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

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

The purpose of this Funding Opportunity Announcement (FOA) is to continue support for the NCI-sponsored Experimental Therapeutics Clinical Trials Network (ETCTN). The ETCTN main role and activities focus on the efficient and comprehensive conduct of early phase clinical trials of NCI Investigational New Drug (IND) agents.

ETCTN investigators design clinical trials in collaboration with NCI staff members and NCI pharmaceutical industry partners. The trial design focuses on both the clinical development and biomarker development relevant to the agent(s). ETCTN trials test agents with Investigational New Drug applications (INDs) held by the National Cancer Institute (NCI) Division of Cancer Treatment and Diagnosis (DCTD), Cancer Therapy Evaluation Program (CTEP, NCI http://ctep.cancer.gov/).

ETCTN clinical trials establish the dose/schedule and address endpoints related to early evidence of therapeutic activity (including "proof of concept", "proof of mechanism", target engagement/inhibition, as well as investigational imaging). These ETCTN studies guide subsequent disease-specific trials to be conducted under other NCI-supported programs, including the National Clinical Trials Network (NCTN) which focus on late Phase 2 and Phase 3 clinical trials.

ETCTN Objectives

The research objective of the ETCTN is for the early-stage clinical development of novel cancer treatments that include NCI-IND agents based on sound preclinical findings, and that are consistent with national priorities for developmental therapeutics clinical cancer research. To meet this objective, all ETCTN awardees jointly will be expected to:

• Use a coordinated and collaborative integrated team science approach in the drug development process.
• Acquire high quality human specimens for ETCTN correlative laboratory studies.
• Integrate scientific rigor into biomarker development and clinical trials.
• Provide efficient and timely activation and conduct of clinical trials that meet regulatory requirements and Good Clinical Practice (GCP) standards and principles.
• Promote collaborations with cancer biology experts to investigate critical pathways and processes in the treatment of oncology patients with investigational drugs.
• Provide clinical study leadership opportunities for early career clinical investigators.
• Commit to enrollment of racial/ethnic and rural populations to decrease cancer disparities.

ETCTN clinical studies conducted during the renewal of the program as described in this FOA are expected to continue to determine the safety of NCI IND agent drug combinations, find early signals of clinical activity of these agents in targeted populations, and perform in-depth analysis of biomarkers of response and resistance. ETCTN investigators will continue to be expected to design and lead ETCTN trials in collaboration with NCI and pharmaceutical partners.

Key Terms for this FOA

Terms related to the organization of the ETCTN:

• 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 (also referred to as NCI-IND agents).
• Lead Academic Organization (LAO): the institution receiving the award under this FOA. An LAO may have Integrated Component(s), i.e., a component of the institution receiving the award, which may be at a different location. The institution must be the same legal entity as the LAO.
• Affiliated Organization (AO): an institution collaborating with the LAO.
• ETCTN site: the institution receiving the award under this FOA (LAO) plus any entities collaborating with the LAO under subcontract/consortium arrangements (also referred to an Affiliated Organizations, AOs) and any Integrated Components.
• Lead Protocol Organization (LPO): An LPO is the LAO or AO of the investigator who leads the clinical trial.

Terms Related to the ETCTN:

• Cancer Therapy Evaluation Program (CTEP), which is responsible for NCI clinical trials.
• Investigational Drug Branch (IDB): The branch of CTEP responsible for the management of ETCTN trials.
• Disease-Focused Clinical Investigator (DFCI): An oncologist with a direct responsibility for opening and encouraging accrual to ETCTN studies in disease-specific oncology clinics, with an emphasis on participation in network-wide phase 2 studies. A Disease-Focused Clinical Investigator may also be an early career clinical investigator.
• Early Career Clinical Investigator (ECI): an investigator who has completed his/her post-oncology fellowship training within the past 10 years and who has not previously competed successfully as PD/PI for a substantial independent NIH research award.
• Project Team Member Applications (PTMAs): a PTMA is an application submitted in response to an NCI request for studies on specific prioritized agents. A PTMA proposes projects, identifies an LPO(s) and project team members, and defines the qualifications of the applicant.

Terms Related to Research:

• Biomarker: A biomolecule present in blood, other body fluids, and/or tissues that is a sign of a normal or abnormal process, or of a condition or disease. A biomarker may be used to see how well the body responds to a treatment for a disease or condition.
• Integral biomarker assay: an analytically and clinically validated biomarker assay that must be performed on each subject as a condition of entry into the clinical trial (e.g., for informing the selection of eligible patients).
• Exploratory biomarkers: biomarkers monitored to examine a potentially important biological and/or mechanistic aspect.

Description of the ETCTN Activities and Organizational Framework

The overarching purpose of the ETCTN is to develop novel NCI-IND anticancer agents and to molecularly characterize tumors to find appropriate biomarkers to select patients most likely to respond to specific agents. In addition to determining safety and tolerability, the clinical trials conducted in the network seek early signals of clinical activity of these agents in targeted populations and perform in-depth analysis of biomarkers of response and resistance. The ETCTN promotes biomarker-rich clinical evaluation of single agent and novel agent combinations and is committed to the conduct of trials in underserved populations and patients with rare tumors.

The ETCTN is assisted by the Investigational Drug Branch (IDB) of NCI’s Cancer Therapy Evaluation Program (CTEP). The ETCTN UM1 awards provide the infrastructure (including clinical sites) and expertise in conducting early phase trials using NCI-IND agents. CTEP currently holds approximately 100 INDs for investigational oncology agents which involve 60 pharmaceutical/biotechnology collaborators. CTEP efforts involve combining novel agents from different pharmaceutical companies which is often difficult to accomplish without NCI support. Agents under evaluation include small molecules, immune-oncology agents, antibodies, antibody-drug conjugates, vaccines, radionuclides, targeted toxins, oligonucleotides, and oncolytic viruses. NCI accepts new agents into its portfolio continuously through the NCI's Experimental Therapeutics (NExT) program and negotiates Collaborative Research and Development Agreements (CRADAs) with pharmaceutical companies and academic investigators to develop and evaluate these agents within the ETCTN. The ETCTN is currently conducting approximately 79 trials, of which 53 trials are those testing novel drug combinations.

NCI-Supported Pipeline for the Development of Experimental Therapeutics. The activities of the ETCTN follow a highly-coordinated process. First, the NCI NExT program is the portal through which NCI brings investigational agents into DCTD/CTEP for development. After a new agent is chosen for development, the Investigational Drug Branch (IDB) Project Team Leader forms an NCI Project Team from the various clinical, translational, and basic biology programs at NCI. Members of the Project Team draft a preliminary drug/biomarker/assay development plan. Once this plan is reviewed and approved by the NCI Senior Advisory Committee (SAC), NCI sends out a request for Project Team Member Applications (PTMAs) to the ETCTN members, NCTN awardees, and other appropriate investigators. The request for PTMA includes publicly available information about the drug and the types and focus of the clinical trials under consideration in the preliminary drug/biomarker/assay development plan. Once the PTMAs have been reviewed and prioritized by NCI, the IDB Project Team Leader will constitute the Drug X Project Team with the PDs/PIs Lead Protocol Organization (LPO) of the approved PTMAs as well as other relevant subject matter experts. This Drug X Project Team presents the drug and biomarker assay development plan to the Investigational Drug Steering Committee (IDSC) for their evaluation. The development plan is then finalized by the Investigational Drug Branch (IDB) and Letters of Intent (LOIs) will be requested from the Drug X Project Team. After approval of the LOIs by CTEP/DCTD, the protocols will be developed in accordance with NCI’s guidance documents and submitted to the CTEP’s Protocol Review Committee (PRC) for final approval.

NCI Organizational Units Involved in the Early Experimental Therapeutics Clinical Trials Network. Due to the diversity in the research scope of the ETCTN activities, several NCI branches/programs/services are active participants within the network. ETCTN clinical trial activities are facilitated by a full suite of centralized clinical trial support services established separately by the NCI CTEP. The ETCTN awardees will be expected to interact, as appropriate, with such NCI branches/programs/services as: CTEP, Biometric Research Program (BRP), Cancer Diagnosis Program (CDP), Cancer Trials Support Unit (CTSU), Central Institutional Review Board (CIRB), Clinical Data Management System (CDMS), Clinical Trials Branch in the Cancer Imaging Program( CIP), Clinical Trials Monitoring Service (CTMS), Oncology Patient Enrollment Network, Regulatory Support Service and Technical Resources International (TRI). NCI provides standardized central operational, regulatory, and administrative support including data management, trial registration, safety reporting, protocol writing, specimen tracking, and Central Institutional Review Board (CIRB) review for ETCTN trials.

Research Objectives for ETCTN Sites

Applicants must be able to organize and implement a comprehensive infrastructure program for the conduct of high-quality clinical trials evaluating novel anticancer agents. Thus, the proposed ETCTN sites must be able to serve as the major resource for rapid, efficient, systematic evaluation and determination of optimal dose/schedule and safety/efficacy for specific agents and combinations of investigational agents sponsored under CTEP INDs, as well as disease-specific treatment evaluation.

To facilitate these responsibilities, the NCI/DCTD/CTEP will provide the ETCTN awardees with standardized central operational, regulatory, and administrative support (through separate contracts beyond the scope of this FOA, see: http://ctep.cancer.gov/investigatorResources/default.htm#guidelines_policies.)

Specific Research Capabilities and Requirements for the ETCTN Sites

ETCTN awardees will be expected to lead a clinical trial center that will support cancer clinical trials from Phase 1 initiation through proof-of-activity and foster seamless Phase 2 clinical development of NCI CTEP IND agents. A range of Phase 1, 1/2, and 2 study expertise is required to provide the program flexibility to rapidly develop a multitude of NCI CTEP IND agents and drug combination studies. ETCTN investigators are expected to develop and lead ETCTN studies and participate in the studies of other ETCTN investigators by promoting accrual to all ETCTN studies at their center.

ETCTN applicants must have the following specific capabilities and be able to meet all the specified requirements:

• Appropriate leadership and team with experience in early phase cancer clinical trials;
• Appropriate expertise in common and uncommon cancers;
• Ability to incorporate biomarkers specific for a given oncologic drug and disease-specific biomarkers into clinical trials, both for eligibility and proof of target engagement;
• Ability to perform disease-specific early phase clinical trials;
• Ability to acquire and evaluate high quality biospecimens (with institutional interventional radiology and research pathology experts) in the context of clinical trials;
• Access to large pools of patients to identify rare subgroups of eligible patients;
• Ability to increase the overall accrual of racial/ethnic and underserved populations to NCI-approved studies; and
• Ability to adapt flexible early phase study design to allow for rapid additions of Phase 2 endpoints into Phase 1 studies when indications of clinical activity are detected.

ETCTN Collaborations. To achieve ETCTN objectives, ETCTN investigators will be expected to collaborate across the Network and with NCI staff members. For example, each ETCTN trial will be led by one designated ETCTN Site. Nevertheless, each ETCN Site will be allowed to enroll patients to any ETCTN trial, including those led by other ETCTN Sites.

Scope of LAO Scientific Activities. The proposed ETCTN LAO and its investigators should be capable of conducting clinical research that covers the following aspects:

• Developing novel clinical trial proposals (further referred to as Letters of Intent ) that describe clinical trial designs based on sound pre-clinical evidence and rationale, and that advance the clinical development of NCI-IND agents;
• Developing clinical trial protocols based on CTEP-approved LOIs that are statistically appropriate and optimized for the agents studied;
• Incorporating validated biomarker assays in clinical study designs that examine mechanistic proof-of-principle concepts regarding NCI-IND agents, including evaluating potential predictive biomarkers of response and pharmacodynamic assays that demonstrate target engagement;
• Evaluating clinical and biomarker data from ETCTN trials and making timely public reports of the outcomes of these trials;
• Evaluating translational endpoints in clinical trials of investigational agents and data from related laboratory studies that assess the nature of drug-drug interactions (additive/synergistic/ antagonistic);
• Exploring the use of patient reported outcomes and implementing, if appropriate, such measures in early phase ETCTN studies for safety and tolerability determinations;
• Developing novel strategies and approaches to monitor risks and mitigate adverse events, as well as improve safety and compliance;
• Accruing patients from underserved populations and those with different types of cancer to early stage clinical trials;
• Conducting studies of special populations;
• Collaborating with other NCI-supported programs and utilizing NCI resources developed through the Precision Medicine and Moonshot Initiatives including the Molecular Characterization Lab (MoCha), Pharmacodynamic Assay Development & Implementation Section (PADIS), Cancer Immune Monitoring and Analysis Centers (CIMACs), PDX Development and Trial Centers Research Network (PDXNet), the Drug Resistance and Sensitivity Network (DRSN), National Clinical Laboratory Network (NCLN) and others currently under development.

Although adolescents may be included in some ETCTN studies, pediatric-focused studies are not within the scope of the ETCTN. NCI conducts pediatric-focused studies through other NCI-funded mechanisms (https://ctep.cancer.gov/investigatorResources/childhood_cancer_resources.htm#pbtc).

Required Organization and Capabilities of the Proposed ETCTN Sites

ETCTN Sites proposed in response to this FOA may constitute a single institution (i.e., a LAO) or a LAO with AOs. In either configuration, the proposed ETCTN Site must be able to meet all the required scientific and organizational requirements outlined below.

Key Capabilities and Attributes

Scientific Leadership and Site Organization

The PDs/PI(s) will be responsible for developing and supervising well-designed precision medicine/biomarker-driven studies that define the biological basis for disease, utilize patient population enrichment strategies, evaluate target and drug effects, and strategically evaluate proof of mechanism, concept and suitable patient candidates. A well-defined plan for communications and collaborations should be in place, described and implemented for individual sites and consortia.

Each ETCTN site will be required to oversee the conduct of early phase therapeutic clinical trials, ensure data and safety monitoring, compliance with the required policies and regulations, and facilitate interactions with other ETCTN and NCI staff. Canadian applicants should have expertise with regulatory filings, drug master files, clinical trials agreements and other activities under Canadian regulatory compliance in concert with the most recent standards within the International Committee on Harmonization (ICH) guidance for Good Clinical Practice.

Relevant Capabilities and Past Performance

Previous affiliation with the NCI Early Phase Clinical Trials Program or ETCTN is NOT required for application to this FOA. However, it is essential that investigators applying for these awards have expertise and well documented past performance in the development and conduct of early stage cancer clinical trials and clinical development of experimental therapeutics. Applicants must also oversee a clinical research enterprise at their institutions that can support the overall objectives of the Network. All qualified applicants that meet the requirements of this FOA are encouraged to apply. Applicants should be able to provide information on past minority and underserved community accrual to early phase clinical trials.

Team Science for Project Development and ETCTN Participation

Each ETCTN awardee will be expected to lead and/or participate in multi-disciplinary, agent specific scientific Project Teams. Therefore, ETCTN investigators must be highly capable of performing inter- and trans-disciplinary team-based research.

Leadership Opportunities for Early Career Clinical Investigators

Each ETCTN site will be expected to organize appropriate leadership enhancement activities. The program should provide adequate mentorship for early career clinical investigators, including opportunities for early career clinical investigators to lead clinical trials and participate in future ETCTN activities and/or initiatives. Early career clinical investigators are encouraged to participate in the ETCTN as Disease Focused Clinical Research Scientists, with responsibilities of advancing ETCTN clinical research in their disease-specific clinics. Mentorship programs for early career clinical investigators by disease expertise or scientific expertise are strongly encouraged.

Clinical Trials Operations

This unit will be responsible for all administrative duties and reside at the contact PD/PI’s institution. Additional capabilities include all regulatory communications, filing adverse event reports, maintenance of all regulatory documents, communications, and toxicity reporting. This unit shall collaborate with NCI support infrastructure (see: Cooperative Agreement Terms and Conditions of Award section).

Biomarker Assay(s) and Molecular Characterization

Each ETCTN site must have the capability to support clinical trials by conducting various laboratory testing of clinical specimens. This includes the requisite expertise in acquiring fresh biopsy specimens from a high percentage of patients on trials (even if invasive procedures are required). Canadian sites and those working with these sites should provide documentation regarding the ability to accept and transfer specimens for clinical trials. Integral biomarker assays must be done in a laboratory certified under Clinical Laboratory Improvement Amendments (CLIA)(

http://www.cms.gov/Regulations-and-Guidance/Legislation/CLIA/index.html?redirect=/clia/).

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

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• U.S. Territory or Possession

Other

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

The only foreign institutions eligible to apply in response to this FOA are Canadian institutions.

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 not allowed.

Applicant Organizations

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

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

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

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

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

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

Individual(s) designated as Program Director(s)/Principal Investigator(s) (PDs/PIs) on the applications for ETCTN awards are expected to be nationally- and internationally-recognized leaders in cancer-related clinical trials of novel therapeutic agents, translational research, and related clinical areas relevant to such studies. These individuals should also be recognized leaders in the relevant areas of science and have documented administrative leadership experience.

In addition, an individual designated as a contact PD/PI must have primary affiliation with the application submitting institution (i.e., the LAO). If additional PDs/PIs are designated, they may be affiliated either with the LAO or participating AO.

If the ETCTN contact PD/PI is not a practicing physician, a physician(s) must be designated to be responsible for overseeing the clinical trial(s) and patient management. This physician must have primary affiliation with the submitting institution (i.e., the LAO).

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

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

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

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

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

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

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

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

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

The letter of intent should be sent to:

S. Percy Ivy, M.D.
National Cancer Institute (NCI)
Telephone: (240) 276-6107
Email: [email protected]

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

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

Sub-Section A. Overview- 6 pages

Sub-Section B. Clinical Program- 12 pages

Sub-Section C. Clinical Trials Operations-- 6 pages

Sub-Section D. Tissue Acquisition and Molecular Characterization- 6 pages

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

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

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

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

Facilities & Other Resources: Provide a succinct description of the early phase clinical trial related resources, infrastructure and facilities that are available for the proposed ETCTN Site at LAO and AOs.

Include documentation for the ability to:

• Meet intensive data collection and regulatory requirements;
• Accrue at least 100 patients per year by the LAO group as a whole;
• Accrue approximately 20 patients per year to early phase experimental therapeutic clinical trials for each participating AO;
• Conduct state-of-the-art imaging; and
• Increase the participation of minority and underserved populations in ETCTN trials.

Investigational Pharmacy. It is essential that all ETCTN sites have access to and use of a pharmacy to conduct investigational drug pharmacy operations required to adequately fulfill obligations related to investigational agents. Provide documentation ensuring that investigational pharmacy operations will be able to adequately fulfill obligations related to investigational agents, security, assuring proper transfer and/or final disposition of investigational agents, and adherence to local, state, and federal regulations. Additionally, each institution must have access to and use of a pharmacy for the use and dispensing of investigational radiopharmaceuticals used in the conduct of clinical trials.

Summarize the policies and procedures regarding the following elements:

• Access to approved protocol documents, amendments, and notification of protocol activation at the site;
• Authorized labeling and dispensing of investigational agents to eligible study subjects on approved protocols;
• Notification of patient enrollment to a given protocol, including notification of signed informed consent prior to agent dispensing;
• Agent management and agent transfer for use of CTEP IND agents for trials (this applies to all satellite dispensing areas that are expected to handle IND agents), including agent receipt, accountability, final disposition and reconciliation of non-clinically usable IND agent supplies. Adequate security of agent(s) with controlled access to authorized personnel. Safe transport of agents within the facility or to approved satellite facilities. Order and receive agent(s) from the supplier as instructed in the clinical protocol;
• Secured access storage space and storage unit(s) necessary to meet storage conditions of agent(s). Limited access areas for secure and safe preparation of agents. Maintenance of continuous proper storage conditions of agent(s) according to supplier instructions. Validation documentation and access to emergency back-up power supplies. Segregation of agents by protocol, strength, unit, formulation, and responsible investigator;
• Temperature monitoring, including frequency, notification systems for temperature failures or deviation and contingency plans for storage unit failures;
• Safe and secure handling, preparation, and disposal of dangerous goods, hazardous substances, and infectious substances. Access to appropriate primary containment equipment, personal protective equipment, and safety equipment;
• Site compliance with CTEP policies and guidelines for IND agent management described on the CTEP website and in the DCTD Investigators' Handbook;
• NCI-supplied agents prescribed only by study-eligible physician investigators who are registered and have an active investigator registration status with the Pharmaceutical Management Branch, CTEP;
• Accurate completion of NCI’s Drug Accountability Record Form (DARF, NIH-2564) as the primary record of all transactions related to the agent(s) and procedures for reconciling deviations; and
• Training of staff and written training documentation for agent handling, storage, and management.

Note: Inter-institutional pharmacy exchange and secondary distribution of investigational drugs and radiopharmaceuticals are NOT permitted.

Other Attachments: Applicants must provide the following additional materials specified below in support of their application. Each attachment should be uploaded as a separate PDF file. The filename provided for each attachment will be the name used for the bookmark in the application image.

Attachment 1. Communication Data (use filename Communications):

Outline existing (in-place) routines for the team periodic (weekly, monthly, quarterly, biannual, ad hoc etc.) meetings to monitor patients as trial participants and discuss safety, trial conduct, summaries and evaluations of trial progress. Include also ongoing efforts to ensure timely publication of study results.

Attachment 2. Regulatory Data (use filename Regulatory):

- Good Clinical Practice and Routine and Expedited Safety Reporting data for U.S.A. and (if applicable) Canadian sites.

Attachment 3. Organizational Charts (use filename Org Charts)

Outline of the organization of the ETCTN sites and organizational structure for coordinating protocol development.

Attachment 4. Standard Operating Procedures Data (use filename SOPs)

- List of relevant Standard Operating Procedures (SOPs) and organization policies to be used by the ETCTN LAO and AOs for clinical research activities. Items on the list may include, but are not limited to: specimen acquisition and handling; tumor banking procedures and policy; Institutional Review Board (IRB) policies; assay validation procedures, etc.

Operation plans, SOPs, investigational agent management procedures, and related procedure and policy documents should not be provided.

Attachment 5. Past Performance (use filename Resource Tables)

- Data on the capabilities and available resources for specific functional units of the ETCTN LAO. Relevant, optional information may be provided in tabular form as listed below. Use of the tables is optional. Applicants may use table templates provided at https://ctep.cancer.gov/initiativesPrograms/etctn_recompetition.htm, if they want to use them. Furthermore, it is suggested that applicants limit the information listed to the top 50 trials and provide only summary information/numbers for the remaining studies.

• "Completed and Ongoing Phase 1 and Phase 2 Clinical Trials": List early phase clinical trials that have been completed during the last 5 years and any ongoing clinical trials for which significant research findings are available. Include first-in-human studies and trials that determined dose and schedule for both single agents and investigational agent combinations. For each trial listed, provide respective National Clinical Trial identifier (NCT number).
• "Other Scientific Achievements for Clinical Trials": List early phase clinical trial scientific achievements that have occurred during the last 5 years.
• "List of Molecular Characterizations Performed During Conduct of Early Phase Clinical Trials": Describe biomarker assays, molecular characterization, and other correlative laboratory studies performed on patient tissue during the last 5 years, especially those that included surgical or image-guided biopsies.
• "Summary Accrual for Screened and Treated Patients on Early Experimental Therapeutic Clinical Trials": Describe the number of patients screened and treated on early phase clinical trials that were/are led by the applicant or where the applicant accrued patients to an early phase clinical trial but was not the lead on the protocol.
• "Operational Timelines for Activation of Clinical Trial Proposals": List timelines for the LAO and any AOs (if applicable). List actual timelines for specific steps in the clinical trial protocol development process, including accrual rate projected and achieved, total accrual, study duration and submission of abstracts and manuscripts. Timelines may be provided as flowcharts;
• "Inclusion Enrollment": Provide one summary table for total accrual for all early phase clinical trials completed over the past 5 years

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

Designate an appropriately qualified PD/PI (or multiple PDs/PIs), including an individual who will be primarily responsible for ETCTN LAO operations and will be designated as contact PD/PI. If desirable, applicants may also designate one PD/PI as primarily responsible for phase 1 trials and another one for phase 2 trials.

The LAO and/or its AO(s) should identify at least one statistician with the skill and expertise in the design and monitoring of early phase clinical trials including adaptive and other designs for phase 1 and 2 trials to support the clinical activities of the site or consortium. Proposed ETCTN sites are expected to have the requisite statistical expertise for trial design/monitoring and coordinating patient enrollment on all clinical trials open in the ETCTN.

Sites with a unique interest in the development of therapeutic radiopharmaceuticals in combinations with CTEP-IND agents are encouraged to include radiation oncologists as key personnel.

For each LAO-based team, designate the following Senior/Key Persons:

• A Translational Scientist who will oversee translational efforts and has expertise in biomarker incorporation into early phase clinical trials;
• A biostatistician who will be responsible for the statistical design and management of ETCTN studies led by the LAO;
• PD(s)/PI(s) associated with LAO, who may also be designated as LAO Disease-Focused Clinical Investigator(s).
• At least four additional faculty Disease-Focused Clinical Investigators with disease-specific early phase clinical trials expertise who will be responsible for participating in ETCTN studies in their disease focused clinics. One of the Disease-Focused Clinical Investigator faculty should/may be a phase 1 investigator;
• An Interventional Radiologist who will be responsible for supervision of the acquisition of research biopsies at the LAO and participate in quality/risk improvement initiatives;
• A Research Pathologist who will be responsible for the processing and quality review of research biopsy specimens and participate in quality improvement initiatives at the LAO site; and
• Physician(s) responsible for patient management if the ETCTN LAO PD/PI is not a practicing physician.

For each participating AO, designate the following Senior/Key Persons:

• An AO site leader who will also serve as a Disease-Focused Clinical Investigator at the given site;
• At least two additional faculty Disease-Focused Clinical Investigators with disease-specific early phase clinical trials expertise, who will be responsible for participating in ETCTN studies in their disease focused clinics (if applicable, a PD/PI associated with a given AO may be designated as AO Disease-Focused Clinical Investigator); and
• An Interventional Radiologist who will be responsible for the acquisition of research biopsies at the AO site

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

Additional guidance applies.

The requested budgets should take into consideration the standardized central operational, regulatory and administrative support that will be provided to ETCTN awardees by NCI. These services will be directly funded by the NCI and respective cost must not be included in the requested budgets.

Senior/Key Persons and Other Personnel. Costs should include estimated costs of salary support (based on level-of-effort) for the PD(s)/PI(s), Disease-Focused Clinical Investigator(s), Translational Scientist, Interventional Radiologist, Research Pathologist, and other collaborators responsible for various aspects of early drug development (but not personnel costs directly related to the conduct of clinical trials at the clinical level).

Each individual designated as a PD/PI must commit a minimum of 1.2 person-months of effort per year. This minimal effort level must be maintained throughout the entire project period.

The designated Disease-Focused Clinical Investigators, Translational Scientist, Interventional Radiologist and Research Pathologist are expected to commit a minimum of 0.6 person- months of effort each per year. Disease-Focused Clinical Investigators listed as Senior/Key Persons should receive partial salary support. The effort level requested should be commensurate with the projected scale of accrual to and opening of clinical trials.

General determination of level of overall funding. The total cost for "eligibility screening" accrual on treatment or primary imaging trials is expected to be $600 per participant. The applicant can allocate the total cost amount across all allowable cost categories in any amount or distribution pattern that the applicant believes is appropriate. The applicant can request more (or less) than the estimated amounts with appropriate budget justification. However, budgets are based on estimated ranges for the infrastructure costs associated with per case management. To justify the budget, the applicant needs to describe in detail in the budget justification the number of patients expected to be accrued for treatment trials in the category for primary imaging trials, and for one patient biospecimen collection for each enrollment on a treatment or primary imaging trial by category site type (main academic site and integral components versus affiliates).

The budget should include funding to be allocated to support research and development, and ETCTN collaboration (in addition to support for scientific leadership, administrative and regulatory activities, data management and analysis, etc.). All costs for on-site data management using Medidata Rave and services provided by CTMS must be fully justified. All costs for the timely development of electronic medical/hospital records to launch early phase clinical trials and mailing or handling research-related patient specimens, forms, and materials should be included. Other consulting costs should be outlined. Protocol development, and statistics and data management for the institution(s) costs is to support the non-accrual responsibilities associated with participating in early-phase experimental therapeutic clinical trials (e.g., CIRB submission, amendment distribution and continuing review, site training, pharmacy set-up, and site administration) that must be met even if patients are never enrolled on a study at an institution. An annual accrual rate of at least 100 patients per year per LAO should be assumed.

Provide the cost for each main budget category (personnel, supplies, travel, etc.) as needed for organizational harmonization; the coordination of ETCTN clinical trials; clinical support and recruitment, regulatory, data management, Electronic Medical Record (EMR) builds, and other organizational activities. Costs of the integration of the 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.

Funds for travel. The ETCTN Site PD(s)/PI(s) will be required to travel to two meetings per year. Include travel funds for two NCI/CTEP Early Drug Development (EDD) meetings per year for four representatives from the ETCTN site (at least one of whom must be the LAO PD/PI). Travel costs for two presenters for major national/international meetings should be included in the budget.

Clinical Trials Research Operations and Research Related Hospital Charges. Requested funds for clinical trials operations must be to support 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, tumor tissue handling and shipping to the tissue bank, performing research imaging studies, etc.).

In planning these expenses, applicants should consider patient Enrollment Costs. Estimated costs of patient accrual for clinical trials should be included. Provide a detailed breakout of costs used to estimate the reimbursable per-patient accrual costs in the budget justification. The net per-patient cost for accrual to ETCTN clinical trials regardless of phase (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 be approximated as part of the entire budgetary request.

Tissue Acquisition. The budget request should include costs for the acquisition of high quality research biopsies and other clinical specimens, as well as biospecimen handling. The anticipated total annual expenses should be based on per-patient costs of the accrual, assuming at least 100 patients per year.

The requested budget items 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 NCI Administrative Supplements or other funding sources;
• 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. Budgets for affiliated consortium component organizations (i.e., AOs ) must be provided as subaward budget attachment forms.

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

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

Specific Aims:

Provide Specific Aims for the entire application. Include key benchmarks such as expected number of clinical trials (by phases), participant accrual levels, etc.

Research Strategy:

The Research Strategy must consist of the following sub-sections A-D as defined below.

Sub-Section A: Overview

In this sub-section, outline a comprehensive and cohesive program for the conduct of high-quality clinical trials evaluating novel anticancer treatments. Underscore the potential and benefits in terms of the accelerated development of experimental anticancer agents. The scientific goals must be based on the demonstrated ability for the LAO/AO applicant group to accrue at least 100 patients per year to ETCTN clinical trials.

Address all the specific aspects identified below.

Relevant Capabilities and Past Performance

Without repeating information in individual biosketches, applicants should summarize their collective ability and experience to conduct early phase clinical trials and experimental therapeutic agent development. Applicants representing current awardees of the ETCTN should cover in this narrative your role and accomplishments under the award. Applicants unaffiliated with the ETCTN should describe experiences, accomplishments, infrastructure, capabilities, etc., relevant to objectives defined in this FOA. Specific information to provide must include (but is not limited to) the following aspects:

• The most significant and strategic capabilities for clinical trials, the scale of operation in terms of the conduct of clinical trials and experimental therapeutic agent development;
• Accrual history of multiple disease-specific clinics within the LAO and within the AOs to early phase cancer clinic trials
• How the collective experience of the entire team will benefit the conduct of ETCTN clinical trials and accelerate experimental therapeutic agent development;
• Highlights of published results from clinical, translational and/or basic research;
• The ability of the LAO and AO (if applicable) to collect a sufficiently high percentage of high quality specimen samples in clinical trials through use of an Interventional Radiologist and Research Pathologist;
• Accomplishments of the applicant’s sites. Accomplishments may include Letters of Intent (LOIs) for clinical trials submitted and approved, clinical protocols approved, clinical trials activated, cumulative and annual patient accrual, and organization of clinical trials. Include relevant dates and milestones.
• Abilities of the LPO to develop, write, implement, and monitor ETCTN protocols at the AO site, and at other ETCTN LAOs; and
• Clinical and laboratory scientific expertise applicable to oncology drug development resident at the LAO and AO(s) and the institution’s willingness to utilize these areas for the conduct of ETCTN studies.

Scientific Leadership and Site Organization

Applicants are required to address at a minimum, without repeating information in biosketches, the following aspects:

Scientific Leadership

• Plans to maintain the proficiency of site personnel;
• Plans to open ETCTN in disease-specific clinics at LAO and AO sites and to encourage accrual to ETCTN studies;
• How PD(s)/PI(s) intend to accomplish productive collaborations, using a team science approach, between participating ETCTN sites and clinical and translational research investigators internal and external to the ETCTN LAO;
• Plans, including benchmarks, to ensure effective interaction, communication, and monitoring of performance within the ETCTN sites. These plans should include, but not be limited to:
• Actions to be taken to address failure by investigators and/or institutions to meet study timelines and objectives;
• Contributions to clinical trial protocol development and conduct;
• Compliance with clinical trial protocol requirements;
• Use and compliance with ETCTN authorship guidelines for ETCTN-related publications (See: https://ctep.cancer.gov/initiativesPrograms/docs/ETCTN_Publication_Policy.pdf);
• Timely submission of required data to NCI centralized clinical trial support systems;
• Timely preparation, presentation, and publication of clinical trial results and research findings at international meetings and scientific journals.

ETCTN LAO(s) and AO(s)Site Organization:

Provide an organizational chart to describe the organization of the proposed ETCTN LAO and site(s). For multi-institution applications, provide justification for selection of participating institutions (including key selection criteria used) and a strong justification for multi-institution participation. Include a description of the criteria used to select AOs. Provide institutional commitment to facilitate participation in ETCTN clinical trials and for utilizing imaging methodologies.

Explain the responsibilities of Disease-Focused Clinical Investigators at the LAO and its AO(s) in terms of ETCTN site portfolio development, developing and opening new ETCTN studies within their discipline, and how Disease-Focused Clinical Investigators will contribute to accrual to ETCTN studies. If applicable, describe senior mentorship support for those Disease-Focused Clinical Investigators who are early career clinical investigators.

Address, at a minimum, the following aspects:

• The Leadership and governance structure for the site committee to oversee all ETCTN participation and clinical trials operations;
• The organizational structure for coordinating protocol development.
• Meeting NCI Operational Efficiency Working Group (OEWG) timelines or other appropriate guidelines.
• Participation in ETCTN administrative and scientific committees;
• Integrating/coordinating activities related to the development and conduct of clinical trials with other ETCTN participants and other NCI-sponsored research programs.

Note: Supporting information pertaining to this Sub-section is requested under Other Attachments (Attachments 1, 3 and 5).

Sub-Section B: Clinical Program

Team Science for Project Development and ETCTN participation

Describe how ETCTN sites will lead and/or participate in multi-disciplinary scientific teams during the development and implementation of ETCTN drug development plans, including but not limited to CTEP lead drug development project teams. Applicants should form a team with PD(s)/PI(s) at the LAO and AOs, one or more Phase 1 and Phase 2 Clinical Trial PIs, a minimum of 4 Disease-Focused Clinical Investigators at each LAO and a minimum of 2 Disease-Focused Clinical Investigators at each AO in distinct oncology sub-specialties, an Interventional Radiologist (IR) and a Research Pathologist (RP). The Phase 2 Clinical Trial PIs may serve as Disease-Focused Clinical Investigators.

Describe the capacity and experience of the proposed team with regard to such aspects as:

• Developing preclinical projects that will guide clinical agent development;
• Participating in early drug development team science initiatives and inter-and intra-disciplinary team projects;
• Developing biomarker-driven drug development plans;
• Biostatistical approaches proposed to analyze combinations of clinical endpoints with various accompanying molecular data; and Leadership Opportunities for Early Career Clinical Investigators

Provide a description of activities and opportunities in experimental therapeutics for early career clinical investigators in the environment of the proposed ETCTN site. Translational research should be an integral part of these activities. Leadership opportunities of early career clinical investigators are expected to include such activities as:

• Clinical trial advising for early career clinical investigators;
• Opportunities for early career clinical investigators to lead and conduct clinical trials, including participation in the ETCTN as Disease-Focused Clinical Investigators with senior mentorship support, as well as participate in experimental therapeutic development activities and/or initiatives;
• Opportunities to enhance skill and experience in the application of principles of experimental therapeutics, molecular pharmacology, and clinical development;
• Integrating translational science into mentoring;
• Developing concepts for clinical trials;
• Including early career clinical investigators as clinical trial study chairs and as participants on scientific committees;
• Protected time for early career clinical investigators to perform clinical research;
• Plans for early career investigators to attend national or international meetings relevant to experimental therapeutics;
• Available seminar series relevant to clinical experimental therapeutics;
• Relevant drug development activities that will be available to early career clinical investigators (e.g., compliance with regulatory requirements for drugs and devices, imaging, biomarker development); and
• Opportunities for early career clinical investigators to enhance expertise in clinical trial related activities (e.g., pharmacology, monitoring, genetics).

Sub-Section C: Clinical Trials Operations

Coordination of Clinical Trials and Associated Activities

Applicants should ensure effective interaction, communication, and monitoring of performance within the proposed ETCTN LAO and sites. Applicants should describe their experience and the proposed management of complex early phase clinical trials. The application should address these items:

Collective skills and accomplishments of the leadership and the team in overseeing and implementing clinical trials of experimental cancer therapeutics;

Procedures for assembling, recruiting, and maintaining appropriate personnel that will support the execution of clinical trials;

• Plans for robust accrual to ETCTN trials across the network, including rare cancers and accrual from special populations (e.g. minority and underserved communities, the elderly, and young adults); and

Plans for the 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.

Protocol Development and Clinical Trial Execution

• Plans and procedures utilized to support the timely development, activation, and completion of early phase clinical trials;
• Procedures for training and maintaining the proficiency of institutional personnel conducting clinical trials;
• Procedures for coordination and tracking of study modifications/ amendments;
• Procedures for determination of patient eligibility and assigning drug dose level;
• Statistical support provided for all aspects of the ETCTN clinical trials;
• Multidisciplinary nature of the protocol development team, including the Interventional Radiologist and Research Pathologist;
• Procedures for timely review and assessment of clinical trial data, interim evaluation, and consideration of measures of outcome consistent with patient safety and Good Clinical Practice (GCP) (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM269919.pdf); and
• Compliance with GCP, safety reporting standards, and human subjects' protections regulations.

Data Management

• Procedures for on-site data management, including interactions with on-site and CTMS data management personnel, data transmittal via Medidata Rave to CTMS, data editing, timely resolution of queries from CTMS, quality control, and verification of submitted data;
• Plans to establish and maintain site, investigator, and associate rosters with the Cancer Trials Support Unit (CTSU); and
• Provision for high-quality data management using an effective quality assurance (QA)/quality control (QC) program, including internal review and oversight of data submission.
• The statistical analysis plans for clinical and biomarker analysis related to outcome.

Data Formats

Address the following:

• Data compatibility plans, including data for clinical trials;
• Procedures ensuring that claims of treatment agent activity are accurate and reliable (e.g., by establishing an independent response review panel), and
• Plans to ensure timely submission of required data to NCI centralized clinical trial support systems.

Note: Supporting information pertaining to this Sub-section is requested under Other Attachments (Attachments 2 and 5).

Sub-Section D: Tissue Acquisition and Molecular Characterization

ETCTN sites are expected to collaborate with NCI and NCI s central laboratories [including the NCI Molecular Characterization Laboratory (MoCha) and the National Clinical Laboratory Network (NCLN)], and research networks to characterize patient’s tumors on a molecular level to select appropriate patients for specific treatments, and to explore mechanisms of resistance and response to assist in defining follow-on treatment or determine future combination therapies.

In this section, describe:

• Genomic screening practices to identify potentially eligible patients using NCI central laboratories;
• Expertise and proficiency in collecting/acquiring high quality fresh and relevant biopsy specimens for biomarker-based and other studies from a high percentage of patients on trials, even if invasive procedures are required;
• Roles of the Interventional Radiologists and Research Pathologist in improving the acquisition of high-quality biopsy specimens
• Planning and implementing appropriate pharmacodynamic and pharmacogenomic studies integrated with clinical trials;
• Ability to perform well-designed biomarker-driven studies that evaluate disease biology and leverage centralized biomarker and assay characterization and analysis resources, including the analysis of integral, integrated and exploratory biomarkers;
• Implementing validated assays for patient selection, stratification, or determination of treatment on patient specimens and reporting of results;
• Proposed imaging methods, use of validated molecular imaging capabilities and timelines to incorporate imaging endpoints into the overall research program, and adequate post-acquisition image storage, processing, and analysis capabilities;
• Tissue handling and storage facilities. Coordinating the acquisition, handling, preparation, evaluation, and shipment of specimens to ETCTN sites and/or tumor banks/biorepositories;
• Evaluating translational endpoints in clinical trials of investigational agents; and
• Analyzing tumors and specimens with genomic and expression, or other biomarker-based studies, to define response and resistance mechanisms and to identify investigational combination treatment regimens.

Note: Supporting information pertaining to this Sub-section is requested under Other Attachments (Attachments 4).

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.
• It is expected that these plans will address data compatibility with required systems developed and maintained by NCI/CTEP.
• Formats, analytical algorithms, computational modeling and visualizations, and other bioinformatics tools resulting from this FOA are expected to be compatible with the NIH-approved bioinformatics platforms, such as those designed and implemented by the NCI Center for Bioinformatics platforms (https://cbiit.cancer.gov/data-sharing).
• The data sharing plan is expected to address procedures ensuring that claims of treatment agent activity are accurate and reliable (e.g., by establishing an independent response review panel).

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:

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

Delayed Onset Study

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

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

Both Renewal and New Applications must add and complete the Delayed Onset Study record and must check the box "Anticipated Clinical Trial?".

Enter "Multiple Delayed Onset Studies" as the title of the delayed onset record.

Justification Attachment: Indicate that clinical trials will be designed and conducted by the ETCTN LAO and AOs during the project period. Each clinical trial protocol developed will be subject to a standardized NCI CTEP approval procedure that involves an initial concept, Letter of Intent, and protocol approval. If the concept and Letter of Intent receive approval, the next step will be to develop a full clinical protocol, which will be subject to review and approval by NCI/CTEP and the NCI Central Institutional Review Board (CIRB) prior to activation in the ETCTN.

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

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

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

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

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

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

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

Important reminders:

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

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

See more tips for avoiding common errors.

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

Many NIH ICs encourage the use of common data elements (CDEs) in basic, clinical, and applied research, patient registries, and other human subject research to facilitate broader and more effective use of data and advance research across studies. CDEs are data elements that have been identified and defined for use in multiple data sets across different studies. Use of CDEs can facilitate data sharing and standardization to improve data quality and enable data integration from multiple studies and sources, including electronic health records. NIH ICs have identified CDEs for many clinical domains (e.g., neurological disease), types of studies (e.g. genome-wide association studies (GWAS)), types of outcomes (e.g., patient-reported outcomes), and patient registries (e.g., the Global Rare Diseases Patient Registry and Data Repository). NIH has established a Common Data Element (CDE) Resource Portal" (http://cde.nih.gov/) to assist investigators in identifying NIH-supported CDEs when developing protocols, case report forms, and other instruments for data collection. The Portal provides guidance about and access to NIH-supported CDE initiatives and other tools and resources for the appropriate use of CDEs and data standards in NIH-funded research. Investigators are encouraged to consult the Portal and describe in their applications any use they will make of NIH-supported CDEs in their projects.

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

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

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

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 particular announcement, note the following:

The overarching goal of this FOA is to maintain and enhance a state-of-the-art network for early phase clinical trials that will accelerate the development of NCI-IND anticancer agents. In this context, assessment of applications under this FOA should take into account institutional capacities to reach the accrual goal, professional experience, and clinical science expertise. Evidence of a strategic plan and institutional commitment to assure accrual to phase 2 studies is a priority.

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

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

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

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

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

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

Specific to this FOA: How strong is the PD(s)/PI(s) and key personnel expertise and experience in the incorporation of biomarkers into early clinical trials? Can the PD(s)/PI(s) contribute, in a significant way, to the development of clinical trials in rare or uncommon molecularly defined subsets of patients as well as disease specific subsets of patients? Are the proposed leadership and governance structure and interactions among key investigators optimal for designing, implementing, conducting and monitoring early phase multi-disciplinary, multi-institutional clinical trials in a range of cancer types and special populations with diverse scientific strategies? Does the applicant team have the appropriate level of experience in performing independent response auditing? How productive were the applicants in terms of the timeliness of the development, implementation, and completion of early phase clinical trials? Can the contributions of the Disease-focused Clinical Investigators, as proposed, significantly advance the goals of the ETCTN?

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

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

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

Does the application adequately address the following, if applicable?

Study Design

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

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

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

Data Management and Statistical Analysis

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

Specific to this FOA: Will the strategies, as proposed, introduce appropriate novel anticancer agents into oncology clinical trials in a timely, safe, and efficient manner? Are procedures to monitor and analyze the data sufficiently rigorous in terms of the safety of patients/participants? 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? Does the application demonstrate adequate procedures to review, analyze, and report data on serious and expedited adverse events? Are plans for the dissemination of the clinical trial results (including peer review publications) robust? Does the applicant demonstrate a sufficient ability to analyze and report on specimens from molecular characterization studies?

Does the applicant demonstrate the potential to overcome critical barriers for robust accrual for ETCTN trials across disease areas, including trials in rare cancers and for special populations, including minority and/or underserved populations?

Does the proposed organization adequately ensure monitoring the performance of the affiliated clinical sites (AOs) in an ongoing manner? Does the application state or reference adequate procedures to assure the safety of patients/participants?

Does the application demonstrate adequate procedures to review, analyze, and report data on serious and expedited adverse events??

Relevant Capabilities and Past Performance

Does the applicant’s plan to increase the overall enrollment of underrepresented populations in ETCTN studies have the potential to be successful?

Coordination of Clinical Trials and Associated Activities

Do the applicants have suitable procedures to ensure Good Clinical Practice and regulatory compliance for all aspects of a clinical trial? Are the activities to maintain the proficiency of institution personnel in the management of early phase clinical trials (including relevant training)

clear and sufficient?

Biomarker Assays and Molecular Characterization

Are the proposed plans for collaborating with NCI central labs and resources to incorporate biomarker assays sufficient in terms of state-of-the-art quality and an understanding of the role and importance of such studies in oncologic drug development?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address

1) the protection of human subjects from research risks, and

2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

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 to this FOA

Do the resources, facilities, and equipment for research pharmacy management demonstrate a regulatory compliant environment? Do the geographic location and institutional environment(s) impact the integration, communications, and specimen transfer between the ETCTN LAOs and AO sites?

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 categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

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

Inclusion of Women, Minorities, and Individuals Across the Lifespan

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

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

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

Not applicable

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

Not applicable

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 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 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 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. A programmatic priority may be given to applications that have particularly strong evidence for patient accrual capabilities, a strategic plan to assure the accrual to phase 2 studies at the required minimal levels or higher and the ability to acquire biopsy specimens suitable for analysis of biomarkers proposed in individual clinical trials.

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 https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-individuals/section-1557/index.html; and https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.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 U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75, 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’s 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, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

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

• Establishing an overall research strategy for ETCTN early phase clinical trials as well as all key components related to the conduct of approved clinical trials;
• Overseeing the development, with CTEP assistance, of appropriate early phase experimental therapeutic clinical trial protocols;
• Ensuring that the UM1 awardee performance benchmarks are met including specifically:
• Accrual of at least 100 patients to ETCTN early phase clinical trials annually (total accrual at all institutions participating in a given UM1 ETCTN award, i.e., LAO and AOs involved);
• At a minimum, having at least six Letters of Intent (LOIs) approved for protocol development annually;
• Approximately 30% participation in the ETCTN by accruing to ETCTN clinical trials not led by the awardee’s own LAO or AO institutions, participation in Project Teams, and attending ETCTN meetings;
• Ensuring that senior investigators, including Disease-Focused Clinical Investigators, clinical investigators, interventional radiologists, research pathologists, and others as applicable lead and/or participate in multidisciplinary scientific teams during the development and implementation of the ETCTN Drug Development Plans and proposals.
• Ensuring that each Disease-Focused Clinical Investigator:

a. is responsible for developing, opening, and supervising ETCTN studies within their

discipline at their institution and at other institutions in the proposed LAO(s) and AO(s)

b. opens a minimum of six ETCTN trials per year at LAO and AO sites

c. accrues in their discipline a minimum of 10 patients per year to ETCTN disease specific

clinical trials

• Ensuring each site has a clinical investigator with phase 1/phase 1 combination expertise.
• Ensuring the Interventional Radiologist performs risk assessments and obtains high quality research biopsies
• Ensuring the Research Pathologist reviews the quality of biopsy specimens and assists in biomarker assay development.

Additional requirements regarding commitments of Senior/Key Persons that must be maintained during the Project Period:

• The LAO and AO(s)PD/PI must commit a minimum of 1.2 calendar months (CM) of effort per year.
• Each LAO is required to have one Translational Scientist, one Interventional Radiologist, one Research Pathologist, and four Disease-Focused Clinical Investigators.
• Each AO is required to have one Interventional Radiologist and two Disease-Focused Clinical Investigators.
• The designated Disease-Focused Clinical Investigators, Translational Scientist, Interventional Radiologist and Research Pathologist are expected to commit a minimum of 0.6 calendar months of effort per year.
• Disease-Focused Clinical Investigators should be either the site Clinical Trial PI or Co-Investigator.
• LAO PD/PIs and AO site PD/PIs may serve also as Disease-Focused Clinical Investigators.
• Disease-Focused Clinical Investigators may be early career clinical investigators with senior mentorship support.

Other Requirements

Pharmacokinetic assays are required for ETCTN clinical trials and will be assigned to one of the two U24 funded ETCTN Pharmacokinetics Reference Laboratory. Assays used for patient selection, stratification, or determination of treatment must be performed in a CLIA-certified laboratory and may be subject to FDA oversight as an Investigational Device Exemption (21 CFR 812).

In addition, as appropriate, each awardee is expected to utilize various biospecimen, biomarker and pharmacodynamic resources developed through the NCI.

The awardee is responsible for ensuring that the NCI CIRB will be the IRB of record for all studies conducted in the ETCTN.

A trans-ETCTN Biospecimen Working Group (EBWG) will be established. ETCTN Translational Scientists, Interventional Radiologists and Research Pathologists are expected to form the EBWG for the acquisition of high quality research specimens. Each Translational Scientist, Interventional Radiologist and Research Pathologist will be required to attend EBWG meetings.

Required Systems Use: The investigator(s) will be required to use systems developed and maintained by NCI/CTEP. These systems are the Clinical Trials Monitoring System (CTMS), Cancer Trials Support Unit (CTSU), Identity and Access Management (IAM), Cancer Therapy Evaluation Program Enterprise (CTEP Enterprise), Medidata Rave (Theradex version), Technical Resources International (TRI), Oncology Patient Enrollment Network (OPEN), the NCI Early Phase Central Institutional Review Board (CIRB), the CTEP Adverse Event Expedited Reporting System (CTEP AERs), ETCTN BioRepository (Nationwide Children s ETCTN Biorepository and Accessioning Center), and WebReporting for aggregated Adverse Event analysis. See: https://ctep.cancer.gov/initiativesPrograms/etctn_infrastructure.htm.

Required Registration: For clinical study participation, site Clinical Investigators and all site Sub-Investigator research staff must register with the NCI and re-register annually using the Registration and Credential Repository (RCR) see: https://ctep.cancer.gov/investigatorResources/default.htm#guidelines_policies

Staff must maintain an applicable, active person-registration status by submitting required documentation necessary for NCI to qualify research site personnel and to be added to the corresponding site roster in Regulatory Support Services (RSS) to allow for participation in the clinical investigations and to access all CTEP and CTSU websites and applications. Documentation submission requirements for qualifying personnel per person registration type are outlined on the CTEP website (https://ctep.cancer.gov/investigatorResources/default.htm).

ETCTN UM1 awardees must comply with the rules for the conduct of clinical research summarized in the following documents:

• 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 https://ctep.cancer.gov/investigatorResources/docs/InvestigatorHandbook.pdf; and
• NCI Guidelines for Monitoring The Experimental Therapeutics Clinical Trials Network (ETCTN) and Other Early Phase CTMS-Monitored Studies at https://ctep.cancer.gov/initiativesPrograms/docs/ETCTN_Monitoring_Guidelines.pdf.

Awardees will retain custody of and have primary rights to the data and software developed under these awards, 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.

Custody of and primary rights to the data and software developed under these awards is subject to Government rights of access consistent with current DHHS, PHS, and NIH policies. 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.

Awardees are permitted 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 awards 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/html5/section_8/8.3_management_systems_and_procedures.htm.

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. All key components of the ETCTN must report Program Income to the NCI on an annual basis (in the non-competitive Type 5 application (Research Performance Progress Report (RPPR)) 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 contact PD/PI and all other PDs/PIs, as well as other senior investigators, will become members of the IDSC and will be required to attend all IDSC meetings.

The ETCTN UM1 awardees will be responsible for implementing and maintaining the NIH Genomic Data Sharing Policy, as well as assuring that an Institutional Certification is requested from the CIRB for any study performing molecular characterization or genetic analysis.

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

Designated NCI Program Director(s) and Medical Officers will have substantial involvement as a Project Scientists. IDB personnel fill the award administrative roles of the ETCTN, and IDB physicians facilitate and monitor ETCTN trials for safety to serve NCI’s responsibility as the sponsor of ETCTN studies.

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:

• Working with ETCTN Awardees to collaboratively manage issues associated with their participation in the conduct of clinical trials across the Network;
• Working as and performing the roles and responsibilities as the agent(s) sponsor as defined in the Code of Federal Regulations;
• 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;
• Reviewing accrual and overall performance of ETCTN clinical trials by site(s);
• Reviewing compliance with applicable regulations for clinical research involving human research participants;
• Advising awardees concerning mechanisms established for quality control of therapeutic and diagnostic modalities used in ETCTN clinical trials;
• Monitoring the progress and performance of the key components of the ETCTN;
• The NCI ETCTN Program Official will periodically evaluate the actual patient accrual to ETCTN studies. The actual patient accrual will be the basis for the release of respective funds for "Patient Enrollment Costs" (see Section IV);
• NCI Leadership and NCI CTEP staff will review proposals from ETCTN investigators for correlative studies to enhance clinical trials and recommend approved studies for funding consideration;
• Facilitating approval of ETCTN LOIs and protocols;
• Reviewing all records related to awardees performance under the award for appropriate collection, review, and distribution of biospecimens collected in association with ETCTN trials:
• Assisting in the coordination of the IDSC and PD/PI participation.

The NCI reserves the right to reduce the budget or withhold an award in the event of substantial awardee underperformance or other substantial failure to comply with the terms of award.

Areas of Joint Responsibility include:

Experimental Therapeutics Clinical Trials Network. PDs/PIs of the ETCTN, NCI ETCTN Program Director(s)/Official(s), CTEP Medical Officers, and designated NCI staff will be members of the Experimental Therapeutics Clinical Trials Network. As part of the ETCTN, all members will:

• Develop appropriate early phase experimental therapeutic clinical trial protocols.
• Participate as active team members on drug development project teams led by IDB Medical Officers. They 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 drug development plans.
• Discuss and resolve any issues raised during the initial review of letters of intent
• Collaborate 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.
• Address other programmatic responsibilities jointly, as needed, by the ETCTN awardees and the NCI staff.
• General aspects of collaboration on study development and conduct especially with respect to compliance with federal regulations for clinical trial research (e.g., ensuring that when new avenues of cancer therapy involving investigational drugs are pursued, trials are designed, when appropriate, such that the clinical information obtained would be acceptable to the FDA for inclusion in a potential licensing application), conduct of Data and Safety Monitoring Boards (DSMBs) for randomized phase 2 trials and other trials with clear licensing potential, development of collaborative trials and international trials, collective management of the ETCTN.
• Review of recommendations from the NCI Clinical Trials and Translational Research Advisory Committee (CTAC) on strategic directions for the ETCTN Program
• PDs/PIs, including contact PDs/PIs, multiple PDs/PIs, co-investigators, will meet on a frequent basis to scientifically and financially manage the award. The cooperative agreement may function as a single institution or a consortium consisting of the contact PD/PI and all other PDs/PIs. For early phase trials the meetings should occur weekly or more frequently if necessary, and on an ad hoc basis to review all ongoing patients and trials. Later phase studies should be managed every other week or less frequently, depending on the complexity of the planned clinical investigation. This ETCTN coordination committee/team will be charged with the safe conduct of clinical trials based on Good Clinical Practice principle and will assure that all regulatory requirements and reporting are fully met for all trials they are conducting. The NCI monitors and audits all these trials in their position as IND sponsor. The ETCTN coordination team will be responsible for reviewing all trials open in the ETCTN that they accrue to which are open at their institution and that appropriate disease specific experts are identified to champion all disease specific phase 1 and 2 trials. This group along with the study PDs/PIs are required to work collaboratively with NCI Program staff to assure that competitive proposals are discussed and submitted to CTEP for review and decision.

The Investigational Drug Steering Committee (IDSC) is a body convened by the NCI Coordinating Center for Clinical Trials (CCCT). The characteristics and activities of IDSC are outlined below.

• The IDSC is constituted by the CCCT to include the following membership: 2 elected chairs, all cooperative agreement contact PD/PIs and other multiple PDs/PIs, ETCTN coordinators who liaise with the NCTN Groups, subject matter experts in the areas of biomarkers, molecular characterization, statisticians, pharmacologists, radiation oncologists, interventional radiologists, research pathologists and others added ad hoc based on need and expertise. Leadership of the trans-ETCTN Biospecimen Working Group (EBWG) will become members of the IDSC.
• The IDSC has a coordination team (CT) consisting of 2 leaders elected from the membership of the IDSC, the NCI Program Director of the ETCTN, the Branch Chief of the Investigational Drug Branch, and other CT leaders.
• The main goal for IDSC is to facilitate ETCTN collaborations and provide scientific and technical expertise related to experimental therapeutics development.
• The IDSC will work in concert with CTEP and the ETCTN Program Director to 1) further the goals and objectives to treat, control, and cure cancer, 2) clinically evaluate investigational agents with an emphasis on translational research to elucidate molecular targets and mechanisms of drug effects, 3) provide advice during all phases of drug development, and 4) facilitate scientific dispute resolution.
• The IDSC will meet at least quarterly.

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 representatives chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two panel members. 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.

In addition to these regulations for dispute resolution, the NCI Coordinating Center for Clinical Trials (CCCT) IDSC has a specific appeals process in place to adjudicate decisions regarding LOI disapproval for ETCTN study proposals. DCTD/CTEP/IDB has in place policies and procedures for the management of investigators who fail to meet the terms of award including performance improvement plans, corrective action plans, and procedures to move to close-out for non-compliance with the terms of award.

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.

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Contact Center Telephone: 800-518-4726
Email: [email protected]

For general inquiries related to ETCTN management and clinical trials, contact

S. Percy Ivy, M.D.
National Cancer Institute (NCI)
Telephone: (240) 276-6107
Email: [email protected]

For inquires related to scientific aspects, contact

Fernanda Arnaldez, M.D.
National Cancer Institute (NCI)
Telephone: (240) 276-5652
Email: fernanda.[email protected]

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

Shane Woodward
National Cancer Institute (NCI)
Telephone: 240-276-6303
e-mail: [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.