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://www.cancer.gov/

Title: AIDS Malignancy Clinical Trials Consortium (Limited Competition U01)

Announcement Type

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

This Funding Opportunity Announcement (FOA) is a reissue of RFA-CA-06-502.

Request For Applications (RFA) Number: RFA-CA-10-502

Catalog of Federal Domestic Assistance Number(s)
93.393, 93.394, 93.395, 93.396, 93.399

Key Dates
Release Date: December 24, 2009
Letters of Intent Receipt Date: February 3, 2010
Application Receipt Date: March 3, 2010
Peer Review Date(s): April-May 2010
Council Review Date: August 2010
Earliest Anticipated Start Date: September 2010
Additional Information To Be Available Date (URL Activation Date): Not Applicable
Expiration Date: March 4, 2010

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

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. Awardee and 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

The purpose of the proposed Funding Opportunity Announcement (FOA) is to continue to provide support to the AIDS Malignancy Clinical Trials Consortium, commonly called the AIDS Malignancy Consortium (AMC) under the guidance of the AMC Chair and the Executive Committee (EC) of the AMC. The goals for the AMC are to continue cooperative activities in the following areas:

1. Maintaining a multidisciplinary research team that will develop and implement the scientific research agenda of the consortium;

2. Conducting, pilot Phase I, Phase II and Phase III clinical trials of novel agents and/or innovative approaches of AIDS-related cancer management;

3. Developing and conducting domestic and international clinical trials in the treatment and/or prevention of AIDS-related cancers and non-aids defining cancers associated with HIV disease; and

4. Developing correlative studies in the context of the clinical trials;

The AMC may request support for various components such as an Operation Center, Core Sites, Affiliate Sites, Network Core Laboratories, and Data management and Statistical Center. Sites will receive patient care costs on a capitation basis and for laboratory correlative studies, clinical pharmacology studies and international studies. The Consortium applicants must focus on at least four scientific disease-oriented themes. These research themes may be led by appropriate working groups (WG) including Working Group oriented on: Kaposi’s sarcoma (KS), lymphoma, HPV-associated cancers, and non-AIDS-Defining Cancers (NADCs). The network laboratories will be responsible for routine clinical trial support activities and pathogenesis-driven correlative studies. All clinical trials conducted by the AMC must be available to subjects of all racial/ethnic groups. It is expected that the AMC will work closely with local patient advocacy groups and institutional community advisory boards (CABs), and that CAB members will serve on the various AMC committees.

The Consortium will be expected to collaborate with NIH-supported HIV/AIDS supported clinical Trials Networks and other NCI-supported cooperative groups, programs and international networks to achieve the goals of the AMC and to leverage NCI funds in areas of mutual research interests.

Background

The spectrum of cancers seen in HIV-infected individuals is diverse and complex, and reflects an ever-changing HIV epidemic. In parts of the world where combination antiretroviral therapy (cART) is available, HIV-infected patients are living longer and are less likely to die of AIDS-defining malignancies within a year or two of developing AIDS. Despite the fact that the incidence of certain AIDS- defining malignancies has decreased in the United States (U.S.), HIV-infected patients continue to develop AIDS-defining or other HIV-related malignancies that substantially contribute to the morbidity and mortality of those infected with HIV. Moreover, the rates of certain non-AIDS-defining cancers (NADCs) are on the rise, with significant increases in Hodgkin disease, anal cancer, oropharyngeal cancer, and lung cancer. In countries in which cART is widely available, cancer is now the most common cause of death in HIV-infected patients, accounting for about one third of the deaths. Half of these cancer-related deaths continue to be from AIDS-defining malignancies. AIDS-related cancers are a growing global concern and are a major cause of morbidity and mortality in Africa and other regions of the developing world, where access to cART is limited. More than two-thirds of the HIV-infected population lives in sub-Saharan Africa, a region that is also an epicenter of for virally-related malignancies such as KS and Burkitt s lymphoma. The AIDS-defining malignancies (KS, aggressive non-Hodgkin lymphomas [NHL], and cervical cancer) are among the most common tumors in this region.

Epidemiological studies have revealed three principal cancer patterns in the HIV-positive population: 1) AIDS-defining cancers such as KS and the AIDS-related lymphomas (ARL) that occur at low CD4 levels; 2) non-AIDS-defining, rare cancers, such as Merkel cell carcinoma, conjunctival carcinoma and sebaceous gland tumors that occur substantially more frequently in HIV-infected individuals than in the general population; and 3) non-AIDS-defining, but otherwise common cancers (i.e. those of the lung, liver, anal, head and neck), that tend to present later in the course of the disease, more common than in the general population, are often more aggressive, occur earlier in life than in HIV-negative individuals, and may be resistant to therapy. All three cancer patterns lead to complex challenges for the clinical community regarding development of standards of care and appropriate treatment regimens.

Despite dramatic declines in HIV mortality rates due to the success of cART, cancer continues to be among the leading causes of death among HIV-infected patients. The introduction of cART led to an initial decline in the incidence of those AIDS-defining cancers that occur with very low CD4 cells, leading to the perception that cancer had been markedly reduced as a problem in this population. However, as HIV/AIDS patients live longer, the number of patients with AIDS has increased in the U.S. and they are at risk for developing cancer for a longer period of time. We are now seeing an increase in certain non-AIDS defining cancers in this population, as well as the late occurrence of KS and other AIDS-related cancers. There is evidence that the survival of patients for a relatively long time with partially compromised immune systems contributes to the development of these tumors. Indeed, as deaths due to AIDS itself or opportunistic infections have declined, cancer is becoming the leading cause of death in HIV-infected patients in areas where cART is available. Moreover, in those areas where cART is not available, AIDS-related tumors continue to be a major cause of morbidity and death.

Objectives and Scope:

The overarching goal for the Consortium is to continue its domestic and international efforts to develop more effective prevention and treatment strategies for cancers associated with HIV/AIDS.

Scientific approaches taken by the Consortium will continue to be broad in scope and will reflect the creativity and capabilities of team participants. Broad areas of study include translational research, optimization of clinical management and cancer prevention studies including those of risk and cancer susceptibility. The AMC will evaluate clinical interventions for treatment and prevention of cancer in HIV-positive patients, investigate the biology of these malignancies in the context of clinical trials, and donate specimens and clinical data to the AIDS and Cancer Specimen Resource (ACSR). In the case of pilot, Phase I, or Phase II clinical trials, laboratory studies to monitor patients (e.g., pharmacokinetics, pharmacodynamics) or to measure a particular biological response (e.g., imaging) that may provide information relevant to the interpretation of the success or failure of the therapy administered are encouraged. Tissue specimens or biological fluids are expected to be collected for use in laboratory studies and for donations to the ACSR.

It is expected that the AMC will substantially expand their international agenda particularly in Africa. This expansion is warranted to meet the challenges and the needs of resource limited nations to find scientific solutions to improve the standard of care of HIV patients with AIDS-related malignancies. This is expected to be accomplished by involving foreign investigators cooperatively in identifying the scientific issues to be addressed, capacity building, appropriate designs of treatment and non-treatment trials as needed.

Examples of research topics that may be pursued include (but are not limited to):

Kaposi’s sarcoma (KS): Despite the dramatic effects that cART had on the incidence of KS, the tumor continues to be the most commonly diagnosed tumor in HIV-positive patients. To date, there is not an accepted standard of care policy for patients on cART, with well controlled HIV infection who develop KS. Research on KS is needed in the following areas:

Non-Hodgkin’s Lymphoma (NHL): HIV-infected individuals are at increased risk for developing NHL. Although cART dramatically decreased the incidence of primary central nervous system lymphoma, conflicting results have been reported for systemic lymphoma. The prognosis for patients with systemic NHL remains poor with median survival duration of 6 months and a 2-year survival rate of 41%. Studies in the following areas are warranted:

Cervical Intraepithelial Neoplasia: Despite that the incidence of cervical cancer in the general population has been decreasing in the last 15 years, it did not change among HIV-seropositive women. The prevalence of HPV infection in HIV-positive women is more than twice that in HIV-negative women. Treatment failure and recurrence is common among HIV-infected women. Cervical cancer continues to be a major problem in developing countries particularly those in sub-Saharan Africa. Addressing the scientific research needs for optimizing prevention, and treatment of cervical cancer in women in those countries is warranted. Areas of interest may include:

Non-AIDS defining cancers: It’s clear we can expect HIV-positive patients with access to HAART to develop many of the more common cancers that occur in the general population.

Anal Intraepithelial Neoplasia (AIN): The incidence and risk for developing AIN and HPV-driven anal cancer occur more commonly in the HIV-positive men and women than in the general population. HAART seems to have a little effect on the natural history of these lesions. The following are some themes that need to be further investigated:

Head and Neck Cancers (HNSCC): People with HIV infection are at elevated risk for HNSCC. The risks of cancers of the tongue, tonsil and oropharynx are greater than expected among HIV-infected individuals in the U.S. and elsewhere. Both molecular and epidemiological data indicate a strong and consistent association between HPV and cancers that arise from the lingual and palatine tonsils within the oropharynx. HPV16 accounts for the overwhelming majority (90-95%) of HPV-associated cases of such cancers. Therefore it is necessary to:

Hodgkin’s Disease (HD):

Other non AIDS Defining Cancers: Other cancers that have been reported to increase among people living with HIV in the era of cART include lung cancer, hepatocellular carcinoma and colon cancer. The factors associated with the risk and susceptibility to these cancers is not well understood. The management of these cancers in the HIV setting needs to be optimized and issues related to the pharmacology and pharmacokinetics of drug-drug interactions of anti-chemotherapeutic cancer agents and antiretroviral therapy need to be determined.

International Research: With over 90 percent of the disease burden occurring in developing countries there is a need to expand AIDS clinical trials groups to these regions. In Africa, KS is now the most commonly diagnosed cancer in men and the second most common cancer in women, trailing behind cervical cancer. The incidence of KS in children has increased 40-fold during the AIDS epidemic in Africa. The oncogenic viruses associated with AIDS-related malignancies are endemic in these regions. Expansion of international collaborative work into Africa and other low- and middle-income countries on other continents is vital for epidemiologic, basic, and clinical research in populations with high prevalence of KS, NHL and cervical cancer and other HPV-related neoplasias. International collaboration should allow investigators to learn more rapidly about of the host, genetic, and viral factors involved in cancer development and susceptibility in this setting and eventually allow health care providers to be able to improve standards of treatment in these populations. Studies to be developed in resource limited countries will need to address local research questions aligned with the research agendas of these communities.

Consortium Organization

The AIDS Malignancy Consortium must include the following components:

  1. Group Chair Administrative Office (Administrative Core);
  2. Operations Center;
  3. Research Program based on disease-oriented scientific Working Groups.
  4. Clinical Trials Sites (encompassing domestic Clinical Core Sites and Affiliated Non-Core Clinical Trial Sites);
  5. Development of International Clinical Trials Sites;
  6. AMC Core Resource Laboratories;
  7. Statistics and Data Management Center (Group Biostatistician); and

The Principal Investigator (PI) of the awardee institution who serves as the AMC Group Chair is responsible for ensuring that the AMC’s major structural components are capable of carrying out their respective responsibilities and operate in a well-coordinated fashion. The Chair will be responsible for the scientific integrity, productivity, governance, and fiscal accountability of the group. The Group Chair may subcontract all or part of operational and fund disbursement activities to a Contract Research Organization approved by the NCI to serve as the Operations Center.

Research Program of the AMC is to be based on the disease-oriented scientific Working Groups. Each Working Group is expected to include as members investigators of appropriate profile from several Core Sites and Affiliated Sites. These Working Groups will contribute to the ongoing refinement and revision of the Network scientific research plan and oversee the development and implementation of clinical trial protocols in their respective areas.

The research activities of each Scientific Working Group are expected to include efforts to develop international clinical trials. The international research agenda should address the needs of resource-limited countries (primarily in Africa) for a specific disease area.

AMC Core Resource Laboratory will be responsible for performing standard testing of various parameters needed for the correlative studies pertaining to clinical trials and preclinical drug screening functions.

The AMC Statistical and Data Management Center must be able to provide biostatistics leadership and central data management capabilities for the AMC clinical research

AMC Governance

AMC will be governed by the Executive Committee and Steering Committee.

Executive Committee. The EC will be responsible for ensuring that the Consortium s major structural components are capable of carrying out their respective responsibilities and operate in a well-coordinated fashion.

Steering Committee. The primary function of the AMC Steering Committee will be to define research directions of the AMC and to assure that the clinical research procedures for the AMC are (a) sufficient to meet the program objectives; (b) protect participants enrolled on AMC studies; and (c) are being followed in the execution of the AMC clinical activities.

For details on the composition and functions of the Executive Committee and Steering Committee see Section VI.2A. Cooperative Agreement Terms and Conditions of Award.

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

Section II. Award Information

1. Mechanism of Support

This funding opportunity will use the U01 cooperative agreement award mechanism. In the cooperative agreement mechanism, the 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".

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

2. Funds Available

The total amount of funding that NCI expects to award through this announcement in FY 2010 is approximately $4.680 million. The total commitment for 5 years of funding is approximately $26,752,000 million from NCI. Although the financial plans of the NCI provides support for this program, award pursuant to this funding opportunity is contingent upon the availability of funds.

The eligible applicant may request a project period of up to 5 years.

Facilities and administrative costs requested by consortium participants are not included in the direct cost limitation, see NOT-OD-05-004.

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

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

The eligibility to apply in response to this limited competition FOA is limited to the current AMC Group Chair recipient institution (U01CA121947).

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research as the 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 programs.

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

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

Although the multiple PDs/PIs option is available, the applicants are encouraged to consider a single PD/PI, if this solution is preferred.

2. Cost Sharing or Matching

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

3. Other-Special Eligibility Criteria

Number of Applications. Applicants may submit only one application in response to this FOA.

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

Renewals. Renewal applications are permitted in response to this FOA

Section IV. Application and Submission Information

1. Address to Request Application Information

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

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 section of the Research Plan, 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 N/A.

3.A. Receipt, Review and Anticipated Start Dates
Letters of Intent Receipt Date: February 3, 2009
Application Receipt Date: March 3, 2010
Peer Review Date(s): April-May 2010
Council Review Date: August 2010
Earliest Anticipated Start Date: September 2010

3.A.1. Letter of Intent

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

  1. Descriptive title of proposed research;
  2. Name, address, and telephone number of the Principal Investigator;
  3. Names of other key personnel;
  4. Participating institutions; and
  5. Number and title of this funding opportunity.

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NCI 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:

Mostafa Nokta, MD, PhD.
Office of HIV and AIDS Malignancy
National Cancer Institute
31 Center Drive, Room 3A33, MSC 2440
Bethesda, MD 20892 -2440 ( for U.S. postal Service regular or express mail)
Bethesda, MD 20892 (for non-USPS delivery)
Telephone: (301) 496-4995
FAX: (301) 480-4137
Email: Mostafa.nokta@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 service)

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

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

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.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

The current AMC Principal Investigator (Group Chair) is responsible for coordinating the preparation of the application that must include all the components defined below.

For the AIDS Malignancy Clinical Trials Network application submitted in response to this FOA, the standard PHS 398 Research instructions for the application preparation are altered as follows:

Table of Contents (PHS 398 Form Page 3): Modify Form Page 3 of the PHS 398 to replace standard sub-sections of Section 3 Research Strategy of the PHS 398 Research Plan with the following new sub-sections A-J:

  1. AMC Overview
  2. Group Chair Administrative Office
  3. Operation Center
  4. AMC Progress Report
  5. Research Program
  6. AMC Clinical Core Sites
  7. Development of International Clinical Core Sites
  8. Affiliated Non-Core Clinical Trial Sites
  9. Statistics and Data Management Center
  10. Network Core Resource Laboratory Component

Budget (PHS 398 Form Pages 4 and 5): Follow the current PHS 398 instructions to provide a detailed budget (direct costs) for the entire application for the first 12-month period (Form page 4) and the entire proposed project period (Form page 5).

Use additional Form Pages 4 and 5 to provide detailed separate budget information (first year and cumulative budgets for the entire project period) for the following individual application components:

RESEARCH PLAN: The standard PHS398 Research Plan is altered as follows:

Other sections of the PHS398 Research Plan remain unmodified and should be completed following standard instructions.

A. Overview of Entire AMC Application (up to 12 pages)

Briefly outline the vision and proposed goals for AMC, organizational and governing structure. Define lines of authority and decision-making processes. Summarize major strengths and critical experience of the team (including key scientific as well as administrative personnel). Describe how the AMC components will interact to address specific scientific research priorities of the AMC Program. Provide organizational chart showing the place of each component in the overall scheme. Summarize special features in the environment and resources that reflect unique strengths of the proposed Consortium.

B. Group Chair Administrative Office (Administrative Core)(up to 12 pages)

In this section, describe the infrastructure to support of the required administrative activities of the Group Chair including, but not limited to, logistics and organizations for various meetings, site visits, preparation of required reports, etc.

C. Operations Center (up to 6 pages)

The Operations Center is expected to provide administrative leadership, central operations, communications and monitoring of domestic and foreign clinical trials AMC Sites. Describe the organizational structure, including lines of authority, decision-making processes, key personnel, policies and procedures for Network communication, committee support, protocol development and implementation. The use of tables, diagrams, flow charts, and organizational charts is strongly encouraged.

D. AMC Progress Report (up to 6 pages)

Referring to the goals and objectives of the current AMC award, describe the following elements:

E. Research Program (up to 12 pages)

F. Domestic AMC Clinical Core Sites (up to 6 pages per Core Site).

Each Core-Site must be able to efficiently and effectively enroll subjects to patients in the clinical research, contribute to the Consortium scientific capabilities, and engage in capacity building at less well-developed clinical research sites.

All proposed Clinical Core Sites, regardless of location, must meet basic requirements for the conduct of clinical research. Basic requirements for the conduct of clinical research include identified clinical investigators, necessary infrastructure for the research proposed such as clinical, laboratory and pharmacy facilities, and evidence of institutional support for the conduct of clinical research under U.S. regulations.

The description for each Core Site must include site expertise, experience in AIDS malignancy clinical research, how the site will contribute to the AMC research and accrual potential. New core sites must be able to initiate subject recruitment within the first 6 months of award.

The applicant clinical research organization and organization of the Site should be described as well as a management and communication plan, including lines of authority, decision-making processes, standard operating procedures, and plans for providing effective oversight of the clinical research site. Applicants should describe the expertise of Core Site director and other key staff s expertise, experience and scientific contributions to the design and conduct of AMC clinical trials; ability to lead, contribute to, and prioritize research activities; and capacity to conduct AIDS-related malignancies clinical research. The rationale for and expected contribution of each clinical research site should be briefly described.

G. Development of International Clinical Trial Sites (up to 6 pages)

The research activities of each Scientific Working Group are expected to include an international research agenda that must address the needs of resource limited countries (primarily in Africa) for a specific disease area.

Describe the plans for selection, vetting and monitoring of the clinical sites. Describe the plans for quality controlling of the laboratory diagnostic capabilities of those sites and plans for capacity building and personnel training. Describe the minimum requirements for a Foreign Site inclusion. Describe the plans for involving the foreign investigators in AMC activities including protocol development. Provide a time line for the process. Each proposed clinical Core Site must have a Lead Senior Collaborator from the foreign Site who will be responsible for the conduct and the performance of the site. A foreign Site may have a US Collaborator from the AMC as a consultant for that Site. The AMC US Collaborator is expected to reserve at least 0.6 months effort for AMC activities if he/she is the Chair of a foreign clinical trial protocol for the duration of the protocol.

H. Affiliated Non-Core Clinical trial Site Instructions (up to 12 pages for all Non-Core Sites combined)

Non-Core Sites may be identified in the application. For each non-Core Site identified provide the Director name, institution, and approximate budget based on anticipated accrual and average capitation costs. Describe any additional unique characteristics of this site that will add value to the AMC as a whole. Indicate if the Site Director is a member of other HIV/AIDS or Cancer clinical research groups.

I. Network Core Resource Laboratories (CRL) (up to 12 pages)

Network Resource Core Laboratories must be capable of performing standard testing of various parameters needed for the correlative studies pertaining to clinical trials and preclinical drug screening functions. The laboratory must use standard good laboratory practice techniques and must maintain a quality assurance/quality control program that will insure the integrity of the data generated.

In this section, describe the following:

J. Statistics and Data Management Center (SDMC, up to 12 pages)

The Statistical and Data Management Center must be proposed in the application to provide biostatistics leadership and central data management capabilities for the AMC clinical research.

In this section, describe the following:

Budget Notes

The budget for the AMC must include the following categories:

Additional information is available in the PHS 398 grant application instructions

Appendix Materials

All paper PHS 398 applications must provide appendix material on CD only, and include five identical CDs in the same package with the application (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-031.html.)

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

Resource Sharing Plan(s)

NIH considers the sharing of unique research resources developed through NIH-sponsored research an important means to enhance the value of, and advance research. When resources have been developed with NIH funds and the associated research findings published or provided to NIH, it is important that they be made readily available for research purposes to qualified individuals within the scientific community. If the final data/resources are not amenable to sharing, this 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: Investigators seeking $500,000 or more in direct costs in any year are expected to include a brief one-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/.

The adequacy of the resources sharing plan and any related data sharing plans will be considered by Program staff of the funding organization when making recommendations about funding applications. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590, http://grants.nih.gov/grants/funding/2590/2590.htm). See Section VI.3. Reporting.

Section V. Application Review Information

1. Criteria

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

2. Review and Selection Process

Review Process

Applications that are complete and responsive to the FOA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the National 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 mission of the NIH is to support science in pursuit of knowledge about the biology and behavior of living systems and to apply that knowledge to extend healthy life and reduce the burdens of illness and disability. As part of this mission, applications submitted to the NIH for grants or cooperative agreements to support biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

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

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

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

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

In addition, specific to this FOA: Is the selection of consortium investigators adequate to the AMC goals? How well does the entire consortium represent a team with broad multidisciplinary expertise in HIV management, management of oncologic morbidities that are common in the HIV-infected patients? To what degree the investigators show understanding of the opportunities and challenges in conducting international U.S.-supported clinical studies particularly in resource poor countries, and in understanding and experience in collaborating with other NIH/NCI clinical cooperative clinical trial groups? Do the identified Working Group Chairs have sufficient abilities to lead specific disease area groups?

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

Approach. Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?

Environment. Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, and/or collaborative arrangements?

In addition to the above review criteria, the following criteria for specific AMC components will be applied in the determination of scientific merit and the impact/priority score.

  1. Group Chair (Administrative Core). Is the justification for the selection of group chair and vice chair sufficiently strong?
  2. Operations Center. How well will the Operations Center serve the needs of AMC? Will the proposed organization and parameters ensure the economic efficiency of the Operation Center?
  3. Progress. Has the applicant shown adequate progress in developing the research infrastructure, collaborations, and clinical trials to serve the overarching goals of AMC? How significant is the contribution of the applicants currently funded AMC to the overall efforts in the field of AIDS and cancer? How well have the applicants accomplished the specific objectives proposed in the original AMC application?
  4. Research Program and Clinical Trial Sites (Core- and Non-Core). Have the proposed clinical studies been judiciously selected so as to make major contributions to the management of HIV-related cancers, were these contributions are unlikely in the absence of the AMC? Are the structure and number of committees and working groups appropriate and well selected? Will these working groups contribute to the ongoing refinement and revision of the AMC research goals, oversee protocol development and implementation, and ensure timely publication of results. What unique approaches have been proposed to accrue patients? To what degree have the proposed studies leveraged other existing clinical trial structures in developing cancer related studies? To what extent is the vision of international studied, relevant to the needs of the population? Are the efforts toward developing international clinical trials sufficient? Are the proposed criteria and evaluation metrics of the clinical core and affiliate sites reasonable and sufficient? Are the proposed procedures for implementing required actions for inadequate performance of sites and /or laboratories adequate? For each proposed clinical trial site (Core- and Non-core): How well does the individual site fit into the AMC structure? Does this site have all the required capabilities to meet the accrual goals specified in the FOA?
  5. Network Core Laboratories. Are the Network Resource Core Laboratories appropriate and sufficiently justified? Will they provide the required resources in all five specified areas?
  6. Statistics and Data Management Center. Are the statistics and data management structure and leadership of Statistics and Data Management Center adequate? Are the plans to collect, monitor, and analyze the data and assure the safety of the patients sufficiently developed?

An overall application score will be assigned based on review and merit of the individual AMC components as well as the merit of the application as a whole. It will not be merely an arithmetic mean of the component subscores.

Additional Review Criteria

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

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

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

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

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

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

Additional Review Considerations

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

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

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

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

Selection Process

The following will be considered in making funding decisions:

Given that AMC is intended to serve as centralized, multi-component and multi-functional infrastructure, NIH will consider the following in evaluating AMC U01 application :

3. Anticipated Announcement and Award Dates

Not applicable

Section VI. Award Administration Information

1. Award Notices

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

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

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official.

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

2. Administrative and National Policy Requirements

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

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

2.A. Cooperative Agreement Terms and Conditions of Award

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

The administrative and funding instrument used for this program will be the cooperative agreement 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, AMC refers to the organizational structure, which is composed of the Consortium lead PI and other key personnel, the Operations Center, the Statistics and Data Center, Network Laboratories, and Member Institutions (i.e., member sites ) and site PIs, all of whom agree to collaborate on research goals of the AIDS Clinical Trials Malignancy Consortium.

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

The principal investigator (or multiple PDs/PIs, if applicable) will have the primary responsibility to define objectives and approaches, and to plan, conduct, analyze, and publish results, interpretations, and conclusions of studies conducted. Specific responsibilities of PD/PI, awardee institution, and other key personnel are defined below.

The AMC Group Chair will oversee the development of the clinical and laboratory research design, including definition of objectives and approaches, planning, implementation, analysis, and publication of results, interpretations, and conclusions of studies. The Network will continue to develop pilot, Phase I, Phase II, and Phase III protocols in accord with the research interests, abilities, and goals of the Network, and submit them to CTEP for review prior to their implementation.

The AMC Group Chair with the assistance of the Operations Center, and the Executive Committee (EC), is responsible for coordinating protocol development, protocol submission, study conduct, quality assurance including quality control and study monitoring, data management, statistical design and analysis, 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. Organization Structure, By-Laws, Standard Operating Procedures (SOPs) and Evaluation Criteria: The Group Chair and the Executive Committee, with support from the Operations Center, are responsible for development and maintenance of an organizational structure for the AMC, including a charter/by-laws for the Group. The organizational structure should include the Scientific and other Committees that the Network needs to support its research objectives. The Operations Center is responsible for the preparation and maintenance of SOPs that cover all aspects of AMC activities and for assistance in development of Evaluation Criteria for Core Sites, Non-Core Affiliated Sites, International Clinical Trial Sites, Protocol Chairs, the Group Chair, Committee Chairs, the Operations Center and the AMC as a whole.

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

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

b. AMC protocols should be preceded by a written Letter of Intent (LOI) from the AMC 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 Network Committees and Network members.

d. The Network will not expend NCI funds to conduct any study disapproved by CTEP unless CTEP's disapproval has been modified by the arbitration process ( Part 1: Section V.E. Arbitration).

e. All protocols 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). When new avenues of cancer therapy involving investigational agents are pursued, the clinical information should be acceptable to the U.S. Food and Drug Administration (FDA) for inclusion in a new drug application (NDA).

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

1. Study Monitoring (http://ctep.info.nih.gov/monitoring/section2.html#2.2.2): The Network is responsible for assuring accurate and timely knowledge of the progress of each study, and therefore must have standard procedures for timely data collection and data management consistent with the more intensive data requirements and the need for rapid reporting necessary for pilot, Phase I, Phase II studies. Standard procedures include (but are not necessarily limited to):

  1. Precise tracking of patient accrual (eligible and ineligible patients) and adherence to protocol-defined accrual goals. In the event that the AMC wishes to continue accrual to a study beyond the protocol-specified total accrual goal for eligible and ineligible patients, the AMC must seek approval from CTEP prior to continuing patient accrual;
  1. Procedures for assigning dose level (for Phase I/dose escalation studies) at the time a new patient is entered, and assuring that the required observation period has elapsed before beginning a higher dose level;
  1. Ongoing assessment of patient eligibility and evalualability;
  1. Adequate measures to ensure timely medical review and assessment of individual patient data;
  1. Adequate measures to ensure timely submission of study data. These measures should include procedures for monitoring compliance with AMC 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., by the DSMC). These summary reports should also be included in the Annual Progress Report;
  1. Rapid reporting of treatment-related morbidity information and measures to ensure communication of this information to all relevant parties;
  1. Interim evaluation of outcome measures and patient safety information;
  1. 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 biannual reports for AMC meeting agendas, and reports for Data and Safety Monitoring Committees;
  1. Adequate policies and procedures for closure of studies. If the AMC 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 protocol in order to facilitate these decisions. In the event that the DSMC has recommended early closure, DSMC procedures regarding notification of CTEP must be followed; and
  1. Data Management Policies and Practices: The responsibilities of the Operations Center for data management related to study monitoring include:

I. Providing for central storage, security, processing and retrieval of study results;
II. Incorporating security features consistent with DHHS guidelines;
III. Implementing procedures for backing up the AMC clinical and administrative data, including intermittent duplication of the database with storage at a remote facility;
IV. 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
V. Providing NCI in a timely manner, upon the request of the NCI 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.

4. Quality Control of AMC Clinical Trials: Quality Control (QC) and Quality Assurance (QA) Programs are inherently linked. The Clinical Trials Monitoring Branch of CTEP provides direct oversight of NCI-sponsored Consortia and Cooperative Group QA/QC programs. The AMC 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 AMC. 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 AMC trials;
ii. Timely and accurate submission of required data;
iii. Conscientious observance of protocol requirements;
iv. Participation in study development and leadership and publication;
v. Participation in Network leadership and/or other Network activities; and
vi. Procedures should be in place for placing institutions on probation for inadequate performance and for removing institutions from the AMC if performance is not adequate during the probationary period or at any time that the institution (or participating site) does not meet established AMC standards.

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

  1. Training for new CRAs in the AMC data submission policies and ongoing training for all CRAs concerning changes to AMC procedures and instructions for data submission in new protocols;
  2. Instruction for Study Chairs on their responsibilities for study monitoring;
  3. Instruction for Core Site Institution Principal Investigators and all members at participating sites on their responsibilities in complying with the AMC’s SOPs and Federal regulations at their institution; and
  4. Training/guidance should also be provided to all participants on how to comply with NCI/NIH policies and procedures (e.g., ethics, conflict of interest, 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).

c. Procedures for central review of major elements that impact on the outcome of clinical trials.

5.On-site Auditing: As a sponsor for investigational agents and the funding agency for other cancer clinical trials, FDA regulations require the NCI to maintain a monitoring program. The Clinical Trials Monitoring Branch (CTMB) of CTEP provides direct oversight of each Cooperative Group’s and Network’s monitoring program, which includes auditing as one component. The purpose of an audit is to document the accuracy of submitted data to verify investigator compliance with protocol and regulatory requirements. In addition, the monitoring program provides an opportunity for the audit team to share with the institution staff information concerning data quality, data management, and other aspects of quality assurance. The AMC 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. 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.

a. On-site auditing of AMC Core Site institutions will be planned to occur at least every 2-3 years.

b. Any serious problems with data verification or compliance with Federal regulations must be reported to the Clinical Trials Monitoring Branch immediately.

c. In the event that the NCI determines that an AMC Core Site Institution failed to comply with these guidelines, the accrual of new patients to AMC protocols at the affected institution shall be suspended immediately upon notice of the NCI determination. The suspension will remain in effect until the AMC conducts the required audit and the audit report or remedial action is accepted by the NCI.

d. 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 Network studies using CTEP IND 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 CTEP IND agents, reporting to CTEP will generally use the CDUS Abbreviated procedures (demographic data only).

c. For clinical trials that do not use CTEP IND agents, the AMC should develop a standard mechanism for providing information on study status and progress, similar to the CDUS Complete system for reporting to CTEP. These reports can be used as a baseline reporting mechanism for providing study updates to non-CTEP sponsors.

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

a. The AMC should have timelines for the development of abstracts and manuscripts based on its clinical trials and should have mechanisms for monitoring the performance of the Operations Center and Protocol Committees in meeting these timelines. Corrective action plans should be in place for when these timelines are not met.

b. Publication or oral presentation of work done via the AMC’s Cooperative Agreement requires appropriate acknowledgment of NCI support.

c. For publications using an agent supplied under a CRADA or CTA, the NCI pharmaceutical collaborator will have 30-day review 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 HHS, PHS and NIH policies.

8. AMC Meetings: The Operations Center is responsible for the organization of biannual meetings to review the Network’s progress, establish priorities, and plan future activities. Additional meetings between AMC 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 as appropriate, including outcome data as appropriate. The Operations Center is responsible for assuring that copies of the Report (electronic and/or hard copy) are distributed to AMC members and NCI program staff; and

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

9. AMC Communications: The Operations Center is responsible for establishing routine electronic communication with Core- and Non-Core Site Institutions to facilitate protocol development and study monitoring and to facilitate the work of the AMC’s Study and Scientific Committees. Relevant communication methods include web site postings, e-mail, teleconferences, and video conferences.

10. Compliance with Federal Regulations Concerning Clinical Research: The Operations Center is responsible for assuring that the Network is in compliance with all applicable federal regulations concerning the conduct of human subject 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 Network Protocols: The Operations Center must assure that each AMC protocol is reviewed and approved by each Core and Non-Core Sites Institution’s IRB prior to patient entry, and must assure that each protocol undergoes continuing review no less than once per year by the IRB so long as the protocol 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: http://ohrp.osophs.dhhs.gov/humansubjects/assurance/engage.htm:

An IRB should determine and document that the Operations Center has 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 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 HHS regulations.

e. IRB Review of Tumor and Tissue Repositories: Any tumor and tissue repository must be in compliance with OHRP regulatory requirements for repositories, including appropriate oversight by an IRB as described in OHRP guidance documents (http://ohrp.osophs.dhhs.gov/humansubjects/guidance/reposit.htm).

f. Registration of AMC Investigators: The Operations Center is responsible for assuring that Network investigators performing trials involving NCI Investigational Agents are NCI registered investigators (Form 1572).

g. 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 protocol (http://ctep.info.nih.gov/reporting/adeers.html).

h. Assuring that the Network is in compliance with CTEP requirements described in the NCI Investigators' Handbook for storage and accounting for investigational agents {including NCI/HHS Drug Accountability Records (DAR) procedures}, and is in compliance with FDA requirements for investigational agents.

i. Data and Safety Monitoring Policy: The AMC must have a Data and Safety Monitoring Policy for its clinical trials that is in compliance with NIH and NCI guidelines for data and safety monitoring for clinical trials (http://grants.nih.gov/grants/guide/notice-files/not98-084.html with additional description at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html). Further information concerning essential elements of data and safety monitoring plans for clinical trials funded by the NCI is available at http://www.cancer.gov/clinicaltrials/conducting/dsm-guidelines. The Network’s policy for Data and Safety Monitoring must be submitted to and approved by the NCI Program Director.

j. A Conflict of Interest Policy in compliance with the requirements of 42 CFR Part 50, Subpart F (Responsibility of Applicants for Promoting Objectivity in Research for which PHS Funding is Sought) and other policies of the NCI and the National Institutes of Health to ensure that there is no reasonable expectation that the design, conduct, or reporting of research conducted by the Network will be biased by any conflicting financial interest of an investigator.

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. Any tumor and tissue repository must be in compliance with OHRP regulatory requirements for such repositories (http://ohrp.osophs.dhhs.gov/humansubjects/guidance/reposit.htm).

12. Fiscal management of the Network, including:

  1. Establishment of Network arrangements with Core Site Institutions to support AMC-related activities at each Core Site Institution.
  1. Funds for Training, International Studies and Community Representatives will be dispersed in accordance with the AMC By-Laws and by direction of the Group Chair and approval NCI Project Officer.
  1. Distribution of funds from the Patient Recruitment and Retention to Core Site institutions and non-core sites to support special clinical research costs for patients accrued onto Network clinical trials. Funds will be disbursed on a capitation basis upon documentation of accrual. It is anticipated that for each Network protocol, the capitation formula for institutional reimbursement required to offset specific research expenses will be reviewed and approved by the Executive Committee.
  1. Establishment of criteria that will reward outstanding non-Core Affiliate Sites to become Core Sites, and the criteria for changing the designation of underperforming Core Sites and budget adjustments.

13. Submission of annual progress reports to the NCI that describe activities and accomplishments during the previous year of funding. The report should include:

a. A summary of the overall performance of the Operations in meeting its responsibilities to the AMC for protocol development, study monitoring, and complying with Federal regulations.

b. Summary data on performance of each AMC Core Site, including protocol accrual, quality and timeliness of submitted data, and involvement in protocol development activities.

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

14. Procedures to allow non-Network institutions to participate in the development and conduct of Network trials. Describe the distinctive expertise or capabilities that would contribute to successful conduct of a Network study.

15. Patient accrual and credit. The AMC is expected to accrue 120 Domestic patients and 80 patients per year in international resource limited settings. A patient entered on an interventional protocol (treatment, vaccine etc.) is one patient, as is one entered for pharmacokinetic studies. Patients entered on non-treatment trials such as natural history studies where patients are followed for more than six months will also count as one patient credit. Such patients cannot simultaneously count towards 2 trials if on natural history studies. All other non-treatment protocols including those involving a single tissue and/or body fluid collection will be counted as half a patient credit.

16. The AMC will use the AIDS and Cancer Specimen Resource (ACSR) as the central resource for the storage of tumor specimens and biological fluids from patients entered onto Network clinical trials for future correlative studies. The ACSR is currently funded as a separate cooperative agreement with the NCI (http://acsr.ucsf.edu).

17. Patient Recruitment and Retention Funds The AMC will maintain A restricted portion (approximately $500,000 in year 1) of the AMC award to support efforts related to patient accrual and retention costs for patients accrued onto AMC clinical trials. The funds will be allocated according to the instructions of the EC and disbursed on a capitation basis after documentation of patient accrual. A primary anticipated use of these funds is to provide incentive to Core Sites for increased accrual above the requirement to maintain core site status and to allow participation of non-core sites. These funds will be restricted for this purpose only and cannot be used for other purposes without permission from the NCI. This restriction will be incorporated into Terms of Award in the Notice of Grant Award.

Clinical Core Site Institutions:

1. Participation of Clinical Core Site Institution investigators in AMC activities, as evidenced by the following:

a. Offering eligible patients participation in AMC studies and entering sufficient patients to meet accrual targets. Core Sites are expected to accrue ten patients per year in three of four disease areas (KS, NHL, HPV and NADC), with a minimum of three patients in any of the disease areas chosen. Core Sites not meeting their accrual target are subject to lose their Core Site status and their funding will be adjusted accordingly.

b. Participating in research design and protocol development,

c. Serving as Protocol Chairs. For each specific clinical protocol, a single Protocol Chairperson will be selected to function as the scientific coordinator for that protocol. He/she will assume responsibility for the development of the protocol and for monitoring the protocol during the actual performance of the clinical trial in accordance with AMC policies and procedures

d. Participating in the Scientific and Administrative Committees needed to support the AMC’s research objectives.

e. Participation in meetings: Appropriately participating in the biannual meetings of the Network (and in other meetings as deemed necessary for performance of Network activities).

f. Following the AMC’s SOPs for the conduct of clinical research and complying with the AMC’s By-Laws.

2. Implementing the core data collection method and strategy of the AMC: It is the responsibility of each Core Site Institution to ensure that the procedures for data submission for each AMC protocol are understood by investigators at the site and that protocol specified data are submitted accurately and in a timely manner to the Operations Center.

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

  1. Pathology: Submission of appropriate materials to allow verification of pathologic diagnosis, when relevant.
  1. Chemotherapy: Submission of appropriate data to allow determination of protocol compliance in dose administration and dosage modification.
  1. On-site Auditing: Participation in the onsite monitoring program established by the AMC.

4. Human Subjects Protection: Each institution must comply with OHRP and FDA regulations concerning protection of human subjects. Core Site Institutions must implement the procedures established by the AMC to meet OHRP and FDA requirements for the protection of human subjects. These include:

a. Assuring that the institution has a current, approved assurance on file with OHRP;

b. Assuring that each protocol is reviewed by the institution’s IRB prior to patient entry;

c. Assuring that each protocol is reviewed annually by the IRB so long as the protocol is active; and

d. Assuring that each patient (or legal representative) gives written informed consent prior to entry on study.

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

6. Investigational agent responsibilities: Implementing the procedures established by the AMC for assuring that AMC investigators performing trials involving NCI Investigational Agents are NCI registered investigators (Form 1572) and for assuring that the AMC is in compliance with CTEP requirements described in the NCI Investigators' Handbook for storage and accounting for investigational agents (including NCI/HHS Drug Accountability Records (DAR) procedures), and is in compliance with FDA requirements for investigational agents.

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

8. Serving as a resource for the conduct of protocol specified laboratory projects (e.g., pharmacokinetic studies, tumor biology studies). The AMC EC Committee will establish a process for the selection of the laboratories to perform these studies. These projects may be supported using the Discretionary Fund of the Network or by independent funding.

9. Participating in AMC procedures for the timely publication of major findings. Publication or oral presentation of work done under this agreement will require appropriate acknowledgment of NCI support. 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 HHS, PHS and NIH policies.

10. Appropriately using Discretionary Funds awarded by the AMC to conduct exploratory, hypothesis driven laboratory studies, for training, international work or community representatives and unforeseen emerging opportunities. The use of these funds requires prior approval of the NCI project officer.

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

12. International Clinical Core Site: An International Core Site will be directed by a Lead Senior Collaborator from the foreign Institution. A foreign Site may have a US Collaborator from the AMC as a consultant for that Site. The AMC US Collaborator may have at least 5 percent effort if he/she is the Chair of a foreign clinical trial protocol for the duration of the protocol. The Sites are expected to meet the minimal requirements of foreign clinical site criteria defined by the AMC for a Foreign Core Site. The sites will be reimbursed for per capita patient accrual. The AMC will conduct an annual performance evaluation of the Sites and will develop correction plans for underperforming Sites who may be subject to termination.

13. Network Resource Core Laboratory: The network laboratory will be responsible for performing standard testing of the correlative science pertaining to clinical trials and preclinical drug screening functions. This laboratory will have five Cores, a Pathology Core (Hematopathology, dermatopathology etc), Virology Core (HPV, EBV, KSHV), Pharmacology Core (clinical pharmacology and pharmacodynamics), Biomarker Core (gene expression, cytokine measurement in tissues and blood and body fluids) and a Preclinical Drug Screening Core (lymphoma, KS and NADC). The network resource laboratory will use standard good laboratory practice techniques and will maintain a quality assurance/quality control program that will insure the integrity of the data generated.

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

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

If the PI (Group Chair) of the AMC is been replaced by a procedural vote by the AMC Steering Committee, the Institution of PI named in the notice of grant award will release the award to the Institution of the new Group Chair upon NCI approval.

2. A.2. NIH Responsibilities

One or two designated NCI Program Directors acting as the Project Scientist/Coordinator(s) will have substantial involvement in the AMC program to a degree that is above and beyond the normal programmatic stewardship responsibilities in the administration of grants. This individual(s) will be the main NCI contact with the awardees for scientific and/or analytic issues.

As needed, additional NCI scientific staff members with relevant expertise may also have substantial involvement (e.g., as Collaborators) in the conduct of the AMC scientific activities.

All NCI staff members who may be substantially involved in the scientific activities of AMC will not attend peer review meetings of renewal (competing continuation) and/or supplemental applications. If such participation is essential, these individuals will seek NCI waiver according to the NCI procedures for management of conflict of interest.

The NCI Program Director acting as the Program Official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. Occasionally, the Program Official may also become substantially involved in the AMC program as a Project Scientist/Coordinator. If this is the case, the Program Official will not participate in the peer review meetings of renewal (competing continuation) and/or supplemental applications. If such participation is essential, this individual will seek NCI waiver according to the NCI procedures for management of conflict of interest.

Main NCI responsibilities include:

  1. Interacting with the PI(s) on a regular basis to monitor study progress (which may include: regular communications with the PI and staff, periodic site visits for discussions with awardee research teams, observation of field data collection and management techniques, quality control, fiscal review, etc., as well as attendance at Steering Committee, Data and Safety Monitoring Committee, and related meetings);
  2. Serving as voting members of the Executive Committee, the Steering Committee and, if applicable, subcommittees;
  3. Assisting in the design and coordination of research activities for awardees;
  4. Coordinating clearances for investigational agents held by NCI (the NCI may reserve the right to cross file or independently file an Investigational New Drug Application form with the FDA);
  5. Contributing scientifically to the process of data collection and participating in data analyses and publication efforts of the Consortium;
  6. Advising on the management and technical performance of the AMC investigations;
  7. Coordinating activities among awardees by assisting in the design, development, and coordination of a common research or clinical protocols and statistical evaluation of data; in the preparation of questionnaires and other data recording forms;
  8. Assisting in the publication of results;
  9. Reviewing and approving clinical trial protocols to ensure that they are within the scope of peer review and are safe, as required by Federal regulations (final drafts of protocols approved by the Executive Committee will be reviewed by the CTEP Protocol Review Committee, see details below);
  10. Monitoring protocol progress and involvement in protocol closure. The NCI Program Director and NCI Scientific Coordinator will monitor protocol progress and may request that a protocol study be closed to accrual for reasons including: (a) accrual rate insufficient to complete study in a timely fashion; (b) accrual goals met early; (c) poor protocol performance; (d) patient safety and regulatory concerns; (e) study results that are already conclusive; and (f) emergence of new information that diminishes the scientific importance of the study question. The NCI will not permit further expenditures of NCI funds for a study after requesting closure (except for patients already on-study);
  11. Reviewing and providing advice regarding the establishment of mechanisms for quality control and study monitoring. For specific Phase I/II trials with NCI-sponsored agents, the NCI will arrange for the CTMS to document regulatory compliance, to maintain a computerized data base, and to produce periodic routine reports of the results and special reports as necessary. For Phase II trials with NCI-sponsored investigational agents not requiring the above described monitoring, NCI will delegate to the AMC the task of providing an independent audit of each research study. The CTMS shall be used to conduct these audits. Random audits by NCI staff will be performed to assure that the awardee is performing the delegated audit duties.
  12. Making recommendations to the EC and the SC on the allocation of monies from the Discretionary Fund.
  13. Providing access to an NIH-supported AIDS and Cancer Specimen Resource for receipt of specimens and clinical data (see http://acsr.ucsf.edu).

Approval of Clinical Trial Protocols by CTEP

Final drafts of protocols approved by the AMC Executive Committee will be reviewed by the CTEP Protocol Review Committee. The NCI CTEP Protocol Review Committee, is composed of the professional staff of the CTEP and additional consultants from other NCI divisions or NIH Institutes, and chaired by the Associate Director, CTEP, or his/her designee, that reviews and approves Phase I, II, and III protocols supported through Cooperative Agreements with CTEP as well as protocols involving NCI investigational drugs. The NCI/CTEP Coordinator will provide the Protocol Chairperson via the Operations Center, with a consensus review that describes recommended modifications and other suggestions as appropriate. The major considerations relevant to protocol review include: (a) the strength of the scientific rationale supporting the study; (b) the medical importance of the question being posed; (c) the avoidance of undesirable duplication with other ongoing studies; (d) the appropriateness of study design; (e) a satisfactory projected accrual rate and follow-up period; (f) patient safety; (g) compliance with federal regulatory requirements; (h) adequacy of data management; and (i) appropriateness of patient selection, evaluation, assessment of toxicity, response to therapy and follow-up.

If a proposed protocol is disapproved, the specific reasons for lack of approval will be communicated to the Protocol Chairperson and the Executive Committee as a consensus review within 30 days of protocol receipt by the NCI. NCI will not provide investigational drugs or permit expenditure of NCI funds for protocols that PRC has not approved. The NCI CTEP Coordinator will be available to assist the Protocol Chairperson and the Steering Committee in developing a mutually acceptable protocol, consistent with the research interests, abilities and strategic plans of the AMC and of the NCI.

The NCI reserves the right to adjust funding, withhold, suspend or terminate the AMC award for poor performance and/or non-adherence to the terms and condition of the award.

2.A.3. Collaborative Responsibilities

Execution of this program will require collaboration among NCI staff, the Group Chair, the Directors of the Core Sites, the Principal Investigator of the Operations Center, the Group or Protocol statistician, the Chair of the Network Laboratory, and other NIH-Funded Clinical Trials Networks. The NCI Program Director will assist in coordinating the activities of the AMC with the other Networks as defined below and will facilitate the exchange of information. Specific tasks and responsibilities in carrying out the activity will be shared among the awardee and NCI staff. NCI reserves the right of final authority to approve all tasks performed in the context of this award.

NCI Staff members and Awardees shall share responsibility for the following activities:

1. Executive Committee: The leadership of the AMC will be vested in the Executive Committee (EC), which will perform the executive and final scientific review functions of the AMC. Its membership will consist of the Group Chair, the Group Vice Chair, a senior representative of the Network Laboratories, the Director of the Operations Center, the Group Statistician, the NCI Program Director and Scientific Director (with one vote between these two NCI representatives) and a community representative. The EC will be responsible for the establishment and amendments and final approval of the AMC’s bylaws and standard operating procedures, review and approval of new protocols for implementation, Core Site and Affiliate Sites performance evaluation, approval of new affiliations with individual sites and cooperative groups, approval of funds from the discretionary funds and final approval of budgets.

2. Steering Committee: The committee that is primarily responsible for the research direction of the Network and for assuring that the clinical research procedures of the Network are being followed and sufficient to meet these objectives and protect participants enrolled on AMC clinical trials. Its membership will be prescribed by the Network By-Laws and should include (but need not be limited to) the AMC Chair, Core Site Directors, Working Group Chairs, the Operations Center Director, the Group Biostatistician, protocol chairs, non-Core Site representation, and patient/family representatives.

The NCI Scientific Coordinator and Program Director (with only one vote between them) will serve as advisory members to the steering committee. Each full member will have one vote. Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering committee.

3. International Resource Sub-committee: The working group responsible for facilitating selection, vetting and accreditation and capacity building of foreign sites. The committee will be responsible for working out the logistics for conduct of clinical trials in international sites. Capacity building will include training for good clinical practices, good laboratory practices, personnel training for clinical management and data collection.

4. Data and Safety Monitoring Committee and Ad Hoc Monitoring Committees. The major emphasis of the Network is on exploratory Phase I and Phase II trials. However, the AMC has the capability to expand to Phase III trials. Phase III trials will require an independent Data and Safety Monitoring Committee (DSMC) established by the Executive Committee; the DSMC is responsible for insuring for each AMC clinical trial the safety of participants, the validity of data, and the appropriate termination of studies for which significant benefits or risks have been uncovered or when it appears that the trial cannot be concluded successfully. The Data and Safety Monitoring Committee will review interim results periodically and report to the EC Committee and the NCI. The NCI Scientific Coordinator, or his designee, will serve as an advisory (non-voting) member of the DSMC.

In all other studies, exploratory Phase I and Phase II trials, where warranted, the NCI Program Director and NCI Coordinator will facilitate, and the awardee shall allow for, interim data and safety monitoring through ad hoc committees established by the Operations Center in accordance with the Data and Safety Monitoring Plan for early phase studies.

Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

2.A.4. Dispute Resolution

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

3. Reporting

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

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

Section VII. Agency Contacts

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

1. Scientific/Research Contacts:

Mostafa Nokta, MD, PhD.
Office of HIV and AIDS Malignancy
National Cancer Institute
31 Center Drive, Room 3A33, MSC 2440
Bethesda, MD 20892 -2440 ( for U.S. postal Service regular or express mail)
Bethesda, MD 20892 (for non-USPS delivery)
Telephone: (301) 496-4995
FAX: (301) 480-4137
Email: Mostafa.nokta@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:

Judy L. Stint
Office of Grants Administration
National Cancer Institute, NIH
6120 Executive Plaza South, Room 243
Bethesda, MD 20892-7150 (regular mail)
Rockville, MD 20852 (express mail
Telephone: (301) 496-7240
FAX: (301) 496-8601
Email: sintj@mail.nih.gov

Amy Connolly
Office of Grants Administration
National Cancer Institute, NIH
6120 Executive Plaza South, Room 243
Bethesda, MD 20892-7150 (regular mail)
Rockville, MD 20852 (express mail
Telephone: (301) 496-8786
FAX: (301) 496-8601
Email: connolla@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.

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

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

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

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

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

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

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

Human Embryonic Stem Cells (hESC):
Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-09-116.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov). It is the responsibility of the applicant to provide in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s) to be used in the proposed research.

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

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

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

URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. For publications listed in the appendix and/or Progress report, internet addresses (URLs) must be used for publicly accessible 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. 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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NIH Funding Opportunities and Notices


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