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/archive/grants/policy/nihgps_2003/index.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) 435-0714, 
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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NIH Funding Opportunities and Notices


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