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

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 enable the provision of support to the AIDS Malignancy Consortium (AMC) to conduct research activities in the following areas:

• Maintaining a multidisciplinary research team that will develop and implement the scientific research agenda of the consortium;
• Conducting pilot phase, Phase I, Phase II, and Phase III clinical trials of novel agents and/or innovative approaches of AIDS-related cancer management;
• 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;
• Developing correlative studies in the context of the clinical trials; and
• Distribution of excess tumor tissue and other relevant biologic fluids to the AIDS and Cancer Specimen Resource for ongoing or future investigations.

To be considered for the renewal award, the Consortium must have disease oriented working groups that will address AIDS-defining and non-AIDS-defining cancers occurring among people living with HIV, such as Kaposi sarcoma, lymphoma, cervical cancer, anal cancer, liver cancer, lung cancer among others.

The proposed AMC must consist of the following functional units:

• An Operation Center;
• Clinical Trial Sites (CTS, domestic and international);
• Network Laboratories; and
• A Statistical Center.

The Network Laboratories will be responsible for routine clinical trial support activities, pathogenesis-driven correlative studies, and clinical pharmacology and pharmacokinetics studies of anticancer/antiviral interactions. All trials conducted by the AMC will be available to subjects of all racial/ethnic groups.

The AMC is expected to continue the conduct 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 (such as 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.

Cancer has been a major feature of the HIV epidemic since its beginning. Three of these cancers, Kaposi sarcoma (KS), high-grade B cell non-Hodgkin lymphoma (NHL), and invasive cervical cancer, are called AIDS-defining cancers (ADC) when they develop in HIV-infected individuals. HIV-infection is also associated with increased risk of a number of other cancers. The spectrum of cancers seen in HIV-infected individuals is complex and is changing as the epidemic evolves.

With the introduction of combination antiretroviral therapy (cART) for treatment of HIV infection in the United States and other developed countries, the incidence of certain AIDS-defining malignancies decreased. However, the incidence of AIDS-defining cancers has more recently stabilized, 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 cancers continue to be among the most common tumors overall. More than two-thirds of the HIV-infected population live in Sub-Saharan Africa, and this region is also an epicenter of KS and other virally-related malignancies such as cervical cancer and Burkitt lymphoma. In this region, AIDS-defining malignancies (KS, aggressive NHL and invasive cervical cancer) are among the most common tumors overall.

In regions in which anti-retroviral therapy is more widely used, HIV-infected patients are living longer, and the population of HIV-infected patients is aging. In part, as a result of this, while the rates of ADC are decreasing the rates of certain non-AIDS-defining cancers (NADCs) are on the rise, with significant increases in anal cancer, lung cancer, liver cancer, oropharyngeal cancer and several other tumors. 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. Some recent studies have shown that in areas where cART is widely available, cancer is now the most common cause of death in HIV-infected patients, accounting for approximately one-third of the deaths.

One cancer that has been increasingly substantially in HIV-infected individuals in the United States and other areas where cART is available is anal cancer. In addition, there has been an increase in the incidence and prevalence of pre-cancerous anal lesions. HIV-infected patients with human papillomavirus (HPV) infection are more likely to have persistent HPV infection and develop precancerous lesions than HIV-uninfected individuals. Also, these patients are less likely to have lesion regression, and more likely to have disease recurrence after standard lesion ablation therapy. Although cART seems to improve tolerability of more aggressive therapy for anal disease in HIV+ patients, toxicity and relapse continue to be a problem and cART seems to have little effect on the natural history of established lesions. Overall, there is a substantial and increasing need for improved prevention and treatment of tumors in HIV-infected patients. Moreover, there is a substantial need for approaches to these tumors as well as other tumors caused by HPV that are appropriate for resource-limited regions.

Given these needs, it is extremely important that a clinical trials program be structured to evaluate and optimize clinical interventions for the treatment and prevention of HIV-associated cancers in the United States as well as resource-limited regions. Such a program should optimally involve investigators with substantial expertise in HIV/AIDS-related malignancies and should include correlative laboratory studies aimed at gaining a better understanding of cancer pathogenesis and parameters related to disease progression and response to treatment. In addition, it is important to support studies on the impact of cART on the pharmacokinetics of the anti-cancer chemotherapy, on toxicity profiles, and the response to treatment.

The overarching goal for the Consortium is to continue its domestic and international efforts to develop more effective prevention and treatment strategies for cancers associated with HIV/AIDS. It is expected that the geographical distribution and composition of the clinical trial sites (CTS) will reflect geographical areas with high HIV/AIDS disease burden.

Scientific approaches taken by the Consortium will continue to be broad in scope and will reflect the creativity and capabilities of team participants. Broad areas of study include translational research, optimization of clinical management and cancer prevention studies including those of risk and cancer susceptibility.

The AMC will evaluate clinical interventions for treatment and prevention of cancer in HIV-positive patients, investigate the biology of these malignancies in the context of clinical trials, and donate specimens and clinical data to the AIDS and Cancer Specimen Resource (ACSR) (https://acsr.ucsf.edu/). In the case of pilot, Phase I, or Phase II clinical trials, laboratory studies to monitor patients (e.g., pharmacokinetics, pharmacodynamics) or to measure a particular biological response (e.g., imaging) that may provide information relevant to the interpretation of the success or failure of the therapy administered are encouraged. Tissue specimens and/or biological fluids are expected to be collected for: AMC genomic and biomarker laboratory studies; donations to the ACSR; and NCI Office of HIV and AIDS Malignancy(OHAM, https://www.cancer.gov/about-nci/organization/oham)-supported projects or projects OHAM has identified as programmatically important for the NCI AIDS malignancy effort.

The research agenda of the consortium is encouraged to include cancer survivorship and quality of life research as applicable. It is expected that the research of the AMC will focus on HIV-infected individuals and be aligned with the criteria for AIDS research as defined by the NIH Office of AIDS Research, https://www.oar.nih.gov/. This research may include however, a limited number of HIV-uninfected patients as controls to optimally study the tumors that most commonly develop in the context of HIV infection.

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

The AMC biobanking needs for clinical trial support (excluding the ANCHOR trial) will be supported by the ACSR.

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

A) AIDS Defining Cancers:

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

• 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;
• Management in pediatric patients with HIV and cancer;
• Evaluation of new classes of molecules with unique and improved features such as better pharmacologic or toxicological properties;
• Integration of immune-based therapeutic approaches in treatment regimens;
• Identify new strategies for the treatment of KS-related fibrosis, including lower extremity edema;
• 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’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. Areas of interest may include:

• Novel pathogenesis-driven therapeutic approaches including relapsed and/or refractory lymphoma;
• Integration of immune-based therapeutic approaches to treatment regimens;
• Identifying and testing biomarkers to identify predictors of response to interventions in symptom management;
• Identifying and testing biomarkers that will identify predictors of cancer risk;
• Identification of host determinants that influence response to therapy;
• 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: Despite that the incidence of cervical cancer in the general population has been

decreasing in the last 15 years, it has not changed substantially 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. Addressing the scientific research needs for optimizing prevention, and treatment of cervical cancer in women in those countries is warranted. Areas of interest may include:

• 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 check point inhibitors, therapeutic vaccination or adjuvants to surgical treatments to improve long term outcomes.

B) Non-AIDS defining cancers:

Anal cancer and its precursors: 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.

• Development of successful treatment and prevention 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 including immunotherapeutic approaches such as therapeutic vaccination and check point inhibitor therapy; and
• Determining the genetic, immunologic, and virologic correlates 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. Therefore, it is necessary to:

• Evaluate the effectiveness of novel therapeutic strategies;
• Identification of biomarkers that may predict cancer risk; and
• Testing different methods of diagnosis and early detection.

Hodgkin’s 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, hepatocellular carcinoma and ocular surface squamous neoplasia, OSSN.

• The management of these cancers in the HIV setting needs to be optimized;
• Identifying the factors associated with the risk and susceptibility to these cancers:
• Testing screening technologies aimed at reducing cancer risk

C) Other Aspects of Interest

Clinical Pharmacology: The NCI has 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.

Cancer Survivorship: The number of cancer survivors in the United States is expected to increase significantly with the aging of the United States population and the improvement in the management of people living with HIV infection. Cancer survivors may experience a host of long-term and late effects of cancer and cancer therapy and many comorbid conditions that require coordinated follow-up care after completion of primary treatment for cancer. The following area of investigation needs to be emphasized:

• Evaluation of late complications, health status, and factors affecting quality of life in cancer survivors, especially those who have been on AMC protocols.
• Evaluation of social determinants and barriers of access to health care and treatment that will affect the outcome and quality of life of cancer patients living with HIV infection.

AMC Operation in International Settings: 

The conduct of international collaborative work into sub Saharan Africa, Latin America and other low- and middle-income countries on other continents is vital for epidemiologic, basic, and clinical research in populations with high prevalence of KS, NHL and cervical cancer and other HPV-related neoplasia. It is expected that the AMC will:

• Continue to expand their research agenda in sub-Saharan Africa and Latin America;
• Develop studies that address research questions aligned with the needs of these communities;
• Develop a research agenda focused on enhancing our knowledge of the host, genetic, and viral factors involved in cancer development that will eventually guide improving upon the current standards of care in these populations;
• Involve the international investigators in developing the AMC international research agenda and take leadership roles in AMC activities; and
• Provide professional development and capacity building for foreign site personnel.

The AIDS Malignancy Consortium must include the following functional units:

1. AMC Chair Administrative Office (Administrative Core);

2. Operations Center;

3. Research Program based on disease-oriented scientific Working Groups;

4. Domestic Clinical Trials Sites (Domestic and International)

5. AMC Core Resource Laboratories; and

6. Statistics and Data Management Center.

The AMC Chair is expected to be Program Director/Principal Investigator (PD/PI) of the applicant institution. AMC 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 AMC 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 and Latin America) 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 and will work closely with the ACSR network which will be providing tumor banking support for AMC trials.

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

Scientific Planning Committee (SPC): In terms of overall strategies and direction, the Consortium will be governed by the SPC. The primary function of the AMC SPC 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 Scientific Planning committees, see Section VI.2. 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.

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

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

Only the current awardees of the AIDS malignancy Consortium supported under RFA-CA-14-502are eligible to apply to this FOA, with the provision that the applicant team may choose, which of the participating institutions will serve as the seat of the AMC Operations Center and as application-submitting institution.

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) 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 to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but all registrations must be in place by time of submission. 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.

Only one application per institution (normally identified by having a unique DUNS number or NIH IPF number) is allowed.

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).

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, 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.

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.
National Cancer Institute (NCI)
Fax: 240-541-4520
Email: [email protected]

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

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

A. AMC Overview: one required ─ 12 pages

B. AMC Chair Office: one required ─ 6 pages

C. Operation Center: one required ─ 6 pages

D. Research Program: one required ─ 12 pages

E. Clinical Trial Sites: one required ─ 12 pages

F. Network Resource Laboratory: one required ─ 6 pages

G. 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:

For each Clinical Trial Site proposed, provide documentation demonstrating 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 must be uploaded as separate 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 process for selecting new clinical sites as "members".
• The process for application and selection of AMC junior investigator trainees.

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

• Table of content of the attachment;
• Summary of the consortium’s most impactful and practice-changing accomplishments relative to HIV+ patients with cancer;
• Summary Tables for completed, active and in development domestic clinical trials by disease area (for years 2015-2019;
• Summary Table for completed, active and in development International Clinical Trials (2015-2019);
• Summary Table for completed AMC Trials (pre-2015);
• 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 2015-2019);
• Accrual Summary Table (for years 2015-2019);
• Summary Table for the ANCHOR Participating Sites. Include columns for lead investigator, date of site certification and subject accrual including numbers of screened and randomized subjects.
• Summary Table for demographics of the ANCHOR trial participants including gender race /ethnicity composition;
• Summary Table providing data on annual Domestic patient accrual to AMC trials by gender and race/ethnicity composition (for years 2015-2019); and
• Summary Table for carrier enhancement activities during the period from 2015-2019, with such information as names of trainee-investigators and mentors, affiliations, and areas of training.

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

• AMC Protocol Development process
• Protocol Intensity Scoring

Attachment 4: Site Performance: Provide the following information as a PDF file with the name Performance Evaluation ).

• Standard operating procedures (SOPs) used for AMC Site Performance Standards and Measures
• Procedures for addressing remediation and defunding poorly performing sites

Attachment 5: Strategic Planning Process. Provide the following information as a PDF file with the name Strategic Planning (not to exceed 2 pages)

• Outline the process for strategic planning of the research agenda for the consortium relative to prioritization of research related activities (e.g. cancer therapy trials, correlative biology/genomics, cancer prevention/intervention trials, cancer survivorship)

Attachment 6: 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.
• Use separate tables for domestic and international sites.

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) (2015-2019);
• Summary Table for samples processed by each of the Core units, indicating the nature of the assay and related studies (2015-2019); and
• AMC Laboratory Quality Assurance process.

Attachment 8: Statistics and Data Management. Provide an organizational flow chart for the Statistical and Data Management Center (use filename "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 Sketches 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 up to approximately 58% of the total budget requested in year one may be allocated for ANCHOR activities, including biobanking and support of investigators meetings. This amount should include an ANCHOR Trial Patient Care Support Fund (approximately $3,000,000 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 $60.8 million in total costs.
• Basic AMC Site Support (approximately 7.6% of the requested budget): Applicants may propose expenses to support an appropriate number of domestic Clinical Trial Sites. The budgetary request should include per capita costs of accrual for four 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 8.5% of the requested budget): Applicants may propose expenses for basic site support for up to 12 foreign institutions. The budgetary request may include costs of personnel, travel, training, and capacity building and compensation for the leadership of the International Program.
• Protocol Implementation Fund (approximately 6.7% of the requested budget): The budget request for this Fund may 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 3.5% of the requested budget): 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-G 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-limited 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 and career enhancement activities for junior investigators. Indicate any major organizational changes proposed for the Consortium renewal.

Progress Report. In this Sub-section, summarize also AMC progress in the current funding period. In addition to standard instructions for Progress Report, address the following elements:

• Major accomplishments during the current funding period;
• Overview of clinical trials conducted, including the ANCHOR trial;
• Progress of the ANCHOR trial performance, choice and certification of performance sites, and patient accrual and demographics; and
• New resources/capabilities established as a result of AMC award and collaborations with other NIH/NCI clinical trial infrastructures.
• Career enhancement research activities of junior investigators

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
• Career enhancement plans for junior investigators: describe plans to incorporate new, minority, and junior investigators into the Network's research 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 and criteria for defunding poorly performing clinical trial sites.

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.
• Provide plan/steps currently in place or that will be implemented to increase the rate of accrual on clinical trials.
• 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 and Latin America.
• Management of the ANCHOR clinical trial. The AMC is currently conducting a large randomized trial (the ANCHOR study), and successfully completing this study will be an important part of the AMC activities. Given the size and complexity of the ANCHOR study, describe coordination, implementation and ongoing efforts to complete accrual and ensure study subject adherence and retention to the trial.
• 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.

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

Sub-section E. Clinical Trials Sites

Under separate subheadings describe Domestic and International Clinical Trial Sites addressing the following aspects:

Part 1: Domestic Clinical Trials Sites

A Domestic Clinical Trial Site is expected to accrue a minimum of four 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.

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.

Part 2: International Clinical Trials Sites

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.
• Training and capacity building

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

Sub-section F. 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 ensure 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.
• Biospecimen collection and banking for the ANCHOR trial.

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

Sub-section G. 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 as provided in the SF424 (R&R) Application Guide, with the following modification:

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

Appendix:

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

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

Given that applicants should not propose any specific clinical trials at the time of application, Study Record should NOT be completed.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).

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

Complete the Delayed Onset Study record and must check box "Anticipated Clinical Trial?"

Study Title-- use:  "Multiple Delayed Onset Studies"

Justification Attachment:  Indicate that the clinical trials will be designed and conducted by the AMC during the Project Period. Each clinical trial protocol developed will be subject to approval through the standard NCI procedure that involves an initial concept submission and subsequent review.  If the concept receives approval, the next stage will be development of the protocol, which also must undergo review and approval by NCI/DCTD Clinical Trial Evaluation Program, prior to activation through the AMC network. Indicate areas of oversight, regulatory compliance monitoring, etc. that will be the responsibility of the AMC.

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

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

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

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

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

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

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 How to Apply Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

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

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

See more tips for avoiding common errors.

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

Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

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

Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

For this particular announcement, note the following:

As this FOA is to support the essential AMC clinical trials infrastructure, reviewers will assess to what degree the proposed Research Base will be able to fulfill all the required functions, including rigorous study design, focus on interventions that address clinically important questions or unmet needs.

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.

A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.

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.

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? 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?

Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those 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?

With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

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?

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?

Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? 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? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects? 

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 individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

Does the application adequately address the following, if applicable

Study Design

Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?

Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

Data Management and Statistical Analysis

Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

Specific to this FOA:

Organizational and governing structure

Is the organizational and governing structure proposed by the applicants adequate for the mission of the AMC? and are the lines of authority and decision-making processes sufficient? Do the AMC units and their interactions as proposed address the specific scientific research priorities of the AMC Program? Are the special features of the Consortium environment and resources reasonable to create unique opportunities to serve the AMC scientific goals and career enhancement activities for junior investigators? Are the organizational changes proposed for the Consortium renewal reasonable?

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 and other cancers developing in HIV-infected individuals, 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?
•      How appropriate are the criteria and processes for ongoing evaluation and problem resolution of all Consortium components and criteria for defunding poorly performing clinical trial sites?
•      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?
•      The ANCHOR study: Given the size and complexity of the ANCHOR study, are the coordination, implementation and ongoing efforts to complete accrual adequate? and are the proposed efforts to ensure study subject adherence and retention to the trial reasonable?
•      Is the correlative science research agenda for the group adequate?
•      Are cross-network collaborations with other NIH-sponsored HIV/AIDS programs and other NCI-supported research networks to achieve the AMC aims and objectives reasonable?
• Are the AMC Consortium policy and procedures for ensuring community input and community representation within the Consortium adequate?

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?

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?

If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?

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.

Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?

Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

For research that involves human subjects but does not involve one of the 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 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.

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 individuals of all ages (including children and older adults) 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.

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

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.

Not Applicable

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

Not Applicable