Part I Overview Information

Department of Health and Human Services

Participating Organizations
National Institutes of Health (NIH), (http://www.nih.gov)

Components of Participating Organizations
National Heart, Lung, and Blood (NHLBI), (http://www.nhlbi.nih.gov)

Title: Investigator Initiated Multi-Site Clinical Trials (Collaborative R01)

Announcement Type
This Funding Opportunity Announcement (FOA) is a reissue of PAR-07-373.

Update: The following updates relating to this announcement have been issued:

• March 1, 2013 - This PAR has been reissued as PAR-13-128.
• June 3, 2011 - See Notice NOT-HL-11-146 Modification of Introduction Requirements for Resubmissions.
• September 29, 2010 (NOT-OD-11-007) - NIH to Require Use of Updated Electronic Application Forms in 2011. Adobe B1 forms are required for due dates on or after May 8, 2011.
• August 16, 2010 - IMPORTANT NOTE! NIH has eliminated the error correction window for due dates of January 25, 2011 and beyond. As of January 25, all corrections must be complete by the due date for an application to be considered on-time. See NOT-OD-10-123.

Program Announcement (PA) Number: PAR-10-096

NOTICE: Applications submitted in response to this Funding Opportunity Announcement (FOA) for Federal assistance must be submitted electronically through Grants.gov (http://www.grants.gov) using the SF424 Research and Related (R&R) forms and the SF424 (R&R) Application Guide.

APPLICATIONS MAY NOT BE SUBMITTED IN PAPER FORMAT.

This FOA must be read in conjunction with the application guidelines included with this announcement in Grants.gov/Apply for Grants (hereafter called Grants.gov/Apply).

A registration process is necessary before submission and applicants are highly encouraged to start the process at least four (4) weeks prior to the grant submission date. See Section IV.

Catalog of Federal Domestic Assistance Number(s)
93.233, 93.837, 93.838, 93.839

Key Dates
Release/Posted Date: January 27, 2010
Opening Date: May 5, 2010 (Earliest date an application may be submitted to Grants.gov)
Letters of Intent Receipt Date(s): Not Applicable
NOTE: On-time submission requires that applications be successfully submitted to Grants.gov no later than 5:00 p.m. local time (of the applicant institution/organization).
Application Due Date(s): Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm
AIDS Application Due Date(s): Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm#AIDS.
Peer Review Date(s): Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward
Council Review Date(s): Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward
Earliest Anticipated Start Date(s): Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward
Additional Information To Be Available Date (URL Activation Date): Not Applicable
Expiration Date: May 8, 2013

Due Dates for E.O. 12372

Not Applicable

Additional Overview Content

Executive Summary

• Purpose. The purpose of this Funding Opportunity Announcement is to provide a vehicle for submitting grant applications for investigator-initiated multi-site Phase II or Phase III randomized, controlled clinical trials. The trials may address any research question related to the mission and goals of NHLBI and may test clinical or behavioral interventions. Investigators should consult the NHLBI's Guidelines for Investigator Initiated Clinical Trials (http://www.nhlbi.nih.gov/funding/policies/clinical.htm) for more detailed instructions and information about multi-site clinical trial grant applications. Additional information about the mission, strategic plan and research interests of the NHLBI can be found at NHLBI's website (http://www.nhlbi.nih.gov/index.htm).
• This Funding Opportunity Announcement is not intended for support of single-center studies or multi-center observational studies that are not testing an intervention.
• Mechanism of Support. This FOA will utilize the NIH Research Project Grant (R01) award mechanism. Awards may be converted by NHLBI to cooperative agreements (U01).
• Funds Available and Anticipated Number of Awards. The total amount awarded and the number of awards will depend upon the numbers, quality, duration, and costs of the applications received. Awards issued under this FOA are contingent upon the availability of funds.
• Budget and Project Period. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary.
• Application Research Strategy Component Length: The R01 application Research Strategy section of the PHS398 may not exceed 12 pages, including tables, graphs, figures, diagrams, and charts. See Table of Page Limits
• Eligible Institutions/Organizations. Institutions/organizations listed in Section III, 1.A. are eligible to apply.
• Eligible Project Directors/Principal Investigators (PDs/PIs). Include individuals with the skills, knowledge, and resources necessary to carry out the proposed research are invited to work with their institution/organization 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 support.
• Number of PDs/PIs. More than one PD/PI (i.e., multiple PDs/PIs) may be designated on the application.
• Number of Applications. Applicants may submit more than one application, provided that each application is scientifically distinct.
• Resubmissions. Applicants may submit a resubmission application, but such application must include an Introduction addressing the previous peer review critique (Summary Statement). See new NIH policy on resubmission (amended) applications (NOT-OD-09-003, NOT-OD-09-016).
• Renewals. Applicants may submit a renewal application.
• Application Materials. See Section IV.1 for application materials.
  
• General Information. For general information on SF424 (R&R) Application and Electronic Submission, see these Web sites:
  • SF424 (R&R) Application and Electronic Submission Information: http://grants.nih.gov/grants/funding/424/index.htm
  • General information on Electronic Submission of Grant Applications: http://era.nih.gov/ElectronicReceipt/
• Hearing Impaired. Telecommunications for the hearing impaired are available at: TTY: (301) 451-5936

Table of Contents

Part I Overview Information

Part II Full Text of Announcement

Section I. Funding Opportunity Description
1. Research Objectives

Section II. Award Information
1. Mechanism of Support
2. Funds Available

Section III. Eligibility Information
1. Eligible Applicants
A. Eligible Institutions
B. Eligible Individuals
2. Cost Sharing or Matching
3. Other-Special Eligibility Criteria

Section IV. Application and Submission Information
1. Request Application Information
2. Content and Form of Application Submission
3. Submission Dates and Times
A. Submission, Review, and Anticipated Start Dates
1. Letter of Intent
B. Submitting an Application Electronically to the NIH
C. Application Processing
4. Intergovernmental Review
5. Funding Restrictions
6. Other Submission Requirements

Section V. Application Review Information
1. Criteria
2. Review and Selection Process
A. Additional Review Criteria
B. Additional Review Considerations
C. Resource Sharing Plan(s)
3. Anticipated Announcement and Award Dates

Section VI. Award Administration Information
1. Award Notices
2. Administrative and National Policy Requirements
3. Reporting

Section VII. Agency Contacts
1. Scientific/Research Contact(s)
2. Peer Review Contact(s)
3. Financial/Grants Management Contact(s)

Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement

Section I. Funding Opportunity Description

1. Research Objectives

• The purpose of this Funding Opportunity Announcement is to provide a vehicle for submitting grant applications for investigator initiated multi-site (Phase II or Phase III) randomized, controlled clinical trials. The trials may address any research question related to the mission and goals of NHLBI and may involve clinical or behavioral interventions. The trials may randomize at the individual (patient) level or at a group level (e.g., randomization of clinics, schools, worksites, etc.).
• Multi-site clinical trials are trials that recruit study subjects from two or more geographically distinct enrollment sites, or centers. The sites are usually distinct in other characteristics (e.g. demographic, socioeconomic, or clinical). Subjects are randomized and study protocols are followed at these sites.
• Applicants should consult NHLBI's Guidelines for Investigator Initiated Multi-Site Clinical Trials for more information about multisite clinical trial grant applications (http://www.nhlbi.nih.gov/funding/policies/clinical.htm).
• This Funding Opportunity Announcement is not intended for support of single-center studies or multi-center observational studies that are not testing an intervention. See http://grants1.nih.gov/grants/guide/search_results.htm?scope=pa-rfa&year=active&text_curr=clinical+trials for other clinical trial FOAs.
• The support of multi-site clinical trials is one strategy NHLBI uses to improve the understanding of the clinical mechanisms of disease and to improve prevention, diagnosis, and treatment. For additional information about the mission, strategic plan, and research interests of the NHLBI, applicants are encouraged to consult the NHLBI web site (http://www.nhlbi.nih.gov/index.htm)

Objectives of this research program

• The proposed research must address a scientifically important question, must provide valuable information to the existing knowledge base, and must have public health applicability. Research topics should be based on the NHLBI's national program plan areas of heart, lung, and blood diseases, and sleep disorders.

Experimental Approach

• The proposed experimental approach should include a randomized design and clear description of the study population, subject eligibility and inclusion/exclusion criteria; recruitment and enrollment plans; methods of randomization; primary and secondary endpoints and outcome measures; treatment and any follow-up procedures. Statistical methods should be proposed that are appropriately matched to the study design and include sample size and power calculations, plans for analyses, and data management and quality control procedures.
• For group-randomized designs, an entire group (such as an entire clinic, school, etc.) is randomly assigned to the intervention or control/comparison condition. Studies with a group-randomized design should indicate eligibility and inclusion/exclusion criteria for the group to be randomized. Since data are collected on individuals who are in the randomized group, appropriate statistical approaches for the hierarchical nature of the data must be employed.
• The information provided in the application should be organized in a manner that will facilitate peer review. The body of the application must present an overview of the state of the science, current status and relevance of the trial, a discussion of the specific protocol, and the approach to data collection and analysis.

The following sections must be included in the research plan of the application:

Specific Aims: (1 page) The specific aims of the trial must be clearly and concisely presented. These should include a clear specification of the primary and major secondary endpoints to be measured, with a clear differentiation of the importance of various endpoints.

The following three sections comprise the Research Strategy and must not exceed 12 pages

Significance: The significance of the proposed clinical trial must be clearly stated. It is particularly important that there be a discussion of how the trial will test the hypothesis proposed. The application should make clear the need for the study with emphasis on how the results will advance our knowledge of theory and practice in this area. A discussion of the costs and benefits of the study should be included for evaluation of the trial's significance.

Innovation: Explain how the application challenges and seeks to shift current research or clinical practice paradigms.

Approach: The studies that led to the proposed clinical trial should be presented. Data from pilot studies which show the need for and the feasibility of the trial should also be presented. Additional supporting data from other research should be included so that the approach chosen is clearly justified. Conceptualization and planning must have progressed to a stage sufficient to allow for an overall assessment of the likelihood of the success of the trial.

The proposed research approach should include

• A randomized design including the rationale for the particular design chosen; a clear description of the study population including the characteristics of this population and why it is an appropriate group to answer the question posed, discussion of the specific protocol, and the approach to data collection and analysis.
• A list of subject eligibility and inclusion/exclusion criteria; or of group eligibility criteria for group-randomized trials.
• Recruitment and enrollment plans, including a discussion of the availability of subjects for the proposed study and the ability of enrollment centers to recruit and retain the proposed number of subjects, including women and minority subjects and data supporting recruitment and retention estimates. For group-randomized trials attention to recruitment of the groups as well as the subjects within the groups is needed.
• Approaches to be used for retention, cooperation and follow up of subjects and to address any anticipated changes in the composition of the study population over the course of the trial.
• Methods of randomization.
• Detailed description of the intervention to be tested (medical or behavioral).
• Descriptions of all clinical, laboratory, physiological, and/or behavioral tests to enable the research questions to be answered.
• Potential biases or challenges in the research protocol proposed and how they will be addressed.
• Data Management and Quality Control: Describe the approach to data management including methods for monitoring the quality and consistency of the intervention(s) and data collection; policies and methods for ensuring blinding of study results; data confidentiality and subject privacy.
• Statistical Methods: The statistical section should describe sample size and power calculations, linking the calculations to the primary and secondary endpoints, the hypotheses to be tested, methods of data preparation and presentation, and data analysis plans and methods appropriate to the level of randomization. Include prototypes of data collection forms in the application.
• Requirement for separate Data Coordinating Center application
  All multi-site randomized controlled trials with direct costs of $500,000 or more (excluding consortium F&A costs) in any year must include plans to submit at least two applications, one of which is for the support of a Clinical Coordinating Center (CCC) and the other which is for support of a Data Coordinating Center (DCC).
• If a separate application for a Data Coordinating Center (DCC) is included details of the data management, quality control and statistical methods should be included in the DCC application.
• Optional separate applications for core functions
  Separate applications for core functions e.g. reading centers, quality of life/economic analyses, imaging centers may be submitted, but are not required. Separate applications for cores should only be submitted if it is scientifically and administratively more efficient and reasonable to have a separate grant award for the core function than, for example, to use a subcontract or fee-for-service agreement under the CCC or the DCC. Justification for separate core applications must be provided.
• The principal investigator for the DCC or the core application cannot be involved in (and cannot be a principal investigator on) any other award associated with the trial. For the purposes of peer review and funding, the DCC, core applications and any other applications submitted as part of the same trial will be considered as a cluster, and each application will receive an identical cluster impact/priority score and summary statement.

Study Organization and Administration

• The application must describe the organization of the study and how the trial will be managed.
• A description of the role of any internal or external advisory committees, including the data and safety monitoring committee must be included. Note that trials that are converted to Cooperative Agreements (U01s) will have a DSMB appointed by the NHLBI.
• The oversight, responsibilities, and coordination of any centers or cores proposed must be discussed.
• The application must describe any sub-contracts or service agreements for personnel or facilities and include in the application documentation of their commitment, co-signed by a business official and the scientific director at the participating center.
• A timetable for completion of the various stages of the trial must be included.

Investigators

• The overall clinical trial must be directed by an investigator with experience in the conduct of clinical trials and expertise in the content area of the trial. Such experience must be carefully documented. Biographical sketches for all key investigators must be provided. Most clinical trial designs will require a multidisciplinary team.
• Each center or core proposed must have a director designated. The experience of each director must be carefully documented. In addition, the authority of each center or core director within the study must be specified.

Facilities

• Clinical, data management, and laboratory facilities and required equipment should be described in detail for all participating institutions.

Human Subjects

• As of October 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html), NIH implemented a policy requiring education on the protection of human research participants for all key personnel submitting applications for grants or proposals for contracts or receiving new or non-competing awards for projects involving human research participants.
• Applicants should refer to Part II of the SF424 Application Guide "Supplemental Instructions for Preparing the Human Subjects Section of the Research Plan."
• Assurances of the protection of human participants and the biohazard safety of employees (if applicable) must be provided both for the overall study and for individual field sites. The applicant must discuss any issues which might lead to concern for the welfare of participants. Master templates of the clinical protocol and forms to be used to obtain informed consent must be included in an appendix. At a minimum, the human subjects sections of data coordinating center applications must address data security measures and confidentiality.

Data Monitoring (and Safety) Plan

As of the October 2000 receipt date (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html), applicants must include a Data and Safety Monitoring (DSM) Plan for all clinical trials that is commensurate with the risk level of the proposed clinical research. All applications or study protocols must include a general description of the monitoring plan, policies, procedures, responsible entities, and approaches to identifying, managing and reporting reportable events (adverse events and unanticipated problems), to the applicable regulatory agencies (e.g., Institutional Review Board [[IRB]), the NHLBI/NIH, the Office of Biotechnology Activities, Office of Human Research Protections, the Food and Drug Administration, and the Data and Safety Monitoring Board (if one is used). The NHLBI Data and Safety Monitoring Policy dated October 31, 2008 is described at (www.nhlbi.nih.gov/funding/policies/dsmpolicy.htm).

The DSM Plan must address the following areas:

• Who will manage and conduct the monitoring
• What will be monitored
• Proposed monitoring time points
• Where the monitoring will occur
• How the reportable events will be managed and reported
• How sites/centers, and participating facilities (labs, pharmacies) will be monitored
• NIH requires the establishment of Data and Safety Monitoring Boards (DSMBs) for multi-site clinical trials involving interventions that entail potential risk to participants (http://grants.nih.gov/grants/guide/notice-files/not98-084.html). The purpose of this board is to provide independent advice to NHLBI concerning scientific issues pertaining to subject safety, data quality, study conduct and study continuation. In monitoring safety in the trial, the board also may recommend termination in the event of early significance of findings or futility, or the determination of unacceptable adverse effects. The DSMB is normally appointed by the NHLBI for studies funded by Cooperative Agreements and consists of individuals who are not associated with the institutions participating in the trial. Potential members of this board should NOT be named in the application.

INSTITUTE STAFF INVOLVEMENT

• Before making an award for an Investigator-Initiated Clinical Trial, NHLBI will routinely consider the desirability of substantial continued staff involvement in a supportive mode. If such involvement is deemed appropriate by the Institute, the award mechanism will be a cooperative agreement (U01). Regardless of the mechanism of support, NHLBI staff will closely monitor progress during the award. This monitoring will include submission of the IRB approved protocol to the NHLBI Program Official, adequate serious adverse event management and reporting, adequate accrual monitoring plans (at http://www.nhlbi.nih.gov/funding/policies/accrual_guidelines.htm), and regular communications with the principal investigator and staff, and may include attendance at the steering committee, data and safety monitoring board, and related meetings.
• The Terms and Conditions for an award for a clinical trial will include recruitment milestones expected to be met by the study as a whole at specific time periods, accrual goals for women and minorities (as appropriate), any requirements regarding minimum effort of specific key personnel, and any other identified requirements for completion of the approved research.
• As with any award, continuation, even during the period recommended for support, is conditional upon satisfactory progress. If, at any time, recruitment falls significantly below the projected milestones for recruitment, the NHLBI will consider ending support and negotiating a phase-out of the award. The NHLBI retains, as an option, periodic external peer review of progress.

See Section VIII, Other Information - Required Federal Citations, for policies related to this announcement.

Section II. Award Information

1. Mechanism of Support

This FOA will use the R01 award mechanism. The Project Director/Principal Investigator (PD/PI) will be solely responsible for planning, directing, and executing the proposed project. Pending awardees will be notified if the proposal will be awarded as a cooperative agreement (U01).

This FOA uses "Just-in-Time" information concepts (see SF424 (R&R) Application Guide). It also uses the modular as well as the non-modular budget formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, a U.S. organization submitting an application with direct costs in each year of $250,000 or less (excluding consortium Facilities and Administrative [F&A] costs) should use the PHS398 Modular Budget component.

U.S. applicants requesting more than $250,000 in annual direct costs and all foreign applicants must complete and submit budget requests using the Research & Related Budget component.

2. Funds Available

Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the IC(s) provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds.

Facilities and Administrative (F&A) costs requested by consortium participants are not included in the direct cost limitation, see NOT-OD-05-004.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

The following organizations/institutions are eligible to apply:

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education
• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Small Businesses
• For-Profit Organizations (Other than Small Businesses)
• State Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribally Designated Organizations
• County Governments
• City or Township Governments
• Special District Governments
• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• U.S. Territory or Possession
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Organizations)
• Other(s):
  • Eligible Agencies of the Federal Government

1.B. Eligible Individuals

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the PD/PI is invited to work with his/her organization 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 support.

More than one PD/PI (i.e., multiple PDs/PIs) may be designated on the application for projects that require a "team science" approach and therefore clearly do not fit the single-PD/PI model. Additional information on the implementation plans and policies and procedures to formally allow more than one PD/PI on individual research projects is available at http://grants.nih.gov/grants/multi_pi. All PDs/PIs must be registered in the NIH electronic Research Administration (eRA) Commons prior to the submission of the application (see http://era.nih.gov/ElectronicReceipt/preparing.htm for instructions).

The decision of whether to apply for a grant with a single PD/PI or multiple PDs/PIs grant is the responsibility of the investigators and applicant organizations and should be determined by the scientific goals of the project. Applications for grants with multiple PDs/PIs will require additional information, as outlined in the instructions below. When considering the multiple PD/PI option, please be aware that the structure and governance of the PD/PI leadership team as well as the knowledge, skills and experience of the individual PDs/PIs will be factored into the assessment of the overall scientific merit of the application. Multiple PDs/PIs on a project share the authority and responsibility for leading and directing the project, intellectually and logistically. Each PD/PI is responsible and accountable to the grantee organization, or, as appropriate, to a collaborating organization, for the proper conduct of the project or program, including the submission of required reports. For further information on multiple PDs/PIs, please see http://grants.nih.gov/grants/multi_pi.

2. Cost Sharing or Matching

This program does not require cost sharing as defined in the current NIH Grants Policy Statement.

3. Other-Special Eligibility Criteria

Number of Applications. Applicants may submit more than one application, provided that each application is scientifically distinct.

Resubmissions. Applicants may submit a resubmission application, but such application must include an Introduction addressing the previous peer review critique (Summary Statement). Beginning with applications intended for the January 25, 2009, official submission due date, all original new applications (i.e., never submitted) and competing renewal applications are permitted only a single amendment (A1). See new NIH policy on resubmission (amended) applications (NOT-OD-09-003, NOT-OD-09-016). Original new and competing renewal applications that were submitted prior to January 25, 2009, are permitted two amendments (A1 and A2). For these "grandfathered" applications, NIH expects that any A2 will be submitted no later than January 7, 2011, and NIH will not accept A2 applications after that date.

Renewals. Applicants may submit a renewal application.

Clustered applications >$500K in direct costs (combined across all applications for the same trial) in any one year are limited to one resubmission.

The Introduction and response to reviewer's critiques should be integrated such that an identical Introduction is provided for each application that is part of a cluster.

At this time, it is anticipated that this FOA will be reissued. Renewals (formerly "competing continuation") applications will be accepted at the receipt dates of this and subsequent reissuances.

Section IV. Application and Submission Information

To download a SF424 (R&R) Application Package and SF424 (R&R) Application Guide for completing the SF424 (R&R) forms for this FOA, use the "Apply for Grant Electronically" button in this FOA or link to http://www.grants.gov/Apply/ and follow the directions provided on that Web site.

A one-time registration is required for institutions/organizations at both:

• Grants.gov (http://www.grants.gov/applicants/get_registered.jsp) and
• eRA Commons (http://era.nih.gov/ElectronicReceipt/preparing.htm)

PDs/PIs should work with their institutions/organizations to make sure they are registered in the NIH eRA Commons.

Several additional separate actions are required before an applicant can submit an electronic application, as follows:

1. Organizational/Institutional Registration in Grants.gov/Get Registered

• Your organization will need to obtain a Data Universal Number System (DUNS) number and register with the Central Contractor Registration (CCR) as part of the Grants.gov registration process.
• If your organization does not have a Taxpayer Identification Number (TIN) or Employer Identification Number (EIN), allow for extra time. A valid TIN or EIN is necessary for CCR registration.
• The CCR also validates the EIN against Internal Revenue Service records, a step that will take an additional one to two business days.
• Direct questions regarding Grants.gov registration to:
  Grants.gov Customer Support
  Contact Center Phone: 800-518-4726
  Business Hours: M-F 7:00 a.m. - 9:00 p.m. Eastern Time
  Email [email protected]

2. Organizational/Institutional Registration in the eRA Commons

• To find out if an organization is already Commons-registered, see the "List of Grantee Organizations Registered in NIH eRA Commons."
• Direct questions regarding the Commons registration to:
  eRA Commons Help Desk
  Phone: 301-402-7469 or 866-504-9552 (Toll Free)
  TTY: 301-451-5939
  Business hours M-F 7:00 a.m. 8:00 p.m. Eastern Time
  Email [email protected]

3. Project Director/Principal Investigator (PD/PI) Registration in the NIH eRA Commons: Refer to the NIH eRA Commons System (COM) Users Guide.

• The individual(s) designated as PDs/PIs on the application must be registered also in the NIH eRA Commons. In the case of multiple PDs/PIs, all PDs/PIs must be registered and be assigned the PI role in the eRA Commons prior to the submission of the application.
• Each PD/PI must hold a PD/PI account in the Commons. Applicants should not share a Commons account for both an Authorized Organization Representative/Signing Official (AOR/SO) role and a PD/PI role; however, if they have both a PD/PI role and an Internet Assisted Review (IAR) role, both roles should exist under one Commons account.
• When multiple PDs/PIs are proposed, all PDs/PIs at the applicant organization must be affiliated with that organization. PDs/PIs located at another institution need not be affiliated with the applicant organization, but must be affiliated with their own organization to be able to access the Commons.
• This registration/affiliation must be done by the AOR/SO or his/her designee who is already registered in the Commons.

Both the PD(s)/PI(s) and AOR/SO need separate accounts in the NIH eRA Commons since both are authorized to view the application image.

Note: The registration process is not sequential. Applicants should begin the registration processes for both Grants.gov and eRA Commons as soon as their organization has obtained a DUNS number. Only one DUNS number is required and the same DUNS number must be referenced when completing Grants.gov registration, eRA Commons registration and the SF424 (R&R) forms.

1. Request Application Information

Applicants must download the SF424 (R&R) application forms and the SF424 (R&R) Application Guide for this FOA through Grants.gov/Apply.

Note: Only the forms package directly attached to a specific FOA can be used. You will not be able to use any other SF424 (R&R) forms (e.g., sample forms, forms from another FOA), although some of the "Attachment" files may be useable for more than one FOA.

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

Prepare all applications using the SF424 (R&R) application forms for this FOA through Grants.gov/Apply and in accordance with the SF424 (R&R) Application Guide (http://grants.nih.gov/grants/funding/424/index.htm).

The SF424 (R&R) Application Guide is critical to submitting a complete and accurate application to NIH. Some fields within the SF424 (R&R) application components, although not marked as mandatory, are required by NIH (e.g., the "Credential" log-in field of the "Research & Related Senior/Key Person Profile" component must contain the PD/PI's assigned eRA Commons User ID). Agency-specific instructions for such fields are clearly identified in the Application Guide. For additional information, see "Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications."

The SF424 (R&R) application has several components. Some components are required, others are optional. The forms package associated with this FOA in Grants.gov/APPLY includes all applicable components, required and optional. A completed application in response to this FOA includes the data in the following components:

Required Components:
SF424 (R&R) (Cover component)
Research & Related Project/Performance Site Locations
Research & Related Other Project Information
Research & Related Senior/Key Person
PHS398 Cover Page Supplement
PHS398 Research Plan
PHS398 Checklist
PHS398 Modular Budget or Research & Related Budget, as appropriate (See Section IV.6., "Special Instructions," regarding appropriate required budget component.)

Optional Components:
PHS398 Cover Letter File
Research & Related Subaward Budget Attachment(s) Form

Foreign Organizations (Non-domestic [non-U.S.] Entities)

NIH policies concerning grants to foreign (non-U.S.) organizations can be found in the NIH Grants Policy Statement at: http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part12.htm#_Toc54600260.

Applications from Foreign organizations must:

• Request budgets in U.S. dollars.
• Prepare detailed budgets for all applications (that is, complete the Research & Related Budget component of the SF424 (R&R) application forms not the PHS398 Modular Budget component)(see NOT-OD-06-096).
• Not include any charge-back of customs and import fees.
• Comply with the format specifications, which are based upon a standard U.S. paper size of 8.5" x 11" within each PDF.
• If appropriate, request funds for up to 8% Facilities and Administrative (F&A) costs (excluding equipment) (see NOT-OD-01-028, March 29, 2001).
• Comply with Federal/NIH policies on human subjects, animals, and biohazards; and
• Comply with Federal/NIH biosafety and biosecurity regulations (see Section VI.2., "Administrative and National Policy Requirements").

Proposed research should provide special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions in other countries that are not readily available in the United States (U.S.) or that augment existing U.S. resources.

SPECIAL INSTRUCTIONS

Applications with Multiple PDs/PIs

When multiple PDs/PIs are proposed, NIH requires one PD/PI to be designated as the "Contact" PI, who will be responsible for all communication between the PDs/PIs and the NIH, for assembling the application materials outlined below, and for coordinating progress reports for the project. The contact PD/PI must meet all eligibility requirements for PD/PI status in the same way as other PDs/PIs, but has no other special roles or responsibilities within the project team beyond those mentioned above.

Information for the Contact PD/PI should be entered in item 15 of the SF424 (R&R) Cover component. All other PDs/PIs should be listed in the Research & Related Senior/Key Person component and assigned the project role of "PD/PI." Please remember that all PDs/PIs must be registered in the eRA Commons prior to application submission. The Commons ID of each PD/PI must be included in the "Credential" field of the Research & Related Senior/Key Person component. Failure to include this data field will cause the application to be rejected.

All projects proposing Multiple PDs/PIs will be required to include a new section describing the leadership plan approach for the proposed project.

Multiple PD/PI Leadership Plan: For applications designating multiple PDs/PIs, the Research Plan section and the Multiple PD/PI Leadership Plan must be included. A rationale for choosing a multiple PD/PI approach should be described. The governance and organizational structure of the leadership team and the research project should be described, and should include communication plans, process for making decisions on scientific direction, and procedures for resolving conflicts. The roles and administrative, technical, and scientific responsibilities for the project or program should be delineated for the PDs/PIs and other collaborators.

If budget allocation is planned, the distribution of resources to specific components of the project or the individual PDs/PIs should be delineated in the Leadership Plan. In the event of an award, the requested allocations may be reflected in a footnote on the Notice of Award (NoA).

Applications Involving a Single Institution

When all PDs/PIs are within a single institution, follow the instructions contained in the SF424 (R&R) Application Guide.

Applications Involving Multiple Institutions

When multiple institutions are involved, one institution must be designated as the prime institution and funding for the other institution(s) must be requested via a subcontract to be administered by the prime institution. When submitting a detailed budget, the prime institution should submit its budget using the Research & Related Budget component. All other institutions should have their individual budgets attached separately to the Research & Related Subaward Budget Attachment(s) Form. See Section 4.8 of the SF424 (R&R) Application Guide for further instruction regarding the use of the subaward budget form.

When submitting a modular budget, the prime institution completes the PHS398 Modular Budget component only. Information concerning the consortium/subcontract budget is provided in the budget justification. Separate budgets for each consortium/subcontract grantee are not required when using the Modular budget format. See Section 5.4 of the Application Guide for further instruction regarding the use of the PHS398 Modular Budget component.

3. Submission Dates and Times

See Section IV.3.A. for details.

3.A. Submission, Review, and Anticipated Start Dates
Opening Date: May 5, 2010 (Earliest date an application may be submitted to Grants.gov)
Application Due Date(s): Standard dates apply, please see http://grants.nih.gov/grants/funding/submissionschedule.htm
AIDS Application Due Date(s): Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm#AIDS
Peer Review Date(s): Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward
Council Review Date(s): Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward
Earliest Anticipated Start Date(s): Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward

3.A.1. Letter of Intent

A letter of intent is not required for the funding opportunity.

3.B. Submitting an Application Electronically to the NIH

To submit an application in response to this FOA, applicants should access this FOA via http://www.grants.gov/applicants/apply_for_grants.jsp and follow Steps 1-4. Note: Applications must only be submitted electronically. PAPER APPLICATIONS WILL NOT BE ACCEPTED. All attachments must be provided to NIH in PDF format, filenames must be included with no spaces or special characters, and a .pdf extension must be used.

Applications that were originally submitted as investigator-initiated R01s but were funded as Cooperative Agreements (U01s) must be submitted for renewal as an R01 using this FOA and the SF424 R&R Application Package for Investigator Initiated Multi-Site Clinical Trials. The grant number (e.g., HL100001) of the previously funded award should be entered into Item 4 (Federal Identifier), and the "Renewal" box must be checked in Item 8 on the SF424 Cover Component.

3.C. Application Processing

3.C.1 Submitting On-Time

Applications may be submitted on or after the opening date and must be successfully received by Grants.gov no later than 5:00 p.m. local time (of the applicant institution/organization) on the application due date(s). (See Section IV.3.A. for all dates.) If an application is not submitted by the due date(s) and time, the application may be delayed in the review process or not reviewed.

All applications must meet the following criteria to be considered "on-time":

• All registrations must be complete prior to the submission deadline
• The application must receive a Grants.gov tracking number and timestamp (or eRA help desk ticket confirming a system issue preventing submission) by 5:00 p.m. local time on the submission deadline date.
• Any system identified errors/warnings must be corrected and the submission process completed within the "error correction window."

Please visit http://era.nih.gov/electronicReceipt/app_help.htm for detailed information on what to do if Grants.gov or eRA system issues threaten your ability to submit on time.

Submission to Grants.gov is not the last step applicants must follow their application through to the eRA Commons to check for errors and warnings and view their assembled application!

3.C.2 Two Day Window to Correct eRA Identified Errors/Warnings

IMPORTANT NOTE! NIH has eliminated the error correction window for due dates of January 25, 2011 and beyond. As of January 25, all corrections must be complete by the due date for an application to be considered on-time. See NOT-OD-10-123.

Once an application package has been successfully submitted through Grants.gov, NIH provides applicants a two day error correction window to correct any eRA identified errors or warnings before a final assembled application is created in the eRA Commons. The standard error correction window is two (2) business days, beginning the day after the submission deadline and excluding weekends and standard federal holidays. All errors must be corrected to successfully complete the submission process. Warnings will not prevent the application from completing the submission process.

Please note that the following caveats apply:

• Initial application submission must be "on-time."
• The AOR/institutions is expected to enforce that application changes made within the error correction window are restricted to those necessary to address system-identified errors/warnings. NIH may reject any application that includes additional changes.
• Proof of "on-time" submission (e.g., Grants.gov timestamp and tracking number) and description of all changes made within the window must be documented in the PHS 398 Cover Letter component of the application.

3.C.3 Viewing an Application in the eRA Commons

Once any eRA identified errors have been addressed, and the assembled application has been created in the eRA Commons, the PD/PI and the Authorized Organization Representative/Signing Official (AOR/SO) have two weekdays (Monday Friday, excluding Federal holidays) to view the assembled application before it automatically moves forward to NIH for further processing.

• If everything is acceptable, no further action is necessary. The application will automatically move forward to the Division of Receipt and Referral in the Center for Scientific Review for processing after two weekdays, excluding Federal holidays.
• Prior to the submission deadline, the AOR/SO can "Reject" the assembled application and submit a changed/corrected application within the two-day viewing window. This option should be used if it is determined that some part of the application was lost or did not transfer correctly during the submission process, the AOR/SO will have the option to "Reject" the application and submit a Changed/Corrected application. In these cases, please contact the eRA Help Desk to ensure that the issues are addressed and corrected. Once rejected, applicants should follow the instructions for correcting errors in Section 2.12 of the SF 424 (R&R) application guide, including the requirement for cover letters on late applications. The "Reject" feature should also be used if you determine that warnings are applicable to your application and need to be addressed now. Remember, warnings do not stop further application processing. If an application submission results in warnings (but no errors), it will automatically move forward after two weekdays if no action is taken. Some warnings may need to be addressed later in the process.
• If the two-day window falls after the submission deadline, the AOR/SO will have the option to "Reject" the application if, due to an eRA Commons or Grants.gov system issue, the application does not correctly reflect the submitted application package (e.g., some part of the application was lost or didn't transfer correctly during the submission process). The AOR/SO should first contact the eRA Commons Helpdesk to confirm the system error, document the issue, and determine the best course of action. NIH will not penalize the applicant for an eRA Commons or Grants.gov system issue.
• If the AOR/SO chooses to "Reject" the image after the submission deadline for a reason other than an eRA Commons or Grants.gov system failure, a changed/corrected application still can be submitted, but it will be subject to the NIH late policy guidelines and may not be accepted. The reason for this delay should be explained in the cover letter attachment.
• Both the AOR/SO and PD/PI will receive e-mail notifications when the application is rejected or the application automatically moves forward in the process after two weekdays.

Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review, NIH. Incomplete applications will not be reviewed.

There will be an acknowledgement of receipt of applications from Grants.gov and the Commons. The submitting AOR/SO receives the Grants.gov acknowledgments. The AOR/SO and the PI receive Commons acknowledgments. Information related to the assignment of an application to a Scientific Review Group is also in the Commons.

Note: Since email can be unreliable, it is the responsibility of the applicant to check periodically on their application status in the Commons.

The NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial merit review unless the applicant withdraws the pending application. The NIH will not accept any application that is essentially the same as one already reviewed. However, the NIH will accept a resubmission application, but such application must include an Introduction addressing the critique from the previous review.

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.

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 renewal award if such costs: (1) are necessary to conduct the project; and (2) 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 renewal 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.

PD/PI Credential (e.g., Agency Login)

The NIH requires the PD(s)/PI(s) to fill in his/her Commons User ID in the "PROFILE Project Director/Principal Investigator" section, "Credential" log-in field of the "Research & Related Senior/Key Person Profile" component.

Organizational DUNS

The applicant organization must include its DUNS number in its Organization Profile in the eRA Commons. This DUNS number must match the DUNS number provided at CCR registration with Grants.gov. For additional information, see "Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications."

PHS398 Research Plan Component Sections

All application instructions outlined in the SF424 (R&R) Application Guide are to be followed, incorporating "Just-in-Time" information concepts, and with the following additional requirements:

• Introduction (required for a resubmission or revision application) is limited to 1 page.
• Specific Aims is limited to 1 page.
• The Research Strategy section of a CCC or DCC application may not exceed 12 pages, including tables, graphs, figures, diagrams, and charts.

See Table of Page Limits

Budget Component

U.S. applicants submitting an application with direct costs in each year of $250,000 or less (excluding consortium Facilities and Administrative [F&A] costs) must use the PHS398 Modular Budget component.

U.S. applicants requesting more than $250,000 in annual direct costs and all foreign applicants must complete and submit budget requests using the Research & Related Budget component.

Specific Instructions for Applications Requesting $500,000 (direct costs) or More per Year

Applicants requesting $500,000 or more in direct costs for any year (excluding consortium F&A costs) must carry out the following steps:

1. Contact IC program staff at least 3 months before submitting the application, i.e. as plans are being developed for the study.

2. Submit a formal letter of request to submit the application to the IC prior to the receipt date (http://www.nhlbi.nih.gov/funding/policies/500kweb.htm).
3. Obtain agreement from the IC that the Institute will accept the application for consideration for award.

4. Include the letter of agreement in the PHS398 Cover Letter component with the application to identify the staff member(s) at the IC who agreed to accept assignment of the application.

5. Consult NHLBI's Guidelines for Applications With Direct Costs of $500,000 or More In Any One Year (http://www.nhlbi.nih.gov/funding/policies/500kweb.htm).

6. If the request is for pre-approval to submit an application with direct costs for any year (excluding consortium F&A costs) greater than the cap for NHLBI Program Project Grants (see Allowable Requested Direct Costs For Program Projects, http://www.nhlbi.nih.gov/funding/policies/grantcaps.htm), consult with institute staff about special pre-approval instructions.

This policy applies to all new, renewal, revision, or resubmission applications. See NOT-OD-02-004, October 16, 2001.

Appendix Materials

Applicants must follow the specific instructions on Appendix materials as described in the SF424 (R&R) Application Guide (See http://grants.nih.gov/grants/funding/424/index.htm).

A copy of the clinical protocol and a copy of the consent form template to be used by each enrollment site must be provided in the Appendix.

Do not use the Appendix to circumvent the page limitations. An application that does not comply with the required page limitations may be delayed in the review process or not reviewed.

Foreign Applications (Non-domestic, non-U.S. Entity)

• Indicate how the proposed project has specific relevance to the mission and objectives of the NHLBI and has the potential for significantly advancing the health sciences in the United States.

Special Instructions for Applications Submitted as Part of a Cluster

• Multiple applications submitted as part of a Phase II or Phase lll clinical trial with direct costs over $500,000 in any year (excluding consortium F&A costs) will be considered as a cluster for the purposes of peer review and funding.
• Each application submitted as a part of a cluster should have the same abstract, title, and cover letter attached.
• All applications submitted as part of a cluster will be reviewed together, and will receive the same impact/priority score and summary statement.
• When multiple applications are submitted as part of a cluster, then all the requirements for applications of $500,000 or more apply when the combined budgets of the clustered applications equal or exceed $500,000. Thus the direct costs of the combined budgets are the unique trigger for applying the $500,000 policy requirements.
• Each application in the cluster must be prepared in response to this Funding Opportunity Announcement and be submitted electronically through Grants.gov (http://www.grants.gov/) using the SF424 Research and Related (R&R) forms and the SF424 (R&R) Application Guide.

• Each application in the cluster must use the Title field to denote clustering using a common base title plus a tag denoting the linkage. The tag identifier should be placed at the end of the title. Commonly used tags for Phase III multi site clinical trials include "Clinical Coordinating Center "(or "CCC"), "Data Coordinating Center" (or "DCC"), "Economics and QOL Core," "Imaging Core," etc.
• The Clinical Coordinating Center or the Data Coordinating Center may be designated as the lead application if applicable, but designating a lead application is not required. If either is considered the lead application, it should be indicated at the end of the tag, and in the abstract.
• The system truncates any title that exceeds the maximum character limit, so titles need to be succinct (i.e., no more than 80 characters).
• Example: "Infant Study of Inhaled Saline in Cystic Fibrosis (ISIS) - CCC - Lead Application" (68 characters)
• Trials with very long titles (i.e., more than 80 characters with tag) should use only an acronym plus the appropriate tag, and the full title should be spelled out in the abstract.
• Example: "ALLHAT DCC " (acronym for "The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Data Coordinating Center")

• In the Cover Letter Component, a PHS398 cover letter is required for each application and must include a list of all applications included in the cluster, including for each the name of the PI; the unique Title (including the Tag); and the Applicant Institution. Each application's cover letter should have attached a copy of the NHLBI approval letter.

• All applications must provide detailed scientific and operational plans as well as funding needs for the entire trial and data analysis period, even if this period exceeds five years. The review of the application will evaluate the entire project. The Institute commitment will be mindful of this total project need although the award period may be for less time.
• Investigators must submit a total overall budget for the entire cluster and a complete, justified, individual budget for each year of support requested. If the trial is designed for more than a five-year period, complete, justified budgets (cluster and individual) for the future years also must be included in the budget justification.
• Separate itemized budgets must be prepared for each subcontract and/or for each collaborating center or core, if multiple centers or cores are proposed.
• All costs requested and all changes in budgets after the first year should be clearly identified and justified.
• If parts of the costs of the trial are to be borne by sources other than NIH, these contributions must be presented in detail in the budget justification along with supporting letters signed by individuals who have the authority to commit the institution. These outsource costs do not constitute cost sharing as defined in the current NIH Grants Policy Statement and should not be presented either as part of the requested budget or as Estimated Project Funding (item 16b) in the SF424 R&R Cover Component. (16b should always be the same as 16a).
• Further information concerning budget preparation may be obtained from the Office of Grants Management contact listed below.

• List of Clustered Applications: For applications submitted as part of a Phase II or Phase III clinical trial with direct costs over $500,000 in any year (excluding consortium F&A costs), a list of the collaborative applications must be included in "Item 11. Other Attachments" in the Other Project Information Component as well as in the cover letter. Each application must include an identical list of all the collaborative applications including for each the name of the PI, the Title+Tag, and the Applicant Institution. In the body of the text, begin the section with a heading indicating "Clustered Applications." When saving the file, name it "Clustered Applications" as well to ensure the application is bookmarked appropriately.

NIH considers the sharing of unique research resources developed through NIH-sponsored research an important means to enhance the value and further the advancement of the research. When resources have been developed with NIH funds and the associated research findings published or provided to NIH, it is important that they be made readily available for research purposes to qualified individuals within the scientific community. If the final data/resources are not amenable to sharing, this must be explained in the Resource Sharing section of the application (see http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm)..

(a) Data Sharing Plan: Investigators seeking $500,000 or more in direct costs in any year are expected to include a brief 1-paragraph description of how final research data will be shared, or explain why data-sharing is not possible. Applicants are encouraged to discuss data-sharing plans with their NIH program contact (see Data-Sharing Policy or http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html)..

(b) Sharing Model Organisms: Regardless of the amount requested, all applications in which the development of model organisms is anticipated are expected to include a description of a specific plan for sharing and distributing unique model organisms and related resources, or state appropriate reasons why such sharing is restricted or not possible (see Sharing Model Organisms Policy, and NIH Guide NOT-OD-04-042)..

(c) Genome-Wide Association Studies (GWAS): Regardless of the amount requested, applicants seeking funding for a genome-wide association study are expected to provide a plan for submission of GWAS data to the NIH-designated GWAS data repository, or provide an appropriate explanation why submission to the repository is not possible. A genome-wide association study is defined as any study of genetic variation across the entire genome that is designed to identify genetic associations with observable traits (e.g., blood pressure or weight) or the presence or absence of a disease or condition. For further information see Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies (NOT-OD-07-088) and http://grants.nih.gov/grants/gwas/.

Foreign Applications (Non-domestic [non-U.S.] Entities)

Indicate how the proposed project has specific relevance to the mission and objectives of the NIH/IC and has the potential for significantly advancing the health sciences in the United States.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process.

2. Review and Selection Process

Review Process

Applications that are complete will be evaluated for scientific and technical merit by an appropriate peer review group convened by NHLBI and in accordance with NIH peer review procedures (http://grants1.nih.gov/grants/peer/), using the review criteria stated below.

As part of the scientific peer review, all applications will:

• Undergo a selection process in which only those applications deemed to have the highest scientific and technical merit, generally the top half of applications under review, will be discussed and assigned an impact/priority score.
• Receive a written critique.
• Receive a second level of review by the appropriate National Heart, Lung, and Blood Advisory Council (NHLBAC).

The mission of the NIH is to support science in pursuit of knowledge about the biology and behavior of living systems and to apply that knowledge to extend healthy life and reduce the burdens of illness and disability. As part of this mission, applications submitted to the NIH for grants or cooperative agreements to support biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

Overall Impact

Reviewers will provide an overall impact/priority score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following five scored review criteria, and additional review criteria (as applicable for the project proposed).

Scored Review Criteria

Reviewers will consider each of the five review criteria below in the determination of scientific and technical merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance. Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Investigator(s). Are the PD/PIs, collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Are the responsibilities of key staff members well-suited to their expertise? Is the effort of the staff member commensurate with the responsibilities involved? Do the clinical centers employ the appropriate personnel to recruit subjects and implement the clinical protocol? Does the application(s) involve the appropriate personnel to ensure appropriate coordination, data management (including quality control), and regulatory and statistical/analytical support?

Innovation. Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Approach. Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed?
If the project involves clinical research, are the plans for (1) protection of human subjects from research risks, and (2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed? Is the planned recruitment timeline feasible? Is there a plan to monitor accrual? Is the primary endpoint adequately powered and appropriate to test the research question? Are data management and quality control procedures adequate? Are planned analyses appropriate for the proposed study design?

Environment. Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements? Is there evidence of institutional support? Are facilities and resources available for the research project adequate? For multicenter applications, is there evidence of the ability of the individual centers to (1) enroll the proposed numbers, (2) adhere to the protocol, (3) collect and transmit data in an accurate and timely fashion, and (4) operate within the proposed organizational structure?

Additional Review Criteria

As applicable for the project proposed, reviewers will consider the following additional items in the determination of scientific and technical merit, but will not give separate scores for these items.

Organization. Is the proposed organizational structure appropriate? What impact does the organizational structure have on the scientific goals of the project? What is the quality of the DSM Plan to monitor sites/centers, and participating facilities (labs, pharmacies)?

Protections for Human Subjects. For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: (1) risk to subjects, (2) adequacy of protection against risks, (3) potential benefits to the subjects and others, (4) importance of the knowledge to be gained, and (5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: (1) the justification for the exemption, (2) human subjects involvement and characteristics, and (3) sources of materials.

Adequacy of Data and Safety Monitoring (DSM) Plan. DSM plan is commensurate with the risk level of the proposed clinical research, includes adequate description of the monitoring plan, policies, procedures, responsible entities, management and reporting of the reportable events, both adverse events and unanticipated problems, to the applicable regulatory agencies (e.g., Institutional Review Board (IRB), the NHLBI/NIH, the Office of Biotechnology Activities, Office of Human Research Protections, and the Food and Drug Administration). The NHLBI Data and Safety Monitoring Policy is described at www.nhlbi.nih.gov/funding/policies/dsmpolicy.htm.

The DSM Plan must address the following areas:

• Who will manage and conduct the monitoring?
• What will be monitored?
• Proposed monitoring time points?
• Where the monitoring will occur?
• How the reportable events will be managed and reported?

Inclusion of Women, Minorities, and Children. When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children.

Vertebrate Animals. The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: (1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; (2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; (3) adequacy of veterinary care; (4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and (5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. . For additional information, see http://grants.nih.gov/grants/olaw/VASchecklist.pdf.

Biohazards. Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmission Applications. When reviewing a Resubmission application (formerly called an amended application), the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Renewal Applications. When reviewing a Renewal application (formerly called a competing continuation application), the committee will consider the progress made in the last funding period.

Revision Applications. When reviewing a Revision application (formerly called a competing supplement application), the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

Additional Review Considerations

As applicable for the project proposed, reviewers will address each of the following items, but will not give scores for these items and should not consider them in providing an overall impact/priority score.

Applications from Foreign Organizations. Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Select Agent Research. Reviewers will assess the information provided in this section of the application, including (1) the Select Agent(s) to be used in the proposed research, (2) the registration status of all entities where Select Agent(s) will be used, (3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and (4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans. Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan (http://grants.nih.gov/grants/policy/data_sharing/data_sharing_guidance.htm); 2) Sharing Model Organisms (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-04-042.html); and 3) Genome Wide Association Studies (GWAS) (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-088.html).

Budget and Period Support. Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Selection Process

Applications submitted in response to this funding opportunity will compete for available funds with all other recommended applications. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

3. Anticipated Announcement and Award Dates

Not Applicable

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 NIH 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.

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.

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 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 and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities.

3. Reporting

When multiple years are involved, awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.

Awardees will be required to report monitoring activities to NHLBI in accordance with the Data and Safety Monitoring (DSM) Plan in the IRB approved clinical protocol. Monitoring activities report should be submitted at a minimum of annually, or at the end of the project if less than one year. Annual reporting should be in conjunction with the Non-Competing Grant Progress report. It should include at a minimum, a summary of safety/reportable events, and summaries of all advisory/monitoring board meetings and recommendations.

A final progress report, invention statement, and Financial Status Report are required when an award is relinquished when a recipient changes institutions or when an award is terminated.

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 (program), peer review, and financial or grants management issues:

1. Scientific/Research Contact(s):

David J. Gordon, M.D., Ph.D.
Division of Cardiovascular Sciences
National Heart, Lung, and Blood Institute
Rockledge 2 Building, Room 8134
6701 Rockledge Drive
Bethesda, MD 20892-7940
Telephone: (301) 435-0564
Fax: 301-480-7921
Email: [email protected]

Gail Weinmann, M.D.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
Rockledge 2 Building, Room 10140
6701 Rockledge Drive
Bethesda, MD 20892-7940
Telephone: (301) 435-0233
Fax: 301-480-3547
Email: [email protected]

Ellen M. Werner, Ph.D.
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
Rockledge 2 Building, Room 9030
6701 Rockledge Drive
Bethesda, MD 20892-7950
Telephone: (301) 435-0050
Fax: 301-480-0868
Email: [email protected]

2. Peer Review Contact(s):

Keary A. Cope, Ph.D.
Division of Extramural Research Activities
Office of Scientific Review
Rockledge 2 Building, Room 7194
6701 Rockledge Drive
Bethesda, MD 20892-7924
Telephone: (301) 435-0288
Fax: (301) 480-3541
Email: [email protected]

3. Financial/Grants Management Contact(s):

Ms. Kimberly Stanton
Division of Extramural Research Activities
Office of Grants Management
Rockledge 2 Building, Room 7167
6701 Rockledge Drive
Bethesda, MD 20892
Telephone: (301) 435-0166
Fax: 301-451-5462
Email: [email protected]

Section VIII. Other Information

Required Federal Citations

Use of Animals in Research:
Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf) as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm) as applicable.

Human Subjects Protection:
Federal regulations (45 CFR 46) 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 institutional review board (IRB) rules, as well as local, states and federal laws and regulations, including the Privacy Rule.

Policy for Genome-Wide Association Studies (GWAS):
NIH is interested in advancing genome-wide association studies (GWAS) to identify common genetic factors that influence health and disease through a centralized GWAS data repository. For the purposes of this policy, a genome-wide association study is defined as any study of genetic variation across the entire human genome that is designed to identify genetic associations with observable traits (such as blood pressure or weight), or the presence or absence of a disease or condition. All applications, regardless of the amount requested, proposing a genome-wide association study are expected to provide a plan for submission of GWAS data to the NIH-designated GWAS data repository, or provide an appropriate explanation why submission to the repository is not possible. Data repository management (submission and access) is governed by the Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088. For additional information, see http://grants.nih.gov/grants/gwas/.

Sharing of Model Organisms:
NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh-Dole Act (see the NIH Grants Policy Statement. Beginning October 1, 2004, all investigators submitting an NIH application or contract proposal are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.

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 SF424 (R&R) application; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: (a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and (b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.

Inclusion of Children as Participants in 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-09-116.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.

NIH Public Access Policy Requirement:
In accordance with the NIH Public Access Policy, investigators funded by the NIH must submit or have submitted for them to the National Library of Medicine's PubMed Central (see http://www.pubmedcentral.nih.gov/), an electronic version of their final, peer-reviewed manuscripts upon acceptance for publication, to be made publicly available no later than 12 months after the official date of publication. The NIH Public Access Policy is available at (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-033.html). For more information, see the Public Access webpage at http://publicaccess.nih.gov/.

Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (HHS) 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 HHS 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. For publications listed in the appendix and/or Progress report, Internet addresses (URLs) or PubMed Central (PMC) submission identification numbers must be used for publicly accessible on-line journal articles. Publicly accessible on-line journal articles or PMC articles/manuscripts accepted for publication that are directly relevant to the project may be included only as URLs or PMC submission identification numbers accompanying the full reference in either the Bibliography & References Cited section, the Progress Report Publication List section, or the Biographical Sketch section of the NIH grant application. A URL or PMC submission identification number citation may be repeated in each of these sections as appropriate. There is no limit to the number of URLs or PMC submission identification numbers that can be cited.

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 FOA 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. 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 Part 52 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 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/.

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