Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Cancer Institute (NCI)
Funding Opportunity Title	NCI Experimental Therapeutics-Clinical Trials Network with Phase 1 Emphasis (ET-CTN) (UM1)
Activity Code	UM1 Multi-Component Research Project Cooperative Agreements
Announcement Type	Reissue of RFA-CA-07-031
Related Notices	March 15, 2013 - See Notice NOT-CA-13-007. Notice of Pre-Application Teleconference Meeting.
Funding Opportunity Announcement (FOA) Number	RFA-CA-13-006
Companion Funding Opportunity	Not Applicable
Number of Applications	Only one application per institution may be submitted in response to this FOA; see Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.395
Funding Opportunity Purpose	The purpose of this Funding Opportunity Announcement (FOA) issued by the National Cancer Institute (NCI) is to support an experimental therapeutics clinical trials program through the creation of a consolidated, integrated NCI Experimental Therapeutics-Clinical Trials Network (ET-CTN). This FOA solicits UM1 cooperative agreement applications for multidisciplinary groups that will conduct early phase experimental therapeutics clinical trials. Members of the ET-CTN will work on investigational agent-specific trans-network project teams to define the drug development plan, and to conduct experimental therapeutic clinical trials filed to the Investigational New Drug (IND) applications by NCI’s Division of Cancer Treatment and Diagnosis (DCTD), Cancer Therapy Evaluation Program (CTEP). The ultimate purpose of the ET-CTN is to define better approaches to the development of novel anticancer agents that capitalize on the ability to characterize tumors molecularly and find appropriate biomarkers to select patients most likely to respond to specific agents. The clinical trials to be conducted by the ET-CTN are intended to provide the dose, schedule, and early evidence of activity that will help guide disease-specific clinical trials to be conducted by the National Clinical Trials Network (NCTN), which will focus on controlled, randomized, Phase 3 trials.

Posted Date	February 8, 2013
Letter of Intent Due Date(s)	March 23, 2013
Application Due Date(s)	August 23, 2013
AIDS Application Due Date(s)	Not Applicable
Scientific Merit Review	October - November 2013
Advisory Council Review	January 2014
Earliest Start Date	February 2014
Expiration Date	August 24, 2013
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the PHS 398 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. While some links are provided, 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.

Looking ahead: NIH is committed to transitioning all grant programs to electronic submission using the SF424 Research and Related (R&R) format and is currently investigating solutions that will accommodate NIH’s multi-project programs. NIH will announce plans to transition the remaining programs in the NIH Guide to Grants and Contracts and on NIH’s Applying Electronically website.

Part 1. Overview Information
Part 2. Full Text of 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 transform the NCI-sponsored cooperative experimental therapeutics clinical trials program from a series of separate organizations conducting early phase cancer treatment trials into a consolidated, integrated NCI Experimental Therapeutics-Clinical Trials Network (ET-CTN). Members of the ET-CTN will work on investigational agent-specific trans-network project teams to define the drug development plan, and conduct experimental therapeutic clinical trials for agents with Investigational New Drug applications (INDs) held by the NCI Division of Cancer Treatment and Diagnosis (DCTD), Cancer Therapy Evaluation Program (CTEP, http://ctep.cancer.gov/).

The clinical trials to be conducted by the ET-CTN are intended to provide the dose, schedule, and early evidence of therapeutic activity including "proof of concept", "proof of mechanism", and target engagement/inhibition that will help guide disease-specific trials to be conducted under other NCI-supported programs, including the National Clinical Trials Network (NCTN) which will focus on controlled, randomized, Phase 3 clinical trials.

The NCI will facilitate formation of multi-institutional, multi-disciplinary project teams to establish a development plan for a series of trials for each novel agent to answer important questions. A drug development plan for each agent will be evaluated by the Investigational Drug Steering Committee (IDSC) run by the Coordination Center for Clinical Trials (CCCT) out of the Office of the Director. The IDSC is composed of ET-CTN contact PDs/PIs (awardees), subject matter experts, NCTN representatives, statisticians, pharmacologists, and NCI staff members with expertise in optimal early drug development. NCI representatives serve as non-voting liaisons. Emphasis will be placed on understanding and assessing both the molecular target(s) of the agent being studied as well as developing appropriate biomarker assays to select patients whose tumors are most likely to respond to the agent. The ET-CTN will focus on the pharmacokinetics (PK)/pharmacodynamics (PD), biomarker assays, and molecular characterizations of the majority of patients enrolled on its clinical trials, with an initial emphasis on genomic evaluation. Drug development will include assays for PD to define target engagement by the investigational agent. Investigators will collaborate with each other and with NCI staff to achieve ET-CTN objectives. The projects outlined in the drug development plan will be submitted as protocols for final approval to CTEP’s Protocol Review Committee (PRC). The ET-CTN will efficiently perform trials with new anticancer agents in compliance with the timelines established by the Operational Efficiency Working Group (OEWG).

ET-CTN members, sites, and selected external participants will have the opportunity to enroll patients on all trials conducted by the ET-CTN, irrespective of the specific ET-CTN site leading the trial. All participating sites will be responsible for monitoring and reporting patient safety information throughout the conduct of their clinical trials. NCI will provide standardized central operational, regulatory, and administrative support including data management, trial registration, and Central Institutional Review Board (CIRB) review for approved, early phase trials.

The goals of the ET-CTN include:

• Evaluation of innovative cancer treatments consistent with national priorities for developmental therapeutics clinical cancer research using a coordinated, collaborative, and inclusive team-based approach for generating ideas for early phase experimental therapeutic clinical trials.
• Prioritization of clinical trials that are designed to answer important questions relevant to the development of specific agents as well as assuring that the trials are not duplicative of research funded by industry or other sources.
• Efficient and timely activation and conduct of clinical trials that meet all regulatory requirements.
• Effective integration of preclinical findings into ET-CTN trials along with acquisition of human samples for correlative laboratory studies.
• Collaborations among institutions and investigators with expertise in various medical specialties and research areas (e.g., molecular characterization, pharmacology, cancer biology, clinical oncology, imaging) relevant to treatment of cancers in adults.
• Enhanced emphasis on career development and mentored training of junior investigators.

NCI's early therapeutics development program funds and oversees clinical development of new agents. The program has:

• Sponsored approximately 200 investigational agent combination clinical trials (147 since 2001). These combinations include 41 new molecular entity (NME)/NME combinations.
• Used new technologies to allow rapid, deep sequencing assessment of DNA mutations, methylation patterns, and gene expression profiles in human tumor samples.
• Conducted studies with genetically defined tumor subtypes to optimize potential benefit to patients and to facilitate characterization of drug effect on the putative target.
• Defined dosing and dose modification licensing recommendations for patients with hepatic and renal dysfunctions.
• Evaluated drug/drug interactions in patients with HIV-associated malignancies receiving Highly Active Antiretroviral Therapy (HAART).

This program has been designed and implemented to ensure that: (1) early phase clinical trial designs can accommodate new therapeutic approaches; (2) early phase clinical trials are conducted safely and efficiently; and (3) potential doses and schedules are determined for use in patients in clinical trials to evaluate agent combinations and/or for Phase 2 testing. NCI currently sponsors 85 early phase clinical trials with novel agent combinations. Approximately two-thirds of the Phase 1 combination studies listed in ClinicalTrials.gov and in published literature have been conducted in the NCI Phase 1 program, which performs only cancer-relevant studies.

Through this program, the NCI promotes exploration of scientifically important clinically-relevant questions in areas that: (1) are not the primary focus of pharmaceutical companies; (2) involve investigational agent combination studies; (3) are aimed at maximizing target inhibition; (4) are aimed at abrogating signaling through parallel and complementary pathways in cancer cells; and (5) molecularly characterize patients tumors to further elucidate mechanisms of therapeutic response and/or resistance.

Through NCI’s Experimental Therapeutics Program, 540 INDs for investigational agents have been filed since 1972. CTEP currently holds approximately 100 INDs for investigational oncology agents which involve 60 pharmaceutical/biotechnology collaborators. CTEP prepares and submits approximately eight to fifteen IND applications to the Food and Drug Administration (FDA) each year. Agents under evaluation include small molecules, antibodies, vaccines, targeted toxins, oligonucleotides, and gene transfer agents.

In recent years, there have been unprecedented increases in the accumulation of data on mutations, epigenetic changes, and other "-omics" aspects with potential significance for various oncogenic molecular pathways. This new information has led to the realization that assessing various cancer-relevant molecular abnormalities is essential for optimal and efficient development of targeted agents designed to exploit specific abnormalities in the therapeutic context. Combination studies with molecularly targeted agents have become an increasingly high priority for NCI, based upon evidence that resistance to initially effective single agents often develops quite rapidly in many adult tumors.

Overview of the Coordination of the Experimental Therapeutics Clinical Trials Network. To address the new opportunities and challenges in the development of novel targeted cancer therapeutics, the NCI has established a systematic approach with several interacting functional components. The NCI Experimental Therapeutics Program (NExT) 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 will form an NCI Project Team from the various clinical, translational, and basic biology programs at NCI. Members of the Project Team will draft a preliminary drug/biomarker/assay development plan. Once this plan is reviewed and approved by the NCI Senior Advisory Committee (SAC), part of the NeXT-approved process, NCI will send out a request for Project Team Applications (PTAs) to the ET-CTN members, awardees of the NCI Phase 2 Contracts Program, NCTN awardees, and other appropriate investigators. The request for PTA will include publically available information about the drug being developed and the types and focus of the clinical trials being considered in the preliminary drug/biomarker/assay development plan. Once the PTAs 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 (LPOs), defined below, of the PTAs that have been approved as well as other relevant subject matter experts. This Drug X Project Team will be charged with refining the drug/biomarker/assay development plan for a team presentation to the IDSC. Following IDSC evaluation, the drug/biomarker/assay development plan will be finalized by the 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 and submitted to DCTD/CTEP for final approval before activation.

NCI Organizational Groups Involved in the Early Experimental Therapeutics Clinical Trials Network

Several NCI organizational groups (branches/programs/services) will have important supporting roles in carrying out the research goals of the ET-CTN. The ET-CTN will be expected to interact as appropriate with such NCI branches/programs/services as: CTEP, Biometric Research Branch (BRB), Cancer Diagnosis Program (CDP), Cancer Trials Support Unit (CTSU), Central Institutional Review Board (CIB), Clinical Data Management System (CDMS), Clinical Trials Branch in the Cancer Imaging Program( CIP), Clinical Trials Monitoring Service (CTMS), Oncology Patient Enrollment Network, and Regulatory Support Service

For the context of this FOA, several terms are used in specific meaning as defined below.

Terms related to the organization of ET-CTN:

• Lead Academic Organization (LAO): the institution receiving the award under this FOA. A 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. For multiple PDs/PIs applications, an Affiliated Organization is defined as academic sites led by the designated multiple PDs/PIs on the application, other than the LAO institution.
• ET-CTN sites: the institution receiving the award under this FOA (also referred to as Lead Academic Organization, LAO) plus any entities collaborating with the LAO under subcontractual/consortium arrangements (also referred to a Affiliated Organizations, AOs) and parts of a LAO that represent the same legal entity, even if their location is different from the main location of the awardee (referred to as LAO integrated components).
• Lead Protocol Organization (LPO): An LPO is the institution of the investigator who leads the clinical trial.

Other terms related to the ET-CTN

• Project Team Applications (PTA): A PTA is an application submitted in response to an NCI request that proposes projects, identifies an LPO(s) and project team members, and states capabilities.
• Biomarker: a biomarker is a validated indicator of a specific molecular disease state.
• Correlative biomarker: a correlative biomarker is a validated biomarker with predictive and/or prognostic significance indicative of treatment outcome.
• Integral biomarker assay: an analytically and clinically validated assay that must be performed on each subject as a condition of entry into the clinical trial. Assay 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/).
• Integrated biomarker assay: this assay is done on most patients, but results will not be used for the treatment of that patient on the trial. Results usually used to validate hypotheses, and analyzed after the trial
• Proof of principle studies (for target effects): such studies are done to demonstrate that an investigational agent hits its intended target and has its expected molecular effect.
• Identity Access Management (IAM): an IAM is a password, user name, and role management to support access to NCI and ET-CTN systems

This FOA will support up to 10 ET-CTN sites dedicated to new agent developmental efforts with emphasis on early phase clinical trials. ET-CTN awards will provide the major resource for rapid, efficient, systematic evaluation and determination of optimal dose/schedule for specific agents and combinations of investigational agents sponsored under CTEP INDs. ET-CTN sites will also be expected to extensively 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.

Scope of Scientific Activities. Consistent with the objectives and priorities of the ET-CTN, each proposed ET-CTN site and its investigators need to be capable of clinical research involving the following main scientific activities:

• Conducting early phase experimental therapeutic clinical trials using single or combinations of novel agents from the NCI CTEP IND portfolio. The emphasis will be on novel agents that target relevant cancer cell signaling pathways and essential cellular machinery involved in the regulation of angiogenesis, cell survival, apoptosis, proliferation, and differentiation.
• Participating on investigational agent-specific Project Teams to define the drug development plan (see details below).
• Assessing PK/PD of the studied agents and establishing relationships between the dose, schedule, exposure, and effect.
• Developing statistically appropriate clinical trial designs, including integral and integrated biomarker trials, accelerated titration, adaptive designs, and other design schemes.
• Studying special populations, including investigations involving patients with hepatic and/or renal dysfunction(s).
• Establishing safe and biologically active treatment schedules for patients with cancer.
• Obtaining mechanistic proof-of-principle data for new agents directed at novel molecular cancer targets.
• Collecting, processing, and, when appropriate, storing biospecimens for biomarker analysis.
• Evaluating data from clinical trials that involve combinations of CTEP IND agents.
• Evaluating data from related laboratory studies that assess the nature of drug-drug interactions (additive/synergistic/antagonistic).
• Evaluating translational endpoints in clinical trials of investigational agents (e.g., the levels of expression and/or activity of molecular targets and/or downstream effectors pertinent to a given agent).

Multi-disciplinary, Agent-specific Project Teams. The ET-CTN is designed to accomplish its objectives by forming multi-institutional, multi-disciplinary Project Teams, which will define early drug development clinical trials of novel drugs and/or combination therapies. All ET-CTN awardees will be expected to participate on Project Teams to define the development plans for specific novel agents/combinations relevant to their expertise and capabilities. Representatives of other NCI-supported programs will also participate on those teams. The NCI will coordinate and support logistically the formation and operation of the Project Teams. As novel agents progress from Phase 1 to Phase 2 clinical trials, investigators representing various relevant NCI-supported programs will collaborate with NCI’s Investigational Drug Steering Committee (IDSC) and its disease-specific steering committees. These Project Teams will develop novel treatments requiring molecularly guided patient selection and pathway-driven investigational combination therapies a wide variety of malignancies.

Additional NCI Support for the ET-CTN sites. The NCI/DCTD/CTEP will provide the ET-CTN awardees with standardized central operational, regulatory, and administrative support. This support will cover such activities as: data management, clinical trial registration, and Central Institutional Review Board (CIRB) review for approved, early phase trials.

Applicants responding to this FOA may include single or multiple institutions, as needed, to propose, develop, and perform early clinical trials, and to analyze the results of such trials. Each of the proposed functions of specific required organizational components for each ET-CTN site are outlined below.

Key Capabilities and Attributes of Required Components

For the outlined goals of ET-CTN, applicants responding to this FOA need to have appropriate capabilities and attributes. These aspects are defined below as key components that are expected to provide a scientific and organizational framework for the ET-CTN.

Experience in Conduct of Clinical Trials and Development of Experimental Therapeutic Agent

It is essential that investigators applying for the ET-CTN awards have considerable expertise and well documented experience and accomplishments (past performance) in the conduct of cancer clinical trials and clinical development of experimental therapeutics. This experience may be acquired through a past performance in the NCI Early Phase Clinical Trials Program with Phase 1 Emphasis. However, previous affiliation with the NCI Early Phase Clinical Trials Program with Phase I Emphasis is NOT required and all qualified applicants are encouraged to apply.

Scientific Leadership

Program Director(s)/Principal Investigator(s) (PDs/PIs) at the ET-CTN sites are expected to be national and international leaders in cancer related clinical trials of novel therapeutic agents, related clinical areas, and translational research relevant to such studies. PDs/PIs should also have documented administrative leadership experience. The emphasis is on a team science approach and the ability to establish productive collaborations among participating clinical and translational research investigators from the proposed ET-CTN site. ET-CTN awardees will be expected to interact with other ET-CTN sites as well as other relevant external programs. Each ET-CTN site will be required to establish a specific structure to oversee the conduct of early phase therapeutic clinical trials, ensure data safety monitoring, compliance with the required policies and regulations, and facilitate interactions with other ET-CTN and NCI staff.

Team Science for Project Development

Each ET-CTN site will be expected to lead and/or participate in multi-disciplinary scientific Project Teams formed during the development and implementation of ET-CTN drug development plans. This objective requires that ET-CTN investigators are highly capable of inter- and trans-disciplinary team-based research efforts, including potential for interactions with investigators from other ET-CTN sites, other NCI-sponsored programs, and NCI staff members.

Pharmacokinetic/Pharmacodynamic (PK/PD), Biomarker Assay, and Molecular Characterization of Patients

Each ET-CTN site must have the capability to support clinical trials by conducting various laboratory testing of clinical specimens as needed. In addition to the standard PK/PD determinations, the required capabilities include such aspects as: developing validated assays; using validated molecular imaging methods; ability to handle biospecimens for transfer to other ET-CTN sites or tumor banks/biorepositories; and participating in the molecular characterization of all patients enrolled on early phase therapeutics trials. The latter aspect includes the requisite expertise in acquiring fresh biopsy specimens from a high percentage of patients on trials (even if invasive procedures are required).

Coordination of Clinical Trials and Associated Activities

The research and managerial coordination component will be responsible for the organization and coordination for all aspects of clinical trials operations, implementation, and safe conduct. The administrative component shall collaborate with NCI support infrastructure to coordinate ET-CTN activities. (Key units of this supporting infrastructure are listed above in the Background section).

Research Pharmacy Management

It is essential that all ET-CTN sites have a dedicated component to conduct investigational drug pharmacy operations required to adequately fulfill obligations related to investigational agents.

Career Development and Mentored Training of Junior Investigators

Each ET-CTN site will be expected to organize appropriate career development and mentored training. The program should provide an adequate mentorship and/or training for new and junior investigators, including opportunities for trainees to lead clinical trials and participate in future ET-CTN activities and/or initiatives.

Funding Instrument	Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH staff will assist, guide, coordinate, and/or participate in project activities.
Application Types Allowed	New The OER Glossary and the PHS 398 Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	NCI intends to fund approximately 10 awards, corresponding to a total cost of $8,500,000, for fiscal year 2014. Future year amounts will depend on annual appropriations.
Award Budget	Application budgets must not exceed $850,000 total costs/year.
Award Project Period	5 years

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

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:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• 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
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Non-domestic (non-U.S.) Entities but only if based in Canada

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply but only if they are based in Canada.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply except for Canadian components.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Only U.S. and Canadian institutions are eligible to apply. Other Foreign institutions may participate in the program through collaborations with either U.S. or Canadian applicant organizations.

Applicant organizations must complete the following registrations as described in the PHS 398 Application Guide to be eligible to apply for or receive an award. Applicants must have a valid Dun and Bradstreet Universal Numbering System (DUNS) number in order to begin each of the following registrations.

• System for Award Management (SAM) must maintain an active entity registration (formerly CCR registration), to be renewed at least annually. Use the Sam.gov Manage Entity function to manage your entity registrations. See the Grants Registration User Guide at SAM.gov for additional information.
• eRA Commons

All Program Directors/Principal Investigators (PD(s)/PI(s)) must also work with their institutional officials to register with the eRA Commons or ensure their existing eRA Commons account is affiliated with the eRA Commons account of the applicant organization.

All registrations must be completed by the application due date. Applicant organizations are strongly encouraged to start the registration process at least6 weeks prior to the application due date.

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 PHS 398 Application Guide.

Provided that other all other qualification requirements are met, the PD/PI or LAO PD(s)/PI(s) may have any of the following degrees: M.D., M.D./Ph.D., D.O., or Ph.D.

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

Only one application per institution may be submitted in response to this FOA.

NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for submission:

1. To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;

2. Of an investigator-initiated application that was originally submitted to an RFA but not paid; or

3. Of an application with a changed grant activity code.

Applicants are required to prepare applications according to the current PHS 398 application forms in accordance with the PHS 398 Application Guide.

It is critical that applicants follow the instructions in the PHS 398 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 research;
• 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.
Investigational Drug Branch
Cancer Therapy Evaluation Program
Division of Cancer Treatment and Diagnosis
National Cancer Institute
NCI Shady Grove
Room 5W458, MSC 9725
9609 Medical Center Drive
Bethesda, MD 20892-9725 (for Express mail, use Rockville, MD 20850)
Telephone: (240) 276-6107
Email: [email protected]

Applications must be prepared using the PHS 398 research grant application forms and instructions for preparing a research grant application. Submit a signed, typewritten original of the application, including the checklist, and three signed photocopies in one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)

At the time of submission two additional copies of the application and all the Appendix files must be sent to:

Referral Officer
Division of Extramural Activities
National Cancer Institute
9609 Medical Center Drive, Room 7W412
Bethesda, Maryland 20892-9750 (for Express mail, use Rockville, MD 20850)
Telephone: 240-276-6390
Fax: 240-276-7682
E-mail: [email protected]

All page limitations described in the PHS 398 Application Guide and the Table of Page Limits must be followed with the following exceptions or additional requirements.

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

A. Overview of Relevant Capabilities and Past Performance 6 pages

B. Scientific Leadership & Site Organization 12 pages

C. Team Science for Project Development 6 pages

D. PK/PD, Biomarker Assays and Molecular Characterization of Patients 6 pages

E. Coordination of Clinical Trials and Associated Activities 12 pages

F. Research Pharmacy Management 6 pages

G. Career Development and Mentored Training of Junior Investigators - 6 pages

The following sections supplement the instructions found in the PHS 398 Application Guide.

The application should be assembled and paginated as one complete document in the following order:

Face Page

Description, Project/Performance Sites, Senior/Key Personnel, Other Significant Contributors, and Human Embryonic Stem Cells

Detailed Budget for Initial Budget Period

Budget for Entire Proposed Period of Support

Budgets Pertaining to Consortium/Contractual Arrangements

Biographical Sketches

Resources

Research Plan

Specific Aims

Research Strategy with the following sub-sections:

• A. Overview of Relevant Capabilities and Past Performance
• B. Scientific Leadership & Site Organization
• C. Team Science for Project Development
• D. PK/PD, Biomarker Assays and Molecular Characterization of Patients
• E. Coordination of Clinical Trials and Associated Activities
• F. Research Pharmacy Management
• G. Career Development and Mentored Training of Junior Investigators

Bibliography and References Cited

Protection of Human Subjects

Inclusion of Women and Minorities

Targeted/Planned Enrollment Table

Inclusion of Children

Vertebrate Animals

Select Agent Research

Multiple PD/PI Leadership Plan

Consortium/Contractual Arrangements

Letters of Support (e.g., Consultants)

Resource Sharing Plan

Appendix

All instructions in the PHS 398 Application Guide must be followed, with the following additional instructions for the application parts listed below.

Modify Form Page 3 of the PHS 398 to replace standard sub-sections of "Research Strategy" with the following new sub-sections:

A. Overview of Relevant Capabilities and Past Performance

B. Scientific Leadership & Site Organization

C. Team Science for Project Development

D. PK/PD, Biomarker Assays and Molecular Characterization of Patients

E. Coordination of Clinical Trials and Associated Activities

F. Research Pharmacy Management

G. Career Development and Mentored Training of Junior Investigators

Follow the current PHS 398 instructions to provide a detailed budget (direct costs) for the entire application for the first 12-month period (Form page 4) and the entire proposed project period (Form page 5).

Use Additional Form Pages 4 and 5 to provide detailed separate budget information (first year and cumulative budgets for the entire project period) for the following individual application components:

• B. Scientific Leadership & Site Organization;
• C. Team Science for Project Development;
• D. PK/PD, Biomarker Assays, and Molecular Characterization of Patients;
• E. Coordination of Clinical Trials and Associated Activities
• F. Research Pharmacy Management;
• G. Career Development and Mentored Training of Junior Investigators

Important Note on Budget: The requested budgets should take into consideration the standardized central operational, regulatory and administrative support provided by NCI. These services will be directly funded by the NCI and respective cost must not be included in the requested budgets.

The budget should include (in addition to support for scientific leadership, administrative and regulatory activities, data management and analysis, and travel, etc.) the following items:

1. Scientific Leadership and Site Organization Funds for travel. The LAO PD(s)/PI(s) will be required to travel to four IDSC meetings per year. Travel funds for two NCI/CTEP Early Drug Development (EDD) meetings per year for three representatives from the ET-CTN site (at least one of whom must be the LAO PD/PI and for two presenters for major national/international meetings should be included in the budget for Scientific Leadership.

2. PK/PD, Biomarker Assays, and Molecular Characterization Research Funds for laboratory studies (e.g., PK and PD studies) performed on specimens (e.g., blood, tumor tissue, buccal cells, etc.) obtained from participants enrolled on ET-CTN clinical trials. Include this within the PK/PD, Biomarker Assays, and Molecular Characterization of Patients budget pages. Note: Biomarker assays will be prioritized and funded separately through administrative supplements. Other biomarker assays will require other sources of funding.

Pharmacology and specimen acquisition to be allocated 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 for PK studies, tumor tissue handling and shipping to the tissue bank or pathology component, and performance of research imaging studies).

3. Coordination of Clinical Trials and Associated Activities Research Funds to be allocated 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 for PK studies, tumor tissue handling and shipping to the tissue bank, and performance of research imaging studies). Include this cost within the Coordination of Clinical Trials and Associate Activities budget pages.

The budget for early clinical trials of new anticancer agents with early-phase emphasis should include funding to be allocated to support research and development and ET-CTN 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. The cost of mailing or handling research-related patient specimens, forms, and materials should be included. Other consulting costs should be outlined.

Coordination of Clinical Trials and Associated Activities (protocol development, and statistics and data management) for the institution(s) costs 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 50 patients per year should be assumed.

4. Career Development and Mentored Training of Junior Investigators Funds (approximately 3% of the total budget request) for activities to develop junior investigators/junior faculty through mentorship and other initiatives. Junior investigator career development and mentored training costs should be addressed in the research plan in the proposed budget.

Budgets for affiliated consortium component organizations (i.e., AOs ) must be provided as individual subcontractual budget pages following the PHS 398 instructions.

In addition to standard information, provide in this section documentation of important capabilities and available resources for specific functional components of the ET-CTN LAO. Relevant information may be provided in tabular form as listed below. Applicants are strongly encouraged to use, as appropriate, table templates provided at http://ctep.cancer.gov/investigatorResources/docs/RFA-CA-13-006_TABLE_TEMPLATES.PDF.

Template Table 1. Leadership Staffing: List the staff in specific leadership positions.

Template Table 2. Completed and Ongoing Phase 1 and Phase 2 Clinical Trials: List Phase 1clinical trials that have been completed during the last 5 years and of 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. Phase 2 trial examples may be provided. A table is recommended that enumerates total actual accrual by year for each clinical trial described.

Template Table 3. Other Scientific Achievements for Clinical Trials

Template Table 4. List of PK/PD Assays and Molecular Characterizations Performed During Conduct of Early Phase Clinical Trials

Template Table 5. Summary Accrual for Screened and Treated Patients on All Early Experimental Therapeutic Clinical Trials.

Template Table 6. Summary of Letters of Intent (LOI) Submitted and Approved, and Protocols Submitted: List Phase 1 clinical trial protocol development activities during the last 5 years, including relevant dates and milestones for LOIs submitted, clinical trial protocols submitted, and clinical trials activated.

Template Table 7. Inclusion Enrollment Report: Provide data on annual patient accrual to early phase clinical trials by gender and race/ethnicity composition as for the PHS 398 Inclusion Enrollment Report form (http://grants.nih.gov/grants/funding/phs398/enrollmentreport.pdf). Group clinical trials by phase of study.

Template Table 8. Operational Timelines for Activation of Clinical Trial Proposals: List timelines for the LAO and any AOs (if applicable).

Template Table 9. Patient Accrual for Individual Clinical Trials: List actual timelines for specific steps in the clinical trial protocol development process, including accrual rate projected and achieved, total accrual, and study duration.

Template Table 10. Summary of Biomarker and Correlative Studies: List biomarker assays and other correlative laboratory studies performed on patient tissue during the previous 5 years, especially those that included surgical or image-guided biopsies.

Template Table 11. List of Procedures and Policies: List the relevant Standard Operating Procedures (SOPs) and LAO policies including, but not limited to: specimen acquisition and handling; tumor banking procedures and policy; Institutional Review Board (IRB) policies, Human Subjects Research Protections (HSRP) policies, safety, and pharmacovigilance procedures and policies, assay validation procedures, etc.

All instructions in the PHS 398 Application Guide must be followed, with the following additional instructions:

Research Strategy: The Research Strategy should consist of the following sub-sections.

A: Overview of Relevant Capabilities and Past Performance

In this sub-section, applicants should summarize their ability and experience to conduct clinical trials and experimental therapeutic agent development. Describe relevant clinical and research activities related to the development of investigational agents either held under IND in collaboration with the NCI or performed as part of other academic pursuits.

• Applicants representing current awardees of the Early Phase Clinical Trials Program: Cover in this narrative your role and accomplishments under the current award.
• Applicants previously unaffiliated with the Early Phase Clinical Trials Program: Describe experiences, accomplishments, infrastructure, capabilities, etc., relevant to the ET-CTN objectives defined in this FOA.
• Specific information to provide must include (but is not limited to) the following aspects:
• Skills and accomplishments of all PDs/PIs in overseeing clinical trials of experimental cancer therapeutics.
• Funded peer-reviewed grants that led to clinical trials or resulted in a clinical trial from hypothesis-driven research funding.
• Highlights of published results from clinical and basic research fostered by or associated with peer-reviewed grant funding.
• The ability of the investigators (documented by past performance) to collect a sufficiently high percentage of specimen samples on clinical trials with correlative science endpoints.
• Summarize accomplishments of the participants in the proposed ET-CTN site with regard to Letters of Intent (LOIs) for clinical trials submitted, LOIs approved, actual patient accrual, and annual accrual.

B: Scientific Leadership and Site Organization

In this Sub-section, describe the qualifications and experience of the scientific leadership, their plans for participating in ET-CTN activities, and the organization of the proposed ET-CTN site.

Specifically, applicants are required to address, at a minimum, the following aspects:

Scientific Leadership

• Provide a brief overview of the qualifications and experience in oncology drug development research of PD(s)/PI(s) and other key personnel at the ET-CTN site. Note that PD(s)/PI(s) are expected to be national and international leaders in the relevant areas of science and have documented administrative leadership experience.
• Outline how the PD(s)/PI(s) intend to accomplish productive collaborations between participating ET-CTN sites and other clinical and translational research investigators from their institution or from other institutions internal and external to the ET-CTN using a team science approach. Plans to ensure effective interaction, communication, and monitoring performance within the ET-CTN sites to facilitate clinical trial protocol development, safety, and timely protocol conduct. These procedures should address:
  • Accrual of adequate number of eligible patients to ET-CTN trials;
  • Timely submission of required data to Medidata Rave;
  • Observance of clinical trial protocol requirements;
  • Contributions to clinical trial protocol development and conduct;
  • Authorship in ET-CTN-related publications;
  • Participation in ET-CTN administrative and scientific committees;
  • Rapid publication of clinical trial and laboratory study results and actions to be taken when time lines for the development of abstracts and manuscripts are not met.
  • Outline plans for the Leadership to assure timely preparation, presentation, and publication of clinical trial results and research findings at international meetings and scientific journals.
  • Describe available biostatistical expertise that will be increasingly needed for ET-CTN studies, including the capabilities of the team in analyses that combine clinical endpoints with sophisticated molecular data. (Biostatisticians with expertise and experience with these types of analyses are required as a part of the leadership team.)
  • List the physician(s) responsible for patient management if the LAO PD/PI is not a practicing physician.

ET-CTN Site Organization:

• Outline the organization of the proposed ET-CTN site, including the awardee institution (i.e., LAO), any LAO Integrated Components, and any participating AOs. Address all items listed below. In addition to the narrative, provide appropriate organizational charts.
• The Leadership structure planned to oversee all clinical trials operations.
• Plans to oversee the conduct of early phase therapeutic clinical trials. Sites are expected to have the requisite statistical expertise for trial design/monitoring and coordinating patient enrollment on all clinical trials open in the ET-CTN.
• Establish an internal committee to oversee and monitor patient safety, protocol compliance, and the review of outcomes and responses.
• Describe the organizational structure and documented procedures for coordinating protocol development, including timelines and actions taken when these timelines are not met. These timelines should include LOI and protocol development, study activation, and completion, activation and submission of abstracts and manuscripts.
• Describe LAO and AO (if applicable) research capabilities, including but not limited to:
  • Abilities of the LPO to develop, write, implement, and monitor ET-CTN protocols at the AO site, and at other ET-CTN LAOs.
  • Clinical and/or basic research experience, training, time availability, research competence, and commitment to early phase experimental therapeutics program participation of the institutional PD/PI, as evidenced by past clinical research contributions and current research efforts relating to oncology early drug development.
  • Documented ability to meet the intensive data collection and regulatory requirements necessary for early phase experimental therapeutic clinical trials. Institutional data management resources and plans for utilizing these resources for timely data submission for early phase experimental therapeutic clinical trials should be described.
  • Documented ability of the LAO to accrue at least 50 patients per year and documented ability of each AO (if applicable) to accrue approximately 25 patients per year to early phase experimental therapeutic clinical trials. Provide documentation and examples of past successful cooperative interactions.
  • Availability of state-of-the-art imaging and the institutional commitment for utilizing these methodologies in the conduct of early phase experimental therapeutics studies when such imaging studies are required.
  • Clinical and laboratory areas of scientific expertise resident at the LAO and AO(s) that are applicable to oncology drug development and that the institutions are willing to utilize these areas for the conduct of early phase experimental therapeutics assays and correlative studies (e.g., PK, pharmacogenomic, and PD monitoring or imaging research studies, laboratories that meet Clinical Laboratory Improvement Amendments [CLIA] standards.
• Outline plans for an internal ET-CTN site committee, including its anticipated composition. It is expected that such an internal committee will generally facilitate interactions of member site investigators. The internal ET-CTN site committee should be able to review progress and treatment-related toxicities, establish priorities, and plan future clinical trial research activities.
• For multi-institution applications, provide evidence of well-established collaborations, clearly described procedures, and a strong justification for multi-institution participation. Include a description of the criteria used to select AOs. Multiple institution applications should provide evidence of a detailed governance plan indicating how scientific and fiscal decisions are made.
• Outline institution commitment to facilitate participation in ET-CTN clinical trials for patients desiring participation.

C: Team Science for Project Development

ET-CTN sites will be expected to lead and/or participate in multi-disciplinary scientific teams during the development and implementation of ET-CTN drug development plans. In this section, describe relevant experience of the applicant team in the conduct and management of team science projects. Address plans with regard to such aspects as:

• Promoting cooperation between investigators across disciplines, and developing preclinical projects that will guide clinical agent development.
• Enhancing existing capabilities and adapting new approaches to reach collaborative team goals by leveraging expertise within and across institutions.
• Procedures for addressing failure by investigators and/or institutions to meet study timelines and objectives.
• Assessing clinical results and defining scientific criteria for subsequent prioritization of agent development.

Provide an example of an inter- and trans-disciplinary team project focused on early drug development (ongoing or previously completed). The example should demonstrate cooperation and coordination among investigators across disciplines in the investigation of a research question in a coherent fashion. The roles for each team member and the methods and/or processes that the team utilizes to promote a team effort in answering complex research challenges should be clearly articulated. These activities should demonstrate enhancements of existing capabilities and new approaches to reach the goals of the collaborative team.

This example may include, but is not limited to, the description of activities such as:

• Research topic selection;
• Identification and integration of scientific collaborators;
• Definition of leadership responsibility;
• Decision-making authority;
• Project coordination;
• Communication within the team;
• Data access;
• Resource management;
• Conflict resolution;
• Guidelines implemented for authorship;
• Management of intellectual property (IP);
• Collective management.

The example to be provided is for purposes of peer review only. There is no expectation that the project described will be implemented or funded within the ET-CTN. It will serve as a representative example of the groups ability to select and constitute a highly multi-disciplinary team project. Examples that go beyond the LAO to include organizations involved in early phase experimental therapeutics are encouraged.

D: PK/PD, Biomarker Assays, and Molecular Characterization of Patients

In this section, outline expertise in PK/PD and acquisition/analysis of clinical specimens. Describe unique molecular characterization capabilities available at ET-CTN sites that can be utilized to analyze patients on ET-CTN trials. Address such elements as:

• Conducting appropriate pharmacology studies in clinical trials.
• Participating in the molecular characterization of all patients enrolled on early phase therapeutics trials, and demonstrating the requisite expertise in acquiring fresh biopsy specimens from a high percentage of patients on trials, even if invasive procedures are required.
• Planning and implementing appropriate PD, pharmacogenomic, and imaging studies integrated with clinical trials conducted by the ET-CTN.
• Developing validated assays -- 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).
• Using validated molecular imaging capabilities as appropriate.
• Coordinating the acquisition, handling, preparation, evaluation, and shipment of specimens to ET-CTN sites and/or tumor banks/biorepositories.
• Evaluating translational endpoints in clinical trials of investigational agents (e.g., the levels of expression and/or activity of molecular targets and/or downstream effectors pertinent to a given agent).
• Analyzing tumors and specimens with genomic and expression arrays or other biomarker-based studies to define response and resistance mechanisms and to identify follow-on therapy and investigational combination treatment regimens.
• Lab-based assays or biomarkers developed into fit for purpose assays ready to be transferred to or already implemented in Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories.
• Describing approaches to development of SOPs for assay validation (molecular).
• Tissue handling and storage facilities.
• Proposed imaging methods, and timelines to incorporate imaging endpoints into the overall research program. Include the availability of adequate post-acquisition image storage, processing, and analysis capabilities.

For patient molecular characterization, applicants should describe their expertise in the acquisition and analysis of high quality clinical specimens. Describe also experience, expertise, and procedures for validating and conducting studies using genomics, expression, analysis, or other assay-driven integral biomarker evaluations such as:

• Genomic analysis of patient specimens with identification and reporting of actionable mutations;
• Expression array analysis of patient specimens, and reporting and analysis of derived data;
• Proteomic or phosphoproteomic evaluation of patient specimens during treatment, and reporting and analysis of results; and
• Assay or biomarker integral or integrated studies on patient specimens, and reporting of results.

E: Coordination of Clinical Trials and Associated Activities

Applicants should describe their experience and the proposed management of complex early phase clinical trials, including protocol development, patient accrual, data and specimen management, and compliance with regulatory statutes. Clinical trials must be conducted in accordance with the Investigator’s Handbook, A Manual for Participants in Clinical Trials of Investigational Agents Sponsored by the Division of Cancer Treatment and Diagnosis, National Cancer Institute (http://ctep.cancer.gov/handbook).

The application should address the items specified below:

Protocol Development and Clinical Trial Execution

• Procedures developed and utilized to support the timely development, activation, and completion of early phase clinical trials for adults with cancer.
• Procedures for training and maintaining the proficiency of institutional personnel in the successful management of early phase therapeutic clinical trials.
• Procedures for coordination and tracking of study modifications/amendments.
• Procedures for determination of patient eligibility and assigning drug dose level.
• Statistical support for all aspects of the ET-CTN clinical trials.
• Personnel needs to support clinical trials performed by the research project team by identifying, recruiting/affiliating, and retaining qualified personnel necessary for the conduct of clinical trials.
• Timely review and assessment of clinical trial data, and interim evaluation and consideration of measures of outcome, as consistent with patient safety and good clinical practice (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM269919.pdf).
• Facilitating member interactions and communications for single institution or multi-institution sites.

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.
• Procedures for complying with onsite auditing, including the use of Medidata Rave and a description of how auditing will be coordinated.
• Plans to establish and maintain site, investigator and associate rosters with the Cancer Trials Support Unit (CTSU).

Regulatory Compliance

• Provide a general description of the data and safety-monitoring plan as part of the research application. This policy should be consistent with NIH and NCI guidelines for data monitoring in early phase experimental therapeutic clinical trials.
• Procedures for expedited reporting of all serious and/or unexpected adverse events via Adverse Event Expedited Reporting System/Cancer Adverse Event Reporting System (AdEERS/caAERs) for investigational agents sponsored by the CTEP IND and expeditious adverse event data sharing (21 CFR part 312.32).
• Data and safety monitoring oversight for patients on all active trials, to include but not limited to:
• Reporting and monitoring safety on all trials enrolling patients at their site.
• Establish an internal committee to monitor and oversee patient safety, protocol compliance, and outcome and response review.
• Collecting and analyzing data by appropriate medical, statistical, and Clinical Research Associate (CRA) staff members.
• Providing high-quality data management using an effective quality assurance (QA)/quality control (QC) program, including internal review and oversight of data submission.
• Monitoring activities to guarantee data integrity and ample auditing.
• Performing statistical evaluations essential for the appropriate design, conduct, and analysis of all clinical trials.
• Procedures for assuring that ET-CTN investigators performing trials involving CTEP IND agents are active NCI-registered investigators and have completed and submitted all required investigator registration documents (Form 1572, Financial Disclosure Form, Supplemental Investigator Data Form and Curriculum Vitae).
• Procedures to meet Office for Human Research Protections (OHRP) requirements for the protection of human subjects, including institution assurances (Federal-Wide Assurance Number), informed consent, and CIRB reviews of protocols, amendments, and adverse events.
• Participating in an NCI-sponsored Central Institutional Review Board (CIRB).
• Conflict of Interest policy consistent with PHS requirements for ensuring there is no reasonable expectation that the design, conduct, and/or reporting of research conducted by the ET-CTN will be biased by any conflicting financial interest of an investigator.
• Procedures for complying with auditing requirements and responding expeditiously to any deficiencies identified during an audit.

Data Formats

• Data compatibility plans, including data for clinical trials. 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 (http://ncicb.nci.nih.gov).
• Procedures ensuring that claims of treatment agent activity are accurate and reliable (e.g., by establishing an independent response review panel).

Protocol templates utilized by the ET-CTN should be referenced using appropriate websites such as the CTEP website, or included in the appendix.

F: Research Pharmacy Management

Describe plans for investigational pharmacy operations to fulfill obligations related to investigational agents. Summarize the existing/implemented and planned policies and procedures regarding the following elements:

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

Infrastructure/Equipment

• Availability of secured access storage space and storage unit(s) necessary to meet storage conditions of agent(s). Maintenance of continuous proper storage conditions of agent(s) according to supplier instructions, including validation documentation such as temperature logs or temperature recordings and access to emergency back-up power supplies. Describe how temperature is monitored and with what frequency, what notification systems are in place in the case of temperature failures, how these situations are handled upon notification, and contingency plans in place for storage unit failures.
• Ability to store and segregate agents by protocol, strength, unit, formulation, and investigator.
• Adequate security of agent(s) with controlled access to authorized personnel. Limited access areas for secure and safe preparation of investigational agents.
• Accurate completion of NCI’s Drug Accountability Record Form (DARF, NIH-2564) as the primary record of all transactions related to the investigational agent(s).
• Access to appropriate primary containment equipment, personal protective equipment, and safety equipment.

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

G: Career Development and Mentored Training of Junior Investigators

A description of career development and mentored training in experimental therapeutics education and training for junior investigators (less than 7 years post oncology fellowship training) is required in this section. The proposed activities should include adequate mentorship and/or training for new and junior investigators that provides opportunities for the trainees to lead clinical trials and participate in future ET-CTN activities and/or initiatives. Training should provide opportunities to enhance skills in conducting clinical trials, skills in molecular pharmacology, and learn principles of clinical development of experimental therapeutics. Translational research ( bench to bedside and bedside to bench ) should be an integral part of these activities. Define and career development and mentored training activities in experimental therapeutics program for Junior Investigators.

The development of junior faculty through mentorship is expected to include such activities as:

• Conducting experimental therapeutics education and training for junior investigators.
• Mentoring and/or training programs for new and junior investigators.
• Providing opportunities for junior investigators to lead clinical trials, as well as participate in experimental therapeutic development activities and/or initiatives.
• Providing opportunities to enhance skill in and teach principles of experimental therapeutics.
• Integrating translational science (bench to bedside and bedside to bench) into the training/mentoring.

Describe any relevant activities and opportunities that will be available to junior investigators in the environment of the proposed ET-CTN site:

• Developing concepts for clinical trials to be proposed in the Career Development LOI.
• Including junior investigators as clinical trial study chairs.
• Providing protected time to junior faculties to perform clinical research.
• Plans for junior investigators to attend national or international meetings relevant to experimental therapeutics.
• Participation of junior investigators in scientific committees.
• Available seminar series relevant to clinical experimental therapeutics, journal clubs, etc.
• Available NIH individual education training grants.
• Relevant trainings that will be available to junior investigators (e.g., training in regulatory requirements for drugs and devices, imaging, biomarker development).
• Opportunities for post-doctoral training of junior investigators in experimental therapeutics.
• Opportunities for junior investigators to work towards additional degrees (e.g., graduate level training in pharmacology).

Protection of Human Subjects: In addition to standard items indicated in the PHS 398 Application Guide, include in this Section SOPs and policies of the proposed ET-CTN related to study monitoring, data monitoring, and conflict of interest issues.

Resource Sharing Plan

Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the PHS 398 Application Guide, with the following modifications:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
• It is expected that these plans will address data compatibility. 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 (http://ncicb.nci.nih.gov). The data sharing plan is also expected to address procedures ensuring that claims of treatment agent activity are accurate and reliable (e.g., by establishing an independent response review panel).

Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix (please note all format requirements) as described in the PHS 398 Application Guide.

• In addition, the following items are recommended for inclusion in the Appendix: two sample institutional early phase experimental therapeutic protocols activated during the preceding award period or the last 3 years, standard operating procedures (other than study, data monitoring and conflict of interest policies), and protocol and informed consent document templates.

Foreign (non-U.S.) Institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the PHS 398 Application Guide.

(Note that the only foreign institutions eligible to apply in response to this FOA are Canadian institutions.)

Part I. Overview Information contains information about Key Dates.

Information on the process of receipt and determining if your application is considered on-time is described in detail in the PHS 398 Application Guide.

Applicants may track the status of the application in the eRA Commons, NIH’s electronic system for grants administration.

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 received on or before the due dates in Part I. Overview Information. If an application is received after that date, it will not be reviewed.

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

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-10-115.

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

The overarching goal of this FOA is to bring novel anticancer agents into early therapeutic clinical trials for cancer patients. This goal requires investigators with outstanding leadership, robust infrastructure, and a strong record of conducting clinical trials. Particularly important for the clinical development of current generations of experimental cancer therapeutics is the ability to integrate clinical trials with translational approaches and additional clinical studies, including the ability to obtain and analyze PK/PD and biomarker data in all patients enrolled on all studies. Essential for ET-CTN will be the awardees' ability to work as part of a network. In this context, the important aspects are whether the applicants have assembled a team of investigators capable of conducting state-of-the-art early phase therapeutics trials and PD-pilot studies in patients with cancer, and whether they will be able to work as a coherent research team to efficiently and expeditiously conduct early phase clinical trials.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the proposed ET-CTN site 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 ET-CTN site 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 program that by its nature is not innovative may be essential to advance a field.

Significance

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

Specific for this FOA: Will the ET-CTN site, as proposed, be able to introduce appropriate novel anticancer agents into oncology clinical trials in a timely, safe, and efficient manner?

Investigator(s)

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

Specific for this FOA:

Does the project have adequate biostatistical expertise to conduct and analyze complex clinical and molecular data? How complete and comprehensive is the expertise of the PD(s)/PI(s) and the entire team of investigators assembled by the applicant(s) in terms of their ability to conduct state-of-the-art early experimental therapeutics studies in patients with cancer? How well do the research experience and qualifications of the PD(s)/PI(s) correspond to the need for multi-disciplinary capabilities (e.g., in medical oncology, radiation oncology, imaging, surgery) and across a broad range of cancer types?

Will these investigators be able to work as a coherent research team to efficiently and expeditiously conduct early phase clinical trials?

Do the PD(s)/PI(s) demonstrate the ability to facilitate collaborations between ET-CTN investigators and other clinical/translational science investigators?

Do the PD(s)/PI(s) have sustained, high-level participation in the scientific leadership of early experimental therapeutics (e.g., serving as scientific committee or protocol/trial study chairs, contributing new trial ideas including participating in LOI development, co-authoring publications on clinical trials research)?

What is the ability of the PD(s)/PI(s) to contribute in a meaningful way to the development of clinical trials in rare cancers?

How capable are the PD(s)/PI(s) of providing meaningful contributions to translational research, PK/PD, biomarker assays, and molecular characterization integral to or integrated into the ET-CTN clinical trials?

Do the PD(s)/PI(s) have adequate and appropriate experience in administering clinical trial research, including organization and management of the infrastructure required for patient recruitment/accrual, data collection, data reporting, and safety monitoring for patients enrolled on clinical trials?

Are the other key personnel appropriately trained and well suited to carry out the work associated with early clinical trials?

Is there sufficient and appropriately experienced support personnel available for the proposed ET-CTN site with the skills needed to develop, implement, and analyze early phase experimental therapeutic clinical trials?

Innovation

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

Specific for this FOA:

Do the applicants propose novel or improved ways and/or methods to enhance or better conduct early clinical trials?

Approach

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

If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?

Specific for this FOA:

Are the overall strategy, methodology, and analyses well reasoned and appropriate to accomplish the specific aims of the ET-CTN site?

How strong are the overall approaches proposed for individual components of the ET-CTN?

Do the research plans demonstrate an appropriate understanding of research opportunities in drug development and of the methodologies available to exploit these opportunities?

Environment

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

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

Relevant Capabilities and Past Performance

How strong are the applicants expertise and experience in early phase clinical trials for patients with cancer? Specifically, how adequate is this experience in terms of collection, management, and analysis of data from single institution or multi-institution clinical trials? What is the level of applicants experience in performing independent response auditing?

How productive were the applicants in terms of the timeliness of the development, implementation, and completion of recently conducted early phase clinical trials?

How accomplished are the applicants in terms of their research contributions (documented by peer-reviewed publications) to multi-institutional early phase experimental therapeutic clinical trials and dissemination of the results of such research?

Leadership, Governance, and Site Organization

To what extent are the proposed leadership and governance structure, decision-making processes, and interactions among key investigators optimal for designing and conduct of multi-disciplinary, multi-institutional clinical trials in a range of cancer types and special populations?

For applications designating multiple PD/PIs, is the leadership approach, including the designated roles, responsibilities, governance, and organizational structure consistent with the aims of the project and the expertise of each of the PD/PIs?

How well are defined the plans for an appropriate governance structure to coordinate activities related to the ET-CTN across the various disciplines and departments at the LAO institution?

Are the proposed leadership efforts and activities reasonably distributed across such areas as patient enrollment, clinical data collection and management? Are these efforts optimally balancing the various disciplines and the roles of clinical departments involved in the clinical trials at the proposed ET-CTN site)? Are these plans in line with the proposed workload and anticipated accrual to clinical trials to ensure/enhance participation in ET-CTN trials by various disciplines at the LAO?

Is the staffing plan appropriate to ensure the efficient governance of the proposed ET-CTN site?

Are the organizational plans for the LAO sufficient and optimal to ensure the LAO’s ability to develop, propose, implement, and monitor ET-CTN clinical trials?

How appropriate is the proposed organization to ensure monitoring the performance of the affiliated clinical sites (AOs) in an ongoing manner?

How adequate is the ET-CTN organization in terms of supporting other aspects of early clinical trials and related activities? How well is the organization of the proposed ET-CTN site matched to its leadership (especially for applications designating multiple PD/PIs)?

Team Science for Project Development

How strong is the potential of the applicants for team science approaches to developing and implementing ET-CTN’s early phase experimental therapeutic studies?

At what level will the proposed ET-CTN site be able to participate (and/or lead) inter- and trans-disciplinary team-based research efforts, including potential for interactions with investigators from other ET-CTN sites, other NCI-sponsored programs, and NCI staff members?

PK/PD, Biomarker Assays, and Molecular Characterization of Patients

Are the proposed plans and capabilities for incorporating PK/PD, and pharmacogenomic endpoints into the clinical trials appropriate and sufficient?

Are the proposed plans and capabilities for incorporating molecular characterization endpoints into the clinical trials appropriate? In particular, is the scope of such efforts sufficient, given the goal to include in these characterizations a high fraction of patients participating in clinical trials? Are the plans and capabilities for incorporating imaging endpoints into the ET-CTN’s overall research program sufficient? How strong is the applicants understanding of the potential of imaging studies to aid drug development?

Coordination of Clinical Trials and Associated Activities

Protocol Development and Clinical Trial Execution. How appropriate are the overall coordination efforts for ensuring timely development of clinical trial protocols and clinical trial execution? Are the measures planned to maintain the proficiency of institution personnel in the management of early phase experimental therapeutic clinical trials clearly defined and sufficient? How appropriate and adequate are the mechanisms of periodic review of QA/QC, data management procedures, and safety monitoring? Will the proposed ET-CTN site have appropriate statistical expertise and support? How appropriate are study designs for early phase experimental therapeutic clinical trials that the applicants used previously? How appropriate are statistical designs for early phase clinical trials proposed for the ET-CTN? Do the ET-CTN sites have sufficient statistical support and utilize appropriate statistical design approaches for early experimental therapeutic clinical trials?

Correlative Studies. Does the applicant demonstrate the ability to obtain, process, and store high-quality specimens? Does the applicant demonstrate the ability to analyze and report on specimens from PK/PD and/or molecular characterization studies?

Data Analysis, Quality Assurance/Quality Control, and Reporting. Are the applicants capabilities for the analyses of data from multi-institutional clinical trials sufficient for the expected scale of activities? Does the application demonstrate adequate procedures to monitor and analyze the data and assure the safety of patients/participants? Are the QA/QC procedures adequate and sufficient to ensure the accuracy, integrity, and security of clinical trials data? Does the application demonstrate adequate procedures to review, analyze, and report data on serious and expedited adverse events? Are procedures for reporting of data from early phase clinical trials to CTEP using CTMS electronic data capture system sufficiently timely and reliable? Are all the critical needs for the required regulatory compliance adequately addressed?

Research Pharmacy Management

Are the resources, facilities, and equipment for research pharmacy management (including appropriate secure storage units) sufficient and in line with all applicable regulations? Do the proposed plans adequately address the needs for proper procedures for handling of experimental agents and maintaining all associated documentation? How complete is evidence that Research Pharmacy in the proposed ET-CTN site will (a) adhere to all applicable regulations with regard to investigational agent handling, (including transport and disposal); and (b) will maintain proper documentation and record keeping, transport, etc?

Career Development and Mentored Training of Junior Investigators

Is there adequate institutional commitment to mentorship, training, and support of junior investigators in experimental therapeutics? What are the overall quality and expected effectiveness of the mentoring plans? How well do the plans incorporate the opportunities for junior investigators to learn the principles of early clinical development of experimental therapeutics and participate (or lead) relevant clinical trials, participate in scientific committees, etc? How sufficient is the intended training in translational research? How valuable are for the ET-CTN goals other training and educational opportunities available to junior investigators?

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Children

When the proposed ET-CTN site involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Human Subjects Protection and Inclusion Guidelines.

Vertebrate Animals

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

Biohazards

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

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

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

Applications from Foreign Organizations

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.

Select Agent Research

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

Resource Sharing Plans

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

Budget and Period of Support

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

How well are the applicants' budget projections aligned with the program objectives and proposed scale of operation? Are the funding allocations for PK/PD studies reasonable, appropriate, and not duplicative of other institutional funding?

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 response to this FOA.

Applications will be assigned to the NCI and 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.
• The adequacy of the resource sharing plans

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons.

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

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

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

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

Any application awarded in response to this FOA will be subject to the DUNS, SAM Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

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

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

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

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

• ET-CTN sites are expected to lead and /or participate in multidisciplinary scientific teams during the development and implementation of the ET-CTN Drug Development Plans
• Development of an overall research strategy for the development of clinical trials for the ET-CTN as well as all key components related to the conduct of approved clinical trials. The awardees programmatic responsibilities for the conduct of the clinical research supported under the Cooperative Agreements are described in the documents listed below and subsequent modifications of these documents. These documents are incorporated by reference as program-specific Terms and Conditions of Award:
  • NCI CTEP Investigator’s Handbook (Manual for Participants in Clinical Trials of Investigational Agents Sponsored by the Division of Cancer Treatment and Diagnosis, NCI) available at http://ctep.cancer.gov/handbook/index.html
  • Guidelines for Auditing of Clinical Trials for Experimental Therapeutics Clinical Trials Network (ET-CTN) at http://ctep.cancer.gov/branches/ctmb/clinicalTrials/docs/ET-CTN_Audit_Guidelines.docx.
• Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, NIH, and NCI policies and within the limits of any accepted binding NCI/NIH collaborative agreements with biotechnology and pharmaceutical partners and as governed by NCI-approved Data Sharing Plans and NCI-approved review for use of biospecimens collected in association with ET-CTN trials.
• Awardees are allowed to accept funds from non-governmental sources to support ET-CTN 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 ET-CTN) and must be reported under the Terms and Conditions of Award for the ET-CTN unless they are associated with an exempted category under the NIH grant policy for program income, available at: http://grants.nih.gov/grants/policy/nihgps_2011/nihgps_ch8.htm#_Program_Income.
• All key components of the ET-CTN must report these funds to the NCI on an annual basis (in the non-competitive Type 5 application the annual progress report) and must indicate the clinical trial that the funds are being used to support (or other functional component if the funds are not provided to support specific trials). The Terms and Conditions of Award for all the Cooperative Agreements under the ET-CTN define the operational principles under which the awardees must function to ensure the independence of the research conducted regardless of whether program income is or is not available for any of the awards.

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

An NCI Program staff member(s) acting as a Project Scientist(s) will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below. Additional NCI staff members may be designated to have substantial involvement (e.g., in the role of Project Managers). The NCI Project Scientist(s)/Managers(s) will not attend peer review meetings of renewal (competing continuation) and/or supplemental applications. If such participation is deemed essential, these individuals will seek NCI waiver according to the NCI procedures for management of conflict of interest.

Additionally, an NCI program director acting as Program Official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. Some Program Officials may also have substantial programmatic involvement (as Project Scientists/Coordinators). In that case, the individual involved will not attend peer review meetings of renewal (competing continuation) and/or supplemental applications or will seek NCI waiver as stated above.

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

• Working with ET-CTN Awardees to collaboratively manage issues associated with their participating in the conduct of clinical trials across the Network;
• Informing the PDs/PIs of scientific opportunities resulting from NCI-supported clinical research programs and facilitating collaborations between the ET-CTN and other NCI-sponsored programs;
• Facilitating scientific involvement in oncology treatment research, including advanced imaging research and radiation oncology research, associated with ET-CTN trials;
• Auditing of ET-CTN sites via their membership in the ET-CTN;
• Reviewing accrual and overall performance of ET-CTN clinical trials by the site;
• Reviewing compliance with applicable HHS, FDA, OHRP, NIH, and NCI regulations for clinical research involving human research subjects;
• Advising awardees concerning mechanisms established for quality control of therapeutic and diagnostic modalities used in ET-CTN clinical trials; and
• Monitoring the progress and performance of the key components of the ET-CTN.

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

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

Areas of Joint Responsibility

The cooperative agreement awardee shall, with CTEP assistance, develop appropriate early phase experimental therapeutic clinical trial protocols. Principal Investigators (PIs) of the ET-CTN awards, NCI ET-CTN Director(s), and CTEP Senior Investigators (Project Scientists) will be members of the ET-CTN.

ET-CTN sites will be expected to participate as active team members on drug development project teams. 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 development of drug development plans. Areas of joint responsibility include:

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

Dispute Resolution:

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

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

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

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

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

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

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone (301) 710-0267
TTY (301) 451-5936
Email: [email protected]

eRA Commons Help Desk (Questions regarding eRA Commons registration, tracking application status, post submission issues)
Phone: (301) 402-7469 or (866) 504-9552 (Toll Free)
TTY: (301) 451-5939
Email: [email protected]

S. Percy Ivy, M.D.
Investigational Drug Branch
Cancer Therapy Evaluation Program
Division of Cancer Treatment and Diagnosis
National Cancer Institute
NCI Shady Grove
Room 5W458, MSC 9725
9609 Medical Center Drive
Bethesda, MD 20892-9725 (for Express mail, use Rockville, MD 20850)
Telephone: (240) 276-6107
Email: [email protected]

Referral Officer
Division of Extramural Activities
National Cancer Institute
9609 Medical Center Drive, Room 7W412
Bethesda, Maryland 20892-9750 (for Express mail, use Rockville, MD 20850)
Telephone: 240-276-6390
Fax: 240-276-7682
E-mail: [email protected]

Shane Woodward
Office of Grants Administration
National Cancer Institute
9609 Medical Center Drive
West Tower, 2W462
Rockville, MD  20850
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 Parts 74 and 92.

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