Required Application Instructions

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

Part 1. Overview Information
Part 2. Full Text of the Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

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). The goals for the AMC are to continue 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, 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 (NADC) associated with HIV disease; and
4. Developing correlative studies in the context of the clinical trials.

The AMC should have specific functional units, including: an Operation Center; Clinical Trials Sites (CTS, domestic and international); Network Core Laboratories; and Data Management and Statistical Center.

The Consortium scientific activities must be oriented on at least four disease-specific "themes", i.e., areas of research focused on specific malignancies relevant to the AIDS context. These research themes may be led by appropriate Working Groups (WGs), including WGs oriented on: Kaposi sarcoma (KS); lymphoma; human papilloma virus (HPV)-associated cancers; and non-AIDS-defining cancers. 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.

In addition, the AMC is expected to continue the development and execution of the "ANCHOR" study, which AMC initiated in the current funding period. The ANCHOR [i.e., Anal Cancer High Grade Squamous Intraepithelial Lesion (HSIL) Outcomes Research] study, with a sample size of 5058 patients, is designed to determine whether treatment of anal HSIL prevents anal cancer. This study is needed before widespread screening for anal HSIL can be adopted.

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

The range of cancers seen in HIV-infected individuals is diverse and complex, and reflects an ever-changing HIV epidemic. Several of these cancers, including KS, high-grade B cell lymphoma, and cervical cancer are called AIDS-defining when they develop in an HIV-infected patient. Patients with HIV-infection also have an increased risk for the development of certain NADCs such as Hodgkin lymphoma, anal, lung, and oropharyngeal cancers.

Soon after highly active antiretroviral therapy (HAART), also called combination antiretroviral therapy (cART), was introduced for the treatment of HIV infection in the United States and other developed countries, the incidence of certain AIDS-defining malignancies decreased in these locales. However, after an initial decrease, the incidence of AIDS-defining cancers has leveled off, and these cancers continue to be a major cause of morbidity and mortality. In Africa and other regions of the developing world where access to cART is more limited, AIDS-defining tumors [KS, aggressive non-Hodgkin lymphomas (NHL), and invasive cervical cancer] continue to be among the most common tumors overall. More than two-thirds of the HIV-infected population lives in Sub-Saharan Africa, and this region is also an epicenter of Kaposi sarcoma (KS) and other viral-related malignancies such as Burkitt lymphoma. On top of these developments in AIDS-defining tumors, a new epidemiologic trend is becoming apparent in regions where cART is extensively used. In these regions, HIV-infected patients are living longer, and the population of HIV-infected patients is aging. In part due to this trend, the rates of certain non-AIDS-defining cancers (NADCs) are on the rise, with significant increases in anal cancer, liver cancer, and several other tumors. The late occurrence of KS and other AIDS-related cancers is increasingly observed. In certain regions where cART is widely available, cancer has been reported to be the most common cause of death in HIV-infected patients, accounting for approximately one-third of the deaths.

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, anus, head and neck) that occur with increased frequency in HIV-infected patients. These latter cancers tend to present later in the course of HIV infection, are often more aggressive, occur earlier in life than in HIV-negative individuals, and may be more resistant to therapy. Various other cancers, such as breast or prostate cancer that affect the general population are not more common in the HIV-infected population. Nonetheless, these cancers do contribute to the complexity of cancer patterns in the HIV-infected population. All these cancer patterns lead to complex challenges for the clinical community regarding development of standards of care and appropriate treatment regimens.

One cancer whose incidence is especially increasing in HIV-infected men and women in recent years is anal cancer. HIV-infected patients with human papillomavirus (HPV)-mediated lesions are less likely to have lesion regression, more likely to have persistent HPV infection, and more likely to have disease recurrence after standard lesion ablation therapy than people in the HIV-negative population. Anal (HSIL) is a precursor of anal cancer that can be treated. Treatment of cervical HSIL can prevent development of cervical cancer, and it is quite possible that treatment of anal HSIL will similarly prevent development of anal cancer. However, detection and treatment of anal HSIL is more difficult than cervical HSIL, there is more treatment-associated morbidity, and relapses are more common, especially in HIV-infected patients. In part for these reasons, national guidelines do not recommend screening for and/or treating anal HSIL. A clinical trial to determine whether treatment of anal HSIL prevents anal cancer is needed before widespread screening will be adopted. To address this issue, the AMC has recently been granted approval and supplemental funding by the NCI to develop the ANCHOR (Anal Cancer HSIL Outcomes Research) study, and the study is expected to open during 2014. ANCHOR is a randomized controlled trial to establish whether treatment of anal HSIL will reduce the incidence of anal cancer among HIV-infected men and women. The study will likely have an impact on changing the standard of care of anal cancer prevention among HIV-infected patients as well as members of other groups at risk for anal cancer. Also, the data from this clinical trial and from associated correlative studies will benefit other at-risk groups in the general population such as: other immunocompromised patients; HIV-uninfected men who have sex with men; patients with other HPV perianal disease; women with high-grade cervical or vulvar intraepithelial neoplasia; and women with cervical or vulvar cancer.

Overall, there is a substantial and increasing need for improved prevention and treatment of tumors in HIV-infected patients. Moreover, there is a particular need for approaches to these tumors that are appropriate for resource-limited regions.

In terms of specific types of malignancies, the main challenges can be summarized as follows.

• Kaposi sarcoma (KS): Despite the dramatic effects that cART had on the incidence of KS, this tumor type 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.
• 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. Though the introduction of cART has improved patient survival substantially, the standards of care for NHL have not been fully optimized in the HIV/AIDS setting.
• Cervical Cancer: Despite the decrease in the incidence of cervical cancer in the general population over the past 20 years, the incidence of cervical cancer remains unchanged 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 are common among HIV-infected women. Cervical cancer continues to be a major problem in developing countries particularly those in sub-Saharan Africa. Efforts to optimize prevention and treatment of cervical cancer in women in those countries are needed and highly warranted.
• Anal Intraepithelial Neoplasia: HIV-infected patients are at increased risk for developing anal cancer as compared to the general population. Anal high-grade squamous intraepithelial lesion (HSIL) is a precursor of anal cancer that can be treated. However, detection and treatment of anal HSIL are challenging; and treatment-associated morbidity and relapses are common among HIV-infected patients. cART seems to have a little effect on the natural history of these lesions.
• 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.

The principal goal for the Consortium is 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. 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, http://acsr.ucsf.edu/). In the case of pilot phase, 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 AMC laboratory studies; for donations to the ACSRR; and support of programs that the NCI Office of HIV and AIDS Malignancy (OHAM, http://oham.cancer.gov/) supports or has identified as programmatically important for the NCI AIDS malignancy effort (such as the HIV-positive Tumor Molecular Characterization Project).

Examples of specific research topics in key areas are listed below. The list is not meant to be comprehensive and various other topics are anticipated to be relevant to the goals of this FOA.

A) AIDS-Defining Cancers:

Kaposi sarcoma (KS):

• Evaluation of pathogenesis-based approaches for treatment of KS, including approaches that target virus-driven, host-directed processes, HHV-8 viral gene targets, angiogenesis, or a combination thereof;
• Evaluation of new classes of therapeutic molecules with improved features such as better pharmacologic or toxicological properties;
• Integration of immune-based therapeutic approaches in treatment regimens;
• Refinement and evaluation of more precise methods for KS tumor assessment;
• Development and refinement of biomarkers for tumor responses that can predict the progression of the natural history of the disease and response to treatment; and
• Evaluation of new hypotheses generated from pathogenesis studies.

Non-Hodgkin Lymphoma (NHL):

• Novel pathogenesis-driven therapeutic approaches including relapsed and/or refractory lymphoma;
• Identification of host determinants that influence response to therapy;
• Evaluation of potential host correlates for tumor development;
• Elucidation of biological determinants of tumor sensitivity/resistance to therapeutic interventions; and
• The effects of therapy on the host innate and adaptive immunity to HIV and EBV as they may affect long-term toxicities and tumor responses.

Cervical Cancer:

• Optimization of chemoradiotherapy for advanced stages of cervical cancer in HIV-infected women;
• Optimization of management of different disease stages in the context of antiretroviral therapy;
• Determination of optimal cervical cancer prevention strategies;
• Determination of the biologic and molecular interactions between HIV and HPV that might influence the natural history of the lesions; and
• Evaluation of novel anti-HPV therapies such as therapeutic vaccination or adjuvants to surgical treatments to improve long term outcomes.

B) Non-AIDS defining cancers:

Anal-Cancer and its Precursors:

• Development of successful treatment strategies for anal HSIL;
• Development of novel approaches for prevention of progression of anal HSIL to cancer;
• Development of effective and well tolerated treatment options for anal HSIL and/or anal cancer; and
• Determining the genetic, immunologic, and virologic correlates of these lesions.

Head and Neck Cancers (HNSCC):

• Evaluate the effectiveness of novel therapeutic strategies; and
• Study the pathogenesis of oral cancer precursor lesions and progression to cancer

Hodgkin Disease (HD):

• Optimization of the treatment strategies of HD in the HIV setting; and
• Elucidation of biological determinants of tumor sensitivity/resistance to therapeutic interventions.

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 and hepatocellular carcinoma. The factors associated with the risk and susceptibility to these cancers are not well understood. Focused clinical research with the goal of optimizing management of these cancers in the HIV setting is needed.

C) Other Aspects of Interest

Clinical Pharmacology: The NCI has recently begun several initiatives aimed at removing barriers to general cancer trial participation among HIV-infected patients. These initiatives focus mainly on non-AIDS-defining cancers. However, the success of such initiatives requires a clear understanding of the issues related to drug-drug interactions between anticancer agents and antiretroviral therapeutics, including pharmacologic interactions. As such, the following area of investigation needs to be emphasized:

• Evaluation of pharmacokinetic interactions of antiretroviral agents and novel and established anti-cancer agents used for treating HIV/AIDS-related and non-HIV/AIDS-related malignancies.

HIV-associated Cancers in the International Setting: It is expected that the AMC will continue and expand their international research agenda. 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. The oncogenic viruses associated with AIDS-related malignancies are endemic in these regions. In parts of Africa, KS is now the most commonly diagnosed cancer in men and the second most common cancer in women, trailing only behind cervical cancer. The incidence of KS in children has increased 40-fold during the AIDS epidemic in Africa. 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, cervical cancer, and other HPV-related neoplasias. International collaboration should allow investigators to learn more rapidly about 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 needs of these communities. To accomplish this objective, the AMC should engage foreign investigators in identifying and prioritizing the scientific issues to be addressed, capacity building, as well as developing and prioritizing of appropriate designs of treatment and non-treatment clinical trials as needed.

The AIDS Malignancy Consortium must include the following units:

1. AMC Chair Administrative Office (Administrative Core);
2. Operations Center;
3. Research Program based on disease-oriented scientific Working Groups;
4. Clinical Trials Sites (Domestic);
5. Clinical Trials Sites (International);
6. AMC Core Resource Laboratories; and
7. Statistics and Data Management Center;

The AMC Chair is expected to be Program Director/Principal Investigator (PD/PI) of the applicant institution. AMC Group Chair will be responsible for ensuring that the AMC’s major structural components are capable of carrying out their respective responsibilities and that they operate in a well-coordinated fashion. The Chair will be responsible for the scientific integrity, productivity, governance, and fiscal accountability of the group.

The Operations Center is expected to provide administrative leadership, central operations, communications, and monitoring of domestic and foreign clinical trials sites, including those involved in the ANCHOR trial.

Research Program of the AMC is to be based on the disease-oriented scientific Working Groups. Each Working Group is expected to include member investigators of appropriate profile from AMC clinical trial sites. These Working Groups will contribute to the ongoing refinement 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.

Domestic and International Clinical Trial Sites must be able to efficiently and effectively enroll subjects for the clinical research, contribute to the AMC scientific research agenda, and engage in capacity building.

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 led by the AMC Chair with assistance of the Executive Committee for the daily operations.

Steering Committee: In terms of overall strategies and direction, the Consortium will be governed by the 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) sufficient to 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.

The program under which the AMC is funded will be subject to external evaluation near the end of the third year of the funding period (to be coordinated by the NCI Program Staff). Such evaluation is part of NIH efforts to optimize the efficiency of the funded research. The evaluation process will involve monitoring and assessing the progress of the AMC toward achieving its goals. This aspect includes evaluating the quality, value, and scientific impact of the research conducted by the Consortium.

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.

Only the current awardees of the AIDS Malignancy Consortium are eligible to apply to this FOA.

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

Applicant Organizations

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

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

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

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

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

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

A PD/PI from the application submitting institution is expected to be designated as AMC Chair.

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

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

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

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

In addition, the NIH will not accept a resubmission (A1) application that is submitted later than 37 months after submission of the new (A0) application that it follows. The NIH will accept submission:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

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

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

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

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

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

The letter of intent should be sent to:

Mostafa Nokta, M.D., Ph.D.
Director, AIDS Cancer Clinical Program
Office of HIV and AIDS Malignancy
National Cancer Institute/NIH
Telephone: 301-496-4995
Fax: 301-480-4137
Email: [email protected]

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed, with the following exceptions:

The Research Strategy should consist of the following sub-sections with the indicated page limits:

1. AMC Overview: one required-12 pages
2. AMC Chair Office: one required-6 pages
3. Operation Center: one required-6 pages
4. Research Program: one required-30 pages
5. Domestic Clinical Trial Sites: one required-12 pages
6. International Clinical Trials Sites: one required-6 pages
7. Network Resource Laboratory: one required-6 pages
8. Statistics and Data Management Center: one required-6 pages

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

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

All instructions in the SF424 (R&R) Application Guide must be followed. Each Clinical Trial Site must be able to efficiently and effectively enroll subjects/patients in the clinical trials, contribute to the Consortium scientific capabilities, and engage in capacity building at less well-developed clinical research sites.

Each International Clinical Trial Site must be able to efficiently enroll subjects to clinical research studies, to be conducted by the Network and contribute to the international research agenda of the AMC.

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

Facilities & Other Resources: Applicants must demonstrate that each Clinical Trial Site proposed has the scientific expertise and capacity to conduct clinical research on AIDS-related malignancies. For each clinical research site provide information on: the infrastructure for the research proposed such as clinical, laboratory, pharmacy, and space for document storage; available resources for routine laboratory testing, such as safety laboratories; facilities for processing and storage of blood and other clinical specimens; and institutional support for the conduct of clinical research under U.S., DHHS, and NIH regulations and policies regarding human subjects.

Other Attachments: Applicants must provide the following additional materials specified below in support of their application.

Each attachment should be uploaded asseparate PDF files. The filename provided for each attachment will be the name used for the bookmark in the application image.

Attachment 1: Organizational Data. Provide the following information as a PDF file with the name Organizational Data :

• Table of content of the attachment
• Flow chart with the organizational structure, leadership, management/administration, scientific Working Groups and committees etc.
• Summary Table for Scientific and Laboratory Working Groups and the International Committee. In the table, list all members of respective groups. Include columns for member’s affiliation and fields of expertise. Other critical characteristics may also be listed, if appropriate.
• Summary Table of Domestic Clinical Trial Sites. For each site/institution, include the most relevant site characteristics.
• Summary Table of International Clinical Trial Sites. For each site/institution identify city and country) and include the most relevant site characteristics.
• AMC SOP for selecting new clinical sites as "members".

Attachment 2: Accomplishment Data. Provide the following information as a PDF file with the name Accomplishments :

• Table of content of the attachment;
• Summary Tables for completed, active and in development domestic clinical trials by disease area (for years 2010-2014);
• Summary Table for completed, active and in development International Clinical Trials (2010-2014);
• Summary Table for completed AMC Trials (pre-2010);
• Summary Table for clinical trials collaborations with other NIH-supported groups;
• Summary Table listing letters of intent (submitted and approved by CTEP) and clinical trials protocols submitted (for years 2010-2014);
• Accrual Summary Table (for years 2010-2014);
• Summary Table for the ANCHOR Participating Sites. Include columns for lead investigator, date of site certification and subject accrual;
• Summary Table Providing data on annual Domestic patient accrual to AMC trials by gender and race/ethnicity composition (for years 2010-2014); and

Attachment 3: Protocol Development SOPs. Provide the following information as a PDF file with the name Protocol Development SOPs :

• AMC Protocol Development SOP
• Protocol Intensity Scoring

Attachment 4: Site Performance SOPs. Provide the standard operating procedures (SOPs) used for AMC Site Performance Standards and Measures (use PDF file name Performance SOPs ).

Attachment 5: Clinical Trial Sites. Provide the following information as a PDF file with the name Clinical Trial Sites :

• Summary Table for participating Clinical Trial Sites. Include columns for the site name, site Clinical Director and protocols opened. Other critical characteristics may also be listed, if appropriate.

Attachment 6: Biorepository SOPs. Provide the SOPs for AMC Biorepository (use PDF filename Biorepository SOPs ).

Attachment 7: Data for Network Resource Laboratory. Provide the following information as a PDF file (use filename Data for Network Resource Laboratory ):

• Table of content of the attachment
• Organizational chart for the Network Resource Laboratory and its specialized Core units;
• Chart for specimen flow across AMC clinical trial operation;
• Summary Table for AMC sample donations to the AIDS and Cancer Specimen Resource (ACSR) (2010-2014);
• Summary Table for samples processed by each of the Core units, indicating the nature of the assay and related studies (2010-2014); and
• AMC Laboratory Quality Assurance SOPs.

Attachment 8: Statistics and Data Management. Provide an organizational flow chart for the Statistical and Data Management Center as a PDF file with the name "SDMC Organization"

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

Each Clinical Trial site must also have a designated Clinical Director. Clinical Directors should have appropriate leadership skills, expertise, and experience (documented by their scientific contributions) to ensure their abilities to design, prioritize, and conduct required research activities. All proposed Domestic and International Clinical Trial Sites should have appropriately skilled clinical investigators.

Biographical Sketches: In addition to standard content, as appropriate for individual researchers, include in the Biographical sketch under "Personal Statement" the following:

• For each individual designated as a clinical Director of a domestic or international Clinical Trial Site, summarize this individual's:
• major strengths, critical experience, and scientific contributions relevant 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.
• For each individual designated as a Director of AMC Laboratory Core unit, summarize this individual's: experience with performing standard testing of various parameters needed for the correlative studies pertaining to clinical trials and/or preclinical drug screening functions.
• For the individual designated as the Director of the Operations Center, describe this individual's critical operational experience with managing multi-center clinical trials networks.

For the individual designated as a Director of the Statistical and Data Management Center, outline the relevant expertise for the statistical and data management support of the AMC clinical research plan.

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

In the budget justification, provide budget breakout for the following categories:

• Conduct and management of the ANCHOR trial. A sum of $12,825,700 annually (in total costs) must be allocated for the ANCHOR activities. This amount should include an ANCHOR Trial Patient Care Support Fund (approximately $3,750,000 total cost). The budget request for this Fund should cover costs for patient care screening, high-resolution anoscopy, reimbursement to patients for transportation, and treatment modalities. The cumulative budget allocated for the ANCHOR trial during the entire project period cannot exceed $64.13 million in total costs.
• Basic AMC Site Support (approximately $1,725,000 total cost): Applicants may propose expenses to support Clinical Trial Sites at up to 25 institutions. The budgetary request should include per capita costs of accrual for three to six patients per site/year depending on the intensity of the protocol. Additional support for sites participating in the ANCHOR trial is permitted.
• Foreign Site Budget (approximately $1,050,000, total cost): Applicants may propose expenses for basic site support for up to six foreign institutions. The budgetary request should include costs of personnel, travel, training, and capacity building and compensation for chair and vice chair of International Committee.
• Protocol Implementation Fund (approximately $1,250,000, total cost): The budget request for this Fund should include costs of per capita patient accrual, protocol-mandated drug purchases, storage, and distribution for international trials, costs for laboratory diagnostics not reimbursed as standard of care, clinical trial insurance, computerized tomography (CT) scans, remote audits of radiotherapy machine output and on-site dosimetry review audits for international trials.
• AMC Clinical Trial Research Fund (approximately $800,000 total cost): The budget request for this Fund should cover costs of support for AMC Resource Laboratory, Clinical Pharmacology and Correlative studies.

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

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

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

Specific Aims: Outline the general strategic objectives for the AMC and the plan to achieve these goals.

Research Strategy: Research Strategy must consist of the sub-sections A-H described below, uploaded as single PDF attachment:

Sub-section A. AMC Overview

Briefly outline the vision and proposed goals for AMC. Include your understanding of the opportunities and challenges for multidisciplinary clinical research on AIDS-related malignancies and strategy for domestic and international clinical studies (particularly in resource-poor countries).

Define organizational and governing structure, lines of authority, and decision-making processes. Describe how the AMC units will interact to address specific scientific research priorities of the AMC Program. Discuss how the special features of the Consortium environment and resources will create unique opportunities to serve the AMC scientific goals. Indicate any major organizational changes proposed for the Consortium renewal.

In this Sub-section, summarize also AMC progress in the current funding period. Address the following elements:

• Major accomplishments during the current funding period;
• Overview of clinical trials conducted, including the ANCHOR trial;
• Progress in the development of the ANCHOR trial, choice and certification of performance sites, and patient accrual; and
• New resources/capabilities established as a result of AMC award and/or reflecting collaborating with other NIH/NCI clinical trial infrastructures.

Note: Supporting documentation for this sub-section is requested under "Other Attachments" (Attachments 1 and 2).

Sub-section B. AMC Chair Office

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

• Describe protocol development and prioritization process
• Plans for New Minority and Junior Investigators: describe plans to incorporate new, minority, and junior investigators into the Network's activities.
• Outline activities intended to increase the role of patient advocate/patient community in AMC.

The applicants are encouraged to designate a vice-chairperson, who would be capable of leading the Executive Committee and the entire AMC in the event that the chairperson is unable to continue serving in this role. Provide rationale for the selection of both AMC Chair and vice-chairperson.

Note: Supporting documentation for this sub-section is requested under "Other Attachments" (Attachment 3).

Sub-section C. Operations Center

The Operations Center is expected to provide administrative leadership, central operations, communications, and monitoring of domestic and foreign clinical trials sites, including those involved in the ANCHOR trial. Describe the organizational structure, including lines of authority, decision-making processes, policies and procedures for Consortium communication, committee support, protocol development, implementation and mandated-regulatory monitoring of clinical trial sites.

• Performance Evaluation. Describe criteria and processes for ongoing evaluation and problem resolution of all Consortium components.

Note: Supporting documentation for this sub-section is requested under "Other Attachments" (Attachment 4).

Sub-section D. Research Program

• High Priority Research Areas. Summarize the ongoing research, and articulate the vision of the AMC and the scientific research agenda of the applicant team for the proposed funding period. The proposed research plan may include the continuation of ongoing clinical trials, with appropriate rationale and brief discussion of how those studies contribute to the proposed research program. Indicate those understudied/underappreciated areas of the management of HIV-related cancers for which AMC efforts may be unique or prevalent.
• Scientific Working Groups. Define disease-specific Working Groups and describe their intended activities and future directions. Outline how these groups will contribute to the ongoing refinement and updating of the AMC research goals, oversee protocol development and implementation, and ensure timely publication of study results. The number of Working Groups and the applicable scientific areas involved must be based on the scientific activities of the Network and reflect the patterns of malignancies that occur among individuals with HIV infection. The Working Groups will need to have an efficient structure with the necessary expertise. New Scientific Working Group(s), if any, need to be described in terms of their research agenda and the plans for implementation and achievement of those objectives. The description of Scientific Working Groups needs to include their current and/or future international research efforts particularly in Africa.
• Plans to continue the ANCHOR clinical trial. Given the size and complexity of the ANCHOR study, various aspects of the plans and the process to conduct this clinical trial need to be described. Provide sufficient details for the reviewers to evaluate the merit of these plans.
• Correlative Research Agenda. Describe the correlative science research agenda for the group.
• Cross-Network Collaborations. Outline how the AMC expects to interact with other NIH-sponsored HIV/AIDS programs and other NCI-supported research networks to achieve the AMC aims and objectives.
• Overall Requirements for AMC Clinical Trial Sites. Identify the approximate number and capacity of the clinical research sites the Consortium will require to efficiently and effectively implement the proposed domestic and international clinical research agenda. Describe the criteria and process used to select them.
• Community Advisors. It is expected that the AMC will work closely with local patient advocacy groups and institutional community advisory boards. Describe the organizational structures and Consortium policy and procedures for ensuring community input and community representation within the Consortium.

Sub-section E. Domestic Clinical Trials Sites

A Domestic Clinical Trial Site is expected to accrue a minimum of three patients on clinical trials per year in any of the following disease areas: KS; lymphomas; and NADCs. HPV-related premalignant disorders can also contribute to the minimum site accrual target (albeit two such patients will count as a single accrual towards the fulfillment of the recruitment quota). New sites must be able to initiate subject recruitment within the first 6 months of award.

In this sub-section, explain how these requirements will be met by specifically addressing the following:

• The rationale for selecting each clinical research site (in the context of site's expertise and experience in AIDS malignancy clinical research);
• Accomplishments of each site in AIDS-related cancer clinical research and past performance in multicenter clinical trials;
• Summary of the active involvement of Site investigators in AMC activities, including service on committees, Working Groups, and group efforts to develop clinical trial protocols; and
• Site expected contribution to AMC, including recruitment of clinical trials subjects.

Note: Supporting documentation for this sub-section is requested under "Other Attachments" (Attachment 5).

Sub-section F. International Clinical Trials Sites

In this sub-section, specifically address the following:

• The rationale for selecting each clinical research site (in the context of the site's expertise and experience in AIDS malignancy clinical research); and
• The expected contribution of each site to AMC research and accrual potential for clinical trials.

Sub-section G. Network Resource Laboratory

The Network Resource Laboratory (NRL) 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, operating through its specialized Core units, 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:

• Management plan for the Network Resource Laboratory and its specialized Core units.
• Address areas of competence and responsibility of each Core unit. The number and types of Core units should relate to projected type, size and complexity of the proposed Consortium clinical research protocols.
• Laboratory expertise and competence that will be available to serve the needs of the Consortium Research Program.
• Procedures for communication across the NRL (among its Core units) as well as with other Consortium parts.
• Procedures for conducting and reporting laboratory studies in the areas necessary to the Consortium clinical research plan, including:(i) procedures for collection, testing, tracking, storage and retrieval of laboratory specimens; and (ii) quality assurance and quality control procedures; (iii) a method for interfacing with Network Statistics and Data Management Center (SDMC) for tracking laboratory specimens and merging laboratory data with clinical data.
• Interaction with the AIDS and Cancer Specimen Resource and AMC/ACSR biorepository.
• Plans for biospecimen collection and banking for the ANCHOR trial.

Note: Supporting documentation for this sub-section is requested under "Other Attachments" (Attachments 6 and 7).

Sub-section H. Statistics and Data Management Center (SDMC)

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

In this section, describe the following:

• Operational, procedural, and overall management plans for the SDMC.
• Biostatistics and data management approaches planned to be used in AMC multi-site clinical trials.
• Any innovative aspects and plans relevant to data collection, processing, statistical workout and data integration, quality control, data related to the safety of the patients, etc.
• Proposed procedures for managing both clinical and laboratory data, including database architecture and plans for improvements of the relevant aspects of the information technology system used.

Note: Supporting documentation for this sub-section is requested under "Other Attachments" (Attachment 8).

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide

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

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

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

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission.

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

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically.

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

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

See more tips for avoiding common errors.

Upon receipt, application will be evaluated for completeness by the Center for Scientific Review and responsiveness by the NCI, NIH. Application that is incomplete and/or not responsive will not be reviewed.

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

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

The emphasis of this FOA is on the ability of the proposed Consortium to provide strong, competent, and comprehensive scientific and statistical leadership for developing, implementing, and analyzing multi-institutional cancer treatment and prevention clinical trials domestically and internationally in the context of HIV. Integration of individual functional components, the ability to adapt their research agenda to reflect the state of the cancer burden in HIV positive individuals, and the ability to overcome the challenges of conducting international trials are particularly important.

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

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

Significance

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

Investigator(s)

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

Specific to this FOA: Is the justification for the selection of AMC chair and vice chair sufficiently strong? 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 do the investigators show understanding of the opportunities and challenges in conducting international U.S.-supported clinical studies, particularly in resource-poor countries? How strong is their experience in collaborating with other NIH/NCI clinical trial infrastructures relevant to AMC? Do the identified Working Group Chairs have sufficient expertise and abilities to lead specific disease area Working 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, 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?

Specific to this FOA:

Research Program and Clinical Trial Sites

• Have the proposed clinical studies been judiciously selected so as to make major contributions to the management of HIV-related cancers, where 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 of the AMC research goals, oversee protocol development and implementation, and ensure timely publication of results?
• 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 studies 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 trial 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: 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?

Statistics and Data Management Center

• Are the statistics and data management structure and leadership of the 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?

AMC Chair Office

• Are the AMC Chair and members of the EC sufficiently effective in terms of increasing patient accrual? How appropriate are the plans for the protocol development and prioritization process? Are the proposed steps to include new and junior investigators in AMC activities sufficient? Are the activities of the AMC Chair and members of EC adequate to increase patient advocate/patient community involvement?

Operations Center.

• How well will the Operations Center serve the needs of AMC in terms of coordinating multiple facets of the AMC clinical trials? Will the proposed organization and procedures ensure the efficiency of the Operation Center?

Network Core Laboratories.

• Are the Network Resource Core Laboratories appropriate and sufficiently justified? Will they provide the required resources in all specified areas?

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

Environment

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

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

Protections for Human Subjects

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

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Children

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

Vertebrate Animals

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

Biohazards

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

Resubmissions

Not Applicable

Renewals

For Renewals, the committee will consider the progress made in the last funding period, including the following aspects.

Has the applicant team shown adequate progress in developing the research infrastructure, collaborations, and clinical trials to serve the overarching goals of AMC? How significant are the contributions of the AMC in the current funding period 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? Was the progress in the development, site selection and certification and patient accrual of the ANCHOR trial adequate?

Revisions

Not Applicable

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

Applications from Foreign Organizations

Select Agent Research

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

Resource Sharing Plans

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

Budget and Period of Support

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

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

As part of the scientific peer review, all applications:

• will be discussed and assigned an overall impact score; and
• Will receive a written critique.

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

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

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.

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

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

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

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

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

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

Cooperative Agreement Terms and Conditions of Award

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

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

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

• 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.
• 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 Working Groups 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 Domestic and International Clinical Trials Sites, Protocol Chairs, the Group Chair, Committee Chairs, the Operations Center, and the AMC as a whole.
• Clinical Trial 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.
  • Clinical trials protocols should be developed, submitted, and implemented in accordance with the NCI Investigator's Handbook" (http://ctep.cancer.gov/investigatorResources/docs/hndbk.pdf).
  • 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 at (http://ctep.cancer.gov/protocolDevelopment/lois_concepts.htm) to [email protected].
  • The Operations Center is responsible for communicating the results of the CTEP Protocol Review Committee to relevant Network Committees and Network members.
  • 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 (see Section VI.2.A.4 Arbitration Process).
  • All protocols utilizing NCI-sponsored investigational agents shall be conducted in accordance with the terms of the Intellectual Property Option to Collaborators (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) 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).
  • 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.
• 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):
  • 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;
  • 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;
  • Ongoing assessment of patient eligibility and evaluability;
  • Adequate measures to ensure timely medical review and assessment of individual patient data;
  • 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;
  • Rapid reporting of treatment-related morbidity information and measures to ensure communication of this information to all relevant parties;
  • Interim evaluation of outcome measures and patient safety information;
  • 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; and
  • 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.
• Data Management Policies and Practices: The responsibilities of the Operations Center for data management related to study monitoring include:
  • Providing for central storage, security, processing and retrieval of study results;
  • Incorporating security features consistent with DHHS guidelines;
  • Implementing procedures for backing up the AMC clinical and administrative data, including intermittent duplication of the database with storage at a remote facility;
  • 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
  • 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.
• 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:
• 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 (http://ctep.cancer.gov/branches/ctmb/clinicalTrials/monitoring_multicenter.htm), 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.
  • On-site auditing of AMC Clinical Trial Site institutions will be planned to occur at least twice during the project period.
  • Any serious problems with data verification or compliance with Federal regulations must be reported to the Clinical Trials Monitoring Branch immediately.
  • In the event that the NCI determines that an AMC Clinical Trial 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.
  • 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.
• Data Report to CTEP: The Consortium will be responsible for assuring accurate and timely monitoring of the progress of each study, and therefore must have standard procedures for timely data collection and data management. Standard procedures include (but are not necessarily limited to):
  • Adequate measures to ensure timely submission of clinical trials data (e.g., adverse events, anticancer response, etc.) from Member Institutions. These measures should include procedures for monitoring compliance with Consortium’s guidelines for data timeliness on an institution and a study basis, including summary reports of data submission timeliness to be used for Institutional Performance Review and to be used for study monitoring (e.g., as specified by the Data and Safety Monitoring Plan)].
  • Rapid reporting of treatment-related morbidity information and measures to ensure communication of this information to all relevant parties. For investigational agents sponsored by the NCI, this involves reporting to the Investigational Drug Branch (IDB), CTEP, via the expedited CTEP-Adverse Event Reporting System (AERS) according to CTEP guidelines specified in each protocol (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm))
  • Preparation of study monitoring reports describing patient accrual and demographics, data timeliness, toxicity, and other items as appropriate. Examples of study monitoring reports include reports prepared for study chairs, the semiannual reports for Consortium meeting agendas, and reports as required to comply with the Consortium’s Data and Safety Monitoring Plan; and
  • Adequate policies and procedures for closure of studies. If the Consortium wishes to close accrual to a study prior to meeting the initially established accrual goal, the interim results and other documentation should be made available to NCI staff for review and concurrence prior to implementation of the decision. It is recommended that statistical guidelines for early closure be presented as explicitly as possible in the clinical trial protocol in order to facilitate these decisions. In the event that the study is recommended for early closure for safety reasons, procedures in the Data and Safety Monitoring Plan regarding notification of CTEP must be followed.
• 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.
  • Publication or oral presentation of work done via the AMC s Cooperative Agreement requires appropriate acknowledgment of NCI support.
  • 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.
  • For Consortium publications associated with NCI-support that do not involve agent(s) supplied under CTEP Collaborative Agreements (except as noted below for press releases), the AMC Program Director must receive a copy of the manuscript 30 days in advance of publication and a copy of abstracts should be provided three days in advance of publication. Unlike the situation for agent(s) supplied under CTEP Collaborative Agreements, however, no review or comments will be provided by CTEP and/or OHAM unless specifically requested by the Consortium. This is simply a confidential notification. Review timing for publications other than abstracts or manuscripts should be discussed with appropriate NCI/OHAM staff.
  • All press releases issued by the NCI and/or the Consortium on primary study findings and results require review by NCI, NIH, and DHHS. Pre-review timing for press releases on study finding and results must be discussed with and approved by the AMC Program Director. The AMC is encouraged to send drafts of press releases on other topics to NCI for pre-review and/or pre-release notice.
• 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:
  • Arranging for appropriate meeting space and accommodations for attendees;
  • Developing and distributing meeting agendas;
  • Providing the Report of Studies (including the ANCHOR trial) 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
  • Preparing summaries as appropriate after each meeting to be sent to AMC members and NCI program staff.
• AMC Communications: The Operations Center is responsible for establishing routine electronic communication with Clinical Trials 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.
• 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:
  • OHRP Assurances: The AMC must assure that each member has a current, approved Federal wide Assurance (FWA), on file with OHRP. Information on assurances is available on the OHRP website at: http://www.hhs.gov/ohrp/. In addition, federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to 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.
  • IRB Review of AMC Protocols: The Central Operations Office must assure that each AMC clinical trial protocol is reviewed and approved by each member institution’s IRB prior to patient entry, and must ensure that each clinical trial protocol undergoes continuing review no less than once per year by the IRB so long as the clinical trial is active.
  • Assuring Appropriate Informed Consent: The AMC must have procedures in place to ensure that each member institution is trained and understands the policies and procedures relevant to ensuring that patients are enrolled on studies with appropriate informed consent per NCI/NIH policy and federal regulations.
  • Institutional Review Board (IRB) Review of the Clinical Research Program and Statistics and Data component: (http://archive.hhs.gov/ohrp/humansubjects/guidance/engage08.html): An IRB should review and approve the research activities related to the receipt and processing of the identifiable private information by the Clinical Research Program and Statistics and Data component. The IRB should ensure that there are sufficient mechanisms in place to adequately protect the privacy of subjects and maintain the confidentiality of the data.
  • Education on the Protection of Human Subjects: NIH policy requires education on the protection of human subject for all investigators submitting NIH applications for research involving human subjects and individuals designated as key personnel. This policy is available on the NIH website at: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.
• 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).
• Fiscal management of the Network, including:
  • 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.
  • Distribution of funds from the Patient Recruitment and Retention to Clinical Trial Site Institutions 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.
  • Allocation, distribution and per capita patient reimbursement plans and major expenditures for the ANCHOR trial recommended by the ANCHOR Trial Coordinating Committee (ATCC) will have to be approved by the AMC EC prior to implementation.
• Progress Report: Submission of annual progress reports to the NCI that describe activities and accomplishments during the previous year of funding. The report should include:
  • 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.
  • Summary data on performance of each AMC Clinical Trials Site, including protocol accrual, quality and timeliness of submitted data, and involvement in protocol development activities.
  • Research plan, changes in procedures and/or staff, and the proposed budget for the coming year.
• Patient accrual and credit: The AMC is expected to accrue 120 domestic patients (U.S.) per year and 80 patients per year in international resource limited settings. A patient entered on an interventional protocol (treatment, vaccine, etc.) is counted as 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 two 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.
• Specimen Banking: The AMC will use the AIDS and Cancer Specimen Resource (AMCR) 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 AMCR is currently funded as a separate cooperative agreement with the NCI (http://acsr.ucsf.edu).
• The release and utilization of tumor specimens and biological fluids, banked from the ANCHOR trial, to AMC investigators or to out of network investigators will require prior approval by OHAM/NCI.
• Protocol Implementation Fund (PIF): The AMC will maintain a restricted portion (approximately $1,125,000 in year 1) of the AMC award to support efforts related to patient accrual and retention costs for patients accrued onto AMC clinical trials (excluding the ANCHOR trial). 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 Clinical Trial Sites for increased accrual above the minimum requirement to maintain Clinical Trial Site status. The PIF will also cover: protocol-mandated drug purchases, storage, and distribution for international trials; costs for laboratory diagnostics not reimbursed as standard of care; clinical trial insurance; computerized tomography (CT) scans; remote audits of radiotherapy machine output and on-site dosimetry review audits for international trials. These funds will be restricted for this purpose only and cannot be used for other purposes without permission from the AMC Program Director. This restriction will be incorporated into Terms of Award in the Notice of Grant Award.
• Member Clinical Trial Site Institutions: The AMC is responsible for having a comprehensive and consolidated membership roster of all its sites and associated investigators and research staff and for maintaining the roster for both auditing and financial management purposes with real-time status of all members. All member institutions/sites must have appropriate and accurate NCI institutional codes approved by NCI. All sites will participate in on-site Monitoring Program established by the AMC and will follow AMC’s SOPs for the conduct of clinical research and complying with the AMC’s By-Laws.
• 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.
• Adverse Event Reporting: All AMC member Institutions will follow the procedures established by the AMC for assuring timely reporting of all serious and/or unexpected adverse events.
• Investigational agent responsibilities: Member institutions will implement 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.
• International Clinical Trial Sites: An International Clinical Trial Site will be directed by a Lead Senior Collaborator from the Foreign Institution. A Foreign Site may have a U.S. Collaborator from the AMC as a consultant for that Site. The AMC U.S. 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 Clinical Trial 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.
• Network Resource 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 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.
• If the PD/PI serving as AMC Group Chair is been replaced by another individual as AMC Chair in a procedural vote by the AMC Steering Committee, the Institution of PD/PI named in the notice of grant award who no longer serves as AMC Chair will release the award to the Institution of the new AMC Chair upon NCI approval.
• Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

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

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:

• Interacting with the PD(s)/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);
• Serving as voting members of the Executive Committee, the Steering Committee and, if applicable, subcommittees;
• Assisting in the design and coordination of research activities for awardees;
• 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);
• Contributing scientifically to the process of data collection and participating in data analyses and publication efforts of the Consortium;
• Advising on the management and technical performance of the AMC investigations;
• 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;
• Assisting in the publication of results;
• 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);
• 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);
• 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 Clinical Trial Monitoring System, 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;
• Making recommendations to the EC and the SC on the allocation of monies from the Discretionary Fund; and
• 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 becommunicated 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.

Areas of Joint Responsibility include:

Execution of this program will require collaboration among NCI staff, the Group Chair, the Directors of the Clinical Trials 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:

• Executive Committee: The leadership of the AMC will be vested in the Executive Committee, 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 Executive Committee 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, Clinical Trials Sites' performance evaluation, approval of new member sites (including ANCHOR trial implementation sites) and cooperative group collaborations, approval of funds from the discretionary, protocol implementation fund and Clinical trial research fund and final approval of budgets including ANCHOR.
• 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, Working Group Chairs, the Operations Center Director, the Group Biostatistician, domestic Clinical Trial Site representation, international Clinical Trial Site representation, and patient/family representatives. Each full member will have one vote, with the exception for NCI representatives, who will jointly have one vote. Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee.
• International Resource Sub-committee: The Working Group responsible for facilitating selection, vetting and accreditation and capacity building of Foreign Clinical Trials 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.
• ANCHOR Trial Coordinating Committee (ATCC): The leadership of the ANCHOR trial will be vested in the ATCC. Its membership will consist of the AMC Chair, ANCHOR trial protocol Chair and 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 ATCC will be responsible for the establishment and amendments and the ANCHOR trial initial site selection, new member sites and performance evaluation, develop a budget plan for the ANCHOR trial, make recommendations to the AMC EC for ANCHOR trial expenditures from the ANCHOR budget set by the NCI.
• 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 the safety of participants for each AMC clinical trial, 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 NCI Program Director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

Dispute Resolution:

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

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

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

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

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

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

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.