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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