of specific etiologic agents
early in the course of infection may impact patient management costs by
earlier administration of appropriate treatment.
Diagnosis of infectious diseases relies on clinical assessment and the need
for more rapid and accurate diagnostics is critical from multiple
perspectives. The epidemiology of pathogens serves as the basis for
empirical antimicrobial drug therapies. The treatment process is dependent on
the clinical microbiology laboratory for specific identification and
susceptibility testing of microbes. However, only in a small portion of
cases can the definitive microbiological diagnosis be achieved. There is
usually a delay of days or weeks until the final results from cultures and
pathogen identification can be achieved for the clinician. The mainstay of
clinical microbiology laboratory diagnosis remains culture of the etiologic
agent on appropriate substrate (cell-free culture media for bacteria and
fungi and cell culture lines for some viruses). While acknowledged as the
gold standard for most infectious agents, culture may require several days to
several weeks, thus delaying appropriate treatment. Furthermore,
interpretation of culture results may not be definitive when the specimens
are collected from non-sterile sites where organisms may be isolated in the
absence of disease (e.g., staphylococci on the skin or pneumococci from
nasopharyngeal aspirates). The need for more rapid and accurate diagnostics
is also critical to address the increasing antimicrobial and multi-drug
resistance, nosocomial and community acquired infection problems.
Appropriate detection of causative organisms early enough in the treatment
process will allow the use of targeted rather than wide-spectrum
antimicrobial drug therapies.
Although modern technology is utilized in the microbiology research
laboratory, there has been a lag in the application and advancement of new
technology in microbiological diagnostic tests. Diagnostic assays cleared or
approved by U.S. Food and Drug Administration (FDA) for use in clinical
microbiology laboratories include at least fifty tests. PCR-based assays
exist, for example, for Mycobacterium tuberculosis, Chlamydia trachomatis,
Neisseria gonorrhea, Group B Streptococcus, Escherichia coli K1 antigen
detection, cytomegalovirus, hepatitis C virus, and human immunodeficiency
virus. Results of many of these tests can only be obtained after the
organism has been grown in culture. The need exists, therefore, to extend
PCR to other targets in clinical samples, and to develop novel diagnostic
methods for use in the clinical laboratory.
Currently, automated technologies for culture of microbes provide state-of
the-art equipment for high throughput clinical laboratories. However,
incorporating molecular technologies with new approaches for the early
diagnosis of infectious disease has the potential to replace culture and
provide alternative diagnostic methods. Developments in gene micro arrays,
molecular imaging and proteomics provide the technological basis to achieve
the goal of early differential detection of the most common causes of sepsis
and community acquired pneumonia. There is the possibility of using a one-
time sample in a platform consisting of multiple formats, e.g., for nucleic
acid or gene detection, antigens or surface molecules, and respective
surrogate markers representing the host defense mechanisms. The assay would
be performed immediately following specimen collection to provide results to
the physician within hours after sample collection. Technologies used in
clinical medicine that could be applied to diagnostic systems include the
measurement of inhaled biological radiotracers, measurement of biomarkers in
respiratory condensates, and improved imaging modalities (high resolution
computed tomography, positron emission tomography). In addition, the human
genome sequence and microbial genomes provide new opportunities for examining
bacterial host defense mechanisms in ways that have not yet been fully
utilized in the clinical setting.
Development of Diagnostics for Bacteremia, Candidemia and Sepsis
Sepsis, triggered by blood stream infection (bacteremia and candidemia), is a
clinical outcome with a broad spectrum of disease symptoms that range from
fever and chills to severe infections in various organs to life threatening
invasive illnesses, including: pneumonia, bacteremia, necrotizing fascitis,
bacterial toxic shock syndrome, organ failure and non-suppurative sequelae
consisting of acute and post infection inflammations. Sepsis is the second
leading cause of death among patients in non-coronary intensive care units
(ICUs) and the tenth leading cause of death overall in the United States. In
addition, sepsis is the number one cause of death in neonatal ICUs for low
birth weight children.
Blood stream infections caused by the top four pathogens, used here as model
organisms (Staphylococcus, Enterobacter, Escherichia and Candida), are a
particular problem in ICUs and comprise the major nosocomial burden in
hospitals today. This RFA seeks research partnerships to bring these top
pathogens into the spotlight for developing a modern diagnostic platform for
early detection of blood stream infections. Once a diagnostic system has been
established for the model microbes encompassed within this RFA, that platform
will be used in the future to detect a broader range of pathogens.
Development of Diagnostics Related to CAP
CAP is one of the most common infectious diseases in the United States and is
responsible for a huge financial and health burden. Pneumonia is the sixth
most common cause of death in the U.S. Annually, two to three million cases
of CAP result in 10 million physician visits, 500,000 hospitalizations, and
50,000 deaths. Despite extensive studies, there are few conditions in
medicine that are so controversial in terms of management. There is no
acceptable gold standard approach for diagnosis of CAP. Treatment is often
ultimately empiric and antibiotics are chosen that have broad-spectrum
activity against the most common pathogens rather than being specific and
directed against a known pathogen. There is a great need to accurately
identify bacteria and viruses that cause CAP to better guide antimicrobial
therapy. The need for better diagnostics is also supported by the fact that
microbiological specimens from patients do not always predict the clinically
relevant pathogens, i.e., identification of several microorganisms in a
specimen, but not all may be contributing to the symptomatic illness. In
addition, rapid diagnostic tests such as PCR are either not commonly
available, or not sufficiently reliable, due to problems with sample
preparation and/or contamination. Prospective studies evaluating the causes
of presumed CAP in adults have failed to identify an etiologic agent in 40-60
percent of cases.
Knowledge of the etiologic diagnosis for CAP can be useful for both
prognostic and therapeutic purposes. Once a causative organism has been
identified, the failure to respond to treatment can be dealt with in a
logical fashion based on the organism and its documented antimicrobial drug
susceptibility, rather than by empiric selection of antimicrobial agents with
an overly broad or inappropriate spectrum. The use of pathogen-directed
therapy also reduces anti-microbial drug overuse and the potential for
developing multi-drug resistant organisms. The identification of CAP
pathogens is very important from an epidemiological point of view to track
changes in etiology and anti-microbial drug resistance in communities.
Historically, the performance of blood cultures for CAP within 24 hours of
admission has been associated with a significant reduction in 30-day
mortality. There are also data indicating that a positive early sputum
culture correlates with more rapid resolution of fever following initiation
of anti-microbial therapy. These findings suggest that the establishment of
rapid, real time etiologic diagnosis is important and has value for patients,
especially those who require hospitalization.
Specific etiologic diagnosis for pneumonia relies on Gram stain, antigen
detection, nucleic acid detection, cultures and serological tests taken by
conventional or (less often) by invasive methods. In 50-60 percent of these
cases no etiologic organism can be found using the technologies currently
available in clinical microbiology laboratories. These methods may not
identify multiple pathogens in specimens from patients with co-infections
(viruses and bacteria) or mixed infections with typical and atypical
pathogens, e.g., pneumococci and Mycoplasma, respectively. These issues
provide the rationale for the development of new technological advances that
may improve diagnostic capabilities and allow for earlier disease detection.
Research Objectives and Scope
The objective of this RFA is to support scientifically sound, original, and
innovative research requiring a comprehensive, multidisciplinary team effort
to advance promising candidate diagnostics for sepsis and CAP through the
product development pathway. At least one of the following organisms must be
included for sepsis: Staphylococcus, Enterobacter, Escherichia and Candida;
and at least one of the following for CAP: Streptococcus pneumoniae,
Nontypable Haemophilus influenzae, Mycoplasma pneumoniae, and respiratory
syncytial virus. The research should focus on development of a single
diagnostic approach using one or more model microbes from each category
(sepsis and CAP), a one-time sample, and the application of technologies such
as: (i) gene micro arrays; (ii) proteomics; (iii) multi-combination formats;
(iv) imaging methodologies; or (v) other novel technological approaches. The
platform should be capable of: detecting molecules relevant to infection;
identifying and differentiating specific microbes; and/or characterizing
immune responses to those microbes. Ideally, the platform would be a single
platform that could be applicable to a wider panel of organisms with
potential diagnostic, prognostic, and therapeutic applications. The platform
must be cost-effective, rapid, sensitive and specific for early differential
diagnostics. Research is not required to result in a final product, but
must advance the development of a candidate product.
All applications should define the proposed project goal, interim objectives
(development milestones), a general description of the potential ultimate
product (a specific product profile that is defined by licensing indication
is not requested or required), and provide a schedule or timeline for
milestone and goal attainment. When appropriate, research plans should
include an awareness of guidelines that govern GLP (as defined by 21 CFR(58))
and GMP (as defined by 21 CFR(211)) manufacturing, and/or IND enabling
studies that will be performed under this award as they apply to eventual
product approval in the U.S.
All applications should include:
o Preliminary data to support the basis of the diagnostic method.
o A description of the capabilities of the method, technology, or assay, and
advantages over currently available diagnostics.
o Plans for determining performance characteristics including; sensitivity;
related to the clinical specimen, including a description of appropriate
clinical sample(s) to be used in the assay for detection of pathogen
and/or biomarkers; methods for proper collection including transport and
handling; methods for rapid sample preparation and processing; and
feasibility of specimen collection and detecting organism(s)/and or
biomarkers in that specimen.
o Process development for manufacturing diagnostic components, including
Quality Assurance (QA) and Quality Control (QC) methods for reagent
production, characterization, purification, identity, stability, etc.;
o Description of internal controls including the appropriateness for the
specific etiologic agent(s) and/or biomarkers using the assay system;
o Applicability in a clinical and/or field setting and evaluation in human
clinical studies; and
o A research and development plan that defines the proposed project goal,
interim objectives (development milestones), and potential ultimate
product and that provides a timeline for milestone and goal attainment.
Tests for use on human samples should consider benchmarks required for FDA
approval (http://www.fda.gov/cdrh) and/or CDC guidelines (NCCLS) for
pathogenic organisms and Quality Assurance and Control for PCR/nucleic acid
testing for pathogens by American Association for Pathology. In general, the
new platform tests have to be benchmarked for current available clinical
microbiology quality assurance for the targeted diagnostic test.
MECHANISM OF SUPPORT
This RFA will use the NIH cooperative agreement (U01), an "assistance"
mechanism, rather than an "acquisition" mechanism, in which substantial NIH
scientific and/or programmatic involvement with the awardee is anticipated
during the performance of the activity. The applicant will be solely
responsible for planning, directing, and executing the proposed project.
This RFA is a one-time solicitation. Future unsolicited, competing-
continuation applications based on this project will compete with all
investigator-initiated applications and will be reviewed according to the
customary peer review procedures. The anticipated award date is June 30,
2005. Applications that are not funded in the competition described in this
RFA may be resubmitted as NEW investigator-initiated applications using the
standard receipt dates for NEW applications described in the instructions to
the PHS 398 application.
The NIH U01 is a cooperative agreement award mechanism in which the Principal
Investigator retains the primary responsibility and dominant role for
planning, directing, and executing the proposed project, with NIH staff being
substantially involved as a partner with the Principal Investigator, as
described under the section "Cooperative Agreement Terms and Conditions of
Award".
The total project period for applications submitted in response to this RFA
may not exceed five years. At this time, the NIAID has not determined
whether and how this solicitation will be continued beyond the present RFA.
This RFA uses just-in-time concepts. Otherwise follow the instructions for
non-modular budget research grant applications. This program does not
require cost sharing as defined in the current NIH Grants Policy Statement at
http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part2.htm.
FUNDS AVAILABLE
The NIAID intends to commit approximately $2.2 million in FY 2005 to fund 5-
7new grants in response to this RFA. An applicant may request a project
period of up to 5 years and a budget for direct costs of up to $500,000 per
year. Applications requesting greater than $500,000 in direct costs per year
will be returned without review. Because the nature and scope of the
proposed research will vary from application to application, it is
anticipated that the size and duration of each award will also vary. Although
the financial plans of the NIAID provide support for this program, awards
pursuant to this RFA are contingent upon the availability of funds and the
receipt of a sufficient number of meritorious applications. At this time, it
is not known if this RFA will be reissued.
ELIGIBLE INSTITUTIONS
The applicant may submit (an) application(s) if the institution has any of
the following characteristics:
o For-profit or non-profit organizations
o Public or private institutions, such as universities, colleges, hospitals,
and laboratories
o Units of State and local governments
o Eligible agencies of the Federal government
o Domestic or foreign institutions/organizations
o Faith-based or community-based organizations
Both domestic and foreign organizations are eligible. Institutions must be
in compliance with U.S. laws and regulations and DHHS and NIH policies in
effect at the time of grant award and during the period of performance of the
research.
FOREIGN ORGANIZATIONS
Several special provisions apply to applications submitted by foreign
organizations.
o Funds for alterations or renovations cannot be requested.
o Charge back of customs and import fees is not allowed.
o Format: every effort should be made to comply with the format
specifications, which are based
upon a standard US paper size of 8.5" x 11."
o Funds for up to 8% administrative costs can now be requested,
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-028.html)
o Organizations must comply with federal/NIH policies on human subjects,
animals and biohazards.
o Organizations must comply with federal/NIH biosafety and biosecurity
regulations.
o Proposed research should provide a unique research opportunity, not
available in the U.S.
INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS
Any individual with the skills, knowledge, and resources necessary to carry
out the proposed research is invited to work with their institution to
develop an application for support. Individuals from underrepresented racial
and ethnic groups as well as individuals with disabilities are always
encouraged to apply for NIH programs.
SPECIAL REQUIREMENTS
Each application must propose a research and development project whose
ultimate goal is to develop diagnostics for early differential detection of
sepsis and/or CAP. The application must document substantive involvement by
the industry partner.
Applications must propose clear project goal(s), including a final product or
stage of development to be completed during the award period. The applicant
must clearly state the interim objectives (developmental milestones) to be
achieved during the project, identify impediments or critical decision points
that could require a revision in the work plan or milestones, and provide a
detailed schedule or timeline for the attainment of each milestone and/or
goal. For applications that contain a clinical study, a mandatory milestone
that must be included is the approval of the final clinical protocol by
NIAID.
Intellectual Property:
The successful development of high priority products for diagnostics will
require substantial involvement and support of private sector industries and
may also involve collaborations with multiple organizations, including
academic and/or non-profit research institutions. It is the intent of this
initiative to support the formation of the appropriate public-private
partnerships that are essential to meet these urgent public health needs.
Applicants are encouraged to reach early consensus with their proposed
partners regarding intellectual property and other legal matters that may
arise during the project. In addition, applicants are expected to exercise
their Bayh-Dole rights in a manner that does not conflict with the goals of
this award or the intent of the Bayh-Dole Act to promote the utilization,
commercialization and availability of U.S. Government-funded inventions for
public benefit.
Applicant is solely responsible for the timely acquisition of appropriate
proprietary rights and materials needed for applicant to perform the project.
Furthermore, prior to, during, and subsequent to the award, the U.S.
Government shall not be required to obtain for applicant any proprietary
rights, including intellectual property rights, or any materials needed by
applicant to perform the project. Applicant is further reminded of the
requirement to report to the U.S. Government all inventions made in the
performance of the project, as specified at 35 U.S.C. Sect. 202 (Bayh-Dole
Act).
Applicants are expected to make new information and materials known to the
research community in a timely manner through publications, web
announcements, and reports to the NIAID or other mechanisms.
Mandatory Meetings
The Principal Investigators, one or two key personnel from each project
designated by the Principal Investigator, and NIAID program staff will meet
annually to review progress and aid program development, and to foster
collaborations among the programs. This meeting will likely be held at the
NIH in Bethesda, MD and applicants should include requests for travel funds
(airfare, and per diem) specifically for this meeting. Funds to support
travel to these annual meetings should be included in the budget request.
COOPERATIVE AGREEMENT TERMS AND CONDITIONS OF AWARD
The following terms and conditions will be incorporated into the award
statement and provided to the Principal Investigator as well as the
institutional official at the time of award.
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 92, and other HHS, PHS, and NIH Grant
Administration policy statements.
The administrative and funding instrument used for this program is the
cooperative agreement (U01), an "assistance" mechanism (rather than an
"acquisition" mechanism), in which substantial NIH scientific and/or
programmatic involvement with the awardee is anticipated during the
performance of the activity. Under the cooperative agreement, the NIH
purpose is to support and/or stimulate the recipient's activity by
involvement in and otherwise working jointly with the award recipient in a
partner role, but it is not to assume direction, prime responsibility, or a
dominant role in the activity. Consistent with this concept, the dominant
role and prime responsibility for the activity resides with the awardees for
the project as a whole, although specific tasks and activities in carrying
out the research will be shared among the awardees and the NIAID Scientific
Coordinator.
1. Monitoring Clinical Studies
When clinical studies or trials are a component of the research proposed,
NIAID policy requires that studies be monitored commensurate with the degree
of potential risk to study subjects and the complexity of the study. AN
UPDATED NIAID policy was published in the NIH Guide on July 8, 2002 and is
available at: http://grants.nih.gov/grants/guide/notice-files/NOT-AI-02-032.html.
The full policy, including terms and conditions of award, is
available at: http://www.niaid.nih.gov/ncn/pdf/clinterm.pdf.
2. Awardee Rights and Responsibilities
Awardees will have primary responsibility for defining the research
objectives, approaches and details of the projects within the guidelines of
the RFA and for performing the scientific activity. Specifically, awardees
have primary responsibility as described below.
The Principal Investigator retains primary responsibility for the performance
of the scientific activity, and agrees to accept close assistance in
coordination, cooperation and participation of NIAID staff in scientific and
technical management of the project in accordance with the terms formally and
mutually agreed upon prior to the award. The responsibility for the
planning, direction, and execution of the proposed project will be solely
that of the Principal Investigator. The Principal Investigator should attend
annual meetings with the relevant NIAID staff in Bethesda, MD.
Publications: The Principal Investigator will be responsible for the timely
submission of all abstracts, manuscripts, and reviews (co)authored by members
of the grant and supported in part or in total under this Agreement. The
Principal Investigator and Project Leaders are requested to submit
manuscripts to NIAID program staff within 2 weeks of acceptance for
publication so that an up-to-date summary of program accomplishments can be
maintained and joint press conferences prepared. Publications or oral
presentation of work done under this Agreement is the responsibility of the
Principal Investigator and appropriate Project Leaders and will require
appropriate acknowledgement of NIAID support. Timely publication of major
findings is encouraged.
3. NIAID Staff Responsibilities
NIAID staff assistance will be provided by the NIAID's Scientific
Coordinator. The NIAID Scientific Coordinator will have substantial
scientific/programmatic involvement during the conduct of awarded activities
through technical assistance, advice and coordination above and beyond normal
program stewardship for this award, as described below. The Scientific
Coordinator will coordinate other appropriate NIAID program staff assistance.
During performance of the award, the NIAID Scientific Coordinator may provide
appropriate assistance, advice, and guidance by: participating in the design
of the activities; advising in the selection of sources or resources (e.g.,
determining where a particular organism can be found); coordinating or
participating in the collection and/or analysis of data; advising in
management and technical performance; or participating in the preparation of
publications. The Scientific Coordinator will serve as a liaison/facilitator
between the awardee, pharmaceutical and biotech industries, and other
government agencies (e.g., FDA, USDA, CDC), and will serve as a resource of
scientific and policy information related to the goals of the awardee's
research. However, the role of NIAID will be to facilitate and not entirely
to direct the activities.
An NIAID Program Official will be responsible for the normal program
stewardship of this award. For clinical studies, a mandatory negotiated
milestone is the approval of the final clinical protocol by NIAID. The
Program Official may also serve as the Scientific Coordinator.
4. Collaborative Responsibilities
The specific timelines, interim objectives and funding levels agreed to by
the Principal Investigator and the NIAID shall be included in the terms and
conditions of award. Given the nature of product development, it is
recognized that timelines and interim objectives may require revision and
renegotiation during the course of the project period. The awardee and NIAID
must agree to all such revisions. Release of each funding increment by NIAID
will be based on NIAID review of progress towards achieving the previously
agreed upon interim objective. Where scientifically appropriate, NIAID may
ask awardees to collaborate or cooperate with other NIAID funded projects
and/or U.S. government agencies such as CDC, FDA and USDA.
5. Arbitration
Any disagreement that may arise on scientific or programmatic matters (within
the scope of the award) between award recipients and the NIAID may be brought
to arbitration. An arbitration panel will be composed of three members - one
selected by the Steering Committee (with the NIAID representation not voting)
or by the individual awardee in the event of an individual disagreement, a
second member selected by NIAID, and the third member selected by the two
prior selected members. This special arbitration procedure in no way affects
the awardee's right to appeal an adverse action that is otherwise appealable
in accordance with the PHS regulations at 42 CFR Part 50, Subpart D and HHS
regulation at 45 CFR Part 16.
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 Parts 74 and 92, and other HHS, PHS, and NIH Grant
Administration policy statements.
WHERE TO SEND INQUIRIES
We encourage inquiries concerning this RFA and welcome the opportunity to
answer questions from potential applicants. Inquiries may fall into three
areas: scientific/research, peer review, and financial or grants management
issues:
o Direct questions about scientific/research issues related to sepsis and CAP
diagnostics to:
Jukka Korpela, M.D., Ph.D.
Division of Microbiology & Infectious Diseases
National Institute of Allergy and Infectious Diseases
Room 4119, MSC-6604
6610 Rockledge Drive
Bethesda, MD 20892-6604
Telephone: (301) 496-7728
FAX: (301) 402-2508
Email: jk398e@nih.gov
o Direct questions about scientific/research issues related to CAP to:
David Klein, Ph.D.
Division of Microbiology & Infectious Diseases
National Institute of Allergy and Infectious Diseases
Room 5053, MSC-6605
6610 Rockledge Drive
Bethesda, MD 20892-6605
Telephone: (301)496-5305
FAX: (301)496-8030
Email: dk27a@nih.gov
o Direct questions about peer review issues to:
Madelon Halula, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 3116, MSC-7614
6700-B Rockledge Drive
Bethesda, MD 20892-7614
Telephone: (301) 402-2636
FAX: (301) 402-2638
Email: mh30x@nih.gov
o Direct questions about financial or grants management matters to:
Mollie Shea
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 2234, MSC-7614
6700-B Rockledge Drive
Bethesda, MD 20892-7614
Telephone: (301) 402-6576
FAX: (301) 480-3780
Email: ms256g@nih.gov
LETTER OF INTENT
Prospective applicants are asked to submit a letter of intent that includes
the following information:
o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel
o Participating institutions
o Number and title of this RFA
Although a letter of intent is not required, is not binding, and does not
enter into the review of a subsequent application, the information that it
contains allows IC staff to estimate the potential review workload and plan
the review.
The letter of intent is to be sent by the date listed at the beginning of
this document. The letter of intent should be sent to:
Madelon Halula, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 3116, MSC-7614
6700-B Rockledge Drive
Bethesda, MD 20892-7614
Telephone: (301) 402-2636
FAX: (301) 402-2638
Email: mh30x@nih.gov
SUBMITTING AN APPLICATION
Applications must be prepared using the PHS 398 research grant application
instructions and forms (rev. 5/2001). Applications must have a DUN and
Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the
Universal Identifier when applying for Federal grants or cooperative
agreements. The D&B number can be obtained by calling (866) 705-5711 or
through the web site at http://www.dunandbradstreet.com/. The D&B number
should be entered on line 11 of the face page of the PHS 398 form. The PHS
398 document is available at
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive
format. For further assistance contact GrantsInfo, Telephone (301) 710-0267,
Email: GrantsInfo@nih.gov.
SUPPLEMENTARY INSTRUCTIONS: See "Research Goals and Objectives" and "SPECIAL
REQUIREMENTS" sections above for additional application instructions.
USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001)
application form must be affixed to the bottom of the face page of the
application. Type the RFA number on the label. Failure to use this label
could result in delayed processing of the application such that it may not
reach the review committee in time for review. In addition, the RFA title and
number must be typed on line 2 of the face page of the application form and
the YES box must be marked. The RFA label is also available at:
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.
SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of
the application, including the Checklist, and three signed, photocopies, in
one package by commercial carrier 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)
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:
Madelon Halula, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 3116, MSC-7614
6700-B Rockledge Drive
Bethesda, MD 20892-7614
BETHESDA, MD 20817 (for express mail or courier service)
Applications must be received on or before December 14, 2004. Applications
that are not received on the receipt date will be judged non-responsive and
will be returned to the applicant.
It is highly recommended that the appropriate NIAID program contact be
consulted before submitting the letter of intent and during the early stages
of preparation of the application. (See program contact under INQUIRIES).
APPLICATION PROCESSING: Applications must be received by the application
receipt date listed in the heading of this RFA. If an application is
received after that date, it will be returned to the applicant without
review.
The NIH will not accept any application in response to this RFA that is
essentially the same as one currently pending initial review, unless the
applicant withdraws the pending application. However, when a previously
unfunded application, originally submitted as an investigator-initiated
application, is to be submitted in response to an RFA, it is to be prepared
as a NEW application. That is, the application for the RFA must not include
an Introduction describing the changes and improvements made, and the text
must not be marked to indicate the changes from the previous unfunded version
of the application.
Although there is no immediate acknowledgement of the receipt of an
application, applicants are generally notified of the review and funding
assignment within 8 weeks.
PEER REVIEW PROCESS
Upon receipt, applications will be reviewed for completeness by the CSR and
responsiveness by the NIAID. Incomplete and/or non-responsive applications,
as well as applications requesting greater than $500,000 direct cost per
year, will be returned to the applicant without further consideration.
Applications submitted by an academic institution alone without an industrial
partner will be considered non-responsive and will be returned without
review.
Applications that are complete and responsive to the RFA will be evaluated
for scientific and technical merit by one or more appropriate peer review
groups convened by the (IC) in accordance with the review criteria stated
below. As part of the initial merit review, all applications will:
o Undergo a selection process in which only those applications deemed to have
the highest scientific merit, generally the top half of applications under
review, will be discussed and assigned a priority score
o Receive a written critique
o Receive a second level review by the National Advisory Allergy and
Infectious Diseases 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. In
the written comments, reviewers will be asked to evaluate the application in
order to judge the likelihood that the proposed research will have a
substantial impact on the pursuit of these goals. The scientific review
group will address and consider each of the following criteria in assigning
the application’s overall score, weighting them as appropriate for each
application.
o Significance
o Approach
o Innovation
o Principal Investigator and Other Staff
o Environment
The scientific review group will address and consider each of these criteria
in assigning the application's overall score, weighting them as appropriate
for each application. The application does not need to be strong in all
categories to be judged likely to have 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.
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?
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? Are the goal(s), plan, and interim objectives/milestones
appropriate and feasible?
INNOVATION: Does the project employ novel concepts, approaches or methods?
Are the aims original and innovative? Does the project challenge existing
paradigms or develop new methodologies or technologies?
PRINCIPAL INVESTIGATOR AND OTHER STAFF: Are the investigator and other
scientific/technical staff 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)? Are the project
management and administrative staff appropriate and qualified?
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?
ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following
items will be considered in the determination of scientific merit and the
priority score:
PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human
subjects and protections from research risk relating to their participation
in the proposed research will be assessed. (See criteria included in the
section on Federal Citations, below)
INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of
plans to include subjects of both genders, all racial and ethnic groups (and
subgroups), and children as appropriate for the scientific goals of the
research. Plans for the recruitment and retention of subjects will also be
evaluated. (See Inclusion Criteria in the sections on Federal Citations,
below).
CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to
be used in the project, the five items described under Section f of the PHS
398 research grant application instructions (rev. 5/2001) will be assessed.
ADDITIONAL CONSIDERATIONS
BUDGET: The reasonableness of the proposed budget and the requested period of
support in relation to the proposed research.
RECEIPT AND REVIEW SCHEDULE
Letter of Intent Receipt Date: November 15, 2004
Application Receipt Date: December 14, 2004
Peer Review Date: April 15, 2005
Council Review: June 1, 2005
Earliest Anticipated Start Date: June 30, 2005
AWARD CRITERIA
Award criteria that will be used to make award decisions include:
o Scientific merit of the proposed project as determined by peer review
o Availability of funds
o Programmatic priorities.
REQUIRED FEDERAL CITATIONS
ANIMAL WELFARE PROTECTION: Recipients of PHS support for activities
involving live, vertebrate animals must comply with PHS Policy on Humane Care
and Use of Laboratory Animals
(http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf), as
mandated by the Health Research Extension Act of 1985
(http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA
Animal Welfare Regulations
(http://www.nal.usda.gov/awic/legislat/usdaleg1.htm), as applicable.
HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that
applications and proposals involving human subjects must be evaluated with
reference to the risks to the subjects, the adequacy of protection against
these risks, the potential benefits of the research to the subjects and
others, and the importance of the knowledge gained or to be gained.
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm
DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required for
all types of clinical trials, including physiologic, toxicity, and dose-
finding studies (phase I); efficacy studies (phase II), efficacy,
effectiveness and comparative trials (phase III). The establishment of data
and safety monitoring boards (DSMBs) is required for multi-site clinical
trials involving interventions that entail potential risk to the
participants. (NIH Policy for Data Safety and Monitoring, NIH Guide for
Grants and Contracts, June 12, 1998:
http://grants.nih.gov/grants/guide/notice-files/not98-084.html).
INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: 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 clinical research projects unless a
clear and compelling justification is provided indicating 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 clinical research should read the AMENDMENT "NIH
Guidelines for Inclusion of Women and Minorities as Subjects in Clinical
Research - Amended, October, 2001," published in the NIH Guide for Grants and
Contracts on October 9, 2001
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html);
a complete copy of the updated Guidelines are available at
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.
The amended policy incorporates: the use of an NIH definition of clinical
research; updated racial and ethnic categories in compliance with the new OMB
standards; clarification of language governing NIH-defined Phase III clinical
trials consistent with the new PHS Form 398; and updated roles and
responsibilities of NIH staff and the extramural community. The policy
continues to require for all NIH-defined Phase III clinical trials that: a)
all applications or proposals and/or protocols must provide a description of
plans to conduct analyses, as appropriate, to address differences by
sex/gender and/or racial/ethnic groups, including subgroups if applicable;
and b) investigators must report annual accrual and progress in conducting
analyses, as appropriate, by sex/gender and/or racial/ethnic group
differences.
INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS:
The NIH maintains a policy 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.
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 is available at
http://grants.nih.gov/grants/funding/children/children.htm.
REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH
policy requires education on the protection of human subject participants for
all investigators submitting NIH proposals for research involving human
subjects. This policy announcement is in the NIH Guide for Grants and
Contracts Announcement, dated June 5, 2000, at
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.
HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research
on hESCs can be found at http://stemcells.nih.gov/index.asp and at
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only
research using hESC lines that are registered in the NIH Human Embryonic Stem
Cell Registry will be eligible for Federal funding (see http://escr.nih.gov).
It is the responsibility of the applicant to provide, in the project
description and elsewhere in the application as appropriate, the official NIH
identifier(s)for the hESC line(s)to be used in the proposed research.
Applications that do not provide this information will be returned without
review.
PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The
Office of Management and Budget (OMB) Circular A-110 has been revised to
provide public access to research data through the Freedom of Information Act
(FOIA) under some circumstances. Data that are (1) first produced in a
project that is supported in whole or in part with Federal funds and (2)
cited publicly and officially by a Federal agency in support of an action
that has the force and effect of law (i.e., a regulation) may be accessed
through FOIA. It is important for applicants to understand the basic scope of
this amendment. NIH has provided guidance at
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.
Applicants may wish to place data collected under this PA in a public
archive, which can provide protections for the data and manage the
distribution for an indefinite period of time. If so, the application should
include a description of the archiving plan in the study design and include
information about this in the budget justification section of the
application. In addition, applicants should think about how to structure
informed consent statements and other human subjects procedures given the
potential for wider use of data collected under this award.
STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The
Department of Health and Human Services (DHHS) issued final modification to
the "Standards for Privacy of Individually Identifiable Health Information",
the "Privacy Rule," on August 14, 2002. The Privacy Rule is a federal
regulation under the Health Insurance Portability and Accountability Act
(HIPAA) of 1996 that governs the protection of individually identifiable
health information, and is administered and enforced by the DHHS Office for
Civil Rights (OCR).
Decisions about applicability and implementation of the Privacy Rule reside
with the researcher and his/her institution. The OCR website
(http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including
a complete Regulation Text and a set of decision tools on "Am I a covered
entity?" Information on the impact of the HIPAA Privacy Rule on NIH
processes involving the review, funding, and progress monitoring of grants,
cooperative agreements, and research contracts can be found at
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.
URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals
for NIH funding must be self-contained within specified page limitations.
Unless otherwise specified in an NIH solicitation, Internet addresses (URLs)
should not be used to provide information necessary to the review because
reviewers are under no obligation to view the Internet sites. Furthermore, we
caution reviewers that their anonymity may be compromised when they directly
access an Internet site.
HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to
achieving the health promotion and disease prevention objectives of "Healthy
People 2010," a PHS-led national activity for setting priority areas. This
RFA is related to one or more of the priority areas. Potential applicants may
obtain a copy of "Healthy People 2010" at
http://www.health.gov/healthypeople.
AUTHORITY AND REGULATIONS
This program is described in the Catalog of Federal Domestic Assistance at
http://www.cfda.gov/ in the following citations: No. 93.855, Immunology,
Allergy, and Transplantation Research and No. 93.856, Microbiology and
Infectious Diseases Research. Awards are made under authorization of Sections
301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284)
and administered under NIH grants policies and Federal Regulations 42 CFR 52
and 45 CFR Parts 74 and 92. This program is not subject to the
intergovernmental review requirements of Executive Order 12372 or Health
Systems Agency review.
The NIH Grants Policy Statement is available at
http://grants.nih.gov/grants/policy/policy.htm. This document includes
general information about the grant application and review process;
information on the terms and conditions that apply to NIH Grants and
cooperative agreements; and a listing of pertinent offices and officials at
the NIH. All awards are subject to the terms and conditions, cost principles,
and other considerations described in the NIH Grants Policy Statement.
The PHS strongly encourages all grant recipients to provide a smoke-free
workplace and discourage the 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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