Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance 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 this Funding Opportunity Announcement (FOA) is to enhance the NCI-supported early development of experimental cancer therapeutics by merging the Phase 2 clinical trials program with the Experimental Therapeutics Clinical Trials Network (ETCTN, funded through RFA-CA-13-006) that is currently focused on Phase 1 clinical trials.

The FOA invites revision applications from ETCTN UM1 awardees to expand the scope of activities by adding capabilities to conduct Phase 2 clinical trials. The goal is to integrate Phase 2 infrastructure and expertise to create a unified network for an efficient and comprehensive conduct of early clinical trials. This integration of the Phase 2 capabilities into the new ETCTN structure will allow for more seamless advancement of experimental agents through early stages of development. Ultimately, the expected increased efficiency of clinical trial management is expected to accelerate the delivery of new cancer therapies to the public.

Key Definitions

In the context of this FOA, several key terms are used as defined below.

CTEP: Cancer Therapy Evaluation Program (CTEP), which is responsible for NCI clinical trials.

ETCTN: The Experimental Therapeutics Clinical Trials Network, the network of sites and infrastructure that is devoted to the early clinical development of anticancer drugs for which NCI/CTEP is the "Investigational New Drug" (IND) holder.

ETCTN "sites": the sites of the existing ETCTN UM1 awardees funded under RFA-CA-13-006 that are currently focused on Phase 1 studies of NCI/CTEP IND agents.

Collaborative Network projects: research projects that utilize data and/or expertise from multiple ETCTN sites, which operate as the network (defined in RFA-CA-13-006).

ETCTN Phase 2 Programs: the additional programs to be proposed in response to this FOA for integration into ETCTN sites.

Lead Academic Organization (LAO): the institution that is the recipient of the parent ETCTN UM1 award.

NCI-IND Agents: Experimental agents for which NCI/CTEP holds an Investigational New Drug (IND) application.

Current Organization of NCI-supported Early Clinical Trials. The early therapeutics development program sponsored by the Cancer Therapy Evaluation Program (CTEP) in the NCI's Division of Cancer Treatment and Diagnosis (DCTD) has contributed to the clinical development of many anticancer agents. This program melds NCI partnerships with pharmaceutical companies that are developing novel agents with the specialized clinical trial expertise of NCI-supported investigators in academic medical centers to develop new agents or novel agent combinations for new clinical indications. NCI accepts new agents into its portfolio through the NCI's Experimental Therapeutics (NExT) program, and negotiates Collaborative Research and Development Agreements (CRADAs) with pharmaceutical companies and academic investigators to develop these agents within the ETCTN. As the IND sponsor, NCI/CTEP assumes responsibility for ensuring that all regulatory requirements are met for CTEP clinical trial protocols using these agents.

Through the ETCTN, NCI creates a "Drug Development Plan" (DDP) that includes Phase 1 and Phase 2 studies. Currently, two separate programs fund Phase 1 and Phase 2 activities.

ETCTN UM1 awards (under RFA-CA-13-006) provide the infrastructure (including clinical sites) and expertise in conducting Phase 1 trials. The corresponding program for CTEP Phase 2 clinical trials consists of seven contracts at major academic medical centers (which include 44 affiliate sites). The activities of both Phase 1 and Phase 2 programs are additionally facilitated by a full suite of centralized clinical trial support services established separately by the NCI (CTEP). The awardees of the Phase 2 program interact with Phase 1 investigators at the ETCTN, and both groups work closely with NCI staff members. These interactions are aimed at developing and executing clinical studies that determine whether or not NCI-IND agents or combinations of these agents offer sufficient potential clinical benefit to justify definitive large multi-institutional Phase 3 trials designed to demonstrate improved clinical outcomes relative to the current therapeutic standards.

New Challenges for Phase 2 Program. The increasing role of new, molecularly targeted agents in the portfolio of NCI-IND agents has created new challenges. The requirements for early phase trials have evolved in several aspects outlined below:

1) The disease-focused context, traditionally associated with Phase 2 trials, is now frequently required in Phase 1 studies, because targeted therapies are tested only against tumors that express the target;

2) Biomarker incorporation into clinical trials, both for eligibility and proof of target engagement, is now usually required in early stage drug development; and

3) Flexible early phase study designs are increasingly needed to rapidly build Phase 2 endpoints into Phase 1 studies when the first indication suggesting clinical activity is detected.

The ongoing changes underscore the notion that the traditional line separating Phase 1 and Phase 2 studies has become blurred and that more flexibility is needed to nimbly develop clinical trials of NCI IND agents. Therefore, it is essential that pharmacology-focused investigators (currently in Phase 1 program) and disease-focused investigators (currently in Phase 2 program) combine their efforts within the same program.

The Phase 1 program, realized through the ETCTN, has been recently modernized to promote a greater role for team science in the formulation of DDPs, and to shorten the time for the activation of initial clinical trials for agents brought into the CTEP program through NExT. This FOA completes this modernization by integrating the Phase 2 program into the ETCTN. Accordingly, all the current contracts for the Phase 2 Clinical Trials will be ended prior to the activation of the ETCTN Revision awards. It is expected that through this integration the entire system of NCI early clinical trials will benefit from broader resources and an elevated role of investigators' creativity.

The overall objective of this FOA is to integrate the Phase 1 and 2 early clinical trials programs by adding Phase 2 Programs to several ETCTN sites that are currently solely focused on Phase 1 clinical trials. Particular emphasis and priority of this revision are on the capabilities that will better address the challenges associated with the entire early development of molecularly targeted agents through a tighter integration of Phase 1 and Phase 2 clinical trials.

ETCTN recipients seeking revision of their ETCTN awards must be able to add to their ETCTN site a program for rigorous and efficient conduct of Phase 2 clinical trials for new cancer therapies that addresses the stated above overall goals and priorities. The prospective ETCTN revision applicants must also be able to meet the following specific capabilities and requirements:

• Appropriate leadership and team with experience in Phase 2 clinical trials;
• Appropriate expertise in cancers of specific organs;
• Ability to incorporate oncologic disease-specific biomarkers into clinical trials, both for eligibility and proof of target engagement;
• Ability to extend disease-focused context, traditionally associated with Phase 2 clinical trials, for Phase 1 studies, when needed;
• Access to appropriately large pools of patients to identify rare subgroups of eligible patients that might be required for specific early phase studies; and
• Ability to adapt flexible early phase study design that would allow for rapid additions of Phase 2 endpoints into Phase 1 studies when indications of clinical activity are detected.

To meet these requirements, ETCTN revision applicants will be expected to create an infrastructure that facilitates a shorter duration from Phase 1 initiation through proof-of-activity, and fosters seamless Phase 2 clinical development of CTEP IND agents coming out of the DCTD NExT pipeline and ETCTN Phase 1 program. By eliminating the separation of programmatic activities and administrative operations of Phase 1 and Phase 2 activities, the ETCTN awardees selected for the revision awards will have the flexibility to expand Phase 1 studies quickly with signals of activity observed in the earliest phase studies within the ETCTN. Since the goal of ETCTN drug development is to hand-off CTEP IND agents to the National Clinical Trials Network (NCTN) with adequate clinical data to justify randomized trials, a range of Phase 1, 1/2, and 2 study expertise will give the program flexibility required to rapidly develop a multitude of CTEP IND agents and drug combination studies.

Partnerships with Phase 2 Teams in Cancer Centers. Because of the stated complex requirements, the proposed Phase 2 clinical sites must have appropriate qualities that have been verified by the peer review process. Therefore, the Phase 2 teams entering into partnerships with the ETCTN UM1 awardees for the Phase 2 revision applications must be from the NCI-designated cancer centers, (NCI-CCs) (for U.S. ETCTN UM1 awardees) or from either NCI-CCs or cancer centers as designated by the relevant Provincial Cancer Agency or ministry of health or equivalent body (for Canadian ETCTN UM1 awardees).

Scope of Scientific Activities. ETCTN Phase 2 programs proposed in response to this FOA and their investigators must be capable of clinical research involving the following main scientific activities:

• Conducting Phase 2 experimental therapeutic clinical trials using single or combinations of novel oncologic agents from the CTEP NCI-IND portfolio. The emphasis will be on novel agents or novel combinations of agents that target relevant cancer cell signaling pathways and essential cellular machinery involved in the regulation of such aspects as angiogenesis, cell survival, apoptosis, proliferation, and differentiation.
• Contributing creatively to defining the drug development plans for specific agents under investigation (through the participation in agent-specific Project Teams).
• Developing and/or using appropriate Phase 2 clinical trial designs, including integral and integrated biomarker trials, accelerated titration, adaptive designs, and other design schemes, as optimal for the agents studied.
• Studying special populations (e.g., patients with rare diseases) as needed.
• Establishing safe and biologically active treatment schedules for patients with cancer.
• Obtaining mechanistic proof-of-principle data for new agents directed at novel molecular cancer targets.
• Evaluating data from clinical trials that involve combinations of NCI-IND agents.
• Evaluating data from related laboratory studies that assess the nature of drug-drug interactions (additive/synergistic/antagonistic).
• Evaluating translational endpoints 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).

Trans-ETCTN collaborations. In the Network, participants will collaborate with each other and with involved NCI staff members to achieve Network goals, objectives, and capabilities as stated in RFA-CA-13-006. Network members, sites, or others (as permitted) will be able to enroll patients on all trials conducted by the ETCTN, irrespective of the specific Network site leading the trial.

Additional NCI Support for the ETCTN sites. Through separate contracts, the NCI/DCTD/CTEP provides the ETCTN awardees with standardized central operational, regulatory, and administrative support. This support will also apply to the Phase 2 Programs. See: http://ctep.cancer.gov/investigatorResources/default.htm#guidelines_policies.

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

Only current ETCTN UM1 awardees may submit revision applications invited by this FOA (including Canadian recipients of the ETCTN award).

These eligible applicants will be required to recruit affiliate sites with Phase 2 capabilities that will enhance patient accrual and scientific expertise relevant to the proposed Phase 2 clinical trials Program. Selected Phase 2 affiliate sites may be affiliated in this capacity with only one LAO within the ETCTN. In addition, the current affiliates of a given ETCTN LAO cannot affiliate for the purpose of the revision application with another ETCTN LAO.

Non-domestic (non-U.S.) Entities (Foreign Institutions) are 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.

The PD/PI (or Contact PD/PI for multi-PD/PI awards) on the parent ETCTN award must remain the same on the revision application. However, regardless of whether or not the parent ETCTN UM1 award uses single- or multi-PDs/PIs model, revision applicants must designate an additional PD/PI to be primarily responsible for the Phase 2 operation. This individual is expected to be the lead scientist of the affiliated Phase 2 team.

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

Each ETCTN awardee may submit only one revision application..

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).

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

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

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

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

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

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

The letter of intent should be sent to:

Jeffrey Moscow, M.D.
Investigational Drug Branch
Cancer Therapy Evaluation Program
Division of Cancer Treatment and Diagnosis
National Cancer Institute
9609 Medical Center Drive, Room 5W524
Bethesda, MD 20892-9739 (for U.S. Postal Service express or regular mail)
Rockville, MD 20850 (for non-USPS delivery

Telephone: (240)-276-6565
Fax: (240)-276-7894
Email: jeffrey.moscow@nih.gov

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

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

A. Overview and Integration: one required -30 pages; and

B. Phase 2 Clinical Trials Program: one required -12 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.

The following additional instructions apply.

Facilities & Other Resources: Provide a succinct overview of Facilities and Resources of the parent ETCTN site.

Describe in detail Phase 2-related resources and facilities that are being proposed for addition to an ETCTN site through this revision. In particular, list changes to the Phase 1 infrastructure to permit integration of the Phase 2 Program into the ETCTN LAO. This information should include resource integration into the specific functional components of the ETCTN LAO as described in the Resources section of the ETCTN LAO parent award. Indicate which current Phase 1 Program resources will be used for the Phase 2 Program.

Other Attachments: Applicants must provide the following additional documentation specified below in support of their Research Strategy.

The filename provided for the attachment will be the name used for the bookmark in the application image.

List of Procedures and Policies (filename "SOPs".

• List the relevant Standard Operating Procedures (SOPs) and organization policies to be used by the Phase 2 Program for ETCTN clinical research activities. These items may include, but are not limited to: specimen acquisition and handling; tumor banking procedures and policy; Institutional Review Board (IRB) policies, Human Subjects Research Protections (HSRP) policies, safety, and pharmacovigilance procedures and policies, assay validation procedures, etc. If utilizing the ETCTN LAO's SOPs and policies, enter "Utilizing ETCTN LAO's SOPs and Policies" on the table and no further information is required. Do not submit the SOPs or policy documents.
• Operation plans, SOPs, investigational agent management procedures, and related procedure and policy documentation, other than informed consent documents and phase 2 clinical trial protocol template(s), should not be provided. A list of these documents or inclusion of a completed Attachment 8, " Procedures-Policies" table in the Resources section is sufficient. SOPs and investigational agent management procedure documentation should not be provided in "Other Attachments".
• If the informed consent documents and phase 2 clinical trial protocol template(s) to be utilized are the same as those utilized by the parent ETCTN LAO, these documents should not be provided.

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

• The applicants must designate an appropriately qualified PD/PI who will be primarily responsible for Phase 2 operation; and
• The applicants must designate a senior investigator as a "Translational Scientist", with an expertise in biomarker incorporation into Phase 2 clinical trials, and who will oversee translational efforts.

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

The following additional instructions apply.

Provide a budget for revision-related costs to integrate the Phase 2 Program into the ETCTN LAO only (i.e., do not include any general ETCTN costs that are already covered by the parent ETCTN award). The request should be based an accrual rate for Phase 2 clinical trials of at least 100 patients per year.

Senior/Key Person 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), Translational Scientist, and other collaborators responsible for various aspects of Phase 2 operation (but not personnel costs directly related to the conduct of Phase 2 clinical trials at the clinical level as indicated below under "Patient Enrollment Costs" ). The PD/PI designated for the Phase 2 operation must commit a minimum of 1.2 person-months effort per year to the revision application and potential award. Also, the designated "Translational Scientist" must commit a minimum of 1.2 person-months effort per year. These commitments cannot be reduced in later years of the award. All these personnel costs combined are expected to be approximately 20% of total budget.

Travel. The PD(s)/PI(s) leading the Phase 2 Program of the ETCTN will be required to travel to four Coordinating Center for Clinical Trials Investigational Drug Steering Committee (IDSC) meetings per year. Travel funds to attend two NCI/CTEP Early Drug Development (EDD) meetings per year for three representatives from the ETCTN Phase 2 Program (at least one of whom must be the PD/PI leading the Phase 2 Program) should be included in the budget. The full cost of travel is expected to amount to approximately 5% of the whole budgetary request.

Patient Accrual and Related Costs. Under "Other Direct Costs" category provide estimated costs of patient accrual for the Phase 2 clinical trials as well as related costs of laboratory studies and specimen acquisition and handling. The anticipated total annual expenses should be based on per-patient costs of the accrual, assuming at least 100 patients per year. Other essential costs for patient accrual may be included but only if such expenses are not already covered under the budget of the parent ETCTN LAO. In aggregate, Patient Accrual and Related Costs are expected to amount to approximately 70% of the whole budgetary request (assuming the scale commensurate with the accrual of at least 100 patients). In planning these expenses, applicants should consider the following additional guidance.

• Patient Enrollment Costs. The net per-patient cost for accrual to Phase 2 clinical trials (i.e., excluding the costs of laboratory studies and biospecimen handling) multiplied by the expected number of patients to be accrued (at least 100 per year) should amount to approximately 55% of the whole budgetary request (these costs may include salary support for physicians, research nurses or other appropriate clinical research personnel who will be directly involved in patient accrual and the performance of ETCTN Phase 2 studies at the clinical research level, i.e., working with patients, and managing clinical trials);
• Laboratory studies. The cost of laboratory studies to be performed on specimens (e.g., blood, tumor tissue, buccal cells, etc.) obtained from participants enrolled on ETCTN Phase 2 clinical trials is expected to amount to approximately 10% of the whole budgetary request; and
• Specimen acquisition, handling, and processing costs. Specimen acquisition-related costs are expected not to exceed 5% of budgetary request and must include only the institutional costs of research that are not considered "a cost of treatment" by medical insurers, and therefore are not reimbursed by insurers (e.g., blood and urine collection and shipping for PK studies, tumor tissue handling and shipping to the tissue bank or pathology component, and performance of research imaging studies). Appropriate costs of mailing or handling research- related patient specimens, forms, and materials can be included.

NOTE: The release of funds for patient- and accrual-related costs will be determined biannually by NCI based on the actual patient accrual to Phase 2 studies.

In the budget justification (in addition to standard justification of proposed expenses) provide the following information:

• Coordination of Clinical Research Activities: indicate total cost for activities related to the integration of the Phase 2 Program with the parent ETCTN LAO and provide cost breakout into main budget categories (personnel, supplies, travel, etc.). These costs may be for: organizational harmonization; the coordination of Phase 2 clinical trials and associated Phase 2 Program activities with those of the parent ETCTN LAO; and other organizational activities essential for integration. Costs of the integration of informatics system with the services provided by the Clinical Trials Monitoring Service (CTMS, see http://ctep.cancer.gov/branches/ctmb/resources.htm) may be included but only for well-justified on-site expenses. Overall, the costs for Coordination of Clinical Research Activities are expected not to exceed 5% of the total budgetary request and 5% of Personnel costs).
• Patient Accrual and Related Costs. Following the guidance above, provide detailed breakout of costs used to estimate the reimbursable per-patient accrual costs.

NOTE: The requested budgets shall NOT include or reflect any costs for the following activities:

• Correlative studies and biomarker assays to enhance specific clinical trials (such studies will be prioritized and supported as needed by separate Administrative Supplements, for which NCI will use an additional set-aside of $1.8 million).
• The NCI-provided standardized central operational, regulatory, and administrative support (as these services will be provided by the NCI at no cost to the applicant); and
• Any costs that are not solely research-related and could be considered "a cost of treatment" by medical insurers

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:

Introduction to Application: Outline succinctly the overall goals of the current ETCTN site and highlight the strategic aspects of adding the Phase 2 Program to it.

Specific Aims: Summarize the Specific Aim(s) of the proposed Phase 2 Program covered by this revision. (Do NOT restate the Specific Aims of the current ETCTN site.)

Research Strategy

Sub-section A: Overview and Integration

In this sub-section, applicants must explain the overall strategy proposed for integrating Phase 2 capabilities by an appropriate qualifying partnership. For these revision applications, the ETCTN UM1 awardees must form partnerships with Phase 2 teams from the NCI-designated cancer centers (NCI-CCs) (for U.S. ETCTN UM1 awardees) or from either NCI-CCs or cancer centers as designated by the relevant Provincial Cancer Agency or ministry of health or equivalent body (for Canadian ETCTN UM1 awardees).

The Phase 2 Program must become tightly integrated into the parent ETCTN award. Therefore, whenever appropriate, applicants should discuss in this sub-section aspects related to integration (e.g., complementarity of capabilities, avoiding duplication, need for harmonization of procedures, geographical issues of integration, etc.).

Applicants must address all the items listed below.

A1) Past Performance and Relevant Capabilities

Address briefly the following aspects:

• Summarize the accomplishments of the parent ETCTN in the current funding period (in terms of organization of clinical Phase 1 trials, the number of LOIs approved, patient accruals, etc.);
• Based on published studies, outline the most salient accomplishments of the parent ETCTN awardee in clinical, translational, and/or basic research;
• Based on the past performance of the proposed Phase 2 team in the past 4-5 years, list the most significant, strategic capabilities for the Phase 2 clinical trials to be added, including:
• the scale of operation in terms of the conduct of Phase 2 clinical trials and experimental therapeutic agent development;
• the main accomplishments in terms of how the team met its goals with regard to Phase 2 study design and execution (e.g., Letters of Intent [LOIs]) for clinical trials submitted, LOIs approved, actual patient accrual, etc.); and
• the ability of the proposed Phase 2 team to collect a sufficiently high percentage of specimen samples in clinical trials involving correlative science endpoints;
• Explain how the collective experience of the entire enlarged team will benefit the conduct of Phase 2 clinical trials and accelerate experimental therapeutic agent development, addressing, as applicable, cumulative expertise (to be shared between the Phase 1 and Phase 2 teams) in relevant areas. Additional optional (but encouraged) expertise may include such areas as:
• the molecular mechanisms of drug resistance;
• the molecular and pharmacologic issues of novel-novel drug combinations; and/or
• the development of qualified biomarkers in clinical trials.

A2) Scientific Leadership.

Describe how the Phase 2 team leadership will be scientifically integrated with the leadership of the parent ETCTN awardee. In particular, explain the capacity of the proposed Phase 2 team for participation in a collaborative, team-based drug development program. Specific information to provide should include (but is not limited to) the following aspects:

• In the light of skills and accomplishments of all PDs/PIs designated to oversee Phase 2 clinical trials of experimental cancer therapeutics, explain the team's strategy for an integrated team science approach;
• Summarize the Phase 2 team's strengths in collaborative science, e.g., based on peer-reviewed, funded collaborative clinical trials and/or clinical trial(s) resulting from funded hypothesis-driven research projects; and/or
• Provide examples/highlights of published clinical and basic research fostered by or associated with peer-reviewed grant funding, addressing, in particular, interactions with the parent ETCTN awardee team (if any).

Sub-section B: Phase 2 Clinical Trials Program

In this subsection, the applicants must propose a comprehensive and cohesive program for the conduct of high-quality Phase 2 clinical trials evaluating novel anticancer treatments. The description should underscore the potential and benefits of the proposed Program in terms of the accelerated development of experimental anticancer agents.

The scientific goals must be based on the demonstrated ability to accrue at least 100 patients annually to Phase 2 studies, which may also involve drug target analyses, molecular characterization of patients, various biomarkers, and/or other innovative translational aspects.

B1: Scientific Goals and Requirements

In the description, applicants must provide detailed information and plans on the items listed below to explain how the proposed Phase 2 Program will meet all the specified requirements and responsibilities.

• The capacity of the team as a whole to conduct disease- and biomarker-specific Phase 2 clinical trials of novel anticancer agents either alone or in combination with other agents;
• Realistic plans for accruing at least 100 patients per year to Phase 2 clinical trials, with the ability to utilize patient population enrichment strategies, as needed;
• Ability to assume responsibility for well-designed, biomarker-driven studies that account for underlying disease biology; including the analysis of biomarkers integral to a study (e.g., for informing the selection of eligible patients); integrated biomarkers (i.e., those biomarkers that are essential to achieve an important secondary objective); or exploratory biomarkers (monitored to examine a potentially important biological and/or mechanistic aspect);
• Demonstrated proficiency and effective processes for collecting/acquiring relevant biospecimens for biomarker-based and other studies, including specimens requiring invasive biopsies, if needed;
• Demonstrated ability to integrate the expertise of the team as a whole to evaluate drug target effects and other drug effects that may be predictive of response as an inherent part of Phase 2 clinical trials;
• Plans for strategic evaluation of proof of mechanism in suitable patients;
• Efficient evaluation of treatment-related emergence of resistance/response patterns or compensatory pathway activation that will inform the most appropriate follow-on treatment or combination therapy approaches;
• Appropriate statistical support for clinical trial design and implementation using approaches that are optimally adapted to the particular clinical question being studied;
• Capability (and appropriate plans) for creative contributions to the development of specific new CTEP IND agents (via the participation in extramural multidisciplinary drug project teams that define the initial DDPs); and
• Ability to identify and evaluate the drug impact on the normal host tissue versus tumor, using pharmacodynamic (PD) assays that are analytically and clinically validated and demonstrated to perform successfully in the intended clinical specimen.

Correlative Studies: In addition to describing their capabilities for the specific aspects listed above, the applicants should also describe their potential to propose and conduct correlative studies and possible areas of such studies.

Note that no specific correlative studies are to be proposed in the application but applicants should anticipate that awardees will be expected to propose (post-award) individualized correlative studies as warranted by the specific ongoing clinical trials. The proposed studies will be subject to review, prioritization, and approval by CTEP. Approved studies will be funded through administrative supplements.

B2: Program Organization and Coordination

Describe the coordination of the Phase 2 Program operation across participating sites and its integration with the parent ETCTN LAO. Applicants are required to address, at a minimum, their plans and/or proposed procedures for the following aspects:

• Leadership structure planned for the oversight of all aspects of Phase 2 clinical trials operation;
• Organization and leadership of a scientific team of translational and clinical investigators;
• Assembling, recruiting, and maintaining appropriate personnel that will support the execution of clinical trials (i.e., conduct, reporting, and analysis at the site), including physicians, nurses, clinical research associates, pathologists, research pharmacists, institutional review boards, and others performing data collection, statistical support, data analysis, patient evaluation, and adverse event reporting;
• Ensuring operational efficiency (by meeting NCI Operational Efficiency Working Group [OEWG] timelines or others appropriate guidelines);
• Plans for integration of the Phase 2 Program into the parent ETCTN site organization and/or governance structures, including participation in ETCTN administrative and scientific committees; and
• Integrating/coordinating activities related to the development and conduct of clinical trials with other Network participants and other NCI-sponsored research programs.

B3: Program Operation: Procedures and Policies

Applicants' operation plans and related procedures and policies should ensure effective interaction, communication, and monitoring performance within the applicant ETCTN site to facilitate clinical trial protocol development, safety, and timely protocol conduct.

At a minimum, address the following aspects:

• Used/proposed procedures for the coordination of Phase 2 protocol development;
• Strategies proposed to ensure the accrual of adequate number of eligible patients to ETCTN Phase 2 trials;
• Procedures to ensure the observance of all applicable regulations for the protection of human subjects, clinical trial protocol requirements, and tracking of study modifications/amendments;
• Conflict of Interest policy ensuring there is no reasonable expectation that the design, conduct, and/or reporting of research conducted by the ETCTN will be biased by any conflicting financial interest of an investigator.
• Mitigation of risks to successful clinical trial completion;
• Ensuring drug security and investigational drug management in order to use CTEP IND agents for trials (this requirement applies to all affiliate sites that are expected to handle IND agents);
• Coordination of various aspects associated with the conduct of Phase 2 clinical trials, including but not limited to: the acquisition and handling of biospecimens, conducting appropriate pharmacology and pharmacodynamics analyses, incorporating imaging endpoints, etc.;
• Plans and procedures to ensure timely reporting and dissemination of complete clinical trial results (with all associated studies, molecular characterizations, etc.), including such aspects as:
• Plans to ensure timely submission of required data NCI centralized clinical trial support systems;
• Policy regarding authorship in Phase 2 related publications;
• Methods by which the complete results from Phase 2 clinical trials and laboratory studies will be published in a timely fashion (including actions to be taken when the mentioned above time lines are not met); and
• Plans to maintain the proficiency of site personnel in managing ETCTN Phase 2 clinical trials, including actions/commitments to facilitate the professional development of participating junior investigators;
• Benchmarks to be used for assessing Program performance; and
• Procedures for complying with auditing requirements and responding expeditiously to any deficiencies identified during an audit.

B4: Research Pharmacy Management

If the proposed Phase 2 team is currently utilizing research pharmacy management provided by the parent ETCTN LAO, indicate this in this section with a brief summary of measures to ensure compliance with local, State and Federal regulations and maintain adequate security for investigational agent management.

If the proposed Phase 2 team, including any proposed new affiliated site, is not currently utilizing research pharmacy management provided by the parent ETCTN LAO, the following aspects must be addressed:

• Access to approved protocol documents, amendments, and notification of protocol activation at the site. Notification of patient enrollment to a given protocol, including notification of signed informed consent prior to agent dispensing.
• Availability of agents when needed. Ability to order and receive agent(s) from the supplier as instructed in the clinical protocol. Procedures regarding authorized dispensing of investigational agents to eligible study subjects on approved protocols and procedures for reconciling deviations.
• Policies and procedures related to safe transport of investigational agents within the facility. Proper documentation of agent transfer to another NCI-sponsored trial and/or final disposition of investigational agents.
• Adherence to local, State, and Federal regulations and laws related to investigational agents. Policies and procedures for safe and secure handling, preparation, and disposal of dangerous goods, hazardous substances, and infectious substances.
• Procedures for assuring that the site complies with CTEP requirements described in the DCTD Investigators' Handbook for storage and accounting for investigational agents [including NCI/NIH/HHS Drug Accountability Records (DAR) procedures] and comply with FDA requirements for investigational agents.
• Procedures to ensure NCI-supplied investigational agents are prescribed only by physicians who are registered and have an active investigator registration status with the Pharmaceutical Management Branch, CTEP.
• SOPs and procedures related to investigational agent management, including agent receipt, accountability, and final disposition.
• Training of staff and training materials.

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

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

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

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

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

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

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

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

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 the 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 NOT-OD-13-030.

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

For this particular announcement, note the following: The overarching goal of this FOA is to create a state-of-the-art Network for early phase clinical trials that will accelerate the development of experimental anticancer agents. In this context, and in addition to the review criteria below, the merit assessment of the revision applications under this FOA should take into account the following two vitally important programmatic priorities.

1) State-of-the-art aspects of Phase 2 Programs with evidence of extensive experience and expertise in conducting clinical trials of anticancer agents, organizational capabilities, robust infrastructure, and proven ability to recruit at least 100 patients per year for Phase 2 studies; and

2) A high degree of integration of these Phase 2 Programs with the existing Phase 1 operations of the parent ETCTN awardees that will allow for creative and flexible approaches to 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? 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?

Specific for this FOA: What is the likelihood that the strategy proposed in the revision to the current ETCTN award will successfully integrate the Phase 2 program into the existing Phase 1 program?

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

Specific for this FOA:

Expertise in Phase 2 Clinical Trials: How do the accomplishments, past performance and expertise of the PD(s)/PI(s) and other senior investigators responsible for the Phase 2 Program demonstrate their capability to provide effective and sustained scientific leadership for state-of-the-art early Phase 2 clinical trials in adults with cancer? What is the level of expertise and record of the designated "Translational Scientist" in incorporating biomarkers into early clinical trials? Does the proposed integration of the Phase 1 and Phase 2 Program leadership show evidence of forming a collaborative, highly integrated, and effective drug development program, taking into account a range of cancer types, transdisciplinary capabilities, and multi-institutional early phase clinical trials research?

Team Science: Is there evidence that the PD(s)/PI(s) are capable of providing important contributions to such aspects as translational science, particularly translational research that is integral to or integrated into the clinical trial (including PK/PD analyses, biomarker assays, and other molecular characterizations that may be expected to be essential for ETCTN Phase 2 trials)?

Administrative Skills: Based on the past accomplishments, what is the level of clinical research-relevant administrative experience and skills that the PD(s)/PI(s) and other senior investigators responsible for the Phase 2 Program have in such aspects as: organization and management of the infrastructure required for patient recruitment/accrual, data collection, data reporting, and safety monitoring for patients enrolled on Phase 2 clinical trials, etc.?

Other Key and Support Personnel: Are the other key personnel appropriately trained and well suited to carry out the work associated with early Phase 2 experimental therapeutic clinical trials? Is there sufficient and appropriately experienced support personnel with the skills needed to develop, implement, conduct, and analyze early Phase 2 clinical trials?

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?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed?

Specific for this FOA:

Required Capabilities: Based on the aggregated capabilities and past performance of the parent UM1 awardee and the proposed Phase 2 team: Is the parent UM1 awardee in sufficiently good standing for Phase 1 aspect (e.g., successful patient enrollment) to be ready to add Phase 2 Program? Has the parent UM1 awardee significantly contributed to CTEP protocol development through submission of approved LOIs and participation on drug project teams? Will the proposed Phase 2 team have all the required capabilities to ensure adequate productivity at the state-of-the-art level in in the development, implementation, and completion of its early Phase 2 clinical trials? How realistic are the plans to recruit at least 100 patients per year for Phase 2 studies while also meeting other requirements with regard to special patient populations? How strong are the plans for the dissemination of the clinical trial results (particularly including peer review publications) and how likely are these plans to be realized?

Integration: Is the parent ETCTN awardee site in sufficiently good standing, well-positioned, and ready to add the proposed Phase 2 Program? Are the proposed plans for adding the Phase 2 Program and its integration with the current Phase 1-centered program at ETCTN LAO well thought-out and realistic? Is there adequate emphasis placed on such aspects as: collaborations between ETCTN investigators and other clinical/translational science investigators; and active participation of PDs/PIs as members in relevant experimental therapeutic committees, task forces, working groups, and team science projects for the ETCTN?

Governance: Are the proposed leadership plan and the decision-making processes optimal for the participation of Phase 2 Program in multi-disciplinary, multi-institutional trials in a range of cancer types and special populations with diverse scientific strategies? Is the proposed multiple PDs/PIs leadership plan clear and consistent in defining individual activities and responsibilities as well as governance relationship between the parent ETCTN LAO and the proposed Phase 2 Program?

Biomarker Assays and Molecular Characterization of Patients: Are the proposed plans for incorporating biomarker endpoints, imaging endpoints, and other molecular characterizations into Phase 2 clinical trials appropriate and sufficient in terms of state-of-the-art quality and an understanding of the role and importance of such studies in oncologic drug development?

Protocol Development and Clinical Trial Execution: Are the proposed procedures appropriate for the timely development of ETCTN early Phase 2 experimental therapeutic clinical trials? Are the activities to maintain the proficiency of institution personnel in the management of early Phase 2 clinical trials (including relevant training) clear and sufficient?

Biospecimens: How sufficient are the applicants' abilities to obtain, process, and store high-quality specimens from Phase 2 clinical trials? Does the applicant demonstrate a sufficient ability to analyze and report on specimens from PK/PD and/or molecular characterization studies?

Data Management: Are the capabilities and procedures for the collection, management, and analysis of data appropriate for both single institution and multi-institution Phase 2 clinical trials? Does the ETCTN Phase 2 site(s) have adequate statistical support and utilize appropriate statistical design approaches for early experimental Phase 2 therapeutic clinical trials? Are procedures to monitor and analyze the data sufficiently rigorous in terms of the safety of patients/participants? Are the procedures for QA/QC for clinical trials data developed by the program appropriate?

Data Reporting: Does the site have appropriate procedures for maintaining the technical integrity and security of its clinical trials data, including appropriate routines for backing up data? Are procedures for reporting of data from early Phase 2 clinical trials to CTEP sufficient to ensure the timely reporting of reliable clinical trials data?

Regulatory Compliance: Do the proposed additional Phase 2 sites have suitable procedures fully ensuring regulatory compliance for all applicable aspects?

Research Pharmacy Management: Is the Research Pharmacy Management for Phase 2 program consistent with the specified ETCTN requirements in terms of facilities, personnel, procedures, adherence to regulations, etc.

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?

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?

Specific for this FOA: Will the geographic location and institutional environments impact the integration between the parent ETCTN and the site of the proposed Phase 2 Program?

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.

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

For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project.

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.

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

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 Wide Association Studies (GWAS) /Genomic Data Sharing Plan.

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

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the 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:

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
• 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 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 Cancer Advisory Board. The following will be considered in making funding decisions:

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

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

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

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

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

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

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

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable 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:

• ETCTN PDs/PIs are expected to lead and /or participate in multidisciplinary scientific teams during the development and implementation of the ETCTN Drug Development Plans.
• Development of an overall research strategy for the ETCTN clinical trials as well as all key components related to the conduct of approved clinical trials.
• Development, with CTEP assistance, of appropriate early phase experimental therapeutic clinical trial protocols.
• The conduct of the clinical research supported under the ETCTN Cooperative Agreements, which must adhere to the guidelines described in the documents listed below (and any subsequent modifications of these documents). These documents are incorporated by reference as program-specific Terms and Conditions of Award:
• NCI CTEP Investigator's Handbook (Manual for Participants in Clinical Trials of Investigational Agents Sponsored by the Division of Cancer Treatment and Diagnosis, NCI) available at http://ctep.cancer.gov/handbook/index.html
• Guidelines for Auditing of Clinical Trials for Experimental Therapeutics Clinical Trials Network (ETCTN) at http://ctep.cancer.gov/branches/ctmb/clinicalTrials/docs/ETCTN_Audit_Guidelines.docx.
• ETCTN Program Guidelines at http://ctep.cancer.gov/initiativesPrograms/docs/ETCTN_Program_Guidelines.pdf
• 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 ETCTN trials.
• Awardees are allowed to accept funds from non-governmental sources to support ETCTN 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/DCTD per case data management funding, support for correlative science studies that use biospecimen or image collections funded by the NCI/DCTD for trials under the ETCTN) and must be reported under the Terms and Conditions of Award for the ETCTN unless they are associated with an exempted category under the NIH grant policy for program income, available at: http://grants.nih.gov/grants/policy/nihgps_2011/nihgps_ch8.htm#_Program_Income.
• All key components of the ETCTN 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 ETCTN 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 (e.g., in the role of Project Managers).

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. Some Program Officials may also have substantial programmatic involvement (as Project Scientists/Coordinators). The main responsibilities of substantially involved NCI staff members include, but are not limited to, the following activities:

• Working with ETCTN 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 ETCTN and other NCI-sponsored programs;
• Facilitating scientific involvement in oncology treatment research, including advanced imaging research and radiation oncology research, associated with ETCTN trials;
• Auditing of ETCTN sites via their membership in the ETCTN;
• Reviewing accrual and overall performance of ETCTN clinical trials by the site;
• Reviewing compliance with applicable HHS, FDA, OHRP, NIH, and NCI regulations for clinical research involving human research subjects;
• Advising awardees concerning mechanisms established for quality control of therapeutic and diagnostic modalities used in ETCTN clinical trials; and
• Monitoring the progress and performance of the key components of the ETCTN.

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 ETCTN trials.

In case of insufficient patient accrual per the protocol specified, inability to meet the scientific aims of the Cooperative Agreement, or noncompliance with the Terms and Conditions of Award, the NCI reserves the right to reduce award budget, withhold support, suspend, or terminate the award.

The following provisions are added for Phase 2 revision awards:

• The NCI ETCTN Program Officer will periodically evaluate the actual patient accrual to Phase 2 studies. The actual patient accrual will be the basis for the biannual release of respective funds for "Patient Accrual and Related Costs".
• NCI CTEP staff members will review proposals from ETCTN investigators for correlative studies to enhance Phase 2 clinical trials and will authorize the release of funds for approved studies.

Areas of Joint Responsibility

PDs/PIs of the ETCTN awards, NCI ETCTN Program Director(s), and CTEP Senior Investigators (Project Scientists) will be members of the ETCTN.

ETCTN sites will be expected to participate as active team members on drug development project teams. The teams will meet quarterly to review studies performed under the award and more often to participate on and provide input for the IDSC, with respect to the development of drug development plans. Areas of joint responsibility include:

• General aspects of collaboration on study development and conduct especially with respect to compliance with federal regulations for clinical trial research and participating in activities related to the collective management of the ETCTN, as appropriate.
• Other programmatic responsibilities to be addressed jointly, as needed, by the ETCTN awardees and the NCI staff.

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 ETCTN Group representatives chosen from the ETCTN 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 ETCTN study proposals and the types of studies supported by the ETCTN.

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

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative 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.

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

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Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Finding Help Online: http://grants.nih.gov/support/index.html
Email: commons@od.nih.gov

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Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)

Telephone: 301-710-0267

Jeffrey Moscow, M.D.
National Cancer Institute (NCI)
Telephone: 240-276-6565
Email: jeffrey.moscow@nih.gov

Referral Officer
National Cancer Institute (NCI)
Telephone: 240-276-6390
Email: ncirefof@dea.nci.nih.gov

Shane Woodward
National Cancer Institute (NCI)
Telephone: 240-276-6303
Email: woodwars@mail.nih.gov

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.