Organ Transplant Infection Detection and Prevention Program

Announcement Type: New.

Funding Opportunity Number: 04132.

Catalog of Federal Domestic Assistance Number: 93.283.

Key Dates: Letter of Intent Deadline: May 25, 2004.

Application Deadline: June 24, 2004.

Executive Summary: The Organ Transplant Infection Detection and Prevention (OTIP) Program will rapidly assess the public health impact of new infection prevention programs in organ transplant recipients through a program of sentinel surveillance, applied research and collaborative prevention studies. Such assessments would be the basis for national prevention programs to eliminate or minimize invasive fungal disease and related mortality in this population. In addition, the program would create a repository of clinically relevant isolates and specimens with relevant patient information from which applied research can further scientific knowledge regarding novel diagnostics and emerging antimicrobial resistance.

I. Funding Opportunity Description

Authority: This program is authorized under the Public Health Service Act, section 317(k)(2) [42 U.S.C. 247b(k)(2)].

Purpose

The purpose of the OTIP Program is to support organ transplant centers participating in existing surveillance or research networks to develop a consortium of centers of excellence in surveillance, infection prevention, and applied public health research involving solid organ and stem-cell transplant recipients. The OTIP should be designed to develop, implement, and evaluate effectiveness of epidemiologic-based strategies to reduce infectious outcomes among organ-transplant recipients. Examples of existing networks include The Centers for Disease Control and Prevention (CDC) Program of Surveillance for Invasive Fungal Infections in Transplant Recipients (TransNet), CDC's Prevention Epicenter Program, and National Marrow Donor Program's Infection Pilot Project.

The goals of the OTIP program are: (1) Support activities at participating transplant centers for enhanced surveillance for fungal infections during the post-transplant period, using similar methods and intensity of case-ascertainment, with development of valid, useful, simple surveillance methods for exportation to non-program transplant centers; (2) support activities at participating transplant centers related to epidemiologic assessments and improved descriptions of established infectious syndromes through a repository of clinical samples (e.g., serial serum, bronchial-alveolar lavage) and identification of novel risk factors for disease (e.g., role of home environment in late onset aspergillosis); and (3) be a national resource for assessing effectiveness of new infection prevention strategies in this population. As invasive fungal infections represent the highest infection-related mortality in this population, initial activities should focus exclusively on these pathogens; other pathogens may be incorporated into later years of the program.

This program addresses the “Healthy People 2010” focus area(s) of Immunization and Infectious Diseases. For the conference copy of “Healthy People 2010”, visit the Internet site: http://www.health.gov/healthypeople.

Measurable outcomes of the program will be in alignment with the performance goal for the National Center for Infectious Diseases (NCID): To protect Americans from infectious diseases by planning, directing, and coordinating a national program to improve the identification, investigation, diagnosis, prevention, and control of infectious diseases in the United States and throughout the world.

Research Objectives

Roughly 18,000 bone marrow/stem cell transplants (SCCs) and over 23,000 solid organ transplants (SOTs) are performed annually within the U.S. Approximately 10-15 percent of recipients will develop an invasive fungal infection post-transplant. In this population, the mortality of invasive aspergillosis can exceed 90 percent; the mortality of invasive candidiasis is approximately 40 percent. The OTIP Program will provide the foundation for applied research designed to fulfill current gaps in scientific knowledge regarding surveillance and prevention of invasive fungal infections in the post-transplant period. Such knowledge includes identification of an efficient and valid surveillance methodology, understanding the utility of novel diagnostics used to detect fungal, bacterial, or viral pathogens, and identification of modifiable risk factors for disease and effective prevention tools. In order to gain this knowledge, the objectives of the OTIP Program should: (1) Identify and validate efficient surveillance methodology exportable to non-program centers; (2) identify modifiable environmental or other factors extrinsic to the transplant patient (e.g., device-specific factors, environmental exposures) which can be addressed to prevent infectious diseases in the post-transplant period; (3) describe the pathogen and infection characteristics of common infections among patients in the post-transplant period; and (4) through knowledge gained from (1)-(3), demonstrate the efficacy of novel prevention measures in reducing post-transplant infectious complications and associated mortality. The types of experimental approaches that may be used to achieve the goals of the program include: development of the “gold standard” approach to surveillance for invasive fungal infections in the post-transplant population and validate efficacy of an exportable surveillance methodology; prospective case-control studies for common invasive fungal infections, such as late-onset aspergillosis, including targeted environmental sampling; establishment of a serum, urine, and/or bronchial-alveolar lavage specimen repository for determining effectiveness of novel diagnostics for infections (e.g., fungal, viral); and using risk-adjusted infection-related outcomes, ascertain the effectiveness of novel prevention program in reducing disease (prophylaxis strategies, educational interventions). Because organ-transplant patients are at risk for prolonged periods post-transplant (i.e., several years), these activities must be conducted within a specialized network of collaborating centers capable of long-term continuity of care of these patients (i.e., over one year). The operational organization of The OTIP Program must include two or more consortiums of two to four transplant centers with sufficient infrastructure (e.g., surveillance staff and laboratory support) supported by the consortium leaders to accomplish the objectives.

Activities

Awardee activities for this program are as follows:

1. Establish a consortium of at least two solid-organ and/or stem-cell transplant centers consistent with the purpose of the OTIP Program.

2. Collaborate with other OTIP Program sites and CDC to operate as the OTIP Program, and facilitate and oversee implementation of core activities (e.g., activities to be done at all centers participating in the OTIP Program). This includes providing resources to investigators at centers participating in the applicant's consortium to support OTIP Program activities. Activities may be prioritized and time-phased. Core activities include:

a. Perform “gold standard” surveillance for invasive fungal infections incorporating the following elements:

i. Active-surveillance using standardized diagnostic evaluations and follow-up of patients among participating sites (e.g., proper training of surveillance personnel, collection and evaluation of fungal isolates).

ii. Design and maintain an aggregate database (e.g., standardized protocol) recording both events and relevant patient data from all organ-transplant recipients to maintain a valid risk-adjusted surveillance system among all transplant sites.

iii. Optionally, include time-phased plans to incorporate other infectious outcomes.

iv. Optionally, include time-phased plans to explore utility of electronic capture of data elements and/or utilization of other existing data systems related to transplant recipients.

b. Epidemiologic assessments to identify modifiable risk factors, focusing on those extrinsic to the patient, for invasive fungal disease in the post-transplant period.

c. Development of a repository of clinical samples and relevant clinical data for assessment of novel diagnostics or pathogen discovery, and outline plans to facilitate making isolates available to a wider public health research community.

d. Develop plans and implement OTIP Network study to assess novel prevention strategies based on (a)-(c) above.

3. Participate in management, analysis, and interpretation data, publish and disseminate important medical and public health information stemming from OTIP Program activities in collaboration with all OTIP Program sites.

4. Monitor and evaluate scientific and operational accomplishments and progress in achieving the purpose of this program.

In a cooperative agreement, CDC staff is substantially involved in the program activities, above and beyond routine grant monitoring.

CDC Activities for this program are as follows:

1. The CDC Staff will have substantial scientific-programmatic involvement during the conduct of these activities, through technical assistance, advice and coordination above and beyond normal program stewardship for grants, including participation in data collection, analysis, interpretation of data, and presentation of research findings.

2. The CDC Staff will facilitate operations of the program through maintenance of a Steering Committee, and coordinate the dissemination of information to Principal Investigators and others.

3. As requested, will serve as a reference laboratory and receive, process, store, and perform evaluation of clinical (e.g., serum repository) or environmental specimens, perform molecular epidemiologic studies, evaluate novel diagnostics, perform confirmatory testing and/or susceptibility testing on fungal isolates obtained in OTIP projects.

4. As requested, serve as a resource for and support data management, bio-statistical and epidemiologic analysis.

5. Assist in the development of surveillance and research protocols for IRB review by all cooperating institutions participating in the research project, as well as CDC approval.

Collaborative Activities for the Program are as follows:

1. Timing, protocol development, and implementation strategy of core activities of the OTIP Program will be decided by Steering Committee consisting of Principal Investigators of each OTIP Program cooperative agreement, CDC, and other select representatives (e.g., participating transplant centers, professional society). The purpose of the Steering Committee is to share scientific information, assess scientific progress, identify new research opportunities, and decide on major aspects of program operations. Decisions will be made by a majority vote of a quorum, with an attempt for consensus when possible. The Steering Committee will convene through both telephone conference and in person.

II. Award Information

Type of Award: Cooperative Agreement.

CDC involvement in this program is listed in the Activities Section above.

Fiscal Year Funds: 2004.

Approximate Total Funding: $350,000.

Approximate Number of Awards: One to two.

Approximate Average Award: $175,000 (This amount is for the first 12-month budget period, and includes both direct and indirect costs).

Floor of Award Range: None.

Ceiling of Award Range: $200,000.

Anticipated Award Date: August 30, 2004.

Budget Period Length: 12 months.

Project Period Length: Five years.

Throughout the project period, CDC's commitment to continuation of awards will be conditioned on the availability of funds, evidence of satisfactory progress by the recipient (as documented in required reports), and the determination that continued funding is in the best interest of the Federal Government.

III. Eligibility Information

III.1. Eligible Applicants

Applications may be submitted by public and private nonprofit organizations, such as:

• Public nonprofit organizations
• Private nonprofit organizations
• Universities
• Research institutions
• Hospitals

III.2. Cost Sharing or Matching

Matching funds are not required for this program.

III.3. Other

If you request a funding amount greater than the ceiling of the award range, your application will be considered non-responsive, and will not be entered into the review process. You will be notified that your application did not meet the submission requirements.

If your application is incomplete or non-responsive to the requirements listed in this section, it will not be entered into the review process. You will be notified that your application did not meet submission requirements.

Other eligibility requirements include: (1) Identification of consortium of transplant centers which in aggregate perform on average 1000 transplants per year and may include a combination of solid-organ and stem-cell transplants; (2) appropriate diagnostic evaluations are performed on patients post-transplant to ascertain etiology of the illness post-transplantation; (3) participating centers have capacity to perform intensive surveillance, epidemiologic assessments, and facilities to ensure efficient processing of patient specimens. Documentation of eligibility can be accomplished by including the following: (1) Infection control or other surveillance data (e.g., from sites currently participating in surveillance networks) from applicants and proposed collaborating sites describing total number of transplants, type of transplants, and percent of transplant patients developing invasive fungal infections; (2) outline of current practice in documenting etiology of post-transplant illness in this population; and (3) a bulleted list of titles of at least one, but no more than five, current or recent epidemiologic and/or prevention research projects or studies undertaken from each proposed collaborating sites (e.g., part of quality improvement projects, infection control, multi-site or single-site epidemiologic studies).

The limitation on eligibility is justified by the essential need to have sufficient numbers of transplanted individuals and sufficient disease incidence to adequately perform studies to achieve objectives of the OTIP Program. In addition, centers must currently practice a standard of care that will maximize identification of infecting pathogens in this population. Finally, demonstration of past performance in conducting epidemiologic investigation and prevention research will ensure applicants ability to perform objectives.

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 CDC programs.

Note:

Title 2 of the United States Code section 1611 states that an organization described in section 501(c)(4) of the Internal Revenue Code that engages in lobbying activities is not eligible to receive Federal funds constituting an award, grant, or loan.

IV. Application and Submission Information

IV.1. Address To Request Application Package

To apply for this funding opportunity, use application form PHS 398 (OMB number 0925-0001 rev. 5/2001). Forms and instructions are available in an interactive format on the CDC Web site, at the following Internet address: http://www.cdc.gov/od/pgo/forminfo.htm.

Forms and instructions are also available in an interactive format on the National Institutes of Health (NIH) Web site at the following Internet address: http://grants.nih.gov/grants/funding/phs398/phs398.html.

If you do not have access to the Internet, or if you have difficulty accessing the forms on-line, you may contact the CDC Procurement and Grants Office Technical Information Management Section (PGO-TIM) staff at: 770-488-2700. Application forms can be mailed to you.

IV.2. Content and Form of Application Submission

Letter of Intent (LOI): Your LOI must be written in the following format:

• Maximum number of pages: One
• Font size: 12-point unreduced
• Single spaced
• Paper size: 8.5 by 11 inches
• Page margin size: One inch
• Printed only on one side of page
• Written in plain language, avoid jargon

Your LOI must contain the following information:

• Descriptive title of the proposed research
• Name, address, e-mail address, and telephone number of the Principal Investigator
• Names of other key personnel
• Number and title of this Program Announcement (PA)

Application: Follow the PHS 398 application instructions for content and formatting of your application. For further assistance with the PHS 398 application form, contact PGO-TIM staff at 770-488-2700, or contact GrantsInfo, Telephone (301) 435-0714, E-mail: GrantsInfo@nih.gov.

Your research plan should address activities to be conducted over the entire project period.

You are required to have a Dun and Bradstreet Data Universal Numbering System (DUNS) number to apply for a grant or cooperative agreement from the Federal government. Your DUNS number must be entered on line 11 of the face page of the PHS 398 application form. The DUNS number is a nine-digit identification number, which uniquely identifies business entities. Obtaining a DUNS number is easy and there is no charge. To obtain a DUNS number, access http://www.dunandbradstreet.com or call 1-866-705-5711. For more information, see the CDC Web site at: http://www.cdc.gov/od/pgo/funding/pubcommt.htm.

This PA uses just-in-time concepts. It also uses the modular budgeting as well as non-modular budgeting formats. See: http://grants.nih.gov/grants/funding/modular/modular.htm for additional guidance on modular budgets. Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular budget format. Otherwise, follow the instructions for non-modular budget research grant applications.

Additional requirements that may require you to submit additional documentation with your application are listed in section “VI.2. Administrative and National Policy Requirements.”

IV.3. Submission Dates and Times

LOI Deadline Date: May 25, 2004.

CDC requests that you send a LOI if you intend to apply for this program. Although the LOI is not required, not binding, and does not enter into the review of your subsequent application, the LOI will be used to gauge the level of interest in this program, and to allow CDC to plan the application review.

Application Deadline Date: June 21, 2004.

Explanation of Deadlines: Applications must be received in the CDC Procurement and Grants Office by 4 p.m. eastern time on the deadline date. If you send your application by the United States Postal Service or commercial delivery service, you must ensure that the carrier will be able to guarantee delivery of the application by the closing date and time. If CDC receives your application after closing due to: (1) Carrier error, when the carrier accepted the package with a guarantee for delivery by the closing date and time, or (2) significant weather delays or natural disasters, you will be given the opportunity to submit documentation of the carriers guarantee. If the documentation verifies a carrier problem, CDC will consider the application as having been received by the deadline.

This announcement is the definitive guide on application submission address and deadline. It supersedes information provided in the application instructions. If your application does not meet the deadline above, it will not be eligible for review, and will be discarded. You will be notified that your application did not meet the submission requirements.

CDC will not notify you upon receipt of your application. If you have a question about the receipt of your application, first contact your courier. If you still have a question, contact the PGO-TIM staff at: 770-488-2700. Before calling, please wait two to three days after the application deadline. This will allow time for applications to be processed and logged.

IV.4. Intergovernmental Review of Applications

Your application is subject to Intergovernmental Review of Federal Programs, as governed by Executive Order (EO) 12372. This order sets up a system for state and local governmental review of proposed federal assistance applications. You should contact your state single point of contact (SPOC) as early as possible to alert the SPOC to prospective applications, and to receive instructions on your state's process. Click on the following link to get the current SPOC list: http://www.whitehouse.gov/omb/grants/spoc.html.

IV.5. Funding Restrictions

Restrictions, which must be taken into account while writing your budget, are as follows: a separate budget should be included for each proposed collaborating center. Within each budget, include line items, if appropriate, for specific funds addressing each respective recipient activity. Funds requested related to activities that are time-specific (e.g., risk factor study in year 2-3, adding repository of clinical specimens in year 2, adding food borne pathogen surveillance in year 3) should appear as line items in the appropriate years only. Cost for semi-annual steering group meetings, training sessions, or related travel/meeting expenses should be separated from other travel.

If you are requesting indirect costs in your budget, you must include a copy of your indirect cost rate agreement. If your indirect cost rate is a provisional rate, the agreement should be less than 12 months of age.

Awards will not allow reimbursement of pre-award costs.

IV.6. Other Submission Requirements

LOI Submission Address: Submit your LOI by express mail, delivery service, fax, or e-mail to: Barbara Stewart, Public Health Analyst, Centers for Disease Control and Prevention, National Center for Infectious Diseases, 1600 Clifton Rd., MS C19, Atlanta, GA 30333, (404) 639-0044, (404) 639-2469, bstewart@cdc.gov.

Application Submission Address: Submit the original and five hard copies of your application by mail or express delivery service to: Technical Information Management-PA# 04132, CDC Procurement and Grants Office, 2920 Brandywine Road, Atlanta, GA 30341.

Applications may not be submitted electronically at this time.

V. Application Review Information

V.1. Criteria

You are required to provide measures of effectiveness that will demonstrate the accomplishment of the various identified objectives of the cooperative agreement. Measures of effectiveness must relate to the performance goals stated in the “Purpose” section of this announcement. Measures must be objective and quantitative, and must measure the intended outcome. These measures of effectiveness must be submitted with the application and will be an element of evaluation.

The goals of CDC-supported research are to advance the understanding of biological systems, improve the control and prevention of disease and injury, 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. 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.

The criteria are as follows:

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? Does the selection of transplant centers participating in the consortium allow for sufficient diversity or number of transplants to ensure success of the program? Are any unique features of the consortium that ensure success with the multi-site nature of the activities? If transplants of only a limited type (e.g., stem-cell only) are represented by the applicant's consortium, will such a homogenous patient mix result in improved scientific productivity and ability to accomplish objectives of the OTIP Program to justify the approach?

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?

Investigator: Is the investigator 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)?

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? Does the proposed consortium of transplant centers build on any existing surveillance and public health research infrastructure to ensure success?

Additional Review Criteria: In addition to the above criteria, the following items will be considered in the determination of scientific merit and priority score:

1. Program priorities include activities focused on invasive fungal infections. Bacterial and Viral pathogens should be phased in over time if funding becomes available.

2. Proposed transplant centers participating in consortium should maximize use of scarce resources (e.g., utilizing same surveillance personnel for both stem-cell and solid-organ transplant patients if both transplant populations are participating, incorporation of some activities into routine infection control activities).

3. Degree of commitment expressed in letters of support from all essential personnel or departments from proposed transplant centers to be in consortium (e.g., infection control, clinical microbiology, transplantation division).

Protection of Human Subjects from Research Risks: Does the application adequately address the requirements of title 45 CFR part 46 for the protection of human subjects? This will not be scored; however, an application can be disapproved if the research risks are sufficiently serious and protection against risks is so inadequate as to make the entire application unacceptable.

Inclusion of Women and Minorities in Research: Does the application adequately address the CDC Policy requirements regarding the inclusion of women, ethnic, and racial groups in the proposed research? This includes: (1) The proposed plan for the inclusion of both sexes and racial and ethnic minority populations for appropriate representation; (2) The proposed justification when representation is limited or absent; (3) A statement as to whether the design of the study is adequate to measure differences when warranted; and (4) A statement as to whether the plans for recruitment and outreach for study participants include the process of establishing partnerships with community(ies) and recognition of mutual benefits.

Budget: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research.

V.2. Review and Selection Process

Applications will be reviewed for completeness by the Procurement and Grants Office (PGO) and for responsiveness by NCID. Incomplete applications and applications that are non-responsive to the eligibility criteria will not advance through the review process. Applicants will be notified that their application did not meet submission requirements.

Applications that are complete and responsive to the PA will be evaluated for scientific and technical merit by an appropriate peer review group or charter study section convened by NCID in accordance with the review criteria listed above. As part of the initial merit review, all applications may:

• Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score.
• Receive a written critique.
• Receive a second level review by the Mycotic Diseases Branch.

Award Criteria: Criteria that will be used to make award decisions include:

• Scientific merit (as determined by peer review).
• Availability of funds.
• Programmatic priorities.

VI. Award Administration Information

VI.1. Award Notices

Successful applicants will receive a Notice of Grant Award (NGA) from the CDC Procurement and Grants Office. The NGA shall be the only binding, authorizing document between the recipient and CDC. The NGA will be signed by an authorized Grants Management Officer, and mailed to the recipient fiscal officer identified in the application.

Unsuccessful applicants will receive notification of the results of the application review by mail.

VI.2. Administrative and National Policy Requirements

45 CFR Part 74 and Part 92

For more information on the Code of Federal Regulations, see the National Archives and Records Administration at the following Internet address: http://www.access.gpo.gov/nara/cfr/cfr-table-search.html.

The following additional requirements apply to this project:

• AR-1 Human Subjects Requirements
• AR-2 Requirements for Inclusion of Women and Racial and Ethnic Minorities in Research
• AR-3 Animal Subjects Requirements
• AR-6 Patient Care
• AR-7 Executive Order 12372
• AR-9 Paperwork Reduction Act Requirements
• AR-10 Smoke-Free Workplace Requirements
• AR-11 Healthy People 2010
• AR-12 Lobbying Restrictions
• AR-15 Proof of Non-Profit Status
• AR-22 Research Integrity
• AR-24 Health Insurance Portability and Accountability Act Requirements

Additional information on these requirements can be found on the CDC Web site at the following Internet address: http://www.cdc.gov/od/pgo/funding/ARs.htm.

VI.3. Reporting

You must provide CDC with an original, plus two hard copies of the following reports:

1. Interim progress report, (use form PHS 2590, OMB Number 0925-0001, rev. 5/2001 as posted on the CDC Web site) no less than 90 days before the end of the budget period. The progress report will serve as your non-competing continuation application, and must contain the following elements:

a. Current Budget Period Activities Objectives.

b. Current Budget Period Financial Progress.

c. New Budget Period Program Proposed Activity Objectives.

d. Budget.

e. Additional Requested Information.

f. Measures of Effectiveness.

2. Financial status report and annual progress report, no more than 90 days after the end of the budget period.

3. Final financial and performance reports, no more than 90 days after the end of the project period.

These reports must be mailed to the Grants Management Specialist listed in the “Agency Contacts” section of this announcement.

VII. Agency Contacts

For general questions about this announcement, contact: Technical Information Management Section, CDC Procurement and Grants Office, 2920 Brandywine Road, Atlanta, GA 30341, Telephone: 770-488-2700.

For scientific/research issues, contact: Dr. Mary Lerchen, Extramural Program Official, CDC, National Center for Infectious Diseases, 1600 Clifton Road, NE., Mailstop: C-19, Atlanta, GA 30333, Telephone: 404-639-0043, E-mail: mlerchen@cdc.gov.

For questions about peer review, contact: Barbara Stewart, CDC, National Center for Infectious Diseases, 1600 Clifton Road, NE., Mailstop: C-19, Atlanta, GA 30333, Telephone: 404-639-0044, E-mail: bstewart@cdc.gov.

For financial, grants management, or budget assistance, contact:

Sharon Robertson, Grants Management Specialist, CDC Procurement and Grants Office, 2920 Brandywine Road, Atlanta, GA 30341, Telephone:770-488-2748, E-mail: sqr2@cdc.gov.

VIII. Other Information

None.