Part I Overview Information

Department of Health and Human Services

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

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

Title: Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Core Clinical Centers (U10)

Announcement Type
August 19, 2016 - This RFA has been reissued as RFA-HL-17-018
This is a reissue of NOT-HL-05-119.

Request For Applications (RFA) Number: RFA-HL-11-013

Catalog of Federal Domestic Assistance Number(s)
93.839, 93.395

Key Dates
Release Date: August 11, 2010
Letter of Intent Receipt Date: September 13, 2010
Application Receipt Date: October 13, 2010
Peer Review Date: March 2011
Council Review Date(s): May 2011
Earliest Anticipated Start Date: July 1, 2011
Additional Information To Be Available Date (Url Activation Date):
Expiration Date: October 14, 2010

Due Dates for E.O. 12372

Not Applicable

Additional Overview Content

Executive Summary

• Purpose. This Funding Opportunity Announcement (FOA) issued by the National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer Institute (NCI), National Institutes of Health, invites applications from investigators willing to participate under a cooperative agreement as Core Clinical Centers in the Blood and Marrow Transplant Clinical Trials Network (BMT CTN), a collaborative multicenter clinical program that promotes the efficient comparison of novel treatment approaches and management strategies for potential benefit of children and adults undergoing hematopoietic stem cell transplantation. This is an open competition for the renewal of an existing network.
• Mechanism of Support. This FOA will utilize the U10 NIH Cooperative Clinical Research Agreement grant mechanism.
• Funds Available and Anticipated Number of Awards. NHLBI and NCI intend to commit up to $63.5 million over six years to fund up to 19 Core Clinical Centers with expertise in hematopoietic stem cell transplantation (HSCT) and a Data Coordinating Center (DCC) to support the program. Investigators interested in applying as DCC for the BMT CTN program should refer to the companion Request for Applications (RFA-HL-11-028).
• Budget and Project Period. An applicant for a Core Clinical Center may request a six- year project period and a base, administrative budget of up to $110,000 direct costs in the first budget period and up to $115,000 direct costs in each of the subsequent budget periods. Protocol-related expenses will be allocated through the DCC.
• Application Research Strategy Length: The U10 Research Strategy section 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). 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. Only one PD/PI may be designated on the application.
• Number of Applications. An applicant institution may submit only one application in response to this FOA.
• Resubmissions. Resubmission applications are not permitted in response to this FOA.
• Renewals. Renewal applications are permitted in response to this FOA.
• Special Date(s). This FOA uses non-standard due dates. See Receipt, Review and Anticipated Start Dates.
• Application Materials. See Section IV.1 for application materials.
  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(s) 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. Address to Request Application Information
2. Content and Form of Application Submission
3. Submission Dates and Times
A. Receipt, Review and Anticipated Start Dates
1. Letter of Intent
B. Sending an Application to the NIH
C. Application Processing
D. Application Assignment
4. Intergovernmental Review
5. Funding Restrictions
6. Other Submission Requirements

Section V. Application Review Information
1. Criteria
2. Review and Selection Process
3. Anticipated Announcement and Award Dates

Section VI. Award Administration Information
1. Award Notices
2. Administrative and National Policy Requirements
A. Cooperative Agreement Terms and Conditions of Award
1. Principal Investigator Rights and Responsibilities
2. NIH Responsibilities
3. Collaborative Responsibilities
4. Dispute Resolution Process
3. Reporting

Section VII. Agency Contact(s)
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

Purpose:

The National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer Institute (NCI) invite applications from investigators interested in participating under a cooperative agreement as Core Clinical Centers in the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). The BMT CTN is a collaborative multicenter clinical program dedicated to improving the safety and efficacy of hematopoietic stem cell transplantation (HSCT), a stem cell therapy used to treat both malignant and nonmalignant diseases. The BMT CTN will rigorously evaluate HSCT strategies by conducting clinical trials and disseminating findings to health care professionals, patients, and the public in a timely manner. The focus of this solicitation is on multicenter Phase II and Phase III studies that provide new information to improve HSCT therapy and address areas of high scientific priority, can be completed within the framework and timeline of this FOA, and require a multicenter Network infrastructure. The BMT CTN may also perform Phase I/II studies evaluating novel cellular therapies to enhance HSCT outcomes.

Background:

Each year, thousands of patients in the United States undergo HSCT. Few patients, however, are offered the option to enroll in a research protocol to study and improve the outcome of this life-saving, but frequently toxic procedure. HSCT can be curative for both malignant and nonmalignant diseases. For patients with hematologic malignancies, 40-50% of those receiving allogeneic grafts currently survive more than five years. For patients treated but not cured by allogeneic HSCT, outcomes can be superior to chemotherapy alone. However, the overall survival for patients receiving this therapy has generally reached a plateau, with toxicities and life-threatening adverse events including graft versus host disease (GVHD), post-transplant infections, disease recurrence (relapse of malignancy), regimen-related toxicities, graft failure, and poor quality of life remaining significant challenges. Patients treated with autologous transplants generally have fewer complications, but the therapy may not be curative. HSCT has the potential to be curative for a variety of rare, nonmalignant diseases including thalassemia, sickle cell disease, aplastic anemia and other diseases of the bone marrow, disorders of immunity, and enzyme deficiencies. However, few multicenter clinical trials have been conducted. Thus, there is a compelling scientific need to pursue HSCT research for these rare disorders and improve the outcomes of patients who undergo this promising therapy.

The major barriers to clinical studies in HSCT include the heterogeneity of conditions, the small numbers of individuals with an indication for HSCT at any one center, the differences in treatment strategies at various centers, and the lack of resources to coordinate national collaborative efforts. Networks utilize a multicenter approach to effectively conduct clinical trials of novel therapies in patients with uncommon conditions. Further, multicenter clinical trials adhere to a common treatment protocol allowing for an accurate evaluation of a particular treatment strategy.

In 2001, the NHLBI and the NCI established the BMT CTN as a mechanism to evaluate promising HSCT therapies in a multicenter setting. Sixteen Core Clinical Centers and a DCC were selected to establish the Network in response to RFA-HL-01-004. The Network was renewed in 2006 (NOT-HL-05-119).

The Steering Committee, which consists of the Principal Investigators (PIs) from each Core Clinical Center, the DCC, and staff from the NHLBI and the NCI, has implemented more than 18 clinical trials (primarily Phase II and III). More than 70 Affiliate Centers (non-Core Clinical Centers) enrolled patients on BMT CTN clinical trials; these centers were reimbursed on a per-patient basis by the DCC. Conducting collaborative HSCT research with rare patient populations and disease indications in a network setting is efficient and cost effective.

During the first funding period (2001-2005), BMT CTN launched nine high-quality multicenter clinical trials evaluating key pressing clinical questions in transplantation. These trials were designed to identify the best graft sources, reduce regimen-related toxicity, prevent and treat GVHD, reduce disease recurrence/relapse, reduce infection, and improve immune reconstitution post HSCT. Six of these studies have completed accrual and are either in a follow-up or analysis phase, or have had their results disseminated. As a result of this effort, and launching additional trials during the second funding period (2006-present), BMT CTN enrolled more than 3,000 subjects in Network trials. During the second funding cycle, BMT CTN launched a trial focused on HSCT in pediatric subjects, a trial addressing HSCT for severe sickle cell disease, and trials to evaluate both alternative and unrelated donor transplants, treatments for acute and chronic graft versus host disease, and novel approaches to reduce regimen-related toxicity and disease recurrence/relapse. In addition, the Network organized the 2007 State of the Science Symposium in Blood and Marrow Transplantation (Biol Blood Marrow Transplant. 2007, Vol. 13 (11):1268-85) to evaluate the most recent scientific advances and identify the most important questions that should be addressed in future HSCT clinical trials. The proposed trials were ranked by a panel of external experts and presented to the transplant community at the American Society of Hematology annual meeting in December 2007. Trials with the highest priority have been launched in the second 5-year project period (2006-2011) by the Network, or in collaboration with the NCI Cancer Cooperative Groups, including:

• A Trial of Single Autologous Transplant with or without Consolidation Therapy Versus Tandem Autologous Transplant with Lenalinomide Maintenance for Multiple Myeloma (BMT CTN 0702, STaMINA).
• A Phase II/III Trial Comparing Sirolimus Plus Prednisone, Sirolimus/Extracorporeal Photopheresis Plus Prednisone, and Sirolimus/Calcineurin Inhibitor plus Prednisone for the Treatment of Chronic GVHD (BMT CTN 0801).
• A Phase II Study of Reduced-Intensity Allogeneic Stem Cell Transplantation for High-Risk Chronic Lymphocytic Leukemia (BMT CTN 0804, trial being led by CALGB).
• A Randomized Trial of Chemotherapy plus Dasatinib versus HCT for Ph+ Acute Lymphoblastic Leukemia (BMT CTN 0805, trial being led by SWOG).
• A Randomized, Multicenter, Phase III Study of Allogeneic Stem Cell Transplantation Comparing Regimen Intensity in Patients with Myelodysplastic Syndrome or Acute Myeloid Leukemia (BMT CTN 0901).

Protocols for BMT CTN clinical trials, and the status of these studies (open or closed to accrual), can be found on https://web.emmes.com/study/bmt2/. These studies may be continuing to enroll subjects at the initiation of the next award period beginning August 1, 2011. Awardees of the new BMT CTN program will be encouraged to enroll subjects on trials that are still underway from the current phase of the program, and will be responsible for enrolling subjects on trials launched by the new program.

Scope:

A number of high-priority research questions in HSCT remain unanswered. A multicenter program is needed to address these questions. NHLBI and NCI intend to support the BMT CTN, to promote the efficient comparison of novel treatment approaches and management strategies for potential benefit of children and adults undergoing hematopoietic stem cell transplantation for another award period (August 1, 2011, to July 31, 2017). The overall goals of this program period are to launch new Phase II and III clinical trials that further improve transplant therapy, address transplant-specific issues, and test HSCT against new or existing treatments. The BMT CTN will also be asked to consider conducting Phase I/II clinical trials which evaluate the efficacy of emerging novel cell-based therapies for patients receiving HSCT, if sufficient safety data are available.

The Steering Committee (membership described below), comprised of the awardees to this FOA and the awardee funded under a separate FOA for the DCC (RFA-HL-11-028), will be charged with identifying the highest priority research areas in HSCT and developing protocols that require a Network infrastructure. Protocol topics will be decided collaboratively by the Steering Committee members.

Core Clinical Centers will be responsible for developing clinical trial protocols; recruiting, assessing, and treating subjects on new BMT CTN clinical trials; participating in data analysis; interpreting the results; and disseminating research findings. Although not a requirement, all Clinical Core Centers will be encouraged to enroll subjects in BMT CTN clinical trials that are still underway from the current phase of the program. A complete description of the protocols, including timeline and enrollment needs, is provided on https://web.emmes.com/study/bmt2/.

The DCC will be funded under a separate FOA (RFA-HL-11-028) and will have responsibility for data management and analysis and coordination of all Network activities in collaboration with the Steering Committee.

Awards for the DCC and a Clinical Core Center will not be made to the same principal investigator to ensure that data analysis is conducted independently of data acquisition. The same institution may apply for both a Core Clinical Center and the DCC award, but these applications must be from different principal investigators.

Organization of the BMT CTN:

BMT CTN is funded using a cooperative agreement mechanism. The Network consists of Core Clinical Centers, a DCC, a Network Chair (who will be selected by NHLBI and may be external to the Network), and NIH staff from the Division of Blood Diseases and Resources, NHLBI, and the Division of Cancer Treatment and Diagnosis, Cancer Therapy Evaluation Program, NCI.

1. Core Clinical Centers are hematopoietic stem cell (HSC) transplant centers which are responsible for proposing and developing BMT CTN clinical trial protocols, conducting the research, and disseminating the research findings. All Core Clinical Centers are required to participate in a cooperative and interactive manner with one another and with the other Network participants listed below. Core Clinical Centers should perform at least 35 allogeneic HSCT per year.

2. The Data Coordinating Center (see RFA-HL-11-028) is responsible for the following activities: Overall program coordination; maintaining and updating the Manual of Operating Procedures; supporting protocol development; implementation and monitoring of Network trials; providing data management and transmission, including preparing data and safety reports for the Data and Safety Monitoring Boards, Network committees, public data files, and manuscripts for publication; identifying Affiliate transplant centers and collaborative groups interested in participating in BMT CTN clinical trials; subcontracting and reimbursing (per-patient) the Core Clinical Centers, Affiliate transplant centers and other collaborating sites and groups; subcontracting with a central laboratory responsible for the long-term storage of biospecimens collected on BMT CTN trials; subcontracting with central laboratories for biospecimen testing per protocol specifications; negotiating with pharmaceutical companies for specific drugs and reagents; supporting administrative and regulatory activities; supporting statistical, study design, and analytical requirements; developing an accrual plan and advertising materials for each study; developing data safety and monitoring plans; providing data management and monitoring activities; coordinating manuscript and presentation development; quality assurance; and coordinating the activities of the Data and Safety Monitoring Board (DSMB), the Protocol Review Committee (PRC), the BMT CTN Steering Committee, the External Advisory Committee, and other BMT CTN committees and subcommittees.

3. The Steering Committee is the main governing body of the BMT CTN. The Steering Committee is composed of the PI of each Core Clinical Center, the PI of the DCC, an NHLBI Program Director, and an NCI Program Director, each of whom shall have one vote. Transplant centers have the option to form a consortium and apply as a single entity for a Core Clinical Center award. In the case of a consortium, there will be one PI who will serve on the Steering Committee and represent the other centers. A Network Chairperson will be selected by NHLBI to oversee and guide Steering Committee activities. The Steering Committee will meet in person an average of three times a year and by teleconference on a monthly basis; additional meetings may be scheduled at the discretion of the Steering Committee Chair and the NHLBI and the NCI Program Officers. All major scientific decisions will be determined by majority vote of the Steering Committee. The Steering Committee will have primary responsibility for the general organization of the BMT CTN, the approval of clinical protocols and protocol changes, the conduct and monitoring of clinical trials, and the expeditious reporting of study results. Topics for new protocols are reviewed and prioritized by the Steering Committee. For each protocol, one Core Clinical Center investigator will take the lead responsibility for drafting the protocol, assisted by a subcommittee (protocol team) composed of representatives from the Core Clinical Centers, Affiliate Centers, and ex officio members from NHLBI and NCI. The Steering Committee has final responsibility for approving the protocols before review by the PRC or DSMB.

Subcommittees are established as necessary and may include experts who are not representatives of the Core Clinical Centers. Examples include the Publications, Pharmacy, Pediatrics and Human Subjects, Biomarkers, Gene and Cell Therapy, Infection and Immune Reconstitution, Graft versus Host Disease, Alternative Donors, Nurse Coordinators Committee, and the individual protocol teams. Committee membership includes physician and nurse investigators from the Core Clinical Centers, representatives from the DCC, and ex officio members from NHLBI and NCI.

4. The NHLBI and the NCI will be responsible for facilitating the activities of the BMT CTN. The NHLBI Program Office and the NHLBI Office of Grants Management will be responsible for stewardship of the awards. NHLBI and NCI Program Staff will be involved substantially with the awardees as a partner, consistent with the Cooperative Agreement mechanism. The NHLBI and the NCI will each have one vote on the Steering Committee.

5. An independent PRC established by the NHLBI provides scientific peer review for each protocol. The PRC will provide a written critique of each proposal and a final recommendation to NHLBI.

6. An independent DSMB established by the NHLBI monitors patient safety and reviews performance of each study. As a part of its monitoring responsibility, the DSMB submits recommendations to the NHLBI regarding the conduct and continuation of each protocol.

7. NHLBI will appoint an External Advisory Committee that will review the Network’s portfolio, and make recommendations to the Institute regarding the progress and scope of the BMT CTN program. It is expected that this Committee will be convened annually.

8. Support for Clinical Trials will depend on the availability of funds and will be provided to the transplant centers by the DCC on a per-patient basis (an average per-patient cost is calculated for each trial). All of the Core Clinical Centers must be willing to pursue this funding arrangement for each new protocol conducted. The exact number and duration of protocols supported in the six-year program will depend on the nature and extent of the protocols developed.

Clinical protocols will be reviewed by the NHLBI PRC and DSMB, approved by the Director of NHLBI (or his/her designee), and approved by the local Institutional Review Boards prior to initiation of trials. It is expected that clinical trial protocols will be developed and launched by year 4 of the award to allow timely completion within the timeframe of the program. The program funded by this FOA is of six-year duration.

Scientific Knowledge to be Achieved Through Research Supported by this Program

Applications to this FOA should propose a concept for a clinical trial that addresses a significant gap in the clinical practice of HSCT. The specific project should address the significance of the research, the need for a multicenter approach, and feasibility considerations.

The NHLBI and NCI expect that the Network will initiate between six to eight new clinical trials within the first four years of the award, and conduct these trials simultaneously. The topics for these trials will be decided cooperatively by the Steering Committee. The Core Clinical Centers will be proposing concepts for clinical trials that address a significant gap in the clinical practice of HSCT. The specific topics are anticipated to address the significance of the research, the need for a multicenter approach, and feasibility considerations. Potential topics should address significant barriers and knowledge gaps in HSCT therapy, including but not limited to testing new agents and strategies to:

• Improve engraftment.
• Improve immune reconstitution.
• Prevent or reduce regimen related toxicities.
• Prevent or treat GVHD.
• Prevent disease relapse.
• Treat nonmalignant hematological diseases.
• Evaluate emerging cellular therapies or engineered grafts designed to address specific complications of HSCT.

While these topics are very important, they are provided only as examples of areas that the applicants may address. Applicants are also encouraged to consider other topics that are responsive to the objectives of this FOA.

BMT CTN studies may be selected by the Steering Committee from those concepts proposed by the successful applicants, but a decision to fund particular Core Clinical Centers will not commit the BMT CTN to develop concepts proposed by these Centers into clinical protocols.

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

Section II. Award Information

1. Mechanism of Support

This funding opportunity will use the NIH Cooperative Clinical Research (U10) award mechanism(s). In the cooperative agreement mechanism, the Project Director/Principal Investigator (PD/PI) retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the Section VI. 2. Administrative Requirements, "Cooperative Agreement Terms and Conditions of Award." At this time it is not known if this FOA will be reissued.

This FOA uses Just-in-Time information concepts. It also uses non-modular budget formats described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/phs398/phs398.html).

2. Funds Available

In response to this FOA (and the companion FOA for the DCC, RFA-HL-11-028), the NHLBI and the NCI intend to commit up to $45 million and $18.5 million in total costs, respectively, for the six-year program period. Up to 19 new and/or renewal applications are anticipated to be funded through this FOA. The direct cost amount for individual awards should not exceed $110,000 in the first budget period, and should not exceed $115,000 in the remaining budget periods. Future year funds will depend upon annual appropriations and on the performance of the Core Clinical Center and recruitment of subjects. Protocol-related expenses will be awarded to the Core Clinical Centers by the DCC on a per-patient basis during the post-award 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. 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 and the receipt of a sufficient number of meritorious applications.

Facilities and administrative 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)
• For-Profit Organizations (Other than Small Businesses)
• Other(s):
  • Eligible Agencies of the Federal Government
  • Faith-based or Community-based Organizations

Organizations should have academically-oriented programs of hematopoietic stem cell transplantation that perform both allogeneic and autologous transplantation. Only sites in the United States are eligible to apply.

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research as the PD/PI is invited to work with his/her institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH program support.

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 one application in response to this FOA.

Resubmissions. Resubmission applications are not permitted in response to this FOA.

Renewals. Renewal applications are permitted in response to this FOA.

The NHLBI and NCI invite applications from both current and prospective members of the BMT CTN to serve as Core Clinical Centers in the Network. The items under Section IV.6 must be addressed satisfactorily for an applicant to be eligible as a BMT CTN Core Clinical Center.

Section IV. Application and Submission Information

1. Address to Request Application Information

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

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

2. Content and Form of Application Submission

Prepare all applications using the PHS 398 application forms and in accordance with the PHS 398 Application Guide (http://grants.nih.gov/grants/funding/phs398/phs398.html).

Applications must have a D&B Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

The title and number of this funding opportunity must be typed in item (box) 2 only of the face page of the application form and the YES box must be checked.

3. Submission Dates and Times

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

3.A. Receipt, Review and Anticipated Start Dates
Letter of Intent Receipt Date: September 13, 2010
Application Receipt Date: October 13, 2010
Peer Review Date: March 2010
Council Review Date: June 2011
Earliest Anticipated Start Date: July 1, 2011

3.A.1. Letter of Intent

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

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

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

The letter of intent is to be sent by the date listed in Section IV.3.A.

The letter of intent should be sent to:

Director, Office of Scientific Review
Division of Extramural Research Activities
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7214
Bethesda, MD 20892-7924 (Express Mail Zip: 20817)
Telephone: (301) 435-0270
FAX: 301-480-0730
Email: [email protected]

3.B. Sending an Application to the NIH

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

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

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

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

Division of Extramural Research Activities
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7214
Bethesda, MD 20892-7924 (Express Mail Zip: 20817)
Telephone: (301) 435-0270
FAX: 301-480-0730
Email: [email protected]

3.C. Application Processing

Applications must be received on or before the application receipt date described above (Section IV.3.A.). If an application is received after that date, the application may be delayed in the review process or not reviewed. Upon receipt, applications will be evaluated for completeness by the CSR and for responsiveness by the reviewing Institute. Incomplete and/or non-responsive applications will not be reviewed.

The NIH will not accept any application in response to this funding opportunity that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to a funding opportunity, it is to be prepared as a NEW application. That is, the application for the funding opportunity must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application.

Information on the status of an application should be checked by the Principal Investigator in the eRA Commons at: https://commons.era.nih.gov/commons/.

4. Intergovernmental Review

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The Grants Policy Statement can be found at 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

For cooperative agreements, awardees must agree to the "Cooperative Agreement Terms and Conditions of Award" in Section VI.2.A "Award Administration Information."

PHS398 Research Plan Sections

All application instructions outlined in the PHS398 Application Instructions are to be followed, with the following additional requirements:

• Introduction (required for a resubmission application) is limited to 1 page
• Specific Aims is limited to 1 page
• Research Strategy, including tables, graphs, figures, diagrams, and charts is limited to 12 pages See Table of Page Limits.

This FOA is open to all applicants with experience in HSCT research, regardless of whether or not they have previously participated in BMT CTN clinical trials. Core Clinical Center applicants must be at an institution with a program in HSCT in place and demonstrate access to a sufficient number of patients for Network protocols. The Core Clinical Center (or Consortium) should perform at least 35 allogeneic HSCT per year. Applications will be judged on the basis of the research proposed and on the ability to participate in clinical trials, as indicated by the information in the application as a whole. Application to participate in the BMT CTN should not be undertaken lightly, as it entails a significant commitment in terms of time, organizational skills, and administrative ability. Successful applicants will be expected to participate during an in-person Steering Committee meeting within two months of award in the Washington D.C. area.

For this FOA, the Research Strategy Section should contain the following five subsections: (1) Proposed Investigation, (2) Investigator Qualifications and Experience in the Conduct of Clinical Trials, (3) Strengths of the Core Clinical Center or Consortium, (4) Data and Biospecimen Collection, and (5) Collaboration and Intent to Participate. If some of the information requested in subsections 1-5 is contained in other portions of the application (i.e., biosketch or environment), include a statement to point the reviewers to that part of the application package.

Subsection 1: Proposed Investigation. Applicants should provide their view of the status of HSCT research in the U.S. and a statement of general areas for future research by the BMT CTN. Applicants should select one of these areas to propose as a concept for a Phase II or Phase III clinical trial that might be undertaken by the BMT CTN. The concept should address a significant unmet need in HSCT and be the basis for the development of a clinical protocol ready for multicenter implementation. The proposed concept will serve as an indicator of the applicant’s knowledge of, and vision for, HSCT research in the United States, and the applicant’s ability to participate in the development and design of cooperative protocols suitable for the Network.

The proposed concept should not replicate studies already conducted or undertaken by the current BMT CTN program (https://web.emmes.com/study/bmt2/), or by an NCI Cancer Cooperative Group, and should identify an important area of investigation that will advance clinical care. Concepts should detail the hypotheses, specific aim(s), background, rationale and available pilot data, design, and statistical considerations including power and trial size. Applicants should address feasibility considerations for the concept and include a description of obstacles to overcome should the proposed trial be undertaken by the BMT CTN. Concepts should be no more than 6 pages in length and include a projected timeline for completing the study. The program funded by this FOA is of 6-year duration; proposed trials should be expected to complete accrual in 3.5 years or less. Appropriate mechanistic/correlative studies linked to the proposal should be described, although funding for these studies will most likely have to be sought through other mechanisms. Concepts should estimate the number of available patients eligible for the protocol at their institution or consortium, and address the appropriate inclusion of children and minorities as subjects, as well as any ethical issues related to the proposed study. The applicants should indicate if additional NIH resources must be leveraged, and collaborations put in place, to address feasibility. Core Clinical Centers funded by this FOA will have the opportunity to submit the concepts included in their application to the Steering Committee. Future clinical trials initiated by the BMT CTN may be selected from those concepts proposed by the successful applicants, but a decision to fund a particular Core Clinical Center will not commit the BMT CTN to develop the concept proposed by the Center into a clinical protocol.

Subsection 2: Investigator Qualifications and Experience in the Conduct of Clinical Trials. Applicants should provide evidence of productivity and relevant past performance in previous or ongoing clinical trials evaluating hematopoietic stem cell therapies, including those with a cooperative or multicenter design. Applicants should indicate whenever applicable (1) where their participation in a single institution study led to the implementation of a multicenter study; (2) contributions in key areas of protocol development and design, accrual planning and monitoring, patient recruitment, retention and study completion, data collection and analysis; and (3) relevant publications.

Applicants who are current BMT CTN Core Clinical Sites (U01 grant holders) should include a description of their participation and contribution to the Network, including:

• Recruitment targets and percent of target achieved.
• Number of patients enrolled in studies.
• Screening approaches to identify subjects for BMT CTN trials within the applicant s institution (consortium).
• Specific roles of the applicant in BMT CTN trials (principal investigator at site, member of protocol committee).
• Other contributions to Network activities (standing subcommittees, elected roles in Steering Committee, and publications).

Applicants who are not current BMT CTN Core Clinical Sites should include a description of their recent experience and participation in clinical trials, including:

• Recruitment targets and percent of target achieved.
• Number of patients enrolled in these studies.
• Screening approaches to identify subjects for clinical protocols within the applicant’s institution (consortium).
• Specific roles of the applicant (e.g., principal investigator, participation in clinical trial design and development, analysis and dissemination of data).
• Number of centers involved and the proportion of patients enrolled from the applicant’s center in multicenter studies.
• Contributions to cooperative group or multi-site clinical trial activities, as appropriate.

Subsection 3. Strengths of the Core Clinical Center or Consortium. Prospective Core Clinical Centers must have an established research program in HSCT and demonstrated access to a sufficient number of patients to accomplish their portion of the proposed protocols (see required data for Human Subjects Section of this application). The Core Clinical Center or Consortium should perform at least 35 allogeneic HSCTs per year.

A detailed description of the transplant program should be provided. Applicant institutions are expected to have a full range of clinical capabilities and support staff, including a research coordinator, needed to participate in clinical trials evaluating HSCT. Full- and part-time research staff members should be designated in the application. The individual staff training, experience, qualifications and prior involvement in clinical trials, and Investigational New Drug Exemption (IND) or Investigational Device Exemptions (IDE) studies should be described for key personnel listed in the application. Describe unique strengths that may be relevant to the BMT CTN. This might include special administrative experience important for aspects of clinical research (IRB, DSMB, advisory boards for clinical research, etc), or specialized laboratories that might be leveraged for centralized testing of biospecimens from BMT CTN trials. Describe institutional resources and process for patient care and follow-up for transplant patients enrolled on clinical trials. Indicate the clinical trials evaluating HSCT therapies performed at your center during the past five years, the number of these studies completing accrual, and the number of studies currently open at your site.

Consortia (i.e., sites with more than one clinical center) should indicate coordination, communication and management plans between the investigative teams. If a multicenter application has a long-standing, well-documented collaboration and interaction among institutions, this should be clearly indicated in the application. Participation of the consortium in previous clinical trials should be indicated. Any unique strengths of the consortium advantageous to the BMT CTN should be described.

Applicants from institutions that have a Clinical and Translational Science Award (CTSA) funded by the NIH National Center for Research Resources, or similar institutional resources, should identify the specific resources that would be available to support the proposed Core Clinical Center or Consortium, commenting on aspects that will enhance administrative, programmatic and scientific contributions of their site to the BMT CTN. The applicant should describe the CTSA or other institutional resources and the proposed interactions. A letter of agreement from the CTSA Principal Investigator, or other similar institutional resource, should be included with the application.

Subsection 4: Data and Biospecimen Collection. Electronic data systems developed by the DCC will be used to collect and analyze data and to track biospecimens from subjects enrolled on BMT CTN studies. Biospecimens collected from subjects enrolled on BMT CTN studies may require short-term storage at the center, but later will be shipped to a central laboratory or a central repository according to protocol. The Core Clinical Center must ensure complete, accurate, and timely submission of biospecimens and data to the DCC. Applicants should describe the training processes at their center to ensure that biospecimens are collected as required by the protocol, appropriately processed and stored, and linked to the clinical data.

Subsection 5: Collaboration and Intent to Participate. Applicants must clearly express their intent to participate in a cooperative manner in the BMT CTN as outlined in this FOA. Letters of Departmental support should be included. Core Clinical Centers are expected to place high priority on BMT CTN clinical trials over studies supported by other sources and should provide a strategy for allocating patients to BMT CTN trials versus other trials. Applicants that are not currently BMT CTN Core Clinical Centers should indicate whether they plan to participate in the BMT CTN trials that are still currently accruing patients; full protocols can be found on the BMT CTN website: https://web.emmes.com/study/bmt2/. While all Core Clinical Centers are encouraged to contribute patients to these trials, this is not a requirement of this FOA. For example, competing protocols or lack of the specific patient population or expertise to conduct the trial may preclude participation. Applicants planning to participate in ongoing BMT CTN trials should describe strategies for allocating patients between these studies and competing studies, and proposed screening and recruitment methods, including the potential number of enrollees from their site.

Similarly, for those proposing a consortium, please provide the number of patients transplanted each year in the consortium for years 2007, 2008, and 2009. Separate tables for the applicant’s institution and for the consortium should be used.

To accomplish the goals of the BMT CTN, each Core Clinical Center is expected to enroll a significant number of transplant patients. A Core Clinical Center or Consortium should perform at least 35 allogeneic transplants per year. Please use the following two tables to provide the total number of patients, and patient characteristics, transplanted in the applicant s institution for years 2007, 2008 and 2009.

Table 1: Graft Sources used for HSCT, 2009
	Related	Mis-Matched Related	Unrelated	Autologous
Bone Marrow
PBSC
Cord Blood (single or double)
Total

Table 2: Number of Patients Receiving HSCTs, annually
	2007	2008	2009
< 18 yrs old
= 18 yrs old
to treat Malignant Diseases
to treat Non-Malignant Diseases
Randomized in Phase III Trials
Enrolled in Multicenter Phase II Trials
Enrolled in Phase I/II HSCT Trials with Novel Cell Therapies

PROTECTION OF HUMAN SUBJECTS.

This section is not included in the 12-page limit of the Research Strategy Section. The application should address: (1) HSCT activity at the applicant’s institution, (2) Willingness to adhere to data and safety monitoring plans of the BMT CTN, (3) Potential Benefits of the Proposed Concept to Human Subjects and Others, and (4) Planned Enrollment Table: completed for subjects from your center/consortium for the trial represented by the concept proposed in the application.

The application should propose a plan that will protect human subjects enrolled in BMT CTN trials by ensuring compliance with all NIH and Federal Regulations. The plan should ensure that the clinical core center participating in the BMT CTN fully complies with all NIH and Federal regulatory requirements including IRB approvals, informed consent and other required regulatory approval documents. Describe your team’s experience in sponsoring INDs or IDEs and managing documents for studies regulated by the Food and Drug Administration. Include previous experience in reporting adverse events and experience in managing human subjects protection issues. Include approaches to protecting subject privacy and confidentiality for participants. .

Applicants should include a statement that they agree to adhere to the data and safety monitoring plans of the BMT CTN and per NHLBI and NCI policies. BMT CTN clinical trials are monitored by an NHLBI-appointed DSMB.

Budget

This FOA uses non-modular budget formats described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/phs398/phs398.html).

For purposes of the grant application, Core Clinical Centers are asked to submit a base core budget. For the first budget period, the base core budget may not exceed $110,000 direct costs; subsequent budget periods should not exceed $115,000 direct costs per year. Base core budgets should include:

• Principal Investigator (PI) and other key Physician Investigators: 1.2 person-months required.
• Additional members of the Investigative Team, including nurse coordinator, research nurse, data entry personnel, and administrative support, as needed.
• Travel to attend an average of three Steering Committee meetings per year (two steering Committee meetings to be held in Washington, D.C., the third is likely to be held in conjunction with the annual CIBMTR/ASBMT meeting).

Total funding of the Core Clinical Center depends on the base core budget (as indicated above) and the reimbursements for subjects enrolled in BMT CTN studies. During the grant cycle covered by this RFA, patient care costs will be awarded to the DCC. The DCC is responsible for distributing patient care costs to the sites as a per-patient reimbursement. The Steering Committee will approve the actual amount of the per-patient reimbursement for each protocol before recruitment begins. Awards will be subject to administrative review annually, and the base core budget adjusted accordingly.

Protocol Budgets (should not be submitted): Core Clinical Centers (and other collaborating transplant centers) will be reimbursed for the conduct of each specific protocol, at a level proportionate to their participation on each study; these costs are part of a protocol’s budget and should not be submitted at this time.

Protocol budgets are developed by the BMT CTN investigators and the DCC. Examples of expenses associated with the conduct of a specific protocol that are considered part of the per-patient reimbursement include:

• Screening patients to determine study eligibility.
• Imaging studies that are not performed as part of routine clinical care.
• Laboratory tests that are not part of routine clinical care.
• Clinic visits that are not part of routine clinical care.
• Expenses related to the use of a research pharmacy, if a pharmacological study is proposed.
• Expenses related to collecting biospecimens if required by protocol

Tests and clinic visits performed as part of routine clinical care can be incorporated into a research protocol, but their costs will be billed to third-party payers.

The patient care funds for new BMT CTN clinical trials, including funds to cover the DCC’s administrative costs associated with protocols, will be part of the DCC award. The DCC will be responsible for reimbursing the Clinical Centers in proportion to recruitment. In the event that a central laboratory is required to analyze specimens, the Clinical Centers will be responsible for obtaining the sample(s); the cost of obtaining the sample and shipping the sample to a central laboratory will be part of the Clinical Center's per-patient reimbursement.

Core Clinical Centers planning to participate on ongoing BMT CTN trials (see https://web.emmes.com/study/bmt2/) will have to accept protocol budgets and the per-patient reimbursement previously set by the current BMT CTN program.

Continuation and level of individual base core budget will be based on actual recruitment and performance of the Core Clinical Center in BMT CTN activities. NHLBI and NCI may make adjustments to a center’s core budget based on accrual and the performance of that Core Clinical Center, using input from the Executive Committee and/or External Advisory Committee.

The overall provision of money for the BMT CTN is subject to availability of NHLBI and NCI funding.

Appendix Materials

All paper PHS 398 applications submitted must provide appendix material on CDs only. Include five identical CDs in the same package with the application. See http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-031.html.

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

Resource Sharing Plan(s)

NIH considers the sharing of unique research resources developed through NIH-sponsored research an important means to enhance the value of, and advance 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 should be explained in Resource Sharing section of the application. See http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm.

(a) Data Sharing Plan: Regardless of the amount requested, investigators 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 where 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 (such as 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, NIH Guide NOT-OD-07-088, and http://grants.nih.gov/grants/gwas/.

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 and responsive to the FOA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the National Heart, Lung, and Blood Institute 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 National Heart, Lung, and Blood Advisory Board or the National Cancer Advisory Board.

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? What is the appropriateness of the proposed area of investigation for implementation in the BMT CTN in terms of the quality of proposed hypotheses/aims and need for a network to accomplish the proposed protocol? What are the relevance and importance of the research proposed to address critical gap areas and challenge existing paradigms in blood and marrow transplantation for either malignant or non-malignant hematological diseases? What is the adequacy of preliminary results for justification of the proposed end points and sample size?

Investigator(s). Are the PD/PIs, collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, 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? What are the expertise, training, and experience of the investigators and staff in HSCT clinical trials; evidence of understanding of randomized, multicenter clinical trials; relevant administrative, clinical and academic qualifications of the Principal Investigator; evidence of scientific leadership in HSCT? What are the qualifications of the clinical research staff; adequacy of time they plan to devote to the BMT CTN program at their site and/or consortium; adequacy of institutional resources and processes committed to Phase II and III HSCT clinical trials, and for long-term follow-up; experience with Phase I/II clinical trials in HSCT using novel cellular therapies?

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?

What is the quality of applicant institution’s history of collaborative research and depth of commitment to HSCT research? What is the indication of willingness to randomize patients and expected commitment to enroll subjects on BMT CTN trials?

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? What is the experience in submitting clinical data electronically, including adverse events? What is the quality of the experiences in collecting and processing biospecimens from subjects enrolled on clinical studies? What is the quality of training program for staff in these two areas? What is the adequacy of quality improvement plan to address problems identified with data collection/submission and biospecimen collection, processing, storage and submission to central laboratories and repositories? What is the experience in submitting clinical data electronically, including adverse events?

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.

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.

Human Subjects and Access to Patients: What is the potential availability of at least 35 allogeneic transplants at the applicant’s institution per year (presented in Tables 1-4); the number of patients that will be eligible for Network protocols; plan for recruitment and retention of subjects enrolled on BMT CTN protocols; plans to ensure appropriate representation by ethnic group, age, gender; description of competing protocols, and the strategy for allocating patients between them; and plans for adherence to the data and safety monitoring plan?

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. Not applicable for this FOA.

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. Not applicable for this FOA.

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. Foreign are not allowed for this FOA.

Select Agents 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

The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by peer review.
• Availability of funds .
• Relevance of the proposed project to program priorities.
• The ultimate selection of the Core Clinical Centers is a programmatic decision that will be based on the needs of the Network at the time of funding.

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 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 Also Section IV.5. Funding Restrictions.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the No A. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part4.htm) and Part II Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part9.htm).

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

2.A. Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when state and local governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

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

2. A.1. Principal Investigator Rights and Responsibilities

The BMT CTN will include Core Clinical Centers with expertise in HSCT, a DCC, and staff from the NHLBI and the NCI. All Core Clinical Centers will be required to participate in a cooperative and interactive manner with one another and with the DCC. All awardees also agree to work collaboratively with the current Centers and DCC in the transition of ongoing protocols and data coordination. Awardees agree to the governance of the Network through a Steering Committee, and agree to work with the DCC, NHLBI, and NCI Staff to achieve the Network s objectives. In-person meetings of the Steering Committee will ordinarily be held in the metropolitan Washington, D.C. area, up to three times a year, and by telephone conference call monthly. Steering Committee members must make every effort to attend Steering Committee meetings and participate in conference calls. The input of each Principal Investigator is fundamental to the progress of the BMT CTN. Should a Principal Investigator find it impossible to attend a Steering Committee meeting or conference call, he/she is required to notify the Program Officer and/or Steering Committee Chair of the expected absence, as well as to ensure the attendance of their designated alternate.

The Steering Committee and the DCC will be responsible for ensuring that there are well-documented policies, procedures, and bylaws to guide all aspects of Network activities and operations.

The Principal Investigators are responsible for:

• Accepting the coordinating role of the DCC and the participatory and cooperative nature of the Network process.
• Identifying priority areas of research.
• Developing and implementing network clinical trials.
• Projecting patient enrollment for each protocol during a specified timeframe.
• Collecting and submitting protocol-specific data to the DCC accurately and in a timely manner.
• Participating in data analysis and interpretation.
• Interpreting data and disseminating results through publications and presentations in a timely manner.
• Complying with the BMT CTN s Manuals of Operations and all federally mandated regulatory requirements.

Core Clinical Centers are responsible for maintaining a high level of performance in the Network. Performance will be evaluated using the following criteria:

• Participation in BMT CTN clinical trials and meeting projected enrollment targets.
• Participation in research design and clinical trial protocol development, including serving as Chair of a clinical trial protocol or as a member of a protocol study team; participation in the scientific and administrative committees needed to support the BMT CTN’s research objectives.
• Compliance with OHRP, FDA, NIH, and applicable DHHS regulations concerning protection of human subjects.
• Timely reporting of all serious and/or unexpected adverse events and all relevant medical information.
• Collection, processing, storage, and shipping of biospecimens per protocol specifications. Providing biospecimen-associated clinical data per protocol specifications.
• Serving as a resource for conduct of protocol-specified laboratory assays and ancillary studies, mechanistic, and biomarker studies. These projects may be supported by the BMT CTN, when approved by NHLBI and NCI, or by independent funding. Some of these projects may be conducted by the central laboratory which will be a subcontract from the DCC.
• Develop presentations and publications following the BMT CTN Publication procedures.
• Compliance with the NIH Conflict of Interest Policy to ensure that there is no reasonable expectation that the design, conduct, or reporting of research conducted by the BMT CTN will be affected by conflicts of interest, financial or otherwise. BMT CTN Core Clinical Sites will be required to accept and implement policies approved by the Steering Committee to the extent consistent with grant regulations.

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

2. A.2. NIH Responsibilities

The NHLBI and NCI will coordinate and facilitate various activities of the BMT CTN. For awards made with cooperative agreements to the BMT CTN, staff members from the NHLBI and the NCI will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below. An NHLBI Project Scientist will be the NIH liaison for all facets of the scientific interaction with awardees and will provide oversight and advice to the awardees on specific scientific and/or analytic issues in addition to programmatic issues. Other NHLBI and NCI program staff members will be substantially involved with the BMT CTN and provide additional oversight and advice.

The NHLBI and the NCI will each appoint one Project Scientist to serve as voting members on the Steering Committee. NHLBI and NCI Project Scientists may serve on protocol teams and other BMT CTN committees, when appropriate. NHLBI and NCI Project Scientists may work with the Network on issues coming before the Steering Committee as appropriate, e.g., recruitment, intervention, follow-up, quality control, adherence to protocol, assessment of problems affecting the study and possible changes in protocol, interim data and safety monitoring, preparation of publications, and development of solutions to major problems such as insufficient participant enrollment.

The NHLBI/NCI reserves the right to terminate or curtail the study (or an individual award) in the event of (1) failure to develop or implement a mutually agreeable collaborative protocol; (2) substantial shortfall in participant recruitment, follow-up, data reporting, or quality control; (3) major breach of the protocol or substantive changes in the agreed-upon protocol with which NHLBI cannot concur; (4) attaining of a major study endpoint before schedule with persuasive statistical significance; or (5) human subject safety or ethical issues that may dictate a premature termination. The NHLBI policy describing the monitoring of adequacy of accrual of participants to NHLBI supported human subjects research can be found at http://www.nhlbi.nih.gov/funding/policies/accrual_guidelines.htm.

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

2.A.3. Collaborative Responsibilities

1. Coordination and Internal Oversight of Network Activities. Awardees agree to the governance of the study through a Steering Committee. Steering Committee voting membership shall consist of the PI (or designated alternate) for each of the Core Clinical Centers, the PI of the DCC, the NHLBI Project Scientist, the NCI Project Scientist, and the Chairperson. Each full member will have one vote. Members of the Steering Committee will be required to accept and implement all policies approved by the Steering Committee. The Executive Committee will consist of the Chair of the Steering Committee, the PI of the DCC, and the NHLBI and NCI Project Scientists. The Executive Committee will plan BMT CTN activities, oversee its functions, and convene by conference call on a monthly basis, or more frequently if needed. The Executive Committee will report to the Steering Committee on a regular basis.

The Steering Committee will develop and ensure compliance with BMT CTN policies and procedures, identify and prioritize topics for investigation, evaluate protocols proposed by the Core Clinical Centers, develop consensus protocols for submission to the NHLBI PRC, and ensure that studies are properly conducted, monitored, and that study results are reported in the scientific literature and disseminated in a timely manner. All major scientific decisions will be determined by majority vote of the Steering Committee. The Steering Committee has final responsibility for approving the protocol before review by the PRC or DSMB. Technical Committees (i.e., Pharmacy, Publication) and subcommittees of the Steering Committee will be established as necessary.

2. Protocol Submission and Approval. A protocol is the detailed written plan of a clinical experiment. Formal protocol review, PRC and DSMB reviews, NHLBI and NCI approval, FDA approval of IND or IDE (as appropriate), and IRB approvals are required prior to activating a clinical trial. An independent PRC will provide external review for each BMT CTN protocol. Study investigators should not communicate with PRC members regarding study issues, except as authorized by the PRC's Executive Secretary. The PRC will be appointed by and be advisory to the NHLBI. It will consist of a chairperson and scientists with expertise in hematopoietic stem cell transplantation, clinical research, clinical trial design, biostatistics, outcome measures, and a patient advocate. Other expertise will be appointed, as needed. The exact number and duration of protocols supported in the six-year program will depend on the nature and extent of the investigations proposed by the Steering Committee. The PRC will evaluate protocols proposed by the Steering Committee based on the importance of the question to be addressed, scientific merit of the experimental design and approach, feasibility, appropriateness for the BMT CTN and consistency with NHLBI/NCI missions and policies. The PRC will provide a written critique of each proposal and a final recommendation to the NHLBI. All study protocols must adhere to current NIH policies for human subjects research. All protocols must be approved by the Director, NHLBI.

The NHLBI Director appoints an independent DSMB advisory to the NHLBI that provides overall monitoring of interim data and safety issues. Meetings of the DSMB are ordinarily held in the metropolitan Washington, D.C. area. An Executive Secretary to the Board, other than the NHLBI Program Official, will be appointed by NHLBI to support the DSMB. Because the DSMB serves as an independent advisory group, study investigators should not communicate with the DSMB members regarding study issues, except as authorized by the DSMB’s Executive Secretary. The DSMB will consist of a chairperson and scientists with expertise in hematopoietic stem cell transplantation, bioethics, clinical research, clinical trial design, biostatistics, and other areas of expertise as needed. The DSMB will provide a written critique of each protocol and a final recommendation to the NHLBI. All study protocols must be reviewed and recommended by the DSMB and approved by the NHLBI before IRB submissions occur. The DSMB is also responsible for monitoring the clinical trials while they are being conducted with particular attention to safety issues.

3. Network Compliance with Federally Mandated Regulatory Requirements. The Network must comply with all FDA regulatory requirements for studies involving investigational devices and agents and with all NIH policies applying to the conduct of research involving human subjects; and be consistent with Office of Human Research Protections guidelines http://www.hhs.gov/ohrp/. These regulations include but are not limited to CFR 21 Parts 50, 56 and 312 and CFR 45 Part 46. Awardees are required to follow established Network procedures for complying with the federally mandated regulations. Each awardee must:

a. Have a current approved multiple project assurance number on file with OHRP or obtain a single project assurance.

b. Have IRB approval for each protocol, amendment, and informed consent document prior to patient entry and at least annually thereafter, as appropriate for the degree of risk of the protocol, as stipulated by 45 CFR 46..

c. Provide the DCC with a current FDA Form 1572 and curriculum vitae for study investigators.

d. Provide evidence that each patient (or legal representative) has given written informed consent prior to entry on study..

e. Assure timely reporting of all serious and unexpected toxicities to the DCC including all relevant medical information; ensure that any additional information requested is reported in a timely manner; the DCC will report these information to NHLBI, NCI and other parties as appropriate.

f. Participate during an on-site audit program according to BMT CTN procedures..

g. Comply with all FDA monitoring and reporting requirements for investigational agents and devices..

4. Reporting Requirements. Reporting requirements will be in agreement with Network procedures, NHLBI and NCI policies, and FDA regulations. Interim reports of each activated and ongoing study shall appear in the minutes of each Network meeting and shall include specific data on patient accrual as well as, when appropriate, detailed reports of treatment-associated morbidity. Monthly accrual and screening information must be provided by the DCC to the NHLBI and NCI Project Scientists for all active studies. A system for providing such information in a timely manner should be in place. Awardees must provide screening data to the DCC in accordance with Network procedures. Annual scientific progress reports will be submitted by each awardee to the NHLBI and NCI.

Awardee(s) will follow Network procedures for data collection and management, as developed by the Steering Committee and the DCC; Network procedures for quality control and monitoring safety of patients; permit concurrent or retrospective review of source documents to assure compliance with the protocols, consistency of evaluation of graft versus host disease, infectious disease reporting, determination of relapse versus graft failure, and other key endpoints.

2.A.4. Dispute Resolution Process

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

3. Reporting

Awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.

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, peer review, and financial or grants management issues:

1. Scientific/Research Contacts:

NHLBI
Nancy DiFronzo, Ph.D.
BMT CTN Program Director
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
National Institutes of Health 6701 Rockledge Drive
Bethesda, MD 20892
Telephone: 301-435-0065
FAX: 301-480-1046
Email: [email protected]

NCI

Roy S. Wu, Ph.D.
Chief, Clinical Grants and Contracts Branch
Cancer Therapy Evaluation Program
Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Boulevard EPN 7009
Bethesda, Maryland 20892
Rockville, Maryland (FEDEX) 20852
Telephone: 301-496-8866
FAX: 301-480-4663
E-mail: [email protected]

2. Peer Review Contacts:

Director, Office of Scientific Review
National Heart, Lung, and Blood Institute
National Institutes of Health
6701 Rockledge Drive, Room 7214
Bethesda, MD 20892-7924
Bethesda, MD 20817 (express/courier service)
Telephone: 301-435-0270
FAX: 301-480-0730
Email: [email protected]

3. Financial or Grants Management Contacts:

John Diggs
Grants Management Specialist
Division of Extramural Research Activities
National Heart, Lung, and Blood Institute
National Institutes of Health
6701 Rockledge Drive, MSC 7926
Bethesda, MD 20892-7926
Telephone: 301-402-4267
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 (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Data and Safety Monitoring Plan:
Data and safety monitoring is required for all types of clinical trials, including physiologic toxicity and dose-finding studies (Phase I); efficacy studies (Phase II); efficacy, effectiveness and comparative trials (Phase III). Monitoring should be commensurate with risk. The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risks to the participants (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

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

Investigators should seek guidance from their institutions, on issues related to institutional policies and local IRB rules, as well as local, state and federal laws and regulations, including the Privacy Rule.

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/.

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.

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 http://grants.nih.gov/grants/policy/nihgps_2003/index.htm). All investigators submitting an NIH application or contract proposal, beginning with the October 1, 2004, receipt date, 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.

Inclusion of Women And Minorities in Clinical Research:
It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: (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 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-033.html) investigators must submit or have submitted for them their final, peer-reviewed manuscripts that arise from NIH funds and are accepted for publication as of April 7, 2008, to PubMed Central (http://www.pubmedcentral.nih.gov/), to be made publicly available no later than 12 months after publication. As of May 27, 2008, investigators must include the PubMed Central reference number when citing an article in NIH applications, proposals, and progress reports that fall under the policy, and was authored or co-authored by the investigator or arose from the investigator’s NIH award. 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 (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information," the "Privacy Rule," on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. For publications listed in the appendix and/or Progress report, internet addresses (URLs) must be used for publicly accessible online journal articles. Unless otherwise specified in this solicitation, Internet addresses (URLs) should not be used to provide any other information necessary for the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site.

Healthy People 2010:
The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This 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 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 NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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