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

This Funding Opportunity Announcement (FOA) is one of two FOAs for the National Cancer Institute (NCI)-supported Cancer Prevention Clinical Trials Network (CP-CTNet). The purpose of CP-CTNet is to perform early phase clinical trials to evaluate the biologic effects of preventive agents and interventions and to determine clinically-relevant correlates in order to advance their development for cancer prevention.

CP-CTNet will support the following two types of components that will be individually awarded through the respective FOAs indicated below:

• CP-CTNet Sites (this RFA), whose role will be to design, perform and report the results of early phase (phase 0-II) cancer prevention clinical trials.
• Data Management, Auditing, and Coordinating Center (DMACC) (see RFA-CA-18-030), which will provide centralized data management and auditing of clinical trials data, as well as administrative support for all CP-CTNet awardees.

Each CP-CTNet Site will consist of a Lead Academic Organization (LAO) and Affiliated Organizations (AOs) that will work together to perform clinical trials. Each CP-CTNet LAO will serve as the research hub for its group and will be the UG1 applicant institution. Each LAO will constitute a multi-institutional clinical trial group and provide the infrastructure to develop, implement, and analyze the studies. The Clinical trials will be performed either by the LAO and/or AOs within each CP-CTNet site or across the CP-CTNet sites (network-wide trials).

Key Definitions for the context of this FOA:

• The terms Clinical Research and Clinical Trials in this FOA follow the NIH definitions (https://grants.nih.gov/policy/clinical-trials/glossary-ct.htm#ClinicalResearch.)
• CP-CTNet Site: UG1 Consortium supported by RFA-CA-18-029 consisting of Lead Academic Organization (LAO, recipient of the UG1 award) and Affiliated Organizations (AOs). Each LAO serves as the research hub for the CP-CTNet Site. A LAO may have parts that represent the same legal entity, even if their location is different from the main location of the awardee (such parts are referred to as "LAO integrated components"). AOs are any institutions collaborating with the LAO on clinical trials under sub-contractual/consortium arrangements.
• Study chair: the investigator who leads a given clinical trial
• Target organ: organ of focus for a given clinical trial. The participants in the trial should be at high risk for developing cancer arising in the target organ.
• NCI Central Institutional Review Board (CIRB): a centralized approach to human subject protection through a process that streamlines local IRB review of selected NCI-sponsored trials for institutions across the country by relying on national experts to ensure trials are reviewed efficiently and with the highest ethical and quality standards (https://www.ncicirb.org/about-cirb/).
• An Accrued Participant is defined as an individual who has completed the informed consent process, has been deemed eligible through all levels of the screening process, and has started the study intervention (e.g., actually received the agent and/or intervention to be tested).
• A Screened Participant is defined as an individual who has signed consent to proceed with evaluation for eligibility for a study after preliminary eligibility (e.g., presence of a risk factor for a specific cancer, history of a specific premalignant lesion, etc.) has been determined.

The search for effective cancer preventive agents, in the context of a rapidly advancing molecular understanding of the process of carcinogenesis, has led to the study of an increasing number of agents that intervene in specific molecular pathways thought to be critical to cancer development. The prospect of an even better understanding of the early phases of cancer development, such as will be provided by the Pre-Cancer Atlas (https://grants.nih.gov/grants/guide/rfa-files/rfa-ca-17-035.html), provides a strong rationale for increased investment in cancer prevention. Similarly, the recognition of the importance of the role of the immune system in tumor development and the recent successes in cancer immunotherapy for the treatment of advanced malignancies have led to a resurgence of interest in immunoprevention. The increasing number and molecularly or immunologically targeted nature of new agents require an efficient clinical trials system for evaluation and screening. These complex trials must also include extensive biomarker analyses, investigation of the biologic effects of the agent on the intended target, and correlation with clinically relevant indicators of potential health outcomes.

The nature of cancer prevention clinical trials requires access to specialized high-risk populations who obtain their care from different subspecialists and expertise in tissue collection and biomarker analysis. A typical phase II trial might examine the effect of an intervention on a histologically-proven premalignancy in participants at risk for cancer. This requires the screening of multiple high-risk individuals with procedures such as a colonoscopy or bronchoscopy to identify those who harbor such premalignancies, followed by post-treatment procedures with biopsies to assess the intervention’s efficacy. Other types of studies employed in cancer preventive agent development include (but are not limited to): phase 0 micro-dosing trials, phase I pharmacokinetic and pharmacodynamic trials, and window-of-opportunity trials performed prior to definitive cancer treatment. Cohorts participating in such studies include healthy volunteers, individuals at high risk for cancer either due to genetic predisposition or the presence of premalignant lesions, and cancer patients either prior to or after definitive surgical, radiation, or chemoradiation treatment. Thus, multi-institutional groups of clinicians from diverse specialties, research nurses, pathologists, translational scientists, statisticians, data managers, and other personnel with expertise in cancer prevention, drug development, and biomarker analysis are needed to successfully perform increasingly complex cancer prevention clinical trials.

NCI supports the systematic development of cancer preventive agents through three major programs managed by the Division of Cancer Prevention (DCP):

• Preclinical agent development is supported through the PREVENT Cancer Preclinical Drug Development Program (https://prevention.cancer.gov/major-programs/prevent-cancer-preclinical).
• The early phase clinical development (phase 0-II clinical trials) of promising cancer preventive agents has been primarily supported by the contract-funded Phase 0-II Cancer Prevention Clinical Trials Program (Phase 0/I/II Cancer Prevention Clinical Trials Program). The goal of this program is to identify preliminary efficacy and safety of preventive strategies. The results of preliminary efficacy studies provide important data to inform decisions to proceed to lengthy, expensive phase III cancer prevention trials, thereby minimizing the risk of failure in phase III. This program fills a critical niche in cancer preventive drug development that is poorly supported by the pharmaceutical industry and not well represented in the investigator-initiated grants portfolio.
• The phase III cancer preventive agent development, aimed at demonstrating definitive efficacy, is supported via the NCI Community Oncology Research Program (NCORP; https://ncorp.cancer.gov/).

The CP-CTNet, as funded by the NCI through this FOA and RFA-CA-18-030, will replace the current contract-funded Phase 0-II Cancer Prevention Clinical Trials Program. Each CP-CTNet Site will perform a variety of early phase cancer prevention trials in appropriately high-risk populations, ranging from phase 0 to phase IIb trials. Agents under study will include those developed by the pharmaceutical industry and provided to NCI for collaborative development, commercially available agents, agents developed by the grantees, and agents developed by NCI.

The overall goal of CP-CTNet is to perform early phase cancer prevention clinical trials to identify agents and interventions that can advance through the various phases of clinical development. Specific objectives are summarized below:

• To efficiently design and conduct early phase clinical trials to assess the cancer preventive potential of a variety of different agents or strategies. Emphasis is on novel agents and interventions that target relevant pathways important in carcinogenesis.
• To characterize the effects of these agents and interventions on their molecular targets, as well as on other biological events associated with cancer development (such as cell proliferation, apoptosis, growth factor expression, oncogene expression, immune response) and correlate these effects with clinical endpoints.
• To develop further scientific insights into the mechanism of cancer prevention by the agent or strategy examined and to continue to develop novel potential markers as determinants of response.

Goals and Scope of Activities for CP-CTNet Sites

The main role of CP-CTNet Sites will be to design and conduct early phase (phase 0-II) cancer prevention clinical trials.

For this role, each CP-CTNet LAO will be expected to serve as the main research infrastructure to support the performance of clinical trials. The LAOs will provide administrative support and oversight to clinical trial performance across their member AOs, as well as develop and perform specific clinical trials within their own institutions. The role of the AOs will be to develop clinical trials in collaboration with the LAOs and to accrue to multi-institutional studies. LAOs and AOs may participate in studies arising within their CP-CTNEt Site as well as within other CP-CTNet Sites.

The LAO will be required to interact closely with the DMACC, which will provide centralized data management, auditing, and network-wide administrative support.

Required Capabilities. Each proposed CP-CTNet Site needs to have expertise, skills, and infrastructure for the proper conduct of the following expected scope of activities:

• Designing and conducting early phase cancer prevention clinical trials using single agents or combinations of agents or other modalities. The emphasis will be on novel agents or strategies that target relevant pathways important in carcinogenesis, such as those involved in proliferation, apoptosis, differentiation, cell signaling, and others.
• Managing all aspects of study operations while adhering to all applicable rules and regulations for the conduct of clinical trials.
• Developing 1-3 new clinical trials per year, with expected accrual of 10-40 or more participants per year (10 in year 1, 40 or more starting with year 2) at each CP-CTNet Site.
• Conducting prevention clinical trials in participants at risk for cancers arising in one of at least 3 different target organs (at least one of which is breast, colon, prostate, or lung and at least one of which is not one of those 4 target organs), with access to populations at high risk for the development of cancer in these organs.
• Developing statistically appropriate clinical trial designs, including novel designs using omic technologies, to rapidly obtain evidence of preliminary efficacy. A variety of clinical trial models, including phase 0 micro-dosing trials, phase I pharmacokinetic and pharmacodynamic (PK/PD) trials, window-of-opportunity trials performed prior to definitive treatment for premalignant lesions or cancer, and Phase IIa or IIb cancer prevention clinical trials, will be used.
• Evaluating translational endpoints in biospecimens obtained from participants in clinical trials of investigational agents (e.g., the levels of expression and/or activity of molecular targets and/or downstream effectors pertinent to a given agent).
• Assessing PK/PD of the studied agents and establishing relationships between the dose, schedule, exposure, and effect.
• Obtaining mechanistic proof-of-principle data for new agents or approaches directed at novel molecular targets important in carcinogenesis.
• Collecting, processing, and storing biospecimens from trial participants for biomarker analysis.
• Evaluating novel technologies (e.g., imaging, blood based, etc.) for assessing the effects of interventions

Agents to be Studied. Agents to be developed will be announced twice yearly via NCI solicitations for Letters of Intent (LOIs) for clinical trials. Agents may be developed for specific indications by individual CP-CTNet Sites or jointly by more than one Site. CP-CTNet Sites are also expected to propose unsolicited LOIs using agents or interventions available to their investigators.

Required Functional Components. To realize the stated objectives, the CP-CTNet Site applicants must organize and include the following two required functional components:

• Clinical Trial Program This functional component must include the scientific leadership capable of developing and conducting early phase cancer prevention clinical trials within each CP-CTNet Site or across Sites within the network and the infrastructure to oversee, support, and to ensure compliance with applicable clinical trial regulations.
• Site Accrual Program This functional component must provide robust accrual of study participants at the LAO and AOs to CP-CTNet trials, including accrual to studies focusing on the identified target organ sites that give rise to less common cancers (e.g., those arising in the oral cavity, esophagus, ovary, bladder, etc.), as well as timely activation of trials and provision of good clinical trial stewardship.

CP-CTNet Network Governance and Trans-Network Activities

Steering Committee: The representatives of CP-CTNet awardees (with the participation of the NCI) will be expected to form a Steering Committee as a self-governing body for the Network. For details on the composition and responsibilities of the Steering Committee, see Section VI.2 under Cooperative Agreement Terms and Conditions of the Award.

Trans-Network Research Activities

All CP-CTNet Sites will be expected to work jointly toward the CP-CTNet network goals by:

• Interacting with the DMACC;
• Participating in trans-network clinical trials; and
• Participating in high priority ancillary studies, including developmental work for new biomarkers.

Additional NCI Support for the Initiative (beyond the scope of the two CP-CTNet FOAs).

NCI/DCP will provide the following additional infrastructure support to CP-CTNet participants:

• Regulatory support, including Investigational New Drug (IND) application preparation and Food and Drug Administration (FDA) reporting
• Agent acquisition, packaging, and distribution
• Central Institutional Review Board (CIRB) review
• Protocol receipt, review, and approval process, and study document submissions and management

NCI anticipates providing long-term storage solutions for the collected biospecimens and access to them for the research community.

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.

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• U.S. Territory or Possession

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.

All individuals designated as PDs/PIs for the CP-CTNet Sites must have their primary affiliation at the application-submitting institution (i.e., the LAO).

These individuals are expected to be nationally and internationally recognized leaders in clinical trials of cancer preventive agents. This expertise should reflect mainly clinical trials of preventive agents (e.g., drugs, small molecules, vaccines/biologics) using measures of drug action and efficacy that include modulation of cancer-related biomarkers.

Additional expertise in other cancer preventive approaches (including medical devices, cancer preventive surgery, risk-reducing surgery, and non-surgical ablative techniques) is also desirable.

The PDs/PIs of applications submitted in response to this FOA must not be named as Senior/Key Personnel or Other Significant Contributors on any teams submitting applications to the companion FOA, RFA-CA-18-030.

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

Applicant organizations may submit only one application per institution (normally identified by having a unique DUNS number or NIH IPF number)..

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).

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

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.

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:

Eva Szabo, MD
Telephone: 240-276-7011
Fax: 240-276-7848
Email: [email protected]

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

• Research Strategy Section is limited to 30 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.

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

Facilities & Other Resources:

In addition to the standard items for this attachment, provide the documentation of main capabilities and available resources for CP-CTNet Site. Relevant information may be provided in table form. Provide documentation on the characteristic of the scientific environment in which the cancer clinical trials and other human subjects research will be conducted. Include such aspects as:

• Characteristics of the AOs (as applicable) that will be accruing participants to CP-CTNet clinical trials. A table can be used to show such information as: the name of entity, responsible AO Site Lead, city and state where the entity is located, and target organs or special high-risk populations that the site will be studying.
• Research pharmacy description (at LAO and AOs). Describe investigational pharmacy operations, procedures, and adherence to local/state/federal guidelines.
• Biospecimen repository storage facilities and summary of procedures for collection, processing, storage, retrieval, and dissemination of biospecimens.

Other Attachments:

Applicants must provide the following additional material specified below. Each attachment should be uploaded as a separate PDF using the indicated filenames (which will serve as application bookmarks).

Attachment 1. Scientific Achievements for Clinical Trials (Use filename: Scientific Achievements): 'Scientific achievements' refers to important information from primary and secondary endpoints of previously performed clinical trials listed in Attachment 3. A table can be used to show such information as the general cancer site category, trial phase, year of publication of study primary outcome or other significant impact, brief title, investigational agent/regimen, description of endpoint or sub-study result, manuscript or abstract reference, and brief description of the importance of endpoint or sub-study result.

Attachment 2: Sample Cancer Prevention Clinical Trial Concepts (Use filename: Sample Concepts): Provide two sample concepts for clinical trials to illustrate the team's approach to preventive agent development. These sample concepts should be realistic and feasible (e.g., the applicants should have sufficient access to agents and target populations proposed.) The concepts are primarily to document applicants' proficiency and may or may not be selected for implementation after grant award.

The two concepts should have the following features:

o Each sample concept should address a different target organ and use different agents/strategies.

o Each sample concept must be no longer than 10 pages.

o At a minimum, each concept should define/address/describe the following elements:

Title (include phase of study),

Key personnel and performance sites (individual designated as study chair, study chair's performance site, all participating sites, other key personnel and their roles),

Target organ and study population,

Rationale/hypothesis,

Agents proposed (including dose, schedule, supplier, and evidence of access to agent),

Objectives (primary and prioritized secondary objectives),

Details of Study Plan, including laboratory correlates/biomarkers, endpoints/statistical considerations, proposed sample sizes, etc.,

Participant recruitment capability (planned duration of accrual, expected monthly accrual rate, accrual capabilities of each performance site), and

The anticipated next steps in the development of the agent/strategy

Attachment 3. Completed and Ongoing Phase 0, I and Phase II Clinical Trials (Use filename: Early Phase Clinical Trials): List Phase 0, I and II prevention clinical trials that have been completed during the last 5 years or are ongoing. Trials conducted by or coordinated by the LAO (whether or not the LAO was an accruing site) as well as trials conducted by up to 3 proposed AOs should be included. A table can be used to show such information as protocol title, trial phase, target organ, years trial was open, and total planned and achieved participant accrual. Indicate whether the LAO or any proposed AOs participated in each trial. Separately (in a separate section in the same table), list up to ten Phase I and II therapeutic clinical trials that have been completed during the last 5 years and any ongoing clinical trials for which significant research findings are available. The lead institution for each trial should be noted. Note: trials coordinated by the LAO or an AO, for which the LAO or that AO did not accrue participants, should also be listed and the 'coordination only' role should be noted.

Attachment 4. Screening and Accrual Summary by Site for Phase I and Phase II Clinical Trials (Use filename: Trial Screening and Accrual): Provide additional screening and accrual information on the trials listed in Attachment 3. Specifically, indicate the number of participants screened and accrued at the LAO and at each proposed AO that participated in the trial (only provide information on institutions involved in the current grant application). A table can be used to show such information as protocol title, years during which the trial was open, number of participants screened, and number of participant accrued (broken out by individual accruing site).

Attachment 5: Trial Development, Participant Accrual and Trial Reporting for Individual Clinical Trials (Use filename: Trial Timelines): For each trial listed in Attachment 3, list actual timelines for the following specific steps in the clinical trial protocol development process: concept submission to approval (if appropriate), protocol development (from concept approval to final protocol approval, as appropriate), annual accrual rate projected and achieved, total accrual, and time from last participant off study to manuscript publication.

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

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

Personnel Costs

• Senior/Key Personnel and Other Personnel. The request under this category may include estimated costs of salary support (based on level-of-effort) for the PD(s)/PI(s), statistician, lead coordinator, and other personnel responsible for the various aspects of the clinical operation within the functional component of the Clinical Trial Program.
• A minimal effort level of 1.2 person-months is required for all designated PDs/PIs and cannot be reduced below that level during the project periods.
• Protocol Chairs and Lead Site Coordinators. Salary requests for Protocol Chairs and Lead Site Coordinators should be commensurate with the efforts needed for their expected involvement in 1-3 new protocols per year.

Costs of Clinical Trial Performance

The costs of prevention clinical trials are expected to vary depending on their complexity (e.g., short intervention in a healthy cohort versus a longer intervention in a cohort that requires eligibility determination via invasive biopsies). A balanced mix of simple and complex trials and resultant patient care costs should be anticipated. The following types of costs may be requested:

• Costs associated with participant accrual and patient care costs (that are not part of standard care). The costs budgeted should assume accrual of a minimum of 10 participants in the first year and an annual accrual rate of at least 40 participants per year in years 2-5 of the project period.
• Institutional costs of research that are not considered a cost of treatment by medical insurers, and therefore are not reimbursed by insurers (e.g., eligibility tests, performance of research biopsies, biospecimen handling and shipping, pharmacy start-up and per participant agent distribution, etc.).
• Costs for obtaining biospecimens to assess the main study endpoints (e.g., biopsies) and for analyses of primary and most important secondary endpoints (assume one primary and two secondary endpoints per typical trial). Standard costs for common analyses (e.g., immunohistochemistry) may be proposed.

Note: The actual costs of clinical trials performed by the CP-CTNet Site will be determined at the time that studies are proposed and conducted. The proposed complexity and maximum accrual of the studies that are performed will be limited by the funds available at the time the studies are proposed. The use of funds budgeted for participant accrual and endpoint analyses will be restricted until specific clinical trial protocols have received final approval from NCI.

Travel Funds

The LAO PD(s)/PI(s) and at least three representatives from the CP-CTNet LAO and/or AOs will be required to travel to one annual investigator meeting per year in Rockville, MD (see section VI.2).

Rapid Response Restricted Fund

An amount of $100,000 per year (direct costs) should be entered as "Rapid Response Restricted Fund" under the "Other Expenses" category in the Budget form for years 2-5. This Fund is intended for participant accrual to cross-network trials and/or novel biomarker development and analysis. Specific projects to use this fund will be proposed post-award and will be subject to Steering Committee approval.

The following costs should not be included in the budget:

• Costs associated with routine patient care that are reimbursable by insurance.
• Costs for alterations and renovations.
• Costs for supporting activities that will be provided by the DMACC or covered by services/functions funded directly by NCI outside of this FOA (listed in Section I).

Budget Justification Additional Instructions:

• In addition to the standard items for this attachment, provide a breakdown of the direct costs to show separate amounts for each functional unit (Clinical Trial Program and Site Accrual Program).

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 Aim: Summarize the overall Specific Aims for the proposed CP-CTNet Site, addressing the development and conduct of early phase cancer prevention clinical trials. Include critical benchmarks for these aims (which should be in line with the requirements outlined in Section I).

Research Strategy: Organize the overall Research Strategy section with sub-sections in the specified order and follow instructions provided below. Start each sub-section with the appropriate sub-section heading.

Sub-Section A: Overview of the Proposed CP-CTNet Site

• Define the intended scientific focus for the proposed CP-CTNet Site and outline the overall strategy and approaches that the applicant team will use to develop and implement its research agenda. Include proposed agents or strategies (minimum of 2) to be developed and target organs (minimum of 3) to be studied. Explain how the proposed agents/strategies would be developed in successive clinical trials (in studies funded by this FOA or subsequently).
• Describe the LAO’s and AOs most important achievements in cancer prevention clinical trials.
• Describe the governance, organizational structure and capabilities, commitment relevant to the award, and general expertise of the senior leadership team.
• Provide an overview of the proposed operations.

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

Sub-Section B: Clinical Trial Program

Applicants should describe the proposed management of complex early phase cancer prevention clinical trials, including LOI development, protocol development, participant accrual, clinical trial auditing, data and specimen management, data analyses and reporting, compliance with regulatory statutes, and analysis and reporting. The description must address (and be consistent with) the requirements of the NCI DCP Standard Operation Procedures (https://prevention.cancer.gov/clinical-trials/clinical-trials-management/2012-consortia-early-phase) for the conduct of prevention clinical trials.

Scientific and Administrative Leadership

• Describe the LAO's and AOs , as appropriate, collective team strengths, expertise, and scientific leadership in development of early phase cancer prevention clinical trials. If experience is primarily in early phase cancer treatment trial development, include this as well. Note that PD(s)/PI(s) are expected to be leaders in the relevant areas of science and have documented administrative leadership experience.
• Explain how the proposed team and collaborations cover the needed range of transdisciplinary expertise. Include appropriate subspecialists (i.e., breast surgeons, dermatologists, gastroenterologists, gynecologists, otolaryngologists, pulmonologists, urologists, etc.) for the clinical care of individuals at high risk for cancer. As applicable, outline the roles of investigators/experts from other fields (oncology and/or non-oncology) in the design, conduct, and/or monitoring of clinical studies. In particular, address the trans-disciplinary needs for studies/clinical trials that will be focused on the identified target organs.
• Outline of how the AOs will be involved in the Site scientific activities (e.g., committee memberships, study chair positions, training programs, etc.).
• Describe available biostatistical expertise, including the capabilities of the team in analyses that combine clinical endpoints with sophisticated molecular analyses. (Biostatisticians with expertise and experience with these types of analyses are required as a part of the leadership team.)
• Describe pathology expertise in characterizing premalignant lesions in the disease areas of focus.

Operational Capacity

• Describe the LAO plans and strategy that will be used to develop new trial concepts. Address the following aspects:

o Planning clinical trials in response to NIH solicitations:

o Exploring original ideas developed by the LAO and/or AOs);

o Selecting concepts from multiple potential ideas; and

o Obtaining access to new agents to be used in studies proposed by the Site investigators.

• Describe how the LAO will provide oversight and coordination of study development, participant accrual, and study conduct. The description should include timelines for LOI and protocol development, study activation and completion, biomarker analyses, and submission of abstracts and manuscripts.
• Outline of plans for an internal CP-CTNet committee(s) to facilitate interactions of member site investigators, including review of progress and agent-related toxicities, establishment of priorities, and plans for future clinical trial research activities.
• Provide plans for procedures to oversee participant safety, protocol compliance, outcome and response review, and regulatory compliance.
• Describe criteria for adding new AOs and for removal of poorly functioning AOs.
• If foreign AOs are proposed, include plans to meet regulatory, drug acquisition/shipment, and translation requirements.

Note: Additional documentation (two samples of potential trial concepts) is requested under Other Attachments (Attachment 2). In addressing the bullets above, refer to these sample concepts as appropriate to illustrate specific points.

Trial Endpoint Evaluation

• Describe approach to selection of biomarker endpoints for phase 0-II trials.
• Outline team expertise in biomarker analyses, PK/PD determinations, and other molecular characterizations of clinical specimens. Delineate ability to conduct assays of frequently used cancer prevention biomarker endpoints, such as assays to measure proliferation and apoptosis, as well as various types of genomic, transcriptomic, and/or proteomic analyses that are applicable to evaluation of participant specimens.
• Describe ability to develop new laboratory assays or biomarkers to be used in fit-for-purpose assays ready to be transferred to or already implemented in Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories.
• Outline approach to and experience with acquisition, handling, storage, and shipment of biospecimens.
• Describe use of validated molecular and standard imaging capabilities as well as innovative experimental imaging techniques if available.

Sub-Section C: Site Accrual Program

Accrual and Study Conduct

• Describe access to healthy volunteers and individuals at high-risk for disease areas of focus for Phase 0-II clinical trials at LAO and AOs.
• Describe the operational efficiency of trial activation and conduct by the CP-CTNet Site.
• Describe the ability of the LAO to conduct trials with proper clinical trial stewardship. This aspect may be illustrated, for example, by audit results from accrual to NCI-sponsored early phase cancer prevention or (if not previously participating in cancer prevention trials) cancer treatment clinical trials.
• Explain how the LAO will ensure the appropriate enrollment of participants across the cancer prevention trials spectrum (healthy to high-risk to early stage cancer) and in diverse populations, (e.g., racial/ethnic minorities, those of varied sexual and gender identities, and other underserved or underrepresented populations (e.g. rural poor)).
• Describe anticipated strategies for recruitment and retention, including any innovations related to accrual/recruitment/retention, and plans/milestones for corrective action.

Note: Supporting documentation for this sub-section is requested under Other Attachments (Attachments 3-5).

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 modifications:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
• Data Sharing Plan is expected to adhere to the guidelines in the NCI Genomic Data Sharing Policy (https://www.cancer.gov/grants-training/grants-management/nci-policies/genomic-data).

Appendix:

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

When involving NIH-defined human subjects research, clinical research, and/or 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:

As all the clinical trials will be subject to concept review and approval, as indicated below, do NOT complete Study Records.

Delayed Onset Study

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

Applications must add and complete the Delayed Onset Study record and must check the 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 CP-CTNet Site 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 full clinical trial protocol, which will be subject to review and approval by NCI prior to activation through the CP-CTNet.

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

Important reminders:

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

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

See more tips for avoiding common errors.

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

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. 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.

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.

For this announcement, note the following:

The overarching goal of this FOA is to bring novel prevention interventions into early phase clinical trials. This goal requires investigators with outstanding leadership, robust infrastructure, and a strong record of conducting clinical trials. Particularly important for the clinical development of new generations of experimental cancer preventive interventions is the ability to integrate clinical trials with translational approaches and additional clinical studies, including the ability to obtain and analyze PK/PD and biomarker data in all participants enrolled on studies.

Essential for CP-CTNet will be the awardees' ability to work as part of a network. In this context, the important aspects are whether the applicants are capable of conducting state-of-the-art early phase prevention trials and biomarker-pilot studies covering a broad range of cancer prevention scenarios (optimally from cancer prevention in healthy individuals, through prevention efforts in high-risk sub-populations, to efforts focused on early stage cancer). Also important is the ability of applicants to work as a coherent research team to efficiently and expeditiously conduct early phase clinical trials.

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 there a strong scientific premise for the project? 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?

Specific for this FOA: What is the likelihood that the proposed CP-CTNet Site will be able to meaningfully contribute to research and clinical trials spanning a broad range of cancer prevention scenarios?

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 for this FOA: How well does the application address the LAO and AO collective team strengths, expertise, and scientific leadership in development of early phase cancer prevention clinical trials? How strong is the PD(s)/PI(s)'s record of scientific leadership of early experimental prevention and/or therapeutic trials (e.g., serving as scientific committee or protocol/trial study chairs, contributing new trial ideas including participating in LOI development, co-authoring publications on clinical trials research)? How well does the team integrate multiple investigators and other clinical/translational scientists, including subspecialists appropriate to the clinical care of high-risk cohorts? How strong is the leadership team's expertise and ability to organize, manage, and implement complex, biomarker-driven early phase clinical trials in individuals at risk for or with early cancer? How well does the organizational structure support the administrative leadership? How strong is the biostatistical expertise to conduct and analyze complex clinical and molecular data? How strong is the pathology expertise in characterizing premalignant lesions in the disease areas of focus? How capable is the team of providing meaningful contributions to prevention intervention development through CP-CTNet clinical trials by conducting biomarker analyses, PK/PD analyses, molecular characterization and imaging? Are sufficient and appropriately experienced research personnel with the skills needed to implement early phase prevention clinical trials available?

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 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 children, 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 for this FOA:

How well will the CP-CTNet LAO and its AOs be able to introduce appropriate novel interventions into cancer prevention clinical trials in a timely, safe, and efficient manner?

How well do the research plans demonstrate an appropriate understanding of research opportunities in preventive agent development and are the proposed plans and capabilities for incorporating biomarkers, PK/PD analyses, and molecular endpoints into the clinical trials appropriate and sufficient to exploit these opportunities?

To what extent are the proposed leadership and governance structure, staffing, decision-making processes, and interactions among key investigators optimal for the design, conduct and oversight of multi-disciplinary, multi-institutional clinical trials in a range of target organ sites and high-risk populations? How will the AOs be involved in the site scientific activities (e.g., committee memberships, study chair positions, training programs, etc.)?

How well do the research plans demonstrate the potential to overcome critical barriers for robust accrual to clinical trials across multiple disease/target organ sites and for special populations, including minority and/or underserved populations?

How will the LAO provide oversight and coordination of study development, participant accrual, and study conduct in terms of timelines for LOI and protocol development, study activation and completion, biomarker analyses, and submission of abstracts and manuscripts? How capable is the CP-CTNet Site of accruing to a variety of prevention clinical trials in the areas of focus in a timely manner?

How well will the proposed accrual strategies support the performance of multiple clinical trials?

How capable is the CP-CTNet Site of conducting a variety of different biomarker analyses from different types of biospecimens, including genomic, transcriptomic, and proteomic analyses? How sound is the proposed approach for selection of biomarker endpoints for Phase II trials, ability to develop lab assays or biomarkers?

What are the criteria for adding new AOs and for removal of poorly functioning AOs?

If foreign AOs are proposed, how sound are the plans to meet regulatory, drug acquisition/shipment, and translation requirements?

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?

Specific for this FOA: How complete is the evidence that the Research Pharmacy in the proposed LAO and its associated AOs will be able to (a) adhere to all applicable regulations with regard to investigational agent handling, (including transport and disposal); and (b) maintain proper documentation and record keeping, (transport, disposal etc.)? How adequate is the biospecimen repository and its processes to ensure that biospecimens will be properly collected, stored, catalogued, and available for analysis for the planned clinical trials as well as for future investigations?

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.

Study Timeline

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 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.

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.

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

Not Applicable.

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.

Not Applicable.

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).

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

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

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 NCI, 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 receive a written critique.

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

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

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

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

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

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.

Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.

ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain applicable clinical trials on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration of all trials whether required under the law or not. For more information, see http://grants.nih.gov/ClinicalTrials_fdaaa/

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that the application as well as all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols. Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).

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

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

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

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

Cooperative Agreement Terms and Conditions of Award

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

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

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

• Development of research strategy for early phase cancer prevention clinical trials and appropriate conduct, monitoring, and results reporting of NCI-approved trials.
• Development of an overall strategy to provide statistical expertise for effective scientific design, conduct, of clinical trials.
• Recruitment of AOs for diverse patient enrollment to CP-CTNet trials and oversight of AOs for the conduct of trials they participate in.
• Use of CP-CTNet’s common data management system including use of DCP reporting tools for adverse event reporting and risk-based central monitoring.
• Mentoring of new/junior investigators as well as patient advocates in clinical trials research/activities.
• Ensuring that all U.S. AOs are members of the NCI CIRBs and use the NCI CIRB for all CP-CTNet multi-site clinical trials.
• Provision of standard operating procedures covering all aspects of clinical trial design, trial conduct (including compliance with Good Clinical Practice (GCP) guidelines), development and compliance with data safety/monitoring plans and Data Safety Monitoring Board policy for applicable trials, and training for Clinical Research Associates (CRAs) at AOs and Study Chairs/Teams about their responsibilities for study monitoring and data management.
• Participation in the collective management of the CP-CTNet.

In addition:

• PDs/PIs may be expected to supply additional progress-related information, in addition to the standard annual Research Performance Progress Report (RPPR) submission.
• 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, NIH, and NCI policies and within the limits of any accepted binding NCI/NIH collaborative agreements with biotechnology and pharmaceutical partners and as governed by NCI-approved Data Sharing Plans and NCI-approved review for use of biospecimens collected in association with CP-CTNet trials.
• Awardees are allowed to accept funds from non-governmental sources to support CP-CTNet research that is not supported in part or in full by the NCI. These funds are considered Program Income (e.g., additional per case data management funding supplementing the NCI/DCP data management funding, support for correlative science studies that use biospecimen or image collections funded by the NCI/DCP for trials under the CP-CTNet) and must be reported under the Terms and Conditions of Award for the CP-CTNet unless they are associated with an exempted category under the NIH grant policy for program income, available at: https://grants.nih.gov/grants/policy/nihgps_2011/nihgps_ch8.htm#_Program_Income.
• All key components of the CP-CTNet must report these funds to the NCI on an annual basis (in the non-competitive Type 5 application the annual progress report) and must indicate the clinical trial that the funds are being used to support (or other functional component if the funds are not provided to support specific trials). The Terms and Conditions of Award for all the Cooperative Agreements under the CP-CTNet define the operational principles under which the awardees must function to ensure the independence of the research conducted regardless of whether program income is or is not available for any of the awards.

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

An NCI Program staff member(s) acting as a Project Scientist(s) will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below. Additional NCI staff members may be designated to have substantial involvement (as Project Scientists).

• Additionally, an NCI program director acting as Program Official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

The main responsibilities of substantially involved NCI staff members include, but are not limited to, the following activities:

• Ensuring that clinical trials proposed are within the research scope of CP-CTNet.
• Evaluating and approving clinical trial concepts, protocols, and amendments of all CP-CTNet trials.
• Serving as a resource for scientific information on trial/study design.
• Working with CP-CTNet Awardees to collaboratively manage issues associated with their participating in the conduct of clinical trials across the Network.
• Informing the PDs/PIs of scientific opportunities resulting from NCI-supported clinical research programs and facilitating collaborations between the CP-CTNet and other NCI-sponsored programs.
• Facilitating formal aspects of collaborations with outside organizations including review of any memoranda of understanding and data/material transfer agreements for compliance with NIH/NCI and Federal policies.
• Reviewing accrual and overall performance of CP-CTNet clinical trials by the site.
• Reviewing compliance with applicable HHS, FDA, OHRP, NIH, and NCI regulations for clinical research involving human research subjects.
• Monitoring the progress and performance of the key components of the CP-CTNet.
• Sponsoring strategy sessions, when indicated, to discuss specific research initiatives.
• Final review and approval of requests for use of any bio-specimens collected per the approved protocol for CP-CTNet trials.

The NCI will have access to all data (including imaging data) collected and/or generated under this Cooperative Agreement and may periodically review the data. The NCI may also review all records related to awardees performance under the award for appropriate collection, review, and distribution of biospecimens collected in association with CP-CTNet trials.

The NCI reserves the right to reduce the budget or withhold an award in the event of substantial awardee underperformance (e.g., vastly insufficient participant accrual per the protocol specified) or other substantial failure to comply with the terms of award.

Areas of Joint Responsibility

Steering Committee: A Steering Committee will be the governing body of CP-CTNet that will integrate the efforts of all CP-CTNet awardees and provide oversight of collaborative activities.

The Steering Committee will consist of the following voting members:

• Two representatives from each CP-CTNet awardee (i.e., from CP-CTNEt Sites and from DMACC), one of whom must be the PD/PI, who will jointly have one vote for the CP-CTNEt award they represent; and
• NCI Project Scientist(s), who will collectively have one vote for NCI.

The NCI Program Official will be a non-voting member of the Steering Committee.

Additional non-voting members may be added to the committee as needed.

The Steering Committee will be chaired by a PD/PI of a CP-CTNEt cooperative agreement award and will be elected by the voting members of the Steering Committee.

Key responsibilities of the Steering Committee include:

• Holding quarterly meetings;
• Developing Network operating policies for the implementation by the CP-CTNet awardees;
• Approving the Manual of Operations for the Network;
• Facilitating the process of joint development of appropriate early phase prevention clinical trial protocols by CP-CTNet Sites and NCI (see below).
• Reviewing and approving the studies that will use Rapid Response Restricted Funds; and
• Developing agenda and co-organizing with the NCI the annual in-person investigator meeting to be held at NCI (https://prevention.cancer.gov/news-and-events/meetings-and-events/2018-investigators-site)
• Other programmatic responsibilities to be addressed jointly, as needed, by the CP-CTNet awardees and the NCI staff.

Subcommittees. The Steering Committee may establish subcommittees for specific purposes (e.g., for joint development of clinical trial protocols by CP-CTNet awardees and NCI staff members, see below). The NCI Project Scientist(s) may serve on such subcommittees, as they deem appropriate. Other NCI staff members may also be involved as needed.

Joint Development of Early Phase Prevention Clinical Trial Protocols by CP-CTNet Awardees and NCI. CP-CTNet awardees will be expected to participate as active team members and work closely with the NCI on the development of appropriate clinical trial protocol. These joint activities will include (but will not be limited to) the following aspects:

• General aspects of collaboration on study development and conduct, especially with respect to compliance with federal regulations for clinical trial research, accrual, and participation in activities related to the collective management of the CP-CTNet, as appropriate;
• Development of concepts for new clinical trials, either in response to specific LOI solicitations from NCI or as unsolicited LOIs developed by the LAOs or AOs.
• Meeting as frequently as needed to assure optimal study performance and to review studies performed under the CP-CTNet awards.

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 CP-CTNet Group representatives chosen from the CP-CTNet Leadership 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.

Note that in addition to these general rules for dispute resolution, a specific appeal process will be in place for decisions regarding approval of CP-CTNet study proposals and the types of studies supported by the CP-CTNet.

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

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

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

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

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten on-time submission, and post-submission issues)

Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application processes and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-945-7573

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

Eva Szabo, MD
National Cancer Institute (NCI)
Telephone: 240-276-7011
Email: [email protected]

Referral Officer
National Cancer Institute (NCI)
Telephone: 240-276-6390
Email: [email protected]

Sean Hine
National Cancer Institute (NCI)
Telephone: 301-276-6291
Email: [email protected]

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 Part 75.