Part I Overview Information


Department of Health and Human Services

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

Components of Participating Organizations
National Cancer Institute (NCI) (http://cancer.gov)
National Institute of Neurological Disorders and Stroke (NINDS) ( http://www.ninds.nih.gov/)

Title: Pediatric Brain Tumor Consortium (U01)

Announcement Type
This Funding Opportunity Announcement (FOA) is a reissuance of RFA-CA-04-501

Update: The following update relating to this announcement has been issued:

Request For Applications (RFA) Number:  RFA-CA-08-026

Catalog of Federal Domestic Assistance Number(s)
93.399

Key Dates
Release Date: June 6, 2008
Letters of Intent Receipt Date: July 15, 2008
Application Receipt Date: August 15, 2008
Peer Review Date: November 2008
Council Review Date:  January, 2009
Earliest Anticipated Start Date: April 1, 2009
Additional Information To Be Available Date (URL Activation Date): Not applicable.
Expiration Date: August 16, 2008

Due Dates for E.O. 12372

Not Applicable.

Additional Overview Content

Executive Summary

Table of Contents


Part I Overview Information

Part II Full Text of Announcement

Section I. Funding Opportunity Description
1. Research Objectives

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

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

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

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

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

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

Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement


Section I. Funding Opportunity Description


1. Research Objectives         

Purpose

This Funding Opportunity Announcement (FOA) is designed to continue the NCI’s support for the development of more effective therapies for children with brain tumors.  To address these needs, the NCI solicits applications for the Pediatric Brain Tumor Consortium (PBTC). The PBTC is expected to ensure that (i) laboratory discoveries relevant to children with brain cancers are rapidly translated into the clinical setting and (ii) novel treatment approaches for children with brain tumors are expeditiously evaluated. In addition, the PBTC should include a dedicated Neuroimaging Center. This center should be utilized in PBTC clinical trials to gain insights into the effects of investigational treatments on both tumor and normal brain tissues.

Continuation of the NCI Pediatric Brain Tumor Consortium program under this FOA will be based on an open competition as an opportunity to reshape the PBTC and better serve the overall goals of the program. Both the current PBTC awardee and other qualifying institutions are encouraged to form teams (with appropriate candidates for Member Institutions) to submit PBTC applications.

Background

NCI is the primary source of research funding for early phase evaluations of new drugs and new treatment approaches for children with cancer, including those with brain tumors. This NCI support has increased the access of pediatric oncology patients to a broad range of new anticancer agents and has helped to identify curative treatments for approximately 80% of affected children.  Nonetheless, 20% of children with cancer succumb to their disease and a large fraction of survivors experience significant short- and long-term toxicities.  High mortality remains a problem among some groups of pediatric patients, especially those with brain tumors (such as diffuse intrinsic brain stem gliomas). Moreover, a substantial proportion of children with brain cancers who survive after receiving current treatments exhibit functional impediments. The PBTC program was initially proposed 10 years ago. This FOA represents a continuation of the NCI’s commitment to clinical research for children with brain tumors as well as a forward-looking program for extending targeted therapeutics into this patient population.

The scientific opportunities for advancing treatment options for childhood brain tumors have expanded considerably.  The molecular characteristics of childhood brain cancers are understood far better today than when the PBTC program was initially established.  These advances are paralleled by an expansion in the number and variety of anticancer agents targeted towards specific signaling pathways that control growth and proliferation of cancer cells.  The combination of both factors, increased understanding of cancer biology and availability of novel therapeutic strategies, create clinical research opportunities for the PBTC to exploit.

PBTC Overall Goals, Research Priorities, Organization, and Specific Requirements

The overall goal for the PBTC is to identify new effective treatments for subsets of patients with tumors that show specific, defined molecular characteristics.  In the coming 5-year funding period, the thrust of the PBTC effort will be in the following two directions (both have to be addressed by all PBTC applicants): 

1.      Conduct of Phase 1, Phase 2, and pilot clinical trials for safe and efficient evaluation of novel treatment approaches suitable for children with brain tumors. This direction should exploit new developments in various venues, including: (i) PBTC member institutions, (ii) the NIH, (iii) other academic institutions, and/or (iv) the for-profit pharmaceutical/biotechnology sector.  The focus should be primarily on clinical trials that require the specialized abilities of the PBTC’s collaborating experienced neurosurgeons, neuro-oncologists, radiation oncologists and/or neuroimagers.

2.      Incorporation of pharmacokinetic and pharmacodynamic endpoints (to include imaging and translational laboratory evaluations as appropriate) into PBTC clinical trials to aid the development of the new treatment approaches. 

Organizational Requirements for the Proposed PBTC are as follows.

PBTC Scientific and Organizational Leadership. Since a single award will cover the entire PBTC, applicants are encouraged to take advantage of the multiple Principal Investigator (PI) option. It is expected that one PI, designated as the “lead PI”, will be responsible for the scientific direction of the PBTC. Another PI should be designated as the director of the Statistics and Data Center (see below).  Either of these PIs may also oversee (as a director) the Operation Center (see below).  Other PIs may be designated as appropriate, e.g. “site” leaders at the individual Member Institutions and PI of the Neuroimaging Center.  The lead PI and center directors may also serve as “site” PIs.

Operations Center. The PBTC must have a single Operations Center that will be responsible for (1) preparing clinical trial protocol documents, (2) arranging meetings for the PBTC; (3) assuring PBTC compliance with the requirements of the Food and Drug Administration (FDA) pertinent to new therapies and Office for Human Research Protections (OHRP) regarding human subjects; and (4) monitoring performance of the PBTC Member Institutions.  The Operations Center will also monitor and provide reports on the PBTC’s performance in meeting pre-determined timelines for: (1) preparation of Letter of Intent (LOI)/concept and development of clinical trial protocol; (2) study implementation; (3) publication of the results of PBTC-conducted studies; and (4) evaluation of Member Institution performance.  The proposed PBTC must have prescribed procedures for corrective actions in case of failure by investigators and/or institutions to meet these timelines.

Statistics and Data Center. The PBTC must have a single Statistics and Data Center that will collect clinical trials data directly from participating institutions using a remote data entry system.  Systems for the management of PBTC clinical and imaging data are expected to be compatible with the cancer Biomedical Informatics Grid (caBIG™, https://cabig.nci.nih.gov/) within the 5-year funding period.

Neuroimaging Center. The proposed PBTC must include a Neuroimaging Center for the central collection and review of imaging studies.  In case of PBTC studies with imaging endpoints, the Neuroimaging Center will develop the imaging research plan for the study (in collaboration with other radiologists and other imaging experts within the PBTC). The Neuroimaging Center will then be responsible for the collecting, analyzing, and archiving imaging data as required by the plan. Applicants are encouraged to plan for the PBTC Neuroimaging Center to collaborate on problems of mutual interest with the Imaging Center of the adult brain tumor consortium and with other NIH imaging networks.

Member Institutions. The proposed PBTC should include up to seven Member Institutions. Collectively, these institutions should be able to complete three to four clinical trials per year and to enroll approximately 100-150 patients (in total at all sites) per year.

Applicants are also advised to maximize their research potential by judicious selection of the participating Member Institutions. For example, the previous PBTC awardee submitting a renewal application may propose a revised membership list with new candidate Member Institutions that are not listed on the current award. Reciprocally, new PBTC applications may include candidate institutions that are Member Institutions on the current award. 

The candidate institutions comprising the PBTC applicant team are expected to have the following attributes:

The renewal of memberships for the fourth and fifth year of project period and the associated subcontractual funding will be subject to review and competition with other institutions. During the third year of the project period, the PBTC Operation Center will evaluate the performance of Member Institutions for years 1 and 2. For those initially selected Member Institutions that will be rated in the lower tertile, membership renewal for years 4 and 5 must be based on an open competition (with non-member institutions also invited to participate). Applicants must describe their plans for performance evaluation and procedures for membership renewal that meet these conditions.

In addition to the required member institutions (up to 7), the PBTC applicants also have the option of establishing collaborations with other institutions with similar capabilities that might be willing to interact with PBTC on a collaborative basis (i.e., using their own funding outside of the support for the PBTC).

Laboratory and Imaging studies. PBTC applicants must plan for patient analyses, biospecimen collection, and laboratory correlative studies (e.g., pharmacokinetic and pharmacodynamic studies) through the following dedicated funds:

Beyond the scope that would be supported by the PBTC award, the PBTC applicants are encouraged to accommodate expansion of pharmacokinetic and correlative studies through other sources of funding. 

Specific Benchmarks for the PBTC

The specific benchmarks for the PBTC in the 2009 – 2014 funding period are listed below.  These benchmarks will be used by the NCI to determine whether the PBTC has satisfactorily contributed to NCI’s clinical research program for children with brain tumors. 

1)       The number of Phase 1, Phase 2, and pilot clinical trials initiated and successfully completed (approximately 3-4 per year), which should correspond to an estimated accrual rate of 100 to 150 patients per year, depending upon the mix of studies (e.g., Phase 1 versus Phase 2) in any given year;

2)       The use of appropriate clinical trial designs to allow for (a) dose determination for Phase 2 studies; (b) the determination of the feasibility and tolerability of new treatment regimens; and (c) the meaningful assessment of clinical activity in Phase 2 studies;

3)       The incorporation of appropriate pharmacokinetic and translational biology studies into PBTC-conducted clinical trials;

4)       The successful incorporation of state-of-the-art imaging studies into the PBTC-conducted clinical trials to address key study endpoints;

5)       The productive incorporation of neurosurgical expertise into PBTC-conducted clinical trials to address important biological and therapeutic questions for childhood brain cancers;

6)       The timely development of clinical trials protocols and activation of corresponding clinical trials (defined as per CTEP timeline requirements);

7)       The timely presentation of results at national/international meetings and timely publication of results in peer reviewed journals;

8)       The use of caBIG-compatible systems for the management of PBTC clinical and imaging data;

9)       The generation of high quality data (ensured through an effective QA/QC program and by review of data submitted to CTEP);

10)   The establishment of formal interactions with other brain tumor research programs (e.g., SPORE grantees and other brain tumor research programs supported through NIH as well as non-NIH funding sources) to demonstrate the openness of PBTC to scientific input and scientific collaboration in developing its research program; and

11)   The transitioning of new treatment approaches studied by the PBTC to the Children’s Oncology Group (COG) Brain Tumor Committee.

All the PBTC applicants must adopt and incorporate the above listed benchmarks in their applications (and shape their specific plans accordingly).

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

Section II. Award Information


1. Mechanism of Support

This funding opportunity uses the NIH U01 cooperative agreement award mechanism.
The Project Director/Principal Investigator (PD/PI) will be solely responsible for planning, directing, and executing the proposed project.

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

In the cooperative agreement mechanism, the Project Director/Principal Investigator (PD/PI) retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the Section VI. 2. Administrative Requirements, "Cooperative Agreement Terms and Conditions of Award."

2. Funds Available

The estimated amount of funds available for the PBTC program is $2.2 million for fiscal year 2009 (with the NCI providing 2 million and NINDS 0.2 million) and up to $11.8 million over the planned 5 year project period (with the total NCI and NINDS contributions of approximately 10.8 and 1.0 million, respectively). Future year amounts will depend on annual appropriations.

These funds will be used to fund one PBTC award as a result of this FOA. In addition, contingent on the availability of funds, the NCI may release during the PBTC project period an RFA for competitive supplements to expand the scope of the PBTC award by innovative clinical trials proposed by non-PBTC institutions.

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

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

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

Section III. Eligibility Information


1. Eligible Applicants

1. A. Eligible Institutions

The following organizations/institutions are eligible to apply:

1. B. Eligible Individuals

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

More than one PD/PI, or multiple PDs/PIs, may be designated on the application for projects that require a “team science” approach that clearly does not fit the single PD/PI model.  Additional information on the implementation plans and policies and procedures to formally allow more than one PD/PI on individual research projects is available at http://grants.nih.gov/grants/multi_pi.

2. Cost Sharing or Matching


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

3. Other-Special Eligibility Criteria

Both current PBTC awardee and other qualifying institutions are encouraged to form teams (with appropriate candidates for Member Institutions) to submit PBTC applications.

Renewal applications will be permitted for this FOA.

Resubmission applications are not permitted in response to this FOA.

Applicants may submit only one application for this FOA.

Section IV. Application and Submission Information


1. Address to Request Application Information

The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. Applicants must use the currently approved version of the PHS 398. For further assistance, contact GrantsInfo -- Telephone: (301) 435-0714; Email: GrantsInfo@nih.gov.

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

2. Content and Form of Application Submission

Applications must be prepared using the current PHS 398 research grant application instructions and forms (version 11/2007 or later if available). Applications must have a D&B Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

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

The applicants must demonstrate in the application their ability to meet the RESEARCH OBJECTIVES of the FOA (described in Section II) and the investigator responsibilities (described in Section VI.2.A.1). 

For the PBTC application submitted in response to this FOA, the standard PHS398 Research Plan (Items 2-5, formerly designed as Sections A-D) is altered as follows:

Section 1: Progress Report (Competing Continuation Applications) or Relevant Past Performance (New Applicants).  In this section, a competing continuation application must include a progress report for the current 5-year funding period.  New applicants must summarize their past performance during the preceding 4-5 years, focusing on multi-institutional clinical trials with direct relevance to the proposed PBTC research scope.  Specific areas to address include, but are not limited to, the following:

a)       Clinical trial protocol development: A listing of clinical trial protocol development activities during the previous funding period (or during the past 4-5 years), including letters of intent (LOIs) submitted, clinical trial protocols submitted, and clinical trials activated, with timelines for specific steps in the clinical trial protocol development process.

b)       A brief description of clinical trials (e.g., 0.5 to 1.0 page per trial) that have been initiated during the prior funding period (or during the past 4-5 years).  This summary of each clinical trial should cover the important aspects of the study (e.g., schedule, target patient population, patients accrued, etc.) and salient findings (e.g., dose levels evaluated and recommended dose for Phase 2 trials, important adverse events observed, pharmacokinetic findings, and anti-tumor activity observed).  Copies of all clinical trial protocols should be provided as appendices, along with the most recent Study Reports prepared by the Statistics and Data Center (or its equivalent for new applicants) for each study.  A table should be included in the Progress Report Section that enumerates patient accrual by year for each study.

c)       Pharmacokinetic and pharmacodynamic research contributions: A description of the research accomplishments for pharmacokinetic/pharmacodynamic studies associated with the clinical trials described above.

d)       Neuroimaging contributions:  A description of the neuroimaging studies that have been incorporated into past clinical trials and the contributions that these neuroimaging studies have made.

e)       Annual accrual to clinical trials during the previous funding period (or during the past 4-5 years) by gender and ethnicity/race composition should be described in the PHS398 Inclusion Enrollment Report form.

f)         Publications during the previous funding period (or during the past 4-5 years) should be listed as per PHS398 instructions.

Section 2: Investigators Qualifications:

Section 3: Research Strategies and Research Plans:  The research strategy and plans for the proposed PBTC to develop new treatment approaches for children with brain tumors through Phase 1, Phase 2, and pilot clinical trials should be described, including:

Section 4: Standard Procedures for the Development of Clinical Trial Protocols. A description of the standard procedures developed and utilized by the applicants to support the timely development of Phase 1, Phase 2, and pilot clinical trials for children with brain tumors.  Describe briefly the procedures listed below and provide benchmarks of their successful implementation:

Section 5: Data Management and Analysis and Standard Procedures for Quality Control/Quality Assurance:  Describe the following elements:

Section 6: Standard Procedures for Regulatory Compliance:  Describe the following elements:

Note: Conflict-of-Interest Policy to be used by the proposed PBTC must be included in the Appendices to the application. This policy and associated procedures must be consistent with PHS requirements for ensuring that there is no reasonable expectation that the design, conduct, and/or reporting of research conducted by the proposed PBTC will be biased by any conflicting financial interests of an investigator.

Section 7: Member Institutions: Provide two types of information as defined below.

A. General Policies and Procedures Regarding Member Institutions. Include (within the page-limited portion of Research Plan) a description of the following aspects:

B. Synopses of Individual Member Institutions. Provide a brief description of how each Member Institution meets the criteria for appropriate research capabilities and for acceptable performance. These pages do not count towards the 50-page limit for the Research Plan but must not exceed two pages per Member Institution. The synopses may include, but are not limited to, the following:

Notes on Budget: The budget for the PBTC should include the items listed below.  Use the provided cost estimates for individual categories as guidelines. Deviations from these estimates are allowable but should be justified.

Applications with Multiple PDs/PIs

When multiple PD/PIs are proposed, use the Face Page-Continued page to provide items 3a – 3h for all PD/PIs. NIH requires one PD/PI be designated as the “contact PD/PI” for all communications between the PD/PIs and the agency. The contact PD/PI must meet all eligibility requirements for PD/PI status in the same way as other PD/PIs, but has no special roles or responsibilities within the project team beyond those mentioned above. The contact PD/PI may be changed during the project period. The contact PD/PI should be listed in block 3 of Form Page 1 (the Face Page), with all additional PD/PIs listed on Form Page 1-Continued. When inserting the name of the PD/PI in the header of each application page, use the name of the “Contact PD/PI, et. al.” The contact PD/PI must be from the applicant organization if PD/PIs are from more than one institution.

All individuals designated as PD/PI must be registered in the eRA Commons and must be assigned the PD/PI role in that system (other roles such as SO or IAR will not give the PD/PI the appropriate access to the application records). Each PD/PI must include their respective eRA Commons ID in the eRA Commons User Name field.

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

Multiple PD/PI Leadership Plan: For applications designating multiple PDs/PIs, a new item of the research plan (item 14 in the November 2007 release of PHS 398 Table of Content), entitled “Multiple PD/PI Leadership Plan” must be included. A rationale for choosing a multiple PD/PI approach should be described. The governance and organizational structure of the leadership team and the research project should be described, and should include communication plans, process for making decisions on scientific direction, and procedures for resolving conflicts. The roles and administrative, technical, and scientific responsibilities for the project or program should be delineated for the PDs/PIs and other collaborators. 

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

Additional information is available in the PHS 398 grant application instructions.

3. Submission Dates and Times

Applications must be received on or before the receipt date described below (Section IV.3.A). Submission times: Not applicable.

3.A. Receipt, Review, and Anticipated Start Dates
Letters of Intent Receipt Date: July 15, 2008
Application Receipt Date: August 15, 2008
Peer Review Date: November 2008
Council Review Date:  January, 2009
Earliest Anticipated Start Date: April 1, 2009

3. A.1. Letter of Intent

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

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 NIH IC staff to estimate the potential review workload and plan the review.

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

The letter of intent should be sent to:

Malcolm Smith, M.D., Ph.D.
Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Boulevard, EPN Room 7025, MSC 7436 Bethesda, MD 20892 (for U.S. Postal Service Express or regular mail)
Rockville, MD 20852 (for express/courier delivery; non-USPS service)
Telephone: (301) 496-2522
Fax: (301) 402-0557
Email: smithm@ctep.nci.nih.gov

3. B. Sending an Application to the NIH

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

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

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

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

Referral Officer
Division of Extramural Activities
National Cancer Institute
6116 Executive Boulevard, Room 8041,
Bethesda, MD 20892-8329 (for U.S. Postal Service express or regular mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: (301) 496-3428
FAX: (301) 402-0275
Email: ncirefof@dea.nci.nih.gov

3. C. Application Processing

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

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

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

4. Intergovernmental Review

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

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

Pre-award costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new or renewal award if such costs: 1) are necessary to conduct the project, and 2) would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new or renewal award.

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

6. Other Submission Requirements and Information

Awardees must agree to the "Cooperative Agreement Terms and Conditions of Award" in Section VI.2.A "Award Administration Information."

Appendix Materials

All paper PHS 398 applications submitted for May 25, 2008, and subsequent due dates must provide appendix material on CD only, and include five identical CDs in the same package with the application.  Paper applications submitted for due dates prior to May 25, 2008, may voluntarily provide the appendix on five identical CDs; if submitting CDs it is not necessary to include a paper appendix (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-031.html).

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

Resource Sharing Plan(s)

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

(a) Data Sharing Plan: Regardless of the amount requested, investigators are expected to include a brief 1-paragraph description of how final research data will be shared, or explain why data-sharing is not possible. Applicants are encouraged to discuss data-sharing plans with their NIH program contact. See Data-Sharing Policy or http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html.

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

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

Section V. Application Review Information


1. Criteria

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

2. Review and Selection Process

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

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

The following will be considered in making funding decisions:

The goals of NIH supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that an application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a meritorious priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. The following general (NIH-wide) criteria appended with aspects specific to this FOA will be used.

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

Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? For applications designating multiple PDs/PIs, is the leadership approach, including the designated roles and responsibilities, governance, and organizational structure, consistent with and justified by the aims of the project and the expertise of each of the PDs/PIs?
In addition, specific to this FOA -- Research Strategies and Research Plans:

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

In addition, specific to this FOA

Investigators: Are the PD/PI(s) and other key personnel appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers? Does the PD/PI(s) and investigative team bring complementary and integrated expertise to the project (if applicable)?

In addition, specific to this FOA

Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support?

In addition to the above NIH-wide review criteria, the following FOA-specific criteria will be applied to applications

Clinical Trial Protocol Development: 

Data Management and Analysis and Quality Assurance:

Regulatory Compliance:

Member Institutions: 

2. A. Additional Review Criteria

In addition to the above criteria, the following items will continue to be considered in the determination of scientific merit and the rating:

Protection of Human Subjects from Research Risk: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed (see the Research Plan section on Human Subjects in the PHS 398 instructions).

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

Care and Use of Vertebrate Animals in Research: If vertebrate animals are to be used in the project, the five points described in the Vertebrate Animals section of the Research Plan will be assessed.

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

2. B. Additional Review Considerations

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

2. C. Resource Sharing Plan(s)   

When relevant, reviewers will be instructed to comment on the reasonableness of the following Resource Sharing Plans, or the rationale for not sharing the following types of resources. However, reviewers will not factor the proposed resource sharing plan(s) into the determination of scientific merit or priority score, unless noted otherwise in the FOA.  Program staff within the NIH IC will be responsible for monitoring the resource sharing.

3. Anticipated Announcement and Award Dates

Not Applicable

Section VI. Award Administration Information


1. Award Notices

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

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General.

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

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

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

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

2. A. Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

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

Throughout these Terms and Conditions of Award, “PBTC” refers to the organizational structure which is composed of the PBTC PI and other key personnel, the Operations Center, the Statistics and Data Center, and Member Institutions, all of whom agree to collaborate on research goals of the PBTC. 

2.A.1. Awardees and Principal Investigator Rights and Responsibilities

The PBTC is responsible for developing the details of its clinical and laboratory research program, including definition of objectives and approaches, planning, implementation, analysis, interpretations and conclusions of studies, and publication of results.  The PBTC will continue to develop Phase 1, Phase 2, and pilot clinical trial protocols in accord with the research interests, abilities and goals of the PBTC, and submit these protocols to CTEP for review prior to their implementation. Specific Rights and Responsibilities for the Operations Center, Statistics and Data Center, Member Institutions, and the Imaging Center are described below.

The following documents (and any subsequent modification to them) are hereby incorporated by reference as terms of award. These documents describe the programmatic responsibilities for the conduct of the research supported by this cooperative agreement.

All awardees must comply with the NCI Clinical Terms of Award (http://deainfo.nci.nih.gov/grantspolicies/ClinicalTrials/Clinical%20Trial%20Terms%20of%20Award.pdf) as required by the NCI policy http://deainfo.nci.nih.gov/grantspolicies/index.htm) for clinical studies and trials when they are a component of any research being funded by the NCI.  The PIs must ensure that their clinical studies and trials are monitored commensurate with the degree of potential risk to study subjects and the complexity of the study.

Responsibilities of Operations Center and Statistics and Data Center:

The Operations Center and the Statistics and Data Center are responsible for coordinating the development of clinical trial protocols, submission of these protocols for review and approval, study conduct (including central data collection and analysis), quality assurance/quality control and study monitoring, protocol amendments/status changes, adherence to requirements regarding investigational drug management and federally mandated regulations and protocol and performance reporting.  Specific responsibilities are listed below.

1)       Organizational Structure and Standard Operating Procedures (SOPs):  The Operations Center, with the guidance of the PI designated as its director, the lead PI (if different) and Steering Committee, are responsible for development and maintenance of an organizational structure and Standard Operating Procedures for the PBTC.

2)       Clinical Trial Protocol Development: It is the responsibility of the PBTC to develop the details of the research design, including definition of objectives and approaches, planning, implementation, analysis, interpretations and conclusions of studies, and publication of results.  The Operations Center is responsible, in accordance with the PBTC’s SOPs, for the preparation and implementation of procedures for development and submission of PBTC clinical trial protocols to the CTEP Protocol and Information Office (PIO) in a timely fashion for review and approval by NCI.

a)       Clinical trial protocols should be developed, submitted, and implemented in accordance with the DCTD “Investigator's Handbook" (http://ctep.cancer.gov/handbook/index.html).

b)       Submission of PBTC clinical trial protocols for review and approval by NCI should be preceded by a written Letter of Intent (LOI) to the CTEP LOI Coordinator declaring interest in conducting a particular study.  LOIs should be submitted using the LOI template (http://ctep.info.nih.gov/guidelines/index.html).

c)       The Operations Center is responsible for communicating the results of the CTEP Protocol Review Committee to relevant PBTC Committees and PBTC members.

d)       The PBTC will not expend NCI funds to conduct any study disapproved by CTEP unless CTEP's disapproval has been modified by the arbitration process (see Section VI.2.A.4 Arbitration Process).

e)       All clinical trials utilizing NCI-sponsored investigational agents shall be conducted in accordance with the terms of the “Intellectual Property Option to Collaborators” (http://ctep.info.nih.gov/industry/ipo.html) and the NCI Standard Protocol Language for Cooperative Research and Development Agreements (CRADAs) and Clinical Trial Agreements (CTAs).

f)         The PBTC’s SOPs should include timelines for the steps involved in the development of LOIs, Concept Proposals, and clinical trial protocols, and should include mechanisms for monitoring the performance of the Operations Center and PBTC members in meeting these time lines.  The PBTC’s SOPs should also include corrective action plans outlining the steps to be taken when these time lines are not met.  Data concerning the PBTC’s performance in meeting timelines for protocol development should be provided in the Annual Progress Report.

3)       Study Monitoring: The PBTC must follow the general guidelines for study monitoring for CTEP-sponsored trials as described at http://ctep.info.nih.gov/monitoring/section2.html#2.2.2.  The PBTC is responsible for assuring accurate and timely monitoring of the progress of each study, and therefore must have standard procedures for timely data collection and data management consistent with the intensive data requirements and the need for rapid reporting necessary for Phase 1, Phase 2, and pilot clinical trials.  Standard procedures include (but are not necessarily limited to):

a)       Precise tracking of patient accrual and adherence to accrual goals defined by clinical trial protocol-defined accrual goals.  If the PBTC wishes to continue accrual to a study beyond the total accrual goal for eligible and ineligible patients specified in the clinical trial protocol, the PBTC must seek approval from CTEP prior to continuing patient accrual.

b)       Procedures for assigning dose level (for Phase 1/dose escalation studies) at the time a new patient is enrolled in a study, and assuring that the required observation period has elapsed before beginning a higher dose level.

c)       Ongoing assessment of patient eligibility and evaluability.

d)       Adequate measures to ensure timely medical review and assessment of individual patient data;

e)       Adequate measures to ensure timely submission of clinical trials data (e.g., adverse events, anticancer response, etc.) from Member Institutions. These measures should include procedures for monitoring compliance with PBTC’s guidelines for data timeliness on an institution and a study basis, including summary reports of data submission timeliness to be used for Institutional Performance Review and to be used for study monitoring (e.g., as specified by the Data and Safety Monitoring Plan).  These summary reports should also be included in the Annual Progress Report.

f)         Rapid reporting of treatment-related morbidity information and measures to ensure communication of this information to all relevant parties.  For investigational agents sponsored by the NCI, this involves reporting to the Investigational Drug Branch (IDB), CTEP, via the Adverse Event Expedited Reporting System (AdEERS) according to CTEP guidelines specified in each protocol (http://ctep.info.nih.gov/reporting/adeers.html).

g)       Preparation of study monitoring reports describing patient accrual and demographics, data timeliness, toxicity, and other items as appropriate. Examples of study monitoring reports include reports prepared for study chairs, the semiannual reports for PBTC meeting agendas, and reports as required to comply with the PBTC’s Data and Safety Monitoring Plan.

h)       Adequate policies and procedures for closure of studies.  If the PBTC wishes to close accrual to a study prior to meeting the initially established accrual goal, the interim results and other documentation should be made available to NCI staff for review and concurrence prior to implementation of the decision.  It is recommended that statistical guidelines for early closure be presented as explicitly as possible in the clinical trial protocol in order to facilitate these decisions.  In the event that the study is recommended for early closure for safety reasons, procedures in the Data and Safety Monitoring Plan regarding notification of CTEP must be followed.

4)       Data Management Policies and Practices:  The responsibilities of the Statistics and Data Center for data management related to study monitoring include:

a)       Providing for central storage, security, processing, and retrieval of study results;

b)       Incorporating security features consistent with the guidelines of the U.S. DHHS;

c)       Implementing procedures for backing up the PBTC’s clinical and administrative data, including intermittent duplication of the database with storage at a remote facility;

d)       Protecting patient confidentiality at all steps in the submission and analysis of clinical trials data and ensuring the technical integrity and security of the data management systems; and

e)       Providing NCI in a timely manner, upon the request of the Grants Management Officer, true copies of data files and supporting documentation for all NCI-supported protocols that have a major impact on patterns of care, as determined by the NCI.

5)       Quality Control of PBTC Clinical Trials: Quality Control and Quality Assurance (QC/QA) Programs are inherently linked.  The Clinical Trials Monitoring Branch (CTMB) of CTEP provides direct oversight of NCI-sponsored Consortia and Cooperative Group QC/QA programs.  The PBTC is responsible for establishing and implementing mechanisms to assure the accuracy and reliability of its clinical trials data.  Quality control is a complex topic spanning the entire range of diagnostic and therapeutic modalities employed by the PBTC.  Key items that should be addressed concerning quality control procedures include:

a)       Institutional performance evaluations. Performance factors to be considered include:

i)         Accrual of adequate number of eligible patients onto PBTC trials;

ii)       Timely and accurate submission of required data;

iii)      Rigorous adherence to clinical trial protocol requirements;

iv)      Participation in study development and in timely publication of study findings;

v)        Participation in PBTC administrative and scientific committees and/or other PBTC activities; and

b)       Procedures for placing Member Institutions on probation for inadequate performance and for removing such institutions from the PBTC if performance is not adequate during the probationary period or at any time that the institution (or participating site) does not meet PBTC standards for institutional performance.

c)       Educational functions that address data collection, data management, and overall data quality. These aspects include, but are not limited to, the following elements:

i)         Training for new CRAs in the PBTC’s data submission policies and ongoing training for all CRAs concerning changes to PBTC procedures and instructions for data submission in new protocols;

ii)       Instruction for Study Chairs on their responsibilities for study monitoring;

iii)      Instruction for Member Institution Principal Investigators and all members at participating sites on their responsibilities in complying with the PBTC’s SOPs and Federal regulations at their institution; and

iv)      Training/guidance should also be provided to all participants on how to comply with NCI/NIH policies and procedures (e.g., Ethics, COI, etc.) in addition to the policies and procedures of other governmental agencies important to the conduct of clinical trials (e.g., Office for Human Research Protections, FDA).

d)       Procedures for central review of major elements that impact on the outcome of clinical trials.  This will include central review of claimed responses and adequacy of imaging studies submitted by member institutions, central review of submitted data with determination of protocol compliance in dose administration and dosage modification, and additional review as necessary.

e)       On-site Auditing: The PBTC’s on-site monitoring program will be coordinated with the Clinical Trials Monitoring Branch (CTMB) of CTEP.  As a sponsor for investigational agents and the funding agency for other cancer clinical trials, FDA regulations require Division of Cancer Treatment and Diagnosis (DCTD) to maintain a monitoring program.  The on-site audit will address issues of data verification, protocol compliance, compliance with regulatory requirements for the protection of human subjects and investigational agent accountability.  The PBTC is responsible for maintaining its on-site auditing program in compliance with the Clinical Trials Monitoring Branch (CTMB, CTEP) guidelines (http://ctep.info.nih.gov/monitoring/guidelines.html) and for submitting the results of audits to the NCI in accordance with the guidelines.  In the event that the NCI determines that a PBTC Member Institution failed to comply adequately with NCI guidelines for conduct of clinical trials, the accrual of new patients to PBTC protocols at the affected institution shall be suspended immediately upon notice of the NCI determination.  The suspension will remain in effect until the PBTC conducts the required audit and the audit report or remedial action is accepted by the NCI.  The Operations Center will be responsible for notifying any affected participating institution of the suspension.  During the suspension period, no funds from this award may be provided to the participating institution for new accruals, and no charges to the award for new accruals will be permitted.

6)       Timely reporting of data to CTEP using the Clinical Data Update System (CDUS).

a)       For most PBTC studies using NCI-sponsored investigational agents, CDUS Complete reporting procedures will be used, which capture demographic, adverse event information (by course), and response data.

b)       For clinical trials that do not use NCI-sponsored investigational agents, reporting to CTEP will generally use the CDUS Abbreviated procedures (demographic data only).

7)       Publications: Timely publication of major findings is central to the PBTC’s mission and is a primary means by which the PBTC’s accomplishments can be evaluated. 

a)       The PBTC will have timelines for the development of abstracts for meeting presentations and manuscripts for submission for publication in scientific journals based on its clinical trials and should have mechanisms for monitoring the performance of the PBTC’s components in meeting these timelines.  Corrective action plans will be implemented when these timelines are not met.

b)       Publication or oral presentation of work conducted under the PBTC’s Cooperative Agreement requires appropriate acknowledgment of NCI support.

c)       For investigations using an agent supplied under a CRADA or CTA, the NCI pharmaceutical collaborator will have an opportunity to review manuscript drafts prior to their submission for publication as per the NCI Standard Protocol Language for CRADAs and CTAs.  The NCI will have access to all data generated under this cooperative agreement and may periodically review the data.  The awardee will retain custody and primary rights to the data consistent with current DHHS, PHS, and NIH policies.

8)       PBTC Meetings: The Operations Center is responsible for the organization of semiannual  meetings to review the PBTC’s progress, establish priorities, and plan future activities.  Additional meetings between PBTC members and meetings with NCI staff may be held as needed.  Relevant responsibilities for meeting organization include:

a)       Arranging for appropriate meeting space and accommodations for attendees; 

b)       Developing and distributing meeting agendas;

c)       Providing the Report of Studies to include information detailing patient accrual and demographics, data timeliness, toxicity experienced by study participants, and other items (e.g., outcome data) as appropriate.  The Operations Center and Statistics and Data Center are responsible for ensuring that copies of the Report (electronic and/or hard copy) are distributed to PBTC members and NCI program staff.

d)       Preparing summaries as appropriate after each meeting to be sent to PBTC members and NCI program staff.

9)       PBTC Communications: The Operations Center must establish routine electronic communication with Member Institutions to facilitate clinical trial protocol development and study monitoring and to facilitate the work of the PBTC’s Study and Scientific Committees.  Relevant communication methods include web site postings, e-mail, teleconferences, and web/video conferences.

10)   Compliance with Federal Regulations Concerning Clinical Research: The PI and Operations Center will be responsible for ensuring that the PBTC is in compliance with all applicable federal regulations concerning the conduct of human subjects research.  Policies and guidelines to be addressed include:

a)       OHRP Assurances: The Operations Center must assure that each participating site has a current, approved assurance on file with OHRP.

b)       IRB Review of PBTC Protocols: The Operations Center must assure that each PBTC clinical trial protocol is reviewed and approved by each Member Institution’s IRB prior to patient entry, and must ensure that each clinical trial protocol undergoes continuing review no less than once per year by the IRB so long as the clinical trial is active.

c)       Assuring Appropriate Informed Consent: The Operations Center must assure that each patient (or legal representative) gives written informed consent prior to entry on study.

d)       IRB Review of the Operations Center and Statistics and Data Center (http://www.hhs.gov/ohrp/humansubjects/assurance/engage.htm): An IRB should determine and document that the Operations Center and Statistics and Data Center have sufficient mechanisms in place to ensure that (i) management, data analysis, and Data Safety and Monitoring (DSM) systems are adequate, given the nature of the research involved; (ii) sample protocols and informed consent documents are developed and distributed to each collaborating institution; (iii) each collaborating institution holds an applicable OHRP-approved Assurance; (iv) each clinical trial protocol is reviewed and approved by the IRB at the collaborating institution prior to the enrollment of subjects; (v) any substantive modification by the collaborating institution of sample consent information related to risks or alternative procedures is appropriately justified; and (vi) informed consent is obtained from each subject in compliance with DHHS regulations.

e)       Registration of PBTC Investigators: The Operations Center is responsible for assuring that PBTC investigators performing trials involving DCTD Investigational Agents are NCI-registered investigators (Form 1572).

f)         Adverse Event Reporting: The Operations Center is responsible for assuring timely reporting of all serious and/or unexpected adverse events.  Adverse events should be reported using the Common Terminology Criteria for Adverse Events (CTCAE), which is the NCI’s standard language for reporting adverse events in clinical trials (http://ctep.cancer.gov/reporting/ctc.html).  For investigational agents sponsored by the NCI, this involves reporting to the Investigational Drug Branch (IDB), CTEP, via the Adverse Event Expedited Reporting System (AdEERS) according to CTEP guidelines specified in each clinical trial protocol (http://ctep.info.nih.gov/reporting/adeers.html). 

g)       Assuring that the PBTC is in compliance with CTEP requirements described in the DCTD Investigators' Handbook for storage and accounting for investigational agents (including NCI/DHHS Drug Accountability Records [DAR] procedures), and is in compliance with FDA requirements for investigational agents.

11)   Managing and coordinating the acquisition and shipping of protocol-specified tumor specimens and biological fluids (with relevant clinical data) to the appropriate laboratories for testing and to a tumor/specimen repository for storage of specimens for future correlative laboratory studies.

12)   The Operations Center will be responsible for establishing a COI Policy for the Group.  This policy should ensure that there is no reasonable expectation that the design, conduct, or reporting of research conducted by the Group will be biased by any conflicting financial interest of an investigator.  The policy should be in compliance with the general policies of the NCI and the NIH.

13)   Fiscal management of the PBTC, including:

a)       Establishment of consortium arrangements with Member Institutions to support PBTC-related activities at each Member Institution;

b)       Administration of the Biology/Pharmacokinetics Fund, including the process for selecting laboratories to perform specific studies (a competitive process is encouraged when feasible); and

c)       Distribution of funds from the Patient Studies Research Fund to member institutions to support special clinical research costs for patients accrued onto PBTC clinical trials.  Funds will be disbursed on a capitation basis upon documentation that the test(s) have been performed.  It is anticipated that for each PBTC protocol, the capitation formula for institutional reimbursement required to offset specific research expenses will be reviewed and approved by the Steering Committee.

14)   Submission of annual progress reports to the NCI that describe activities and accomplishments during the previous year of the PBTC.  The report will use the PHS 2590 and include:

a)       A summary of the overall performance of the Operations Center and Statistics and Data Center in meeting their responsibilities to the PBTC for clinical trial protocol development, study monitoring, and complying with Federal regulations;

b)       Summary data on performance of each PBTC Member Institution, including clinical trial accrual, quality and timeliness of submitted data, and involvement in clinical trial protocol development activities; and

c)       Research plans, changes in procedures and/or staff, and the proposed budget for the coming year.

15)   Procedures to allow non-PBTC institutions to participate in the development and conduct of PBTC trials in those limited situations in which an institution has distinctive expertise or capabilities that would contribute to successful conduct of a PBTC study.

16)   The PBTC will be responsible for conducting a competition in year 3 of the project period in which those institutions rated in the lower tertile of performance in the first two years of the award must compete with non-PBTC institutions to maintain their position in the PBTC.  The PBTC must submit a specific plan for recompetition of this subset of its member institutions to CTEP by the end of year 2 of the project period.  Following approval of the plan by CTEP, the PBTC will conduct the recompetition process in year 3.

17)   Contingent on the availability of funds, the NCI may release during the PBTC project period an RFA for competitive supplements to expand the scope of the PBTC award by innovative clinical trials conducted in non-PBTC institutions. The PBTC will be responsible for identifying appropriate candidate non-PBTC institutions and working jointly with them to prepare applications for such competitive supplements.  These applications will undergo regular NIH peer review process by an NCI-managed peer review committee. Supplemental funds will be awarded only if one or more of the applications (and the proposals within them) are determined to be of sufficiently high scientific merit through peer review and through the NCI’s programmatic decision-making process.  If one or more supplements is/are funded, then PBTC would make subcontract(s) to the selected non-member institutions.

Responsibilities of Member Institution:

1)       Participation of Member Institution investigators in PBTC activities, as evidenced by the following:

a)       Offering participation in PBTC studies to eligible patients and entering sufficient number of patients to meet accrual targets;

b)       Participating in research design and clinical trial protocol development, including:

i)         Serving as clinical trial protocol Chairs or as members of protocol study teams; 

ii)       Participating in the Scientific and Administrative Committees needed to support the PBTC’s research objectives;

c)       Participation in meetings: Appropriately participating in the semiannual  meetings of the PBTC (and in other meetings as deemed necessary for performance of PBTC activities);

d)       Following the PBTC’s SOPs for the conduct of clinical research.

2)       Implementing the core data collection method and strategy of the PBTC: It is the responsibility of each Member Institution to ensure that the procedures for data submission for each PBTC clinical trial protocol are understood by investigators at the site and that protocol-specified data are submitted accurately and in a timely manner to the Statistics and Data Center.

3)       Complying with mechanisms for quality assurance and quality control of therapeutic and diagnostic modalities employed in PBTC trials. Institutional responsibilities for quality control include, but are not limited to, the following:

a)       Chemotherapy: Submission of appropriate data to allow determination of clinical trial protocol compliance in dose administration and dosage modification;

b)       Imaging: Submission of appropriate imaging studies to allow central review of claimed responses and adequacy of imaging and to allow the imaging research objectives of the PBTC to be met.

4)       On-site Auditing: Participation in the on-site monitoring program established by the PBTC.

5)       Human Subjects Protection: Each institution must comply with OHRP and FDA regulations concerning protection of human subjects. Member Institutions must implement the procedures established by the PBTC to meet OHRP and FDA requirements for the protection of human subjects.

6)       Adverse Event Reporting: Implementing the procedures established by the PBTC for assuring timely reporting of all serious and/or unexpected adverse events.

7)       Investigational agent responsibilities: Implementing the procedures established by the PBTC for assuring that PBTC investigators performing clinical trials involving DCTD Investigational Agents are NCI registered investigators (Form 1572) and for assuring that the Member Institution PBTC complies with CTEP requirements described in the DCTD Investigators' Handbook for storage and accounting for investigational agents (including NCI/DHHS Drug Accountability Records [DAR] procedures), and is in compliance with FDA requirements for investigational agents.

8)       Submission of specimens: Acquisition and submission of protocol-specified tumor specimens, biological fluids and relevant clinical data to the appropriate laboratories where these specimens will be tested or stored for future studies.

9)       Serving as a resource for the conduct of protocol-specified laboratory projects (e.g., pharmacokinetic studies, tumor biology studies).  The PBTC Steering Committee will establish a process for the selection of the laboratories to perform these studies.  These projects may be supported using the Biology/Pharmacokinetics Funds of the PBTC or by independent funding.

10)   Participating in PBTC procedures for the timely publication of major findings.

11)   Conflict of Interest: Complying with the Conflict of Interest Policy of the PBTC to ensure that there is no reasonable expectation that the design, conduct, or reporting of research conducted by the PBTC will be biased by any conflicting financial interest of an investigator.

Responsibilities of Imaging Center:

1)       Developing a correlative imaging research program, in collaboration with other PBTC investigators, which directly contributes to the PBTC’s ability to incorporate imaging endpoints into its overall clinical research program.

2)       Directing the primary analysis of the PBTC’s imaging studies and serving as a repository for research imaging studies.

3)       Serving as a coordinator for imagers at Member Institutions sites to facilitate common imaging protocols as appropriate.

4)       Serving as a resource for the PBTC Steering Committee.

5)       Participating in the development of clinical trial protocols, particularly for imaging components.

6)       Participating in the Scientific and Administrative Committees needed to support the PBTC’s research objectives.

7)       Participation in meetings: Appropriately participating in the semi-annual meetings of the PBTC (and in other meetings as deemed necessary for performance of PBTC activities).

8)       Human Subjects Protection: It is anticipated that the Imaging Center will be retrospectively reviewing images without patient identifiers.  However, as applicable the Center must be in compliance with OHRP and FDA regulations concerning protection of human subjects.

9)       Participating in PBTC procedures for the timely publication of major findings.

10)   Collaborating, as appropriate, on problems of mutual interest with the Imaging Center of the NCI Adult Brain Tumor Consortium and with other NIH imaging networks.

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 DHHS, PHS, and NIH policies.

2.A.2. NIH Responsibilities

The NCI and NINDS will coordinate and facilitate various activities of the PBTC.  The NCI and NINDS staff members will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards.  The NCI Program Director serving as Project Scientist will be the main NCI contact for all facets of the scientific interaction with the awardees and will provide oversight and advice to the awardee on specific scientific and/or analytic issues in addition to programmatic issues.  The NINDS Program Director serving as Project Coordinator will also provide oversight, advice, and coordination of efforts with NINDS-supported activities and initiatives.   Additional NCI and NINDS staff members may also be involved as needed (for example, by acting as Collaborators or Coordinators).

Specific responsibilities of NIH Program Staff will include the following:

1)       Monitoring PBTC progress:  Actions necessary for monitoring may include, but are not limited to, the following: regular communications with the PI and staff members, periodic site visits for discussions with awardee research teams, response audits to confirm activity reported from a PBTC clinical trial, observation of field data collection and management techniques, fiscal review, review of clinical trial reports submitted by the PBTC to NCI, review of the PBTC’s annual progress report, and attendance at PBTC meetings.  The NCI retains, as an option, the right to conduct periodic external reviews of progress.

2)       Scientific Liaison:  Serving as a resource with respect to other ongoing NCI and NINDS activities that may be relevant to the PBTC research efforts to identify promising new leads, to facilitate compatibility with other NCI and NINDS research projects, and to avoid unnecessary duplication of effort.

3)       CTEP Assistance in Clinical Trial Protocol Development:  The clinical trial protocol must be a detailed written plan of a clinical experiment mutually acceptable to the PBTC and to the CTEP Protocol Review Committee (PRC).  Communication at the various stages of protocol development is encouraged as necessary to promote protocol development and implementation.  Protocols should be preceded by a written Letter of Intent (LOI) from the PBTC declaring interest in conducting a particular study. The PRC will formally review the LOI.  Following review, the NCI Project Scientist will provide a Program response to the PBTC and will address the following issues: (a) the existence and nature of concurrent clinical trials in the area of research, pointing out possible duplication of effort; (b) information including relevant pharmacokinetic and pharmacodynamic data concerning investigational agents; (c) availability of investigational agents; (d) the PRC's assessment of the scientific rationale and value of the proposed study, its design, and statistical requirements; (e) appropriate inclusion of NCI Standard Protocol Language for CRADAs and CTAs in the protocol; and (f) the implementation of the study, if indicated.  The LOI mechanism is designed for preliminary review and is recommended to expedite clinical trial protocol development and implementation and to facilitate agreement on study priority and design (for further discussion of these mechanisms, see the DCTD Investigator's Handbook at http://ctep.cancer.gov/handbook/).

4)       CTEP Review of Proposed Clinical Trial Protocols:  All PBTC protocols, including protocols utilizing agents not sponsored by NCI, will be reviewed by the PRC, which meets weekly and is chaired by the Associate Director, CTEP.  Ad hoc reviewers, external to NCI, will be utilized when deemed appropriate by the PRC chairperson.  Following the review of the clinical trial protocol by the PRC, the NCI Project Scientist will provide the PBTC with a consensus review that describes recommended modifications and other suggestions, as appropriate (see the DCTD Investigator's Handbook, for further information regarding protocol review at CTEP).  The major considerations relevant to Protocol Review by CTEP include:

a)       the strength of the scientific rationale supporting the study;

b)       the clinical importance of the question being posed;

c)       the avoidance of unnecessary duplication with other ongoing studies;

d)       the appropriateness of study design;

e)       consistency with development plans for particular IND agents;

f)         a satisfactory projected accrual rate and follow-up period;

g)       patient safety;

h)       compliance with federal regulatory requirements;

i)         adequacy of data management;

j)         appropriateness of patient selection, evaluation, assessment of adverse events, response to therapy and follow-up; and

k)       methods of monitoring and reporting to NCI to be used.

If a proposed clinical trial protocol is disapproved, the specific reasons for lack of approval will be communicated in writing by the NCI Project Scientist to the PBTC as a consensus review within 30 days of protocol receipt by the NCI.  NCI will not provide investigational agents or permit expenditure of NCI funds for a clinical trial protocol that it has not approved.  The NCI Project Scientist will be available to assist the PBTC in developing a mutually acceptable protocol, consistent with the research interests, abilities and strategic plans of the PBTC and of the NCI.

5)       CTEP Protocol Amendment Review:  Any change to the protocol document subsequent to its approval by CTEP must be submitted in writing for review and approval prior to implementation (see Section 8.6 – The Investigator’s Handbook for further discussion of these procedures). 

6)       CTEP Involvement in Auditing of Member Institutions: The Clinical Trials Monitoring Branch of CTEP will coordinate with the PBTC the performance of on-site audits at PBTC Member Institutions, which are to occur at approximately 2-3 year intervals.  The Clinical Trials Monitoring Branch will review audit results and the corrective plans developed by the PBTC in response to the audits.

7)       CTEP Involvement in Imaging Research:  The NCI Imaging Research Coordinator will advise the PBTC Steering Committee (through the NCI Project Scientist) with respect to ongoing NCI activities and research opportunities related to the application of imaging in drug development.  He/she will participate in CTEP review of PBTC protocols with imaging components and will assist the NCI Project Scientist and the NINDS Project Coordinator in the overall review of PBTC imaging research activities and accomplishments.

8)       CTEP Involvement in Radiation Oncology Research:  The NCI Radiation Oncology Research Coordinator will advise the PBTC Steering Committee (though the NCI Project Scientist) with respect to ongoing NCI activities and research opportunities related to radiation therapy for pediatric brain cancers.  He/she will participate in CTEP review of PBTC protocols with radiation therapy components and will assist the NCI Project Scientist in the overall review of PBTC radiation oncology research activities and accomplishments.

9)       CTEP Involvement in Clinical Trial Protocol Closure: Protocol closure is primarily the responsibility of the PBTC and the specific Protocol Committee.  The NCI Project Scientist will also monitor clinical trial protocol progress and may request protocol closure to further patient accrual for the following reasons: (a) insufficient accrual rate; (b) accrual goal met; (c) poor protocol performance; (d) patient safety or regulatory concerns; (e) study results are already conclusive; and (f) emergence of new information that diminishes the scientific importance of the study question.  NCI will not provide investigational agents or permit expenditures of NCI funds for a study after requesting closure (except for patients already on-study).

10)   Data Management and Analysis Review: NCI Biometrics Research Staff will review mechanisms established by the PBTC for data management and analysis.  When deemed appropriate, staff will make recommendations to ensure that data collection and management procedures are adequate for quality control and analysis and as simple as appropriate in order to encourage maximum participation of physicians entering patients and to avoid unnecessary expense.  The NCI will have access to all data, although they remain the property of the awardee institution.  Data must also be available for external monitoring as required by NCI's agreement with the FDA relative to the NCI's responsibility as drug sponsor.

11)   Data and Safety Monitoring Plan:  The NCI Program Official, assisted by the Biostatistical Research Branch (BRB) staff, will assess PBTC compliance with NCI and NIH established policies on Data and Safety Monitoring Plans.  The NCI Project Scientist must review and approve the PBTC’s Data and Safety Monitoring Plan. One or more CTEP staff will serve as non-voting members on the PBTC’s Data and Safety Monitoring Committee (DSMC), should the Data and Safety Monitoring Plan (DSMP) specify a DSMC.

12)   PBTC Meetings:  The NCI Program Official and Project Scientist as well as the NINDS Project Coordinator will attend semiannual PBTC meetings to discuss relevant scientific information, to discuss progress in the clinical trials, and to discuss the status of newly available investigational agents and other research opportunities in order to plan future activities. Other NCI staff members (e.g., from the Investigational Drug Branch, Radiation Research Program, and Diagnostic Imaging Program) and NINDS staff members will attend as needed.

13)   CTEP Involvement in Investigational New Drug (IND) Applications:  The NCI Program Official and Project Scientist, assisted by the Chief, Regulatory Affairs Branch (RAB), CTEP, will advise investigators of specific requirements and changes in requirements concerning IND sponsorship that the FDA may mandate. Investigators performing trials under cooperative agreements will be expected, in cooperation with the NCI, to comply with all FDA monitoring and reporting requirements for investigational agents.

14)   CTEP Review of Federally Mandated Regulatory Requirements:  The Chief, Clinical Trial Monitoring Branch (CTMB), through the NCI Program Official and Project Scientist, will advise the PBTC regarding mechanisms to meet FDA regulatory requirements for studies involving DCTD-sponsored investigational agents and OHRP requirements for the protection of human subjects by PBTC institutions.

15)   Access to Data:  The NCI will have access to all data generated under this cooperative agreement and may periodically review the data.  Data must also be available for external monitoring as required by NCI's Drug Master File Agreement with the FDA relative to the responsibility of the NCI as an IND agent sponsor.  Data from studies of non-NCI-sponsored agents must be available for external monitoring as described in the policies and procedures established by the PBTC for on-site auditing of clinical trials data.  The awardee will retain custody and primary rights to the data consistent with current HHS, PHS and NIH policies. The awardee will comply with the data access provisions of applicable CTAs and CRADAs, and when these agreements are in place the Industry Sponsor will have complete access to the data for any and all regulatory filings.

16)   Access to Agents for Pre-Clinical Testing: For NCI-sponsored IND agents, NCI will facilitate transfer of material to investigators with a Materials Transfer Agreement (MTA).

17)   CTEP Review of Progress:  Performance of the PBTC will be reviewed at least annually by the NCI Project Scientist and Program Official on the basis of the information provided at the semiannual and other meetings, in the annual progress reports and in the CDUS reports submitted to CTEP for each of the PBTC’s clinical trials.  Insufficient patient accrual or progress, or noncompliance with the terms of award, including these Terms and Conditions of Award, may result in a reduction of budget, withholding of support, suspension, or termination of the award.

18)   Potential Expansion of PBTC Scope: Contingent on the availability of funds, NCI staff members in conjunction with NINDS will be responsible for developing an RFA for competitive supplements to expand the scope of the PBTC award by innovative clinical trials conducted in non-PBTC institutions. 

The NCI Project Scientist and the NINDS Project Coordinator as well as other NIH staff members acting as Collaborators or Coordinators will not attend peer review meetings of renewal (competing continuation) and/or supplemental applications.  If such participation is essential, the NCI Project Scientist will seek NCI waiver according to the NCI procedures for management of conflict of interest if such participation is deemed necessary.  The NINDS Project Coordinator will seek analogous waiver.

Additionally, an NCI Program Director acting as Program Official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.  The NCI Program Official and Project Scientist may be the same person.  In that case, the individual involved will not attend peer review meetings of renewal (competing continuation) and/or supplemental applications or will seek NCI waiver as stated above.

2.A.3. Collaborative Responsibilities

The PBTC will have a Steering Committee as a governing body.  The Steering Committee will include as voting members the PBTC lead PI, one representative from each Member Institution (site PI or another designated investigator), the PI(s) directing the Operations Center and Statistics and Data Center, and a patient/family representative. Each voting member will have one vote. The NCI Project Scientist will serve as an advisory (non-voting) member to the Steering Committee.  The NINDS Project Coordinator as well as additional NIH representatives may participate as advisors and observers in the Steering Committee meetings as needed and will also not have voting rights.

The Steering Committee will be responsible for the approval of any changes to the PBTC organizational structure and PBTC Standard Operating Procedures.  The Steering Committee will have primary responsibility to establish priorities, and to develop and provide preliminary approval of protocols (prior to submission to NCI and final NCI approval), and to review progress. The Steering Committee will be responsible for reviewing on a regular basis the performance of the Operations Center and Statistics and Data Center and the performance of the ancillary scientific activities (imaging, pharmacology, and biologic studies).  The Steering Committee will be responsible for assuring that deficiencies identified during these reviews are adequately addressed in a timely manner.   The Steering Committee will be responsible for reviewing Member Institutions for adequate performance, and will have the authority to place on probation and to suspend Members and to add new Members to replace any members suspended from the PBTC. The Steering Committee will also establish a process for the selection of the laboratories to perform laboratory studies associated with individual clinical trial protocols.  The Steering Committee will authorize the spending of funds from the Biology/Pharmacokinetics Fund and the Patient Studies Research Fund.

2. A. 4. Arbitration Process

Any disagreement that may arise on scientific/programmatic matters (within the scope of the award), excluding patient safety issues or regulatory compliance, between award recipients and the NIH may be brought to arbitration.  An Arbitration Panel composed of three members will be convened to review the CTEP decision and recommend an appropriate course of action to the Director, DCTD.  It will have three members: a designee of the Steering Committee; one NCI designee; and a third designee with expertise in the relevant area who is chosen by the other two.  In the case of individual disagreement, the first member may be chosen by the individual awardee. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and DHHS regulations 45 CFR Part 16.

3. Reporting

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

A suggested format for PBTC-specific information relevant to the progress summary section of the Form PHS 2590 will be provided.  Performance of the PBTC in developing new LOIs and protocols should be discussed, as should the performance of Member Institutions in participating in PBTC studies and the performance of reference laboratories.  An update on clinical trials that were approved, activated, closed and/or completed during the relevant budget period should be discussed in the progress summary.  Plans pertaining to clinical trial activities for the next budget period should be addressed as well.

Clinical trials reporting requirements will be in agreement with FDA regulations and NCI procedures. Interim reports of each activated and ongoing clinical trial should be prepared for each PBTC semiannual meeting and shall include specific data on patient/participant accrual as well as detailed reports of treatment-associated morbidity. Quarterly accrual reports must be provided as appropriate to CTEP for all active trials through the NCI’s Instructions and Guidelines for CDUS reporting are at http://cancer.gov/reporting/cdus.html.

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

Section VII. Agency Contacts


We encourage your inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues:

1. Scientific/Research Contacts:

NCI Contact:

Malcolm Smith, M.D., Ph.D.
Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Boulevard, EPN Room 7025, MSC 7436 Bethesda, MD 20892 (for U.S. Postal Service Express or regular mail)
Rockville, MD 20852 (for express/courier delivery; non-USPS service)
Telephone: (301) 496-2522
Fax: (301) 402-0557
Email: smithm@ctep.nci.nih.gov

NINDS Contact:

Jane W. Fountain, Ph.D.
Program Director
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard, Room 2110, MSC 9521
Bethesda, MD 20892-9521 (for U.S. Postal Service Express or regular mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: 301-496-1431
FAX: 301-402-2060
Email: fountai@ninds.nih.gov

2. Peer Review Contacts:

Referral Officer
Division of Extramural Activities
National Cancer Institute
6116 Executive Boulevard, Room 8041, MSC 8329
Bethesda, MD 20892-8329 (for U.S. Postal Service regular or express mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: (301) 496-3428
FAX: (301) 402-0275
Email: ncirefof@dea.nci.nih.gov

3. Financial or Grants Management Contacts:

Eileen M. Natoli
Office of Grants Administration
National Cancer Institute
6120 Executive Boulevard, EPS Room 243, MSC 7150.
Bethesda, MD 20892-7150 (for U.S. Postal Service Express or regular mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: (301) 496-8791
Fax: (301) 496-8601
Email: natolie@mail.nih.gov

Section VIII. Other Information


Required Federal Citations

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

Human Subjects Protection:
Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

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

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

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

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

Access to Research Data through the Freedom of Information Act:
The Office of Management and Budget (OMB) Circular A-110 has been revised to provide access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this funding opportunity in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award.

Sharing of Model Organisms:
NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh Dole Act (see the NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm). All investigators submitting an NIH application or contract proposal, beginning with the October 1, 2004 receipt date, are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.

Inclusion of Women And Minorities in Clinical Research:
It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.

Inclusion of Children as Participants in Clinical Research:
The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all clinical research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them.

All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects (http://grants.nih.gov/grants/funding/children/children.htm).

Required Education on the Protection of Human Subject Participants:
NIH policy requires education on the protection of human subject participants for all investigators submitting NIH applications for research involving human subjects and individuals designated as key personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

Human Embryonic Stem Cells (hESC):
Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov). It is the responsibility of the applicant to provide in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s) to be used in the proposed research. Applications that do not provide this information will be returned without review.

NIH Public Access Policy Requirement:
In accordance with the NIH Public Access Policy (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-033.html) investigators must submit or have submitted for them their final, peer-reviewed manuscripts that arise from NIH funds and are accepted for publication as of April 7, 2008 to PubMed Central (http://www.pubmedcentral.nih.gov/), to be made publicly available no later than 12 months after publication. As of May 27, 2008, investigators must include the PubMed Central reference number when citing an article in NIH applications, proposals, and progress reports that fall under the policy, and was authored or co-authored by the investigator or arose from the investigator’s NIH award.  For more information, see the Public Access webpage at http://publicaccess.nih.gov/.

Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule", on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR).

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

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

Healthy People 2010:
The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This FOA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

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

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

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


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