A Data Coordinating Center application will be considered non-responsive if it lacks demonstrated experience in any of the following requirements:

Organization of the Network for Cardiothoracic Surgical Investigations in Cardiovascular Medicine:

The Network for Cardiothoracic Surgical Investigations in Cardiovascular Medicine (Network) is a cooperative clinical network consisting of up to seven Clinical Centers (CC), a single Data and Coordinating Center (DCC), the NIH (NHLBI and NINDS), and the ICRH. The responsibilities of each component of the Network are described below:

NHLBI:

The NHLBI will oversee the organization of the Network and thus will be substantially involved with the awardees in a partnership relationship. The NHLBI Program Official will monitor patient recruitment and study progress, ensure disclosure of conflicts of interest, and ensure adherence to NHLBI policies. NHLBI will appoint the Network Chairperson(s), all members of the Protocol Review Committee (PRC), and the Data and Safety Monitoring Board (DSMB). The Network Chairperson(s) will be responsible for ensuring that there are well-documented policies, procedures, and bylaws to guide all aspects of Network activities and operations.

NINDS:

The NINDS staff will participate on the steering committee that will include representatives from the DCC and CC’s and other institutions that are contributing to the program. The NHLBI and the NINDS will share responsibilities with the Network for developing the neurology-specific content and will share all communications, verbal or otherwise, including progress reports and correspondence, concerning this program.

ICRH:

ICRH will provide and administer a portion of the protocol funds for CC awarded to successful principal investigators located in Canada. ICRH staff will work with NHLBI to assess responsiveness, collaborate with the NHLBI concerning the peer review process and administration, and advise the NHLBI on matters related to the Network for Cardiothoracic Surgical Investigations.

Clinical Centers (CCs):

CCs will propose protocols, participate in their overall development, recruit patients, conduct the protocols, and disseminate research findings. All individual CCs will be required to participate in a cooperative and interactive manner with one another and with the DCC in all aspects of the Network. CCs will likely be major medical centers with existing relationships with private or community hospitals and physician practices. It is expected that individual CCs will vary in nature and experience, and thus may represent both different patient populations and unique expertise in the area of cardiothoracic surgery. The CC must demonstrate clinical research excellence and a proven ability to recruit patients from various racial/ethnic groups. It is critical to establish collaborations with cardiologists for the conduct of trials that bridge both specialties, and with basic researchers for the orderly translation of basic science and bioengineering concepts into clinical studies, and other specialties as applicable to the protocol being conducted. As a whole, the Network intends to enroll eligible patients and to perform clinical interventions on a broad range of cardiovascular diseases. Potential applicants should review the additional information contained in Section IV, Application Submission Instructions.

The Principal Investigator (PI) and Co-PI at each CC will be responsible for establishing collaborations with cardiologists and basic researchers, proposing protocols suitable for collaborative multi-center research, estimating their costs, and participating in their overall development, conducting the research, assuring quality of patient care and protocol adherence, ensuring the accurate and timely transmission of data collected in conjunction with the DCC, and disseminating research findings. A minimum time commitment of 10% is expected from the surgical physician leader (Principal Investigator), and 30% is expected from a physician Co-Investigator at each Clinical Center. This is a guideline; applicants with differing management plans should justify according to their organizational structure and recruiting procedures. Each CC will be subject to annual administrative review.

As specific protocols are developed, support will depend on the availability of funds and will be provided on a per patient basis. All of the Clinical Centers must be willing to accept this funding arrangement for each new protocol conducted. Clinical protocols must be approved by local Institutional Review Boards. The exact number and duration of protocols supported in the five-year program will depend on the nature and extent of the protocols developed.

Data and Coordinating Center (DCC):

The DCC will coordinate, administer, and support all Network clinical research activities. These activities include, but are not limited to administrative and salary support for the Network Chair(s), scientific leadership and committees, reimbursement for patient accrual, and organization of investigator, Data and Safety Monitoring Board, and Protocol Review Committee meetings. The DCC will assist in final protocol development, provide statistical leadership for each study design, and prepare operational timetables. The DCC will develop a data collection system and manuals of operations, determine sampling and randomization schemes, and assist in defining primary and secondary outcomes and analytical approaches for the protocols. The DCC will also provide regulatory guidance and facilitate interactions with regulatory authorities. The DCC will subcontract with external laboratories as needed. The DCC will manage and distribute all funding for centralized core laboratory(ies) should they be required for a specific protocol(s).

The DCC will develop procedures for quality control, training and certification, and data management. It will monitor the quality and quantity of data received from the CCs, provide relevant reports to the NHLBI, CCs, and Steering Committee (SC), and serve as a central repository for study data. The DCC is responsible for any site visits necessary for training, quality control, data management and at a minimum will visit each site during the course of each protocol. The DCC will prepare protocols for submission to the Protocol Review Committee (PRC), and to the FDA, Centers for Medicare and Medicaid Services (CMS), or other government agencies as required, and prepare confidential data analyses and reports for the DSMB. The DCC will support manuscript preparation through data analysis, statistical consultation, editorial support, and meeting coordination. It will schedule and make arrangements for all meetings of established committees and boards. The DCC will manage and distribute protocol funds to participating Clinical Centers as a per patient fee for service arrangement after a protocol has been approved and the NHLBI has released the funds for distribution. A minimum time commitment of 50% is expected from the Principal Investigator.

The DCC will be subject to annual administrative review.

Steering Committee (SC):

The SC will be the main governing body of the Network. Voting members of the SC include, at a minimum, the Network Chair(s), the PIs of the CCs and of the DCC (or their designated alternate) and the NHLBI Program Official. The Network Chair(s) will be appointed by NHLBI, in consultation with ICRH, and may or may not be Network Investigators. The Network Chair(s) will plan Network activities, oversee its functions, and conduct SC meetings. The SC will develop and ensure compliance with Network policies and procedures, identify and prioritize topics for investigation, evaluate protocols proposed by the CCs, and develop consensus protocols for submission to the PRC. The SC will ensure that studies are properly conducted and monitored, that data are appropriately analyzed and interpreted, and that study results are reported in the scientific literature in a timely manner and promptly disseminated to those directly involved in the care of cardiovascular disease patients in accordance with NHLBI and ICRH policies. The SC may meet as often as three to six times in the first 12 months of the study, two to four times per year thereafter, and by teleconference on a biweekly basis. All major scientific decisions will be determined by majority vote of the SC. The Steering Committee has final responsibility for approving the protocol before review by the PRC or DSMB.

Subcommittees of the SC will be established as necessary and would be expected to include a Publications and Presentations Subcommittee and an Ancillary Studies Subcommittee. The Publications and Presentations Subcommittee will facilitate and supervise preparation of manuscripts prior to submission for publication. The Ancillary Studies Subcommittee will consider the appropriateness of proposed ancillary studies and collaborations. The Steering Committee in conjunction with the DCC will develop procedures and subcommittees for other issues including the need for Core Labs, the evaluation of protocols from outside investigators, quality assurance activities, and others as necessary.

Protocol Review Committee (PRC):

The independent PRC will be appointed by and be advisory to the NHLBI in consultation with ICRH. It will consist of a chairperson and scientists with expertise in cardiac surgery, cardiovascular medicine, clinical trial design, biostatistics, bioethics, outcome measures, and other areas of expertise as needed. The exact number and duration of protocols supported in the five-year program will depend on the nature and extent of the investigations proposed by the SC.

The PRC will evaluate protocols proposed by the SC based on the importance of the question to be addressed, scientific merit of the experimental design and approach, feasibility, appropriateness for the Network and consistency with NHLBI missions and policies. The PRC will provide a written critique of each proposal and a final recommendation to the NHLBI. All study protocols performed by the Network must be recommended by the PRC and approved by the NHLBI before initiation. Each CC is expected to participate in all protocols undertaken by the Network. It is anticipated that more than one protocol will be active at any given time.

Data and Safety Monitoring Board (DSMB):

NHLBI, in consultation with ICRH, will establish a DSMB in accordance with established policies to ensure data quality and participant safety and to provide independent advice to the NHLBI regarding progress and the appropriateness of continuing each study (see http://www.nhlbi.nih.gov/funding/policies/dsmb_inst.htm). Funds for the expenses related to managing the DSMB will be budgeted in the DCC.

Clinical Research Skills Development Core

The Network presents a rich environment for young clinical investigators to be exposed to and to develop additional research skills. To assist new clinical investigators, the NHLBI will permit applicants for a CC to request up to $100,000 in direct costs per year for a Clinical Research Skills Development Core. A maximum of two clinical research skills development core awards will be made. The objective of the Core is to support activities to assist new clinical investigators in progressing to more senior status by enhancing their research skills. This support is in addition to the direct costs budget for the CC.

A Clinical Research Skills Development Core is not required, however, and its absence will not disadvantage an applicant. The quality of the Clinical Research Skills Development Core, if proposed, will be evaluated based on the specific components listed below. The priority score of the Core will have no effect on the overall score of an application.

Developmental opportunities that provide experience with new technologies and skills are encouraged for inclusion in the Core. Innovative strategies should be proposed for cross-disciplinary career development to achieve the goal of exposing new clinical investigators to additional research techniques and opportunities. Examples include a program of seminars focusing on scientific topics that include surgical and other interventions for cardiovascular disease or the development and/or improvement of core courses designed as in-depth instruction in the fundamental skills, methodology, and theory necessary for the well-trained, independent, clinical researcher. In addition to developing the research skills of new clinical investigators, the Cores must ensure that the participating new clinical investigators receive the mentoring they need to foster their research careers. The Clinical Research Skills Development Core is intended for staff investigators with limited clinical research experience, including fellows and junior faculty members. Investigators who have had a previous K series award are not eligible to participate as new investigators under this program. Individuals with an active K grant can participate until the end of the award period for the K grant, but may not receive salary on the Skills Development Core. The Skills Development Core does not include salary support of any kind. The Core should also address other skills necessary for a successful research career, such as grant writing, ethical conduct of research, and clinical trial design.

If a Clinical Research Skills Development Core is proposed, it must be directed by an investigator with strong educational and mentoring credentials who will devote a minimum of 5 percent effort as its Leader. To facilitate mentoring and multidisciplinary developmental activities, active involvement by the principal investigator and other senior investigators within the Network is strongly encouraged. An application for a Clinical Research Skills Development Core will be evaluated in terms of its potential effectiveness in developing the skills and research capabilities of new clinical investigators as reflected in the following required elements of the application:

• A summary of the types of skills that would be developed and a description of proposed project-specific activities.
• A detailed discussion of how mentoring and the professional development of the new clinical investigators will be achieved, including their progression to more independent status.
• A plan by which new clinical investigators are to be recruited and selected including plans to recruit women and minorities.
• The credentials and track records of the Clinical Research Skills Development Core Leader, the Principal Investigator, and other participating senior staff in developing new investigators.
• A plan for coordinating the activities of participating senior investigators.
• A plan for monitoring the progress of the new clinical investigators.
• A description of existing opportunities within the Applicant's institution for supporting investigator development and steps taken to avoid overlap with or duplication of these efforts.
• A detailed development plan for each proposed new investigator (or a representative plan and proposals for tailoring it to needs of multiple new investigators) including required course work and scientific enrichment activities such as special lectures, visiting scientist symposia, seminars, and workshops.

An application for a Clinical Research Skills Development Core will be evaluated in terms of its potential effectiveness in developing the skills and research capabilities of new clinical investigators as reflected in the required application components identified above. Applicants should read the specific requirements and other instructions for applying at http://www.nhlbi.nih.gov/funding/policies/ntwk_skill.htm.

Section II. Award Information

1. Mechanism(s) of Support

This funding opportunity will use the Cooperative Agreement (U01) award mechanism.

This funding opportunity uses the just-in-time budget concepts. It also uses the non-modular budget format described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/phs398/phs398.html). A detailed categorical budget for the "Initial Budget Period" and the "Entire Proposed Period of Support" is to be submitted with the application.

The NIH U01 is a cooperative agreement award mechanism. In the cooperative agreement mechanism, 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 VI. 2. Administrative Requirements, "Cooperative Agreement Terms and Conditions of Award." Plans to continue this RFA beyond the current funding opportunity are indefinite.

2. Funds Available

• The NHLBI intends to commit $33M and the NINDS intends to commit $2M, for a total of $35M over five years to this project.
• ICRH intends to commit a maximum of approximately $1.25 million over a five year period toward meritorious grants from Canadian institutions. ICRH will consider allocating funding toward both protocol costs and Clinical Skills Research Development Cores. Applicants who wish to have their projects considered for funding by ICRH should include with their application a letter stating that their application and summary statement may be shared with ICRH
• $5M in FY 2007 will fund up to seven Clinical Centers and one Data Coordinating Center.
• It is anticipated that the FY 2007 award for the Data Coordinating Center will be approximately $2.6M total direct costs, which will include $1.5M to support protocol and associated patient costs; and during years 2-5, the DCC will receive a total of $4.3M in direct costs, which will include $2.9M to support protocol and associated patient costs.
• Clinical Center awards will be for core costs only and may not exceed $250,000 direct costs per year.
• The anticipated start date is July 1, 2007.
• Facilities and administrative costs requested by consortium participants are not included in the direct cost limitation, see NOT-OD-05-004.
• A maximum of two Clinical Skills Development Core awards will be made for up to $100K per year (direct costs).

1. Eligible Applicants

1.A. Eligible Institutions

You may submit (an) application(s) if your organization has any of the following characteristics:

• For-profit organizations
• Non-profit organizations
• Public or private institutions, such as universities, colleges, hospitals, and laboratories
• Units of state government
• Units of local government
• Eligible agencies of the federal government
• Domestic or Canadian Institutions
• Faith-based or community-based organizations
• Units of state Tribal government
• Units of local Tribal government

1.B. Eligible Individuals

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/ICRH programs. A minimum time commitment of 10% is anticipated from the surgical physician leadership (Principal Investigator) and 30% from a physician Co-Investigators at each Clinical Center site. A minimum time commitment of 50% is anticipated from the individual Principal Investigator at the Data Coordinating Center.

2. Cost Sharing or Matching
Cost sharing is not required under this program.

The most current Grants Policy Statement can be found at: http://grants.nih.gov/grants/policy/nihgps_2003/nihgps_Part2.htm#matching_or_cost_sharing.

3. Other-Special Eligibility Criteria

Awards for a Clinical Center and a Data Coordinating Center will not be made to the same Principal Investigator to ensure that data analysis is performed independently of data acquisition. The same institution may apply for both a Clinical Center and a Data Coordinating Center award, but the applications for each must be from different individuals and must be submitted as separate applications.

Section IV. Application and Submission Information

1. Address to Request Application Information

The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. Applicants must use the currently approved version of the PHS 398. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: [email protected].

Telecommunications for the hearing impaired: TTY 301-451-5936.

2. Content and Form of Application Submission

Applications must be prepared using the most current PHS 398 research grant application instructions and forms. Applications must have a 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.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

The title and number of this funding opportunity must be typed on line 2 of the face page of the application form, and the YES box must be checked.

Clinical Center Applicants

Clinical Center applicants will be judged on the basis of the research plan proposed and on the ability to participate in multicenter clinical trials as indicated by the information in the application as a whole. Since a Clinical Center is expected to draw on clinical resources of its entire Institution, submission of multiple applications from a single Institution would be considered unresponsive to the RFA.

Each applicant should propose two protocols that could potentially be used in the Network environment and conducted in a 2-3 year time frame. The proposed protocols should demonstrate detailed knowledge of the conduct of multi-center clinical trials in the field of cardiac surgery and should involve sufficient subjects to require the use of a network with multicenter participation. At least one protocol should be a randomized design. Applicants should indicate knowledge of the number of patients required for the study based on appropriately powered sample-size calculations. The two protocol proposals will serve as indicators of the applicant’s ability to participate in the development and design of protocols for cooperative clinical investigations. Proposed protocols should meet the objectives of the program and demonstrate the investigator’s strength and expertise in cardiac surgery and cardiovascular medicine. Proposed protocols should be written specifically for this Network and will serve as a key factor in evaluation of the application.

The proposed protocols should include: a one-page overview that presents the key research objective and a diagram depicting the initiation and duration over a 5-year period; descriptions that include the background and rationale, hypothesis being tested, specific research aims, primary and secondary endpoint or outcome measures, study design, target population, sample size, and power calculations. The application, including the overview and descriptions, should not exceed 25 pages in total (Sections a-d).

Qualifications and experience

Applicants for Clinical Centers must have demonstrable experience and expertise to conduct complex multicenter clinical studies in cardiac surgery. Prospective Clinical Centers must have an established research program in the scientific areas of interest and demonstrated access to a sufficient number of patients to accomplish their portion of the proposed protocols (approx. 1/5 of the total). A minimum time commitment of 10% is expected from the surgical physician leader (Principal Investigator) and 30% is expected from a physician Co-Investigator at each Clinical Center. The Principal Investigator or another member of the physician investigative team is expected to be readily available to respond directly to questions about Network matters on a daily basis, preferably through e-mail, and should indicate this in the application. The Principal Investigator must have a demonstrated track record of successful leadership of a multi-disciplinary team, including the ability to communicate with and ensure collaboration among surgeons, cardiologists, anesthesiologists, nurses, and other related subspecialists.

For Clinical Center applicants, the application should demonstrate expertise in protocol development, patient enrollment, and regulatory submissions (IRB, FDA). Specific expertise in translational research including the integration of new treatment modalities into clinical practice should be highlighted.

Study population

Clinical Center applicants should have sufficient patients to support recruitment in a variety of studies in the Network. Applications should include a table with the following information for each of the past three years: the total number of open heart surgical cases, the total number of cardiac catheterizations performed and the proportion of surgical patients who do not live in the hospital's local geographic area and thus would find it difficult to return to the center for protocol follow-up testing. In order to have sufficient patients to participate in Network protocols, a minimum of 500 major cardiac surgical cases per year are necessary.

Patient access may be accomplished by establishing links with other groups in addition to the applicant's institution. If this is planned, there must be a well-described plan for the coordination of Network activities among the linked entities.

The application should include detailed sample size calculations based on the primary end point or outcome for the proposed study as a whole. Each Clinical Center applicant is expected to contribute approximately 1/5 of the patients. Applications should include, for their site only, the number of patients with the applicable characteristics that are seen each year for the past three years, and also the proportion of these patients who would meet the inclusion criteria for actual enrollment in the study.

Willingness to participate in the Network

Applicants should state their general support of collaborative research and interaction with other Clinical Centers, the NHLBI, ICRH, and the Data Coordinating Center through this Network concept. Letters of institutional and departmental support for participation in the Network are requested, which should include assurances that in the case of studies competing for the same patient population, NHLBI/ICRH Network studies will take priority. Clinical Center applicants must be able to interact with the Data Coordinating Center to transmit and edit data and should discuss their capability to participate in a distributed data entry system.

Budget Information

For purposes of the grant application, Clinical Centers will be asked to submit budgets for core budget costs as well as for protocol costs to conduct the proposed studies. The protocol budget is to be included as an example only to facilitate peer review of the application. During the grant cycle covered by this RFA, all protocol costs will be awarded to the DCC, which will then be responsible for distributing funds to Clinical Centers once per patient budgets are approved for each protocol and recruitment begins.

Core budget costs may not exceed $250,000 direct costs, and include:

• A minimum of 10% effort for the surgical physician leadership (Principal Investigator).
• A minimum of 30% effort for a physician Co-Investigator.
• A minimum of 100% effort for a nurse coordinator. This effort can be for an individual or can be shared among two or more individuals.
• A minimum of 50% for data entry and administrative personnel.
• Travel for the Principal Investigator and Co-Investigator and the nurse coordinator to an average of 3 Steering Committee meetings per year. Steering Committee meetings usually are held in Bethesda, Maryland.
• Supplies and equipment.
• Fees for translation of Network protocol materials into a second language.
• Other items as appropriate.

Protocol costs include expenses associated with the conduct of a specific protocol, such as:

• Screening of patients to determine study eligibility.
• Imaging studies that are not performed as part of routine clinical care.
• Laboratory tests that are not part of routine clinical care.
• Clinic visits that are not part of routine clinical care.
• Expenses associated with family or patient travel, such as mileage, parking, meals, or housing.
• Modest patient incentives to encourage enrollment and retention can be included within the limits set by local IRBs. Consideration should be given to avoiding the appearance of potential coercion in establishing the level of any such incentives.
• Specialized consultation, such as neurologists and neurocognitive specialists to perform standardized testing.
• Expenses related to the use of a research pharmacy, if a pharmacological study is proposed.
• Study supplies, such as imaging media.

Tests and clinic visits performed as part of routine clinical care can be incorporated into a research protocol, but their costs will be billed to third-party payers. The pool of protocol funds, including funds to cover the administrative costs associated with protocol activities, will be part of the Data Coordinating Center grant. A per patient budget for each Network protocol will be developed by NHLBI, in consultation with ICRH and Network investigators. The Data Coordinating Center will be responsible for apportioning the per patient monies among the Clinical Centers in proportion to recruitment. Nevertheless, Clinical Centers are asked to develop a per patient budget for their proposed protocols as part of their application. Applications should identify the potential source(s) for any drugs, substances, or devices that are being considered for clinical protocols that are currently unavailable commercially. If the protocol proposed by a Clinical Center applicant includes obtaining blood or tissue samples, the applicant should delineate how such specimens will be handled and analyzed. In the event that a central laboratory is required to analyze specimens, the Clinical Centers will be responsible for obtaining and shipping the sample(s), and the cost of obtaining them will be part of the Clinical Center's per patient expense. Investigators should prepare budgets only for their own Clinical Center to conduct the proposed trial and not for the entire Network.

Investigators involved in the NHLBI Network clinical studies may find it advantageous to seek additional support from or other involvement by industry or other third parties (e.g., the VA, CMS, charitable foundations) for the studies themselves, for substudies, and for ancillary studies. Awardees will be expected to follow NHLBI policy concerning third party agreements if collaborations are established with Industry or other third parties. http://www.nhlbi.nih.gov/funding/policies/thirdparty.htm

Awards will be subject to administrative review annually.

Clinical Research Skills Development Core (Core)

The Network presents a rich environment for young investigators to be exposed to and develop additional research skills. To assist the Network awards in enhancing the developmental environment for their new clinical investigators, NHLBI in collaboration with ICRH will permit Clinical Center applicants to request up to $100,000 in direct costs per year for a Clinical Research Skills Development Core. A Core is not a required component of an CC, and its absence will not disadvantage an applicant. The priority score on the Core will have no effect on the overall score of an application. If a Network application includes an application for a Core, then the Core should be mentioned in both the Abstract and the Table of Contents. Up to four additional pages may be used to describe the proposed Clinical Research Skills Development Core. The Core proposal should be inserted at the end of the Network application. This text will not be counted toward the 25-page limit for the total Application specified by the Form 398 instructions. Requests for Core funds should not be included in the body of Network applications as it is expected that this aspect of the Network will be supported by separate funds. Thus, applicants should provide a separate budget page for the Core and add the cost of the Core as a line item into the total request for funds.

Applicants to lead the Clinical Skills Development Cores must be investigators with strong educational and mentoring credentials who will devote a minimum of 5 percent effort to the Core. To facilitate multidisciplinary developmental activities and appropriate mentoring, active involvement by the Principal Investigator and other senior investigators within the applicant center is strongly encouraged. Applicants should read the specific requirements and other instructions for applying at http://www.nhlbi.nih.gov/funding/policies/ntwk_skill.htm.

Data Coordinating Center Applicants

Qualifications and experience

Applicants for a Data Coordinating Center must demonstrate experience in the conduct of multi-center clinical studies, coordinating all phases of multi-center clinical studies, protocol and manual of operations development, data collection and management, data safety and confidentiality, adverse events, quality assurance, data analysis, distributed data entry, electronic communications, and administrative management and coordination.

Study Design and Management

Data Coordinating Center applicants should discuss various aspects of study design that would be important in developing clinical cardiac surgical protocols, for example: eligibility criteria; baseline and outcome measures; methods of randomization; important considerations for making sample size and power calculations; methods and frequency of data collection and entry; monitoring accuracy of data collection; quality control procedures including training and certification for multiple protocols, some of which may occur simultaneously; managing labeling and handling of blood samples (see below); and plans for statistical analysis. Applicants also should describe any experience with cardiac surgery and cardiovascular medicine and their ability to provide leadership in cardiac surgery to support the clinical studies envisioned under this RFA. In addition, they should describe their plans for administrative management of the DSMB, the PRC, the Steering Committee, and associated subcommittees. A plan should also be included for the development and maintenance of a web site with both public and secure components that would include information for families and investigators.

Network protocols may require central laboratories for uniform interpretation of key study data, such as laboratory samples or imaging studies. The specific central lab(s) needed will depend on the protocols ultimately selected. However, for purposes of the application, Data Coordinating Center applicants should describe in detail how they will identify and secure the necessary central lab(s) once specific protocols are approved. Some protocols will include echocardiography; hence, Data Coordinating Center applicants should describe the development and maintenance of a central lab for echocardiography. The application also should describe how blood or tissue specimens would be stored and shipped for central interpretation.

Budget Information

Budgets should be prepared for five 12-month periods. The Data Coordinating Center may request up to $1.1M direct costs in year 1 and $1.4M per year in direct costs for years 2-5. Approximately $13M direct costs will also be awarded over the 5 years for costs associated with the protocols. The budget justification for each year should include a table that apportions the direct costs among the following categories: core costs, costs of protocol initiation, and costs of protocol support as described in the RFA. Data Coordinating Center applicants should assume that one protocol may be active in the first year, and multiple thereafter during the period covered by this RFA. Studies begun in this grant period must be concluded by the end of the grant period. Data Coordinating Center budgets should include, but are not limited to:

• A minimum of 50% effort for the PI.
• Additional staff as appropriate to the multiple and complex tasks of the Network.
• Expenses related to managing the DSMB and the PRC. It can be assumed that the DSMB will include about 7 members and will meet twice a year in Bethesda, Maryland, and an additional two times per year by conference call. The PRC will meet no more than once a year in person in Bethesda, Maryland, and two to four times per year by conference call.
• Steering Committee expenses. The Steering Committee meets an average of three times a year and conducts biweekly conference calls and monthly subcommittee calls for each active protocol subcommittee. Travel of Steering Committee members will be budgeted by Clinical Centers.
• Approximately three visits to each of up to seven Clinical Centers during the five-year grant period and conference call expenses for one or two conference calls per Clinical Center to follow up on any recruitment issues.
• Expenses associated with application to the Food and Drug Administration (FDA) for Investigational New Drugs (INDs) and Investigational Device Exemptions (IDEs). Expenses associated with procuring and operating centralized laboratories. The expense of transferring the data or specimens to the central lab(s), training technicians to obtain the data in a uniform manner, and instituting quality control measures (e.g., provision for re-reading a proportion of the studies to determine accuracy of interpretation) will be included in the Data Coordinating Center budget. Expenses associated with obtaining the specimens or data will be included in the Clinical Center budgets.
• Expenses associated with training the Nurse Coordinators at the beginning of each protocol.
• Support for the Network Chair(s) at 20% effort, travel to 5 meetings a year, and modest administrative expenses.
• Other expenses as appropriate.

The award will be subject to administrative review annually. It is expected that all protocols will be performed in a manner consistent with United States Food and Drug Administration guidelines.

Foreign Organizations

Several special provisions apply to applications submitted by foreign organizations:

• Charge back of customs and import fees is not allowed.
• 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."
• Funds for up to 8% administrative costs (excluding equipment) can now be requested (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-028.html).
• Organizations must comply with federal/NIH policies on human subjects, animals, and biohazards.
• Organizations must comply with federal/NIH biosafety and biosecurity regulations. See Section VI. 2. Administrative Requirements, "Cooperative Agreement Terms and Conditions of Award.

Proposed research should provide a unique research opportunity not available in the U.S.

3. Submission Dates and Times

Applications must be received on or before the receipt date described below (Section IV.3.A). Submission times N/A.

3.A. Receipt, Review and Anticipated Start Dates

Letter of Intent Receipt Date: July 28, 2006
Application Receipt Date(s): August 28, 2006
Peer Review Date: February/March 2007
Council Review Date: June 2007
Earliest Anticipated Start Date: July 1, 2007

3.A.1. Letter of Intent

Prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed research
• Name, address, and telephone number of the Principal Investigator
• Names of other key personnel
• Participating institutions
• Number and title of this funding opportunity

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:

Chief, Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Two Rockledge Center, Room 7214
6701 Rockledge Drive
Bethesda, MD 20892-7924 (Express 20817)
Telephone: (301) 435-0270
FAX: (301) 480-0730
Email: [email protected]

ICRH requests that Canadian applicants notify Elissa Hines Reimer ([email protected]) of their intent to apply. As applications to this initiative are accepted in English only, ICRH will arrange for translation of French applications if requested at the letter of intent stage.

3.B. Sending an Application to the NIH

Applications must be prepared using the research grant applications found in the PHS 398 instructions for preparing a research grant application. Submit a signed, typewritten original of the application, including the checklist, and three signed photocopies in one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)

Personal deliveries of applications are no longer permitted (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-040.html).

At the time of submission, two additional copies of the application and all copies of the appendix material must be sent to:

Chief, Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Two Rockledge Center, Room 7214
6701 Rockledge Drive
Bethesda, MD 20892-7924 (Express 20817)
Telephone: (301) 435-0270
FAX: (301) 480-0730
Email: [email protected]

Using the RFA Label: The RFA label available in the PHS 398 application instructions 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/labels.pdf.

3.C. Application Processing

Applications must be received on or before the application receipt date described above (Section IV.3.A.). If an application is received after that date, it will be returned to the applicant without review. Upon receipt, applications will be evaluated for completeness by the CSR and responsiveness by the NHLBI. Incomplete and non-responsive applications will not be reviewed.

The NIH will not accept any application in response to this funding opportunity 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 a funding opportunity, it is to be prepared as a NEW application. That is, the application for the funding opportunity 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 eight (8) weeks.

4. Intergovernmental Review
This initiative is not subject to intergovernmental review.

5. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

Pre-Award Costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new or competing continuation award if such costs are necessary to conduct the project and would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new or competing continuation award.

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project. See NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part6.htm.

6. Other Submission Requirements

Patient Resources:

Clinical Center Applicants must conduct a minimum of 500 major cardiac surgical procedures per year to have sufficient patient resources to participate in the Network. Applications that do not satisfy this requirement will be determined to be non-responsive and will be returned to the applicant prior to review.

Dissemination Section: Applicants must include in their application/proposal a plan for dissemination of research results and such a plan should include:

Plan for Sharing Research Data

The precise content of the data-sharing plan will vary, depending on the data being collected and how the investigator is planning to share the data. Applicants who are planning to share data may wish to describe briefly the expected schedule for data sharing, the format of the final dataset, the documentation to be provided, whether or not any analytic tools also will be provided, whether or not a data-sharing agreement will be required and, if so, a brief description of such an agreement (including the criteria for deciding who can receive the data and whether or not any conditions will be placed on their use), and the mode of data sharing (e.g., under their own auspices by mailing a disk or posting data on their institutional or personal website, through a data archive or enclave). Investigators choosing to share under their own auspices may wish to enter into a data-sharing agreement. References to data sharing may also be appropriate in other sections of the application.

All applicants must include a plan for sharing research data in their application. The data sharing policy is available at http://grants.nih.gov/grants/policy/data_sharing. All investigators responding to this funding opportunity should include a description of how final research data will be shared, or explain why data sharing is not possible.

The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score.

Sharing Research Resources
Not applicable

Section V. Application Review Information

1. Criteria

The following will be considered in making funding decisions:

• Scientific merit of the proposed project as determined by peer review
• Availability of funds
• Relevance of program priorities

2. Review and Selection Process

Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NHLBI and ICRH. Incomplete and/or non-responsive applications will not be reviewed.

Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by NHLBI/ICRH in accordance with the review criteria stated below.

As part of the initial merit review, all applications will:

• 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.
• Receive a written critique.
• Receive a second level of review by the National Heart, Lung, and Blood Advisory Council (NHLBAC).

The goals of NIH and CIHR supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that an 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. Protocols in the application will reflect the ability of investigators to design feasible clinical studies important to the practice of cardiovascular surgery and medicine. The protocols actually performed in the Network will be determined by the Steering Committee.

Review Considerations for Clinical Centers

Reviewers will be evaluating Clinical Center applications on the basis of the applicants overall ability to participate in a multi-center Network and to put together a research team, as well as on the specific research protocols proposed (two are required). Adequate patient resources are essential. Evidence that the research team can enroll and randomize patients and adhere to protocols should be provided. All Clinical Center applications will be reviewed with respect to the following:

Significance: Do the studies proposed by the applicants address important problems? If the aims of the application are achieved, how will scientific knowledge or clinical practice be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Are the proposed clinical protocols suitable for collaborative multicenter research, do they have significance to clinical practice and public health, and research questions that will be unlikely to be supported by industry or to benefit specific commercial interests? Does the applicant sufficiently acknowledge potential problem areas and consider alternative tactics?

Innovation: Is the project original and innovative? For example: Does the project challenge existing paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area?

Investigators: Is the expertise, training, and experience of the investigators and staff in cardiac surgical clinical trials including randomized trials, sufficient for the effective functioning of the Clinical Center as part of a multi-center Network? Are the administrative abilities of the PI and the level of commitment to the program sufficient?

Collaborative Research Experience: Is there evidence of a willingness and ability to participate fully in all protocols and to adopt and follow standard operating procedures including randomization of patients according to protocol procedures? Is there evidence from past experience of an ability to conduct rigorously designed trials including a clinically relevant and testable hypothesis, well described patient population, explicit selection criteria, effective control of bias and so forth? Has the applicant shown a willingness and ability to establish collaborations with cardiologists and other clinical specialties for conducting trials that bridge both the surgical and medical therapies, and with basic researchers for the orderly translation of basic science and bioengineering concepts into clinical studies? Is there evidence of a willingness to work collaboratively as part of the Network and with NHLBI Project Scientists?

Patient Resources: Are the plans to recruit, randomize, and retain study populations adequate for the proposed studies? Do the Clinical Center Applicants demonstrate that they conduct a minimum of 500 major cardiac surgical procedures per year to have sufficient patient resources to participate in the Network.

Institutional Resources: Are institutional resources adequate for patient care and follow-up: including personnel, space, and special laboratory facilities?

Review Considerations for the Data Coordinating Center

The Data Coordinating Center applications will be reviewed with respect to the following:

Significance: Does the proposal address an important problem? If the aims of the application are achieved, how will scientific knowledge or clinical practice be advanced? What will be the effect of the DCC contribution to the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Are the proposed plans for acquisition, transfer, management, and analysis of data, quality control of data collection and monitoring, and overall coordination of Network activities adequate? Does the applicant acknowledge potential problem areas and consider alternative tactics? Are the administrative, supervisory, and collaborative arrangements appropriate for achieving the goals of the program, including willingness to cooperate with the participating Clinical Centers and the NHLBI?

Innovation: Is the project original and innovative? For example: Does the project challenge existing paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area?

Investigators: Is the expertise, training, and experience of the investigators and staff, including the administrative abilities of the Principal Investigator, Co-Investigator, and the time they plan to devote to the program sufficient for the effective coordination of the Network?

Collaborative Research Experience: Has the applicant demonstrated an understanding of the scientific, statistical, logistical, and technical issues presented by multi-center studies, including issues related to management of surgical cardiovascular conditions? Is there evidence of an ability to assume a leadership role in study design, statistics, logistics, data acquisition management, patient confidentiality, handling of laboratory specimens, quality control, data analysis, and Network coordination?

Institutional Resources: Are the facilities, equipment, and organizational structure adequate to coordinate Network activities effectively and to assist Clinical Centers in implementing the Network protocols? Are there provisions for specialized laboratory testing and collecting data?

Review Considerations for Clinical Research Skills Development Cores

The Clinical Research Skills Development Core will receive a priority score based on the review criteria below, but the priority score will be separate from and will not enter into the overall Network application priority score. The Clinical Research Skills Development Core will be evaluated for its effectiveness in developing the skills and clinical research capabilities of new investigators. This will include an evaluation of:

2.A. Additional Review Criteria:

In addition to the above criteria, the following items will continue to 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 the Research Plan, Section E on Human Subjects in the PHS Form 398).

Inclusion of Women, Minorities and Children in Research: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated (see the Research Plan, Section E on Human Subjects in the PHS Form 398).

Biohazards: If materials or procedures are proposed that are potentially hazardous to research personnel and/or the environment, determine if the proposed protection is adequate.

2.B. Additional Review Considerations

Budget: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. The priority score should not be affected by the evaluation of the budget.

2.C. Sharing Research Data

Data Sharing Plan: The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score. The presence of a data sharing plan will be part of the terms and conditions of the award. The funding organization will be responsible for monitoring the data sharing policy.

2.D. Sharing Research Resources
Not applicable

3. Anticipated Announcement and Award Dates

Section VI. Award Administration Information

1. Award Notices

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part4.htm).

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official (designated in item 12 on the Application Face Page). If a grantee is not email enabled, a hard copy of the NoA will be mailed to the business official. Applicants co-supported by ICRH will also receive a CIHR Authorization for Funding and a decision letter by mail.

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs. See Also Section IV.5. Funding Restrictions.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part4.htm) and Part II Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part9.htm).

The following Terms and Conditions will be incorporated into the award statement and will be provided to the Principal Investigator as well as to the appropriate institutional official, at the time of award.

2.A. Cooperative Agreement Terms and Conditions of Award

The following 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 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement U01, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined above.

2.A.1. Principal Investigator Rights and Responsibilities

The Network for Cardiothoracic Surgical Investigations in Cardiovascular Medicine (Network) will be a cooperative clinical network consisting of up to seven Clinical Centers (CC), a single Data and Coordinating Center, and the NHLBI and include a Steering Committee, Protocol Review Committee (PRC), Data and Safety Monitoring Board (DSMB) and Clinical Research Skills Development Core(s).

The awardee(s) will have lead responsibilities in all aspects of the Network studies, including any modification of study designs; conduct of the studies; quality control; data analysis and interpretation; preparation of publications; and collaboration with other investigators, unless otherwise provided for in these terms or by action of the Steering Committee. Awardee(s) agree to the governance of the study through a Steering Committee.

The Clinical Center Principal Investigators will be responsible for proposing protocols, estimating their costs, participating in their overall development, recruiting subjects, conducting the research, assuring quality of subject care and protocol adherence, assuring the accurate and timely transmission of data collected in conjunction with the Data Coordinating Center, and disseminating research findings.

The DCC will coordinate, administer, and support all Network clinical research activities. The Data Coordinating Center Principal Investigator will be responsible for oversight of protocol development, data collection, data safety and confidentiality, quality assurance, data analysis and distributed coordination.

A Clinical Research Skills Development Core may be included in an award to support activities to assist new clinical investigators in progressing to more senior status by enhancing their research skills.

Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to government rights of access consistent with current HHS, PHS, and NIH policies.

The collaborative protocol and governance policies will call for the continued submission of data centrally to the coordinating center for a collaborative database; the submission of copies of the collaborative datasets to each principal investigator upon completion of the study; procedures for data analysis, reporting and publication; and procedures to protect and ensure the privacy of medical and genetic data and records of individuals. The NHLBI Program Scientist, on behalf of the NHLBI, will have the same access, privileges and responsibilities regarding the collaborative data as the other members of the Steering Committee.

Support or other involvement of industry or any other third party in the study may be advantageous and appropriate. However, except for licensing of patents or copyrights, support or involvement of any third party will occur only following notification of and concurrence by NHLBI. Awardees must follow NHLBI policy concerning third party agreements.

Study investigators are encouraged to publish and to release publicly and disseminate results and other products of the study in accordance with study protocols and governance. Within three years of the end of the period of NHLBI support for the project, data not previously released and other study materials or products not previously distributed are to be made available to individuals who are not study investigators, provided such release is consistent with the study protocol and governance and with the above paragraph. In addition, study investigators must establish a plan for making data sets and materials available to the scientific community and to the NHLBI immediately upon completion of the three-year period following the end of the period of NHLBI support.

Upon completion of the project, awardees are expected to put their intervention materials and procedure manuals into the public domain and/or make them available to other investigators, according to the approved plan for making data and materials available to the scientific community and the NHLBI and ICRH, for the conduct of research at no charge other than the costs of reproduction and distribution.

2.A.2. NIH Responsibilities

The NHLBI will oversee the organization of the Network and thus will be substantially involved with the awardees in a partnership. NHLBI will appoint the Network Chairperson(s), all members of the Protocol Review Committee (PRC), and the Data and Safety Monitoring Board (DSMB). The Network Chairperson(s) will be responsible for ensuring that there are well-documented policies, procedures, and bylaws to guide all aspects of Network activities and operations.

A NHLBI Project Scientist will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below.

The NHLBI Project Scientist will serve on the Steering Committee; he/she or other NHLBI scientists may serve on other study committees, when appropriate. The NHLBI Project Scientist (and other NHLBI staff) may work with awardees on issues coming before the Steering Committee and, as appropriate, other committees, e.g., recruitment, intervention, follow-up, quality control, adherence to protocol, assessment of problems affecting the study and possible changes in protocol, interim data and safety monitoring, preparation of publications, and development of solutions to major problems such as insufficient participant enrollment.

The NHLBI reserves the right to terminate or curtail the study (or an individual award) in the event of (1) failure to develop or implement a mutually agreeable collaborative protocol; (2) substantial shortfall in participant recruitment, follow-up, data reporting, or quality control; (3) major breach of the protocol or substantive changes in the agreed-upon protocol with which NHLBI cannot concur; (4) attaining of a major study endpoint before schedule with persuasive statistical significance; or (5) human subject ethical issues that may dictate a premature termination.

Additionally, a NHLBI Program Official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. The NHLBI Program Official will monitor subject recruitment and study progress, ensure disclosure of conflicts of interest, and ensure adherence to NHLBI policies.

2.A.3. Collaborative Responsibilities

Awardee(s) agree to the governance of the study through a Steering Committee. Steering Committee voting membership shall consist of the Principal Investigators (or designated alternates) of the CCs and the DCC (i.e., cooperative agreement awardees), the NHLBI Project Scientist, and the Network Chairperson(s). Each full member will have one vote. The Network Chair(s) will plan Network activities, oversee its functions and conduct SC meetings. The SC will develop and ensure compliance with Network policies and procedures, identify and prioritize topics for investigation, evaluate protocols proposed by the CCs, develop consensus protocols for submission to the PRC, and ensure that studies are properly conducted, monitored, and that study results are reported in the scientific literature and disseminated in a timely manner. All major scientific decisions will be determined by majority vote of the SC. The SC has final responsibility for approving the protocol before review by the PRC or DSMB. Subcommittees of the SC will be established as necessary and would be expected to include a Publications and Presentations Subcommittee and an Ancillary Studies Subcommittee. Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee. Meetings of the Steering Committee will ordinarily be held by telephone conference call or in the metropolitan Washington Area.

An independent Protocol Review Committee (PRC), established by the NHLBI, will provide peer review for each Network protocol. Because the PRC serves as an independent group advisory to the NHLBI, study investigators will not communicate with PRC members regarding study issues, except as authorized by the PRC's Executive Secretary. The independent PRC will be appointed by and be advisory to the NHLBI. It will consist of a chairperson and scientists with expertise in cardiac surgery, cardiovascular medicine, clinical research, clinical trial design, biostatistics, enabling technologies, outcome measures, and other areas of expertise as needed. The exact number and duration of protocols supported in the five-year program will depend on the nature and extent of the investigations proposed by the SC. The PRC will evaluate protocols proposed by the SC based on the importance of the question to be addressed, scientific merit of the experimental design and approach, feasibility, appropriateness for the Network and consistency with NHLBI missions and policies. The PRC will provide a written critique of each proposal and a final recommendation to the NHLBI. All study protocols performed by the Network must be recommended by the PRC and approved by the NHLBI before initiation.

A Data and Safety Monitoring Board will be appointed by the Director, NHLBI to provide overall monitoring of interim data and safety issues. Meetings of the Data and Safety Monitoring Board will ordinarily be held in Bethesda, MD. An NHLBI scientist, other than the NHLBI Program Official, shall serve as Executive Secretary to the Board.

2.A.4. Arbitration Process

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to arbitration. An Arbitration Panel composed of three members will be convened, including a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two. In the case of individual disagreement, the first member may be chosen by the individual awardee. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

3. Reporting

Awardees will be required to submit the PHS Non-Competing Grant Progress Report, Form 2590 annually (http://grants.nih.gov/grants/funding/2590/2590.htm) and financial statements as required in the NIH Grants Policy Statement. NHLBI policy requires that the Data Coordinating Center report quarterly on recruitment in all Network Studies that propose to enroll more than 150 patients.

Section VII. Agency Contacts

We encourage your inquiries concerning this funding opportunity 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:

1. Scientific/Research Contacts:

NHLBI

Marissa A. Miller D.V.M., M.P.H.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Dr.
Rockledge II, 9180
Bethesda, MD 20892
Telephone: (301) 594-1542
FAX: (301) 480-1336
Email: [email protected]

NINDS

Claudia S. Moy, Ph.D.
Program Director, Clinical Trials
National Institute of Neurological Disorders and Stroke
Neuroscience Center, Room 2214, MSC 9520
6001 Executive Blvd.
Bethesda, MD 20892
Telephone: 301/496-2789
FAX: 301/480-1080
Email: [email protected]

ICRH

Elissa Hines Reimer
Assistant Director-Ottawa
Institute of Circulatory and Respiratory Health
Telephone: 613/954-0544
FAX: 613/954-1800
Email: [email protected]

2. Peer Review Contacts:

Chief, Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Two Rockledge Center, Room 7214
6701 Rockledge Drive
Bethesda, MD 20892-7924 (Express 20817)
Telephone: (301) 435-0270
FAX: (301) 480-0730
Email: [email protected]

3. Financial or Grants Management Contacts:

Mr. David Reiter
Division of Extramural Affairs
Grants Operations Branch
6701 Rockledge Drive MSC7926
Bethesda, MD 20892
Telephone: (301) 435-0177
FAX: 301-451-5462
Email: [email protected]

Section VIII. Other Information

Required Federal Citations

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). Monitoring should be commensurate with risk. The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risks to the participants (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

Sharing Research Data:
Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing).

Investigators should seek guidance from their institutions, on issues related to institutional policies and local IRB rules, as well as local, state and federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score.

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 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 funding opportunity 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.

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 "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is 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: (1) 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 (2) 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 Clinical Research:
The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all clinical 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 (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 applications for research involving human subjects and individuals designated as key personnel. The policy is available 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 (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.

NIH Public Access Policy:
NIH-funded investigators are requested to submit to the NIH manuscript submission (NIHMS) system (http://www.nihms.nih.gov) at PubMed Central (PMC) an electronic version of the author's final manuscript upon acceptance for publication, resulting from research supported in whole or in part with direct costs from NIH. The author's final manuscript is defined as the final version accepted for journal publication, and includes all modifications from the publishing peer review process.

NIH is requesting that authors submit manuscripts resulting from (1) currently funded NIH research projects or (2) previously supported NIH research projects if they are accepted for publication on or after May 2, 2005. The NIH Public Access Policy applies to all research grant and career development award mechanisms, cooperative agreements, contracts, Institutional and Individual Ruth L. Kirschstein National Research Service Awards, as well as NIH intramural research studies. The Policy applies to peer-reviewed, original research publications that have been supported in whole or in part with direct costs from NIH, but it does not apply to book chapters, editorials, reviews, or conference proceedings. Publications resulting from non-NIH-supported research projects should not be submitted.

For more information about the Policy or the submission process please visit the NIH Public Access Policy Web site at http://publicaccess.nih.gov/ and view the Policy or other Resources and Tools including the Authors' Manual (http://publicaccess.nih.gov/publicaccess_Manual.htm).

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 PA 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/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52, 42 CFR Part 63a, and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

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.

Loan Repayment Programs:
NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The LRP is an important component of NIH's efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40-hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov.

The Institute of Circulatory and Respiratory Health (ICRH) supports research into the causes, mechanisms, prevention, screening, diagnosis, treatment, support systems, and palliation for a wide range of conditions associated with the heart, lung, brain (stroke), blood vessels, blood, [critical care, and sleep]. ICRH works towards international leadership by fostering an environment of extraordinary openness, excitement, energy, commitment and excellence in highly ethical, partnered initiatives focused on research, research training, and research translation for the circulatory and respiratory sciences and for the betterment of the health of Canadians. More details can be found under research priorities and in our Annual Report (http://www.cihr-irsc.gc.ca/e/8653.html).

ICRH is one of 13 institutes of the Canadian Institutes of Health Research (CIHR), the Government of Canada's agency for health research. CIHR's mission is to create new scientific knowledge and to catalyze its translation into improved health, more effective health services and products, and a strengthened Canadian health care system. CIHR provides leadership and support to close to 10,000 health researchers and trainees across Canada. More information about CIHR’s Clinical Research Initiative may be found at: http://www.cihr-irsc.gc.ca/e/22113.html

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NIH Funding Opportunities and Notices

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