Department of Health and Human Services
Part 1. Overview Information

 

Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Heart, Lung, and Blood Institute (NHLBI)
National Cancer Institute (NCI)

Funding Opportunity Title

Limited Competition: Data Coordinating Center for the Blood and Marrow Transplant Clinical Trials Network (U24)

Activity Code

U24 Resource-Related Research Projects – Cooperative Agreements

Announcement Type

Reissue of RFA-HL-11-028

Related Notices
Funding Opportunity Announcement (FOA) Number

RFA-HL-17-019

Companion Funding Opportunity

RFA-HL-17-018, UG1 Clinical Research Cooperative Agreements - Single Project

Catalog of Federal Domestic Assistance (CFDA) Number(s)

93.839, 93.395

Funding Opportunity Purpose

This Funding Opportunity Announcement (FOA) announces a limited competition opportunity to support the Data Coordinating Center (DCC) for the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). Only the current awardees of the BMT CTN DCC are eligible to apply.

This collaborative multi-center clinical program promotes the efficient comparison of novel treatment approaches and management strategies for potential benefit of children and adults undergoing hematopoietic stem cell transplantation (HCT), either alone or in combination with novel cell-based therapies. Collaboration among the Core Clinical Centers, the DCC, the NHLBI, the NCI, and other stakeholders will permit multi-center evaluation of new HCT approaches with attention to treatment of malignant and non-malignant blood diseases. During this funding cycle, the BMT CTN will have the flexibility to conduct early phase multi-center HCT trials incorporating novel cell therapies, and to expand the use of promising products from highly selected to more heterogeneous patient populations. The overall goals of the BMT CTN are to improve HCT outcomes, evaluate promising novel cell therapies, and rapidly disseminate study results to improve the scientific basis for the treatment of patients in need of HCT therapy. The awardee to this FOA will provide the relevant medical and scientific expertise, as well as overall coordination, data management, regulatory, statistical/analytical, and operational support for the program.

There is a separate Funding Opportunity Announcement (FOA) for BMT Core Clinical Centers/Consortium (RFA-HL-17-018).

Key Dates

 

Posted Date

August 19, 2016

Open Date (Earliest Submission Date)

October 10, 2016

Letter of Intent Due Date(s)

October 10, 2016

Application Due Date(s)

November 10, 2016, by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on this date.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

AIDS Application Due Date(s)

Not Applicable

Scientific Merit Review

March 2017

Advisory Council Review

May 2017

Earliest Start Date

July 2017

Expiration Date

November 11, 2016

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the Research Instructions for the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.


Table of Contents

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information


Part 2. Full Text of Announcement
Section I. Funding Opportunity Description
Purpose

This Funding Opportunity Announcement (FOA) announces a limited competition opportunity to support the Data Coordinating Center (DCC) for the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). Only the current awardee of the BMT CTN DCC is eligible to apply. The awardee to this FOA will provide the relevant medical and scientific expertise, as well as overall coordination, data management, regulatory, statistical/analytical, and operational support for the program.

There is a separate Funding Opportunity Announcement (FOA) for BMT Core Clinical Centers/Consortium (RFA-HL-17-018).

Background and Objectives

In the US, approximately 21,000 patients receive HCT annually for rare and diverse hematological indications. Most HCT centers conduct relatively small numbers of transplants (70% of centers transplant fewer than 50 patients), with less than half of the patients receiving cells from allogeneic donors. And although toxicity, unsatisfactory immune reconstitution, and even death may occur following HCT, transplant is the only curative option for many rare acquired and congenital blood diseases (e.g., severe aplastic anemia, sickle cell disease, thalassemia, immune deficiencies and bone marrow failure diseases) and hematological malignancies. Incorporation of new drugs, novel cell therapies or genetically-modified cells into HCT therapy may make transplant safer and more effective. However, not every patient eligible for HCT may benefit from this procedure because of a lack of an available matched donor. This is particularly true for minorities who are less likely than Caucasians to have a non-family member (allogeneic unrelated donor) who can provide available matched hematopoietic stem cells for transplant. While cord blood or haploidentical transplants may overcome the limitation of donor availability, HCT approaches using these donor sources require optimization to prevent graft failure, minimize graft versus host disease (GVHD), and reduce toxicity. Thus rare diseases, small patient populations in need of HCT, rapidly evolving HCT approaches, and the need to engage many centers to obtain sufficient patient numbers make HCT trials challenging. A clinical trials network provides a critical mass of investigators, increases patient availability and opportunity, and provides centralized and efficient approaches to conduct well-designed and well-coordinated trials.

The NHLBI and the NCI have sponsored the BMT CTN since 2001. This Network has effectively addressed key issues for HCT, including donor availability, GVHD, post-transplant infection, disease control, organ and regimen-related toxicity, cost-effectiveness, and quality of life through the implementation of 37 trials, of which approximately half were Phase II and half Phase III. Many of these trials were guided by the scientific community input obtained through the Blood and Marrow Transplant Clinical Trials Network State of the Science Symposia conducted in 2007 and 2014. To advance HCT therapy, BMT CTN has collaborated with other networks and groups, including the NCI's cancer cooperative groups (currently the NCI Clinical Trials Network, or NCTN), NCI's AIDS Malignancy Consortium, the Canadian Blood and Marrow Transplant Group, the National Institute of Allergy and Infectious Diseases, the National Institute on Minority Health and Health Disparities, the NIH Office of Rare Diseases Research, and NHLBI's Sickle Cell Disease Clinical Research Network. In addition, the BMT CTN has implemented trials funded by NIH grants awarded to non-BMT CTN investigator teams as well as pharmaceutical companies. There are six to eight clinical studies active at all times. The Network's past and ongoing activities can be found at https://web.emmes.com/study/bmt2/

During this funding cycle, the BMT CTN will direct more efforts towards the use of HCT and novel cell/gene therapies and to refining HCT approaches for non-malignant blood disorders. In particular, clinical studies that advance HCT approaches for non-malignant blood diseases and bone marrow failure syndromes where toxicity must be minimized will be considered key priorities. Trials evaluating ex vivo manipulated or genetically-modified cells in non-malignant and malignant blood diseases will be encouraged. Trials evaluating new approaches for stem cell mobilization, or that incorporate novel cell products to improve HCT safety and efficacy, reduce regimen-related toxicity and GVHD, and/or enhance immune function, will also be considered for implementation.

Network funds will be available to support six to eight clinical trials to address the most important HCT problems for non-malignant blood diseases and hematological malignancies. The BMT CTN will be transitioned from a classic clinical trials network model into a flexible platform upon which studies funded by a variety of sources can be conducted. The Network may also be leveraged to co-support trials addressing some broader clinical priorities, such as mitigating risks related to transfusion needs and thrombotic complications during HCT. The BMT CTN has already demonstrated the ability to forge public-private partnerships. It is expected that additional trials and ancillary studies will be conducted as collaborative studies funded through other means such as investigator-initiated R01s, industry, or relevant clinical trial groups. Trials comparing HCT with chemotherapy or evaluating maintenance therapy to control disease progression or relapse will be conducted in collaboration with the NCTN, usually with NCTN leading the trial.

Protocols for ongoing BMT CTN clinical trials are listed on https://web.emmes.com/study/bmt2/. All new protocol topic areas supported by this FOA and its companion FOA will be decided cooperatively by the BMT CTN Steering Committee, comprised of each Core Clinical Center/Consortium PD/PI, the PD/PI of the DCC, and NHLBI and NCI staff. Two NHLBI-appointed Data Safety Monitoring Boards (DSMBs) will review all protocols before initiation and also advise NHLBI on research design issues, data quality and analysis, and ethical and human subjects protection matters.

The DCC will work with the NHLBI, the NCI, and the Core Clinical Center awardees to improve patient outcomes following HCT through clinical trials and other clinical studies for patients with malignant and non-malignant blood diseases. In this funding cycle and as compared to the previous phases of the program, BMT CTN is expected to direct more efforts towards the use of HCT and novel cell/gene therapies and refining HCT approaches for non-malignant blood disorders. In particular, clinical studies that advance HCT approaches for non-malignant blood diseases and bone marrow failure syndromes where toxicity must be minimized will be considered key priorities. Trials evaluating ex vivo manipulated or genetically-modified cells in non-malignant and malignant blood diseases will be encouraged. Trials evaluating new approaches for stem cell mobilization, or that incorporate novel cell products to improve HCT safety and efficacy, reduce regimen-related toxicity and GVHD, and/or enhance immune function, will also be considered for implementation.

This FOA will support a DCC, while a companion FOA will support up to 18 Core Clinical Centers that may be single sites or a consortium of multiple sites (RFA-HL-17-018). It is anticipated that up to eight BMT CTN-led studies will be conducted depending on their complexities. This FOA seeks a comprehensive plan from the current DCC of the BMT CTN that addresses the overall project coordination, administration, data management, statistical support, and regulatory support that are necessary to successfully support the next phase of the BMT CTN with attention to the following goals:

1) Provide medical and scientific leadership to enhance the overall effectiveness of the BMT CTN.

2) Provide a plan for the BMT CTN to identify and, when appropriate, launch HCT trials in non-malignant diseases and trials using adoptive cell therapy or genetically-modified cells to improve transplant outcomes or cure blood diseases.

3) Provide overall management of scientific activities around study development, trial launch, data analysis and results dissemination, including completing ongoing trials.

4) Provide all administrative activities for the BMT CTN.

5) Provide all logistical and other support services for the BMT CTN.

Organization and Governance

Data Coordinating Center (DCC)

The DCC is responsible for the overall coordination and administration of the BMT CTN program; maintaining and updating the Manual of Operating Procedures; protocol finalization and prioritization, accrual plans and advertising materials for each BMT CTN trial; facilitating safety monitoring of Network trials; regulatory support; facilitating trials in rare hematological diseases and trials using novel cell therapies; tracking and compilation of data in secure data management systems, quality control, and data analyses; preparing minutes and reports for Network committees/ subcommittees, and the NHLBI; identifying, qualifying and subcontracting with Affiliate transplant centers and other collaborators for BMT CTN clinical trials; reimbursing (per-patient) participating centers; subcontracting with a central laboratory responsible for the long-term storage, retrieval, and shipment of biospecimens; subcontracting with central laboratories as well as pharmaceutical companies for specific drugs and reagents; statistical support, study design, and data analyses; preparing data and safety reports for the DSMBs; coordinating manuscript and presentation development; and coordinating meetings and activities of the DSMBs, the BMT CTN Steering Committee, the External Advisory Committee, and other BMT CTN committees and subcommittees. 

Core Clinical Centers

Core Clinical Centers/Consortia are supported by a separate award, described in detail in RFA-HL-17-018. the Core Clinical Centers/Consortia are responsible for conducting HCT clinical trial protocols consistent with the mission of the BMT CTN. BMT CTN investigators are responsible for identifying, recruiting and retaining study subjects; entering data promptly and accurately into a web-based data collection system provided by the DCC; and contributing to manuscripts and otherwise disseminating research findings in a timely manner. Protocols will be submitted as part of applications to RFA-HL-17-018. In conjunction with the DCC and Steering Committee (SC), Core Clinical Centers will be responsible for finalizing and prioritizing these protocols, developing common definitions and standardization across protocols, and analyzing and interpreting research results. Core Clinical Centers will also participate intellectually in all aspects of the Network governance, including developing Network procedures and subcommittees, finalizing clinical trial protocols and costs, developing a collaborative IRB process, and writing template informed consents. The PD/PI is directly responsible for ensuring that all aspects of BMT CTN protocols conducted at their Core Clinical Center/Consortium are being followed. The PD/PI will be expected to propose and conduct sub-studies and participate fully in Network committees. The PD/PI will be expected to develop regular communication with investigators and clinical coordinators from his/her Core/Consortium to identify and address enrollment, screening, adherence to protocols, and other Network issues. 

The Core Clinical Centers will also be responsible for the planning and collection of high-quality biospecimens that will permit the longitudinal molecular analysis of disease pathogenesis and recovery, as well as disease stratification and mechanistic studies.  These samples will be available to the wider scientific community for mechanistic work conducted under other funding mechanisms.  Samples will be stored at a central laboratory repository at the DCC or at a subcontractor to the DCC.

NHLBI & NCI

NHLBI and NCI staff are responsible for organizing and providing overall support for the BMT CTN. NHLBI Program staff and Office of Grants Management staff are responsible for the overall management of the grants for the Network. In addition to regular grant stewardship, the NHLBI and the NCI Project Scientists will be involved substantially with the awardees as a partner, consistent with the Cooperative Agreement mechanism.

Steering Committee (SC)

The SC will provide overall scientific governance for the BMT CTN and will be comprised of each Core Clinical Center/Consortium PD/PI, the PD/PI of the DCC, and NHLBI and NCI staff. A subcommittee from the SC nominates the Chair, but NHLBI reserves the right to approve the nomination and may otherwise appoint a Chair for the SC. The Chair rotates every two years. The SC formulates and implements all policy decisions related to the work of the BMT CTN and establishes its scientific agenda. 

Protocols conducted during the project period may be one of those proposed by a funded Core Clinical Center PD/PI in an application to this FOA or may be a modified or combined version of one of these protocols.  The SC will prioritize and select the protocol(s) to be conducted during the funding period from among those submitted in response to this FOA; the decision to fund a particular Core Clinical Center will not commit the BMT CTN to develop that Center's proposed protocol.  All Core Clinical Centers are expected to participate in most of the protocols selected by the SC for the project period. The SC will appoint Protocol Teams, set timelines for protocol development and trial implementation, and ratify changes to the overall BMT CTN Manual of Procedures including updating to include procedures and guidelines for collaborative trials. The SC meets in-person up to three times annually and by teleconference monthly between the in-person meetings to monitor the progress of the Network and consider special issues that arise. Administrative support for the SC will be provided by the DCC.

Executive Committee (EC)

The EC and the DCC provide the day-to-day scientific management of the Network.  The EC, a subset of the SC, will be comprised of the SC Chair, the immediate past Chair, the rising Chair, PD/PI(s) of the DCC, and the NHLBI and NCI Project Scientists. The EC sets the agenda for the SC meetings and calls, and makes the necessary day to day decisions between SC meetings.

External Advisory Committee (EAC)

An independent External Advisory Committee, appointed by the NIH and funded through the DCC, periodically reviews the activities of the BMT CTN and provides input on the direction and progress of the program. The BMT CTN will have an opportunity to provide input on the expertise and responsibilities of the potential Board members.

Data and Safety Monitoring Board (DSMB)

Two NHLBI-appointed DSMBs monitor patient safety and review the performance of each study. As a part of their monitoring responsibility, the DSMBs submit recommendations to the NHLBI regarding the conduct and continuation of each clinical study. 

Single Institutional Review Board of Record (sIRB)

The BMT CTN will utilize a single Institutional Review Board of Record (sIRB). An sIRB is expected to streamline IRB approvals, provide the ethical review, and maintain patient safety while reducing the inefficiencies and burden of each clinical site conducting their own IRB review. All BMT CTN Core Clinical Centers/Consortia members must agree to participate in a registered sIRB that will be engaged and implemented on the Network's behalf by the DCC.

Administrative & Technical Committees

The BMT CTN's scientific and administrative work is assisted by a variety of committees whose membership is drawn from the Core Clinical Centers, the DCC, staff from the NHLBI and the NCI, and additional experts as needed.  Committees may include protocol development committees, a publications committee, a finance committee, a biospecimen and core lab committee, a clinical research associate committee, a pharmacy committee, and an ancillary studies committee.  Other committees may be needed to support future BMT CTN activities, and members will be drawn from the DCC or from the Core Clinical Centers/Consortia and outside consultants, as needed.

Participation in BMT CTN Trials and Selection of new BMT CTN Trials

As per the intent of the NHLBI and NCI in supporting the BMT CTN, multiple trials will be conducted during the project period. It is anticipated that each Core Clinical Center/Consortium will participate in BMT CTN trials that are currently enrolling. Additionally, protocols will be selected and developed by the SC from the protocols proposed in applications to this FOA by the awarded Core Clinical Centers. Trials for non-malignant blood diseases that include mechanistic studies are encouraged.

The BMT CTN FOAs will support the network infrastructure for seven years and anticipate that up to eight new BMT CTN trials or studies may be initiated, launched, and completed during that period.  The exact number of protocols and mechanistic studies supported in the program will depend on the nature and extent of the investigations proposed and on available funds.  Protocols proposed in applications to this FOA should be completed during this funding cycle.

Additional new protocols supported through collaborations with R01-funded investigators, other clinical trial groups, or pharmaceutical companies may be implemented by the BMT CTN as appropriate.  As protocols are developed, support will depend upon the availability of funds, and per-patient funding and protocol costs made available through agreements with the DCC.  It is anticipated that each Core Clinical Center/Consortium will be able to participate in most of the protocols or enroll at least 18 participants to BMT CTN trials annually.  Up to eight new clinical trials led by the BMT CTN will be reviewed by a sIRB facilitated by the DCC for the Network; clinical trials conducted in collaboration with the NCTN and led by the NCTN will be reviewed by an NCI central IRB.

See Section VIII. Other Information for award authorities and regulations.

Section II. Award Information
Funding Instrument

Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities. See Section VI.2 for additional information about the substantial involvement for this FOA.

Application Types Allowed

New
The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.

Funds Available and Anticipated Number of Awards

NHLBI intends to commit total costs of up to $1,745,200 in FY 2017, $2,745,200 in FY 2018, $4,745,200 in FY 2019 through 2022, and $5,745,200 in FY 2023.

NCI intends to commit total costs of up to $2,850,000 per year in FY 2017 through FY 2023.

This FOA will fund one award.

Award Budget

Application budgets may not exceed direct costs of up to $3,830,000 in FY17, $4,650,000 in FY18, $6,315,000 in FY19, $5,965,000 in FY20 through FY22, and $6,965,000 in FY23.

Award Project Period

The maximum project period is seven years.  

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
Eligible Organizations

Eligibility is limited to current awardees of the NHLBI-funded BMT Data Coordinating Center award (RFA-HL-11-028).

Foreign Institutions

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are not allowed.

Required Registrations

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

  • Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
  • System for Award Management (SAM) (formerly CCR) – Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code – Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM. 
  • eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
  • Grants.gov – Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account.  PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Eligible Individuals (Program Director/Principal Investigator)

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

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

2. Cost Sharing

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

3. Additional Information on Eligibility
Number of Applications

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time.  This means that the NIH will not accept:

  • A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
  • A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
  • An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).
Section IV. Application and Submission Information
1. Requesting an Application Package

Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research Instructions for the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

For information on Application Submission and Receipt, visit Frequently Asked Questions – Application Guide, Electronic Submission of Grant Applications.

Letter of Intent

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.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

  • Descriptive title of proposed activity
  • Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
  • Names of other key personnel
  • Participating institution(s)
  • Number and title of this funding opportunity

The letter of intent should be sent to:

Director, Office of Scientific Review
Division of Extramural Research Activities
National Heart, Lung and Blood Institute
National Institutes of Health
6701 Rockledge Drive, Room 7214
Bethesda, MD 20892-7924 (Express Mail Zip: 20817)
Telephone: 301-435-0270
Email: nhlbichiefreviewbranch@nhlbi.nih.gov

Page Limitations

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

Instructions for Application Submission

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

SF424(R&R) Cover

All instructions in the SF424 (R&R) Application Guide must be followed.  

SF424(R&R) Project/Performance Site Locations

All instructions in the SF424 (R&R) Application Guide must be followed.  

Facilities and Other Resources: Applicants must include a brief description of the features of the institutional environment that are relevant to the effective implementation of the proposed DCC. As appropriate, describe available resources, geographic distribution of space and personnel, and consultative resources.

SF424(R&R) Other Project Information

All instructions in the SF424 (R&R) Application Guide must be followed.

Other Attachments: The attachments listed below must be provided or the application will not be peer reviewed. Upload each attachment as a separate pdf file with the names specified below.

1.  DCC Management Plan

A management plan describing staffing and roles and responsibilities should be provided as an attachment that may not exceed 3 pages called "DCC Management Plan.pdf", and be reflected in the final image bookmarking for easy access for reviewers. 

The DCC is a consortium of three organizations, with the PD/PI from the applicant institution responsible for the overall direction and activities of the DCC. Without repeating information in the multiple PD/PI Leadership Plan, the DCC Management Plan should describe the approach for collaboration and interactions among the organizations. The roles and responsibilities of personnel other than the PDs/PIs in each organization, and plan for supervision, training, certification, data handling, quality assurance, communications, and effective cost management should also be included.

The DCC Management Plan should also address the designation of a replacement for the contact PD/PI. The plan should describe the procedure for selecting a proposed replacement for the PD/PI, should the need arise. The NHLBI must approve any request to replace the PD/PI.

2.  Clinical Research Capabilities

A detailed table of all multi-site HCT clinical trials coordinated by the applicant (as the DCC) that demonstrate the applicant's experience in trial coordination and management must be provided as an attachment called "Clinical Research Capabilities.pdf", and be reflected in the final image bookmarking for easy access for reviewers.   

The table should include the following columns:

Column A:  Name of the study/trial

Column B:  Brief description of the study/trial

Column C:  IND or IDE (yes or no)

Column D:  Mean Planned Monthly Enrollment at Steady-state

Column E:  Mean Actual Enrollment at Steady-state

Column F:  Number of Enrolling Sites

Column G: Time from IRB approval to first patient enrolled

Column H: Was the trial completed on schedule or not (yes or no) - if not what was the magnitude of the delay (number of months)

Column I:  Publication reference(s)

Column J:  Impact to the Field

3.  Project Management Plan

A Project Management Plan should be provided as an attachment that may not exceed 6 pages called "Project Management Plan.pdf" and be reflected in the final image bookmarking for easy access for reviewers. The Project Management Plan should describe the evidence-based strategy that will be used throughout the project by the DCC to ensure that the unique goals of the BMT CTN are met within the constraints of time and funding permitted under this FOA.

Project management planning should directly support the goals of the FOA, approach to identify barriers, make timely responses, and optimize the allocation of limited resources. The project management plan should describe the key processes to evaluate scientific and fiscal performance.  A description of the standards and processes governing resource management, study deployment, operations/execution, and study closure should be included. The management plan should also describe how the DCC, in collaboration with the SC, the NHLBI and the NCI, will proactively evaluate and prioritize issues that jeopardize study goals and development of corrective responses to resolve fiscal and logistical issues (risk planning) in a timely manner. The Plan should describe processes required for orderly project closure.

The Plan should address how enrollment data will be shared on a regular basis with NHLBI, including any proposed use of electronic enrollment data reports directly to NHLBI's clinical trial data management system.

4. US Transplant Center Activity

A summary of Transplant Center activity in the US should be provided as an attachment called "US Transplant Center Activity.pdf" and be reflected in the final image bookmarking for easy access for reviewers.

Using the most current data available for 2013 and 2014, report the information requested below by year for each US transplant center reporting data to the CIBMTR database.  

1)  Number of HCT recipients

2)  Number of autologous HCT recipients

3)  Number of allogeneic HCT recipients

4)  Number of HCT recipients with malignant blood diseases

5)  Number of HCT recipients with non-malignant blood diseases

SF424(R&R) Senior/Key Person Profile

All instructions in the SF424 (R&R) Application Guide must be followed. 

The PD(s)/PI(s) must be experienced in the conduct of multi-center HCT trials for either adult or pediatric patients. In addition, the application should propose at least one team member with expertise in either clinical non-malignant hematology or cell therapy, and engage another expert, when appropriate; other team members are individuals required to facilitate the implementation of all aspects of BMT CTN trials.

All Key Personnel should demonstrate strong administrative, technical, and management expertise in the areas that are critical to the success of the application, including experience with working productively in collaborative environments; and experience with administrative management of resource-based operations important for HCT. Key Personnel who are major contributors to the DCC must provide an NIH Biosketch whether or not they are budgeted.

R&R Budget

All instructions in the SF424 (R&R) Application Guide must be followed with the following additional instructions.

Application budgets must plan for the following:

For all non-protocol costs, applicants may request direct costs of up to $1,430,000 in Fiscal Year 2017, $1,750,000 in Fiscal Year 2018, $2,415,000 in Fiscal Year 2019, and $3,065,000 in Fiscal Years 2020-2023.

The application budget should include:

  • All costs (travel, honoraria, and liability insurance, as appropriate) associated with the activities of two DSMBs. This includes up to four in-person meetings annually, as well as travel and lodging for DSMB members, and costs for three in-person SC meetings annually.
  • The DCC should assess the need for liability insurance for DSMB members and provide a plan commensurate with the risk of the trial. The budget should include provision for executing the plan proposed. The DCC should also include a plan for assessing DSMB member conflict of interest.
  • Costs to engage an sIRB for up to six BMT CTN-led trials.
  • All travel costs for five members of the External Advisory Committee that will be appointed by NHLBI after the Core Clinical Centers and DCC have been awarded.
  • Support for publication, data sharing, and dissemination of results.
  • Costs to support teleconferences/webcasts for the SC, protocol teams, and all technical and other committees supporting the BMT CTN.

For protocol development and patient-related costs (e.g., clinical costs that are not part of routine clinical care such as laboratory tests, sample and data collection, supplies, drugs), applicants may request direct costs of up to $2,400,000 in Fiscal Year 2017, $2,900,000 in Fiscal Year 2018, $3,900,000 in Fiscal Year 2019, $2,900,000 in Fiscal Years 2020-2022, and $3,900,000 in Fiscal Year 2023.

R&R Subaward Budget

All instructions in the SF424 (R&R) Application Guide must be followed.

PHS 398 Cover Page Supplement

All instructions in the SF424 (R&R) Application Guide must be followed.  

PHS 398 Research Plan

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions: 

Research Strategy: The Research Strategy must discuss the overall approach to coordinate and administer all aspects of multi-center HCT trials conducted by the BMT CTN.

The following criteria must be addressed in the research strategy:

Significance:  Describe the significance of the proposed DCC team to the success of multi-center HCT trials for pediatric and adult patients; trials aimed at treating blood diseases (malignant and non-malignant); trials aimed at addressing HCT-related issues (i.e., donor source, regimen-related toxicity and complications, quality of life); and trials incorporating novel cell/gene therapies. Discuss how the DCC team of HCT and medical experts, biostatisticians, operations, administrative and regulatory experts will contribute to the completion of current BMT CTN trials, and the development, implementation, and completion of new trials (either Pilot/phase I, II, and III) that are expected to include rare patient populations and use adoptive cell therapy or genetically-modified cells, or biomarker-driven HCT approaches. 

Innovation: Applicants should describe:

  • Plans to employ unique or novel methodologies to enhance the clinical trial design, management, or methods of data analysis.
  • Innovation of planned approaches to project coordination and logistical support.
  • Plans to utilize the best practices to improve and implement BMT CTN clinical trials.
  • Plans to integrate activities of all of the BMT CTN Cores/Consortia and Affiliate transplant centers to leverage existing resources and minimize the duplication of effort.
  • The approach to advance trials in non-malignant blood diseases and bone marrow failure syndromes and to identify new opportunities for HCT trials that incorporate adoptive cell therapy or genetically-modified cells. 
  • The potential challenges of developing and implementing these studies, and any novel methodologies or approaches to overcome these challenges.

Approach: Applicants should describe:

  • Planned approaches to trial design, study coordination, data management (including data security procedures), data monitoring and reporting, as well as statistical support, noting any novel aspects. Discuss how these approaches will contribute to the overall success of the BMT CTN. 
  • Plans for coordination of the project, overall timeline for the program, communication strategies, study design, milestone plan development and monitoring for each trial, trial implementation and accrual, data collection and case report forms, management and quality control, use of specimens from trials for ancillary studies, and dissemination of results. 

Specifically address:

  • Project Coordination: Describe plans for coordinating and completing within the BMT CTN timeframe all ongoing (accruing, in follow-up, in final analysis for primary endpoints and publication) BMT CTN clinical trials, up to eight new clinical trials led by BMT CTN, and several trials led by non-BMT CTN investigators.  Provide an anticipated capacity to support clinical trials within the BMT CTN seven year timeframe including how many multi-site clinical trials could be conducted simultaneously. Include plans for providing administrative and operational support. Describe staffing support during the development, execution, and completion of studies.  Describe how the DCC will interact and collaborate with the Core and Affiliate Centers, including transmission of data in an accurate and timely fashion, and monitoring activities.  Describe how the DCC plans to facilitate implementation of trials conducted in collaboration with other clinical trial groups including the NCTN, NIH grant-funded investigators, and pharmaceutical companies. 
  • Study Design: Given time and resource limitations, describe the approach for guiding the BMT CTN in prioritizing, developing and implementing BMT CTN-led studies, and for partnering with the NCTN on NCTN-led trials. Describe the approach for developing, launching and monitoring Network protocols, including protocol maintenance and twice annual reporting of study data to the DSMBs, and completing trials on time and on budget. 
  • Data Management, Data Systems and Quality Control: Describe the approach to data management, including data management systems, data entry, case report forms, methods for monitoring the safety, quality and consistency of the intervention(s); policies and methods for ensuring blinding of study results; data confidentiality and subject privacy.  Describe the system for quality control for data entry, queries and audits. Discuss the approach to site monitoring and quality assurance activities, including site visits as needed, and remote monitoring consistent with FDA guidance. Describe plans for data cleaning and preparation of datasets to ensure that analyses of the data can be completed in a timely manner.
  • Acquisitions and Storage of Biospecimens:  Describe plans to collect, process, label, track, store, retrieve, and distribute high-quality biospecimens. Describe plans to ensure that biospecimen information can be reliably linked to the corresponding participant's clinical and other data.
  • Accrual Plans: Describe the process for projecting study timelines and accrual targets, and approaches to increase accrual of minorities.  For trials that are accruing slower than expected, describe the approach to identify the barriers and potential solutions.
  • Statistical Analysis Plan: Describe the approach for statistical analysis of BMT CTN trials, including key methods used in the analysis of the primary outcomes data, methods of bias control, and methods for handling missing data (as applicable). Discuss the evaluation by race/ethnicity and gender, and the plans for separate and adequately powered analyses. Discuss the potential use of adaptive designs.
  • Regulatory Support:  Discuss the approach to support investigational new drug applications (INDs) and investigational device exemption (IDE) applications and to either serve as the Authorized Representative for BMT CTN-led trials, or upon request, to hold INDs or IDEs for specific trials.  Describe the approach for training investigators for BMT CTN protocols and Good Clinical Practice as needed.
  • Reports, datasets and study documentation:  Describe the approach for preparing reports of data and safety for the DSMB, FDA, and Office of Human Subjects Protection. Discuss the approach to notify stakeholders of patient safety concerns or trial continuation; preparation of data reports for Network subcommittees, and public-use data files. Describe a plan to evaluate the performance of centers annually, as well as the overall performance of the Network.  Describe the approach to provide an on-line tool to track the progress of all Network publications and key metrics for the DCC and writing teams. Describe other reports needed for announcing and tracking BMT CTN scientific contributions.
  • sIRB: All BMT CTN Cores/Consortia members will participate in a registered sIRB that will be engaged and implemented on the Network's behalf by the DCC. The sIRB will carry out the functions required for institutional compliance with IRB review set forth in the HHS regulations at 45 CFR 46, and allow research to proceed as expeditiously as possible without sacrificing ethical principles and protections for participants enrolled in BMT CTN studies. Provide a plan to establish and implement a sIRB for BMT CTN-led trials and provide reliance agreements for all US sites participating on BMT CTN trials, as needed. Describe the respective authorities, roles, responsibilities and communication between the sIRB and the sites participating in the BMT CTN.
  • DSMB Support: Discuss the plan for assessing and managing DSMB member conflicts of interest relative to BMT CTN trials. Describe a plan to provide liability coverage to DSMB members who request this insurance for their monitoring role of BMT CTN-led trials. Options for providing coverage may include reimbursing individual DSMB members who obtain their own liability insurance, extending the DCC’s liability coverage to DSMB members, or purchasing a liability policy for the DSMB. 
  • Budgets: Describe the approach to preparing protocol budgets based on per-patient costs; monitor the ongoing expenditure of protocol funds, and prepare financial reports as requested.  Discuss the approach used to negotiate and manage contractual arrangements with transplant centers, laboratories, pharmaceutical companies and contributors; and to distribute funds to support BMT CTN trials.  Describe the approach to issue Requests for Proposals, coordinate selection, and execute subcontracts for study-supplied medications, core labs and the manufacturing of novel cell therapies when required by a study.
  • Manage Core BMT CTN operations:  Describe the approach to manage meetings and calls for the SC, EC, DSMBs, Protocol Development Committees, and other committees essential to the conduct of the Network; provide the logistical support necessary to run an efficient and productive Network; maintain and update the BMT CTN website to include information about studies and summaries of study results; include a summary for patients and laypersons.
  • Coordinate logistics and other support services:  Maintain the infrastructure necessary to support all Network activities, including conference calling and webinar capabilities, electronic billing and payment capabilities, and maintenance of the public and administrative Network websites and electronic data capture systems; execute master agreements and protocol rider agreements with all Cores and NCTN partners, as well as Affiliate sites which are often needed to meet recruitment sample sizes; handle travel arrangements for consultants as needed; develop processes to facilitate collaborations with NCTN; develop a plan to advance HCT trials for non-malignant blood diseases and bone marrow failure diseases, and to early phase trials using adoptive cell therapy or genetically-modified cells.  
  • Data Systems: Describe the potential interactions with the CIBMTR data systems and other relevant data systems.

Letters of Support: Letters of institutional and departmental support for participation in the BMT CTN are required.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

  • All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Appendix:  Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

PHS Inclusion Enrollment Report

When conducting clinical research, follow all instructions for completing PHS Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

PHS Assignment Request Form

All instructions in the SF424 (R&R) Application Guide must be followed. 

3. Unique Entity Identifier and System for Award Management (SAM)

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

4. Submission Dates and Times

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

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

Pre-award costs are allowable only as described in the NIH Grants Policy Statement. Specific to this FOA:

  • Awards issues under this FOA will be incrementally funded for up to 7 years. These will not be Multi-Year Funded.
  • Awards issued under this FOA will be excluded from automatic carryover.  All carryover actions will require NHLBI prior approval.
  • Awards issued under this FOA will not be provided the authority to automatically extend the final budget period.  All extensions, including the first, will require NHLBI prior approval.
  • Awards issued under this FOA will be excluded from SNAP.
7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide.  Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

Section V. Application Review Information
1. Criteria

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of 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 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 review criteria and additional review criteria (as applicable for the project proposed).

Scored Review Criteria

Reviewers will consider each of the review criteria below in the determination of scientific 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 proposed Data Coordinating Center address the needs of the research network that it will serve? Is the scope of activities proposed for the Data Coordinating Center appropriate to meet those needs?  

Specific to this FOA:

How strong is the DCC's evidence of collaboration in multi-center HCT trials and studies for pediatric and adult patients? Will the proposed plan to explore new opportunities for HCT trials for non-malignant disease or using adoptive cell therapies and genetically-modified cells in the context of HCT help address key research priorities and advance HCT therapy? 

Investigator(s)

Are the PD(s)/PI(s) and other personnel well suited to their roles in the Data Coordinating Center? Do they have appropriate experience and training, and have they demonstrated experience and an ongoing record of accomplishments in managing clinical research? Do the investigators demonstrate significant experience with coordinating collaborative clinical research? If the Center is multi-PD/PI, do the investigators have complementary and integrated expertise and skills; are their leadership approach, governance, plans for conflict resolution, and organizational structure appropriate for the Data Coordinating Center? Does the applicant have experience overseeing selection and management of subawards, if needed?

Specific to this FOA:

How strong is the application in demonstrating that the DCC can coordinate and manage all aspects of the data collection and analysis of the BMT CTN?  How strong is the ongoing level of accomplishments in managing DCCs?

How well-defined are their roles and responsibilities?  How strong is the application in demonstrating that the PDs/PIs and Key Personnel have the experience and capabilities in multidisciplinary DCC functions, including project coordination, administration, study design, data management and quality control, acquisition and storage of biospecimens, statistical/analytic support, monitoring safety, regulatory support and fiscal management, to simultaneously manage several multi-center trials and protocols underdevelopment? 

Does the DCC include expertise in nonmalignant hematology or cell/gene therapy to facilitate conducting HCT trials in nonmalignant blood diseases or HCT trials using novel cell products or genetically-modified cells?

Innovation

Does the application propose novel organizational concepts, or management strategies in coordinating the research and conduct of multi-center trials that the Data Coordinating Center will serve? Are the concepts of strategies novel to one type of research program or applicable in a broad sense? Is a refinement, improvement, or new application of organizational concepts or management strategies proposed?

Specific to this FOA:

Where appropriate, does the proposed DCC utilize current best practices to improve the knowledge and/or skills of the Network?

Does the application include scientific capabilities that may develop and expand the scientific productivity of the BMT CTN?

Does the applicant propose innovative approaches to leverage institutional resources to augment the capabilities and mission of the BMT CTN?  

Approach

Are the overall strategy, operational plan and organizational structure of the DCC well-reasoned and appropriate to accomplish the goals of the clinical trials network that the DCC will serve? Will the investigators promote strategies to ensure a robust and unbiased scientific approach across the network, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? Are an appropriate plan for work-flow and a well-established timeline proposed?  Have the investigators presented adequate plans to ensure consideration of relevant biological variables, such as sex, for clinical research?

Specific for this FOA:

What are the strengths and weakness of the DCC's approaches to study development, launch and dissemination of results, manage operations, administration, oversee regulatory responsibilities, and coordinate logistics and other support services as described in this FOA?

Does the Project Management Plan adequately address the critical parameters for the launch, conduct and completion of multiple trials simultaneously? 

Are the data management and quality control procedures adequate to ensure the safety of participants in multi-institutional clinical trials? How strongly does the planned approach enable BMT CTN to leverage other existing data systems such as CIBMTR?

How strong is the evidence of the ability of the DCC to operate within the proposed organizational structure, communicate with individual sites, and collect and transmit data in an accurate and timely fashion?

How strong is the evidence of the ability of the DCC to coordinate the collection, tracking, storage, and retrieval of high quality biospecimens for use by BMT CTN and non BMT CTN investigators?

How strongly does the application demonstrate the ability of the DCC to facilitate HCT trials conducted under regulations set by the Food and Drug Administration and to monitor NIH conflict of interest requirements?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

Has the applicant proposed adequate plans to support the NHLBI-appointed DSMB(s) and implement a sIRB for BMT CTN trials?

Environment

Will the institutional environments in which the Data Coordinating Center will operate contribute to the probability of success in facilitating the research network it serves? Are the institutional support, equipment and other physical resources available to the investigators adequate for the Data Coordinating Center proposed? Will the Data Coordinating Center benefit from unique features of the institutional environment, infrastructure, or personnel? Are resources available within the scientific environment to support electronic information handling?

Specific to this FOA:

Are data management systems flexible enough to accommodate the changing needs of the program over time?

What is the evidence that the facilities and resources available for the DCC infrastructure will support and enable the conduct of BMT CTN trials and assist clinical centers in implementing Network protocols?

Additional Review Criteria

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

DCC Management Plan

Based on the information in the attachment titled "DCC Management Plan", how comprehensive is the DCC's management plan for the proposed DCC consortium?  How likely is the proposed succession (replacement) plan for the PD/PI to be successful?

Clinical Research Capabilities

Based on the information in the attachment titled "Clinical Research Capabilities", how strong is the ability of the DCC in coordinating prospective multi-center HCT trials, including trials in non-malignant blood diseases and using cell therapies in the context of HCT, and studies conducted under IND(s)?

Project Management Plan

In the attachment titled "Project Management Plan", is the proposed project management plan sufficient to fully support the BMT CTN?

US Transplant Center Activity

Does the information presented in the attachment titled "US Transplant Center Activity" facilitate the DCC in identifying and engaging Affiliate Centers to support the portfolio of BMT CTN trials?

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. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Children 

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals

Not Applicable

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.

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

Additional Review Considerations

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

Applications from Foreign Organizations

Not Applicable

Select Agent Research

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

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3)  Genomic Data Sharing Plan (GDS).

Authentication of Key Biological and/or Chemical Resources:

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Budget and Period of Support

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

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the NHLBI Office of Scientific Review, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

  • May 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 overall impact score.
  • Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

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

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. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

Section VI. Award Administration Information
1. Award Notices

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. 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.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website.  This includes any recent legislation and policy applicable to awards that is highlighted on this website.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General  and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency.  HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements.  FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award.  An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS.  The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 “Federal awarding agency review of risk posed by applicants.”  This provision will apply to all NIH grants and cooperative agreements except fellowships.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

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 Part 75 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.

The PD(s)/PI(s) will have the primary responsibility for:

The DCC PDs/PIs play an important role in all aspects of BMT CTN studies, including participating in protocol development, preparing protocol budgets in collaboration with the Core Clinical Centers, modifying proposals if indicated, monitoring recruitment of study participants, assuring the quality of study participant protocol adherence, assuring the accurate and timely transmission of data, analyzing and interpreting data, preparing publications, and working with the Core Clinical Centers and the NHLBI and NCI to disseminate research findings in a timely manner.  The DCC will also be responsible for working with the Core Clinical Center awardees to develop common definitions and standardization across protocols wherever appropriate.  Awardees must agree to the governance of the study through a Steering Committee.  Investigators will be required to project patient enrollment for a specific protocol during a specified time frame; continuation and level of funding will be based on actual recruitment.

The BMT CTN program includes the Core Clinical Centers, 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 Core Clinical Centers and the DCC to complete ongoing protocols.  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. 

The Principal Investigators of the Core Clinical Centers are responsible for the following: Accepting the coordinating role of the DCC and the participatory and cooperative nature of the Network process; Identifying new priority areas of research; Developing and implementing Network clinical trials; Accurately 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 all applicable DHHS regulations concerning protection of human subject; 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, or by independent funding. Some of these projects may be conducted by the central laboratory which will be a subcontract from the DCC; and Other scientific contributions such as develop presentations and publications following the BMT CTN publication procedures. 

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.  Data not previously released and other study materials or products not previously distributed are to be made available to individuals who are not study investigators, within three years of the end of the period of NHLBI support, provided such release is consistent with the study protocol and governance and according to NHLBI Policy (http://www.nhlbi.nih.gov/research/funding/human-subjects/data-sharing). 

Support or other involvement of industry or any other third party in the study may be advantageous and appropriate.  Participation by the third party; involvement of study resources, citing the name of the study or NHLBI support, or special access to study results, data, findings or resources requires notification and concurrence by NHLBI.  Except for licensing of patents or copyrights, support or involvement of any third party will occur only following notification of and concurrence by NHLBI.

Study PDs/PIs are encouraged to publish and disseminate results and other products of the study in accordance with study protocols and governance.  For applicable studies, data not previously released and other study materials or products not previously distributed are to be made available to individuals who are not study investigators, within three years of the end of the period of NHLBI support, provided such release is consistent with the study protocol and governance.

NIH staff will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

NIH Project Scientists will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, and will assist with development of research protocols, monitor patient recruitment and study progress, ensure disclosure of conflicts of interest, and ensure adherence to NHLBI policies.  NHLBI will appoint Data and Safety Monitoring Boards (DSMBs).  The Steering Committee Chair will be responsible for ensuring that there are well-documented policies, procedures, and bylaws to guide all aspects of Network activities and operations.

In addition to the NHLBI Project Scientist, a separate NHLBI Program Official will be responsible for the normal program stewardship of the cooperative agreement, and will be identified in the Notice of Award.  However, NHLBI may elect to have a dual-role approach where a single individual may act as the NHLBI Project Scientist and Project Officer.  Final decision-making authority on matters of budgetary and funding actions, grants management actions, and management of intellectual property issues is assigned to NHLBI staff other than the Project Scientist. The responsibility for final decision making may reside with Senior Institute management, separate organizational components and/or oversight committees.  Because it is anticipated that the Project Scientist/Program Official will participate in activities that rise to a level of involvement that results in conflicts of interest, for example, co-publication, other staff members such as direct line supervisors and/or other Senior NHLBI Program management staff will serve as agency Program Officials and will be responsible for the normal scientific and programmatic stewardship of the award.

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

Areas of Joint Responsibility include:

BMT CTN Steering Committee:

Awardee(s) agree to the governance of the study through a Steering Committee.  The Steering Committee will have primary responsibility for identification of priority areas for research, the conduct of protocols, data analysis and the preparation of publications and dissemination products. The Steering Committee will be responsible for ensuring that there are well-documented policies, procedures, and bylaws to guide all aspects of Network activities and operations.

Steering Committee voting membership shall consist of all Principal Investigators (i.e., cooperative agreement awardees), one NHLBI Project Scientist, and one NCI Project Scientist.  Each full member will have one vote. Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee.  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 DSMB.  Technical Committees (i.e., Pharmacy, Publication) and subcommittees of the Steering Committee will be established as necessary. A protocol is the detailed written plan of a clinical experiment; DSMB reviews, NHLBI approval (with NCI consultation), FDA approval of IND or IDE (as appropriate), and IRB approvals are required prior to activating a clinical trial All study protocols must adhere to current NIH policies for human subjects research.  All protocols must be approved by NHLBI. The PD/PIs will establish mutually agreed upon milestones with the steering committee for the development of each clinical research protocol and trial implementation; milestones may include such things as time to DSMB approval, time to a signed institutional contract for per-patient reimbursement, first patient enrolled, etc. Trial performance should be consistent with the NIH, and NHLBI policies, including the Milestone Accrual Policy.  NHLBI will appoint and External Advisory Panel to advise on the performance of the network and the portfolio of trials conducted by the BMT CTN.

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. Should the PD/PI find it impossible to attend a Steering Committee meeting or conference call, he/she is required to notify the NHLBI Program Officer and/or Steering Committee Chair of the expected absence and ensure attendance by 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 NHLBI and NCI Project Scientists will serve on the Steering Committee and other study committees, when appropriate. The Project Scientists may work with awardees on issues coming before the Steering Committee such as recruitment, protocol development, follow-up, quality control, adherence to protocol, possible changes to the protocol, interim data and safety monitoring, final data analysis and interpretation, preparation of publications, and development of solutions to major problems such as insufficient participant enrollment.

NHLBI-appointed DSMB:

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.

Single Institutional Review Board of Record (sIRB):

In this renewal, the BMT CTN will utilize a single Institutional Review Board of Record (sIRB) for BMT CTN-led trials. A sIRB is expected to streamline IRB approvals, provide the ethical review, and maintain patient safety while reducing the inefficiencies and burden of each clinical site conducting their own IRB review. The DCC will engage and implement this board on the Network's behalf.  The sIRB will carry out the functions required for institutional compliance with IRB review set forth in the HHS regulations at 45 CFR 46, and allow research to proceed as expeditiously as possible without sacrificing ethical principles and protections for participants enrolled in BMT CTN studies.  Reliance agreements will delineate the respective authorities, roles, responsibilities and communication between the sIRB and the U.S. sites participating in BMT CTN-led trials.  All BMT CTN Core Clinical Centers/Consortia members have to agree to participate in the registered sIRB engaged and implemented on the Network's behalf by the DCC.   

Dispute Resolution:

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

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later.  All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000.  See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period.  The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS).  This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313).  As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available.  Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 – Award Term and Conditions for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

Application Submission Contacts

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: https://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726

Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

Scientific/Research Contact(s)

Nancy L. DiFronzo, PhD
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0065
Email: nancy.difronzo@nih.gov

William Merritt, PhD
National Cancer Institute (NCI)
Telephone: 240-276-6137
Email: merrittw@mail.nih.gov

Peer Review Contact(s)

Director, Office of Scientific Review
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0270
Email: nhlbichiefreviewbranch@nhlbi.nih.gov

Financial/Grants Management Contact(s)

Jennifer Cho
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-402-6090
Email: jennifer.cho@nih.gov

Shane Woodward
National Cancer Institute (NCI)
Telephone: 240-276-6303
Email: woodwars@mail.nih.gov

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Authority and Regulations

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.

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