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

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

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

Due to the introduction of the NIH policy, set forth in "NOT-OD-16-147," to create funding opportunity announcements (FOAs) that are specifically designed for applications that involve clinical trials, the National Cancer Institute (NCI) has established two R01 investigator-initiated clinical trials required program announcements: [this FOA, PAR-18-560] which seeks applications for support of phase 0, I, and II medical imaging and oncologic interventional clinical trials relevant to the mission of the NCI's Division of Cancer Treatment and Diagnosis (DCTD); and [PAR-18-559] which seeks applications for support of cancer prevention and control clinical trials relevant to the missions of NCI's Division of Cancer Prevention (DCP) and NCI's Division of Cancer Control and Population Sciences (DCCPS), respectively. Applicants should be aware of the types of scientific programs that each named NCI Division manages to determine the appropriate FOA for submission of applications. In addition, applicants who want to request R01 support for clinical and translational cancer research projects that do not involve clinical trials can submit their application to the "NIH-wide Parent R01 No Clinical Trials Allowed program announcement."

The purpose of this FOA is to support research projects that include and implement early phase (Phase 0, I, and II) investigator-initiated clinical trials on cancer-targeted diagnostic and therapeutic interventions of direct relevance to the research mission of the NCI's DCTD. All applications submitted to this FOA should address the mission and priorities of one or more of the following programs: the Cancer Therapy Evaluation Program (CTEP, DCTD); the Cancer Imaging Program (CIP, DCTD); the Cancer Diagnosis Program (CDP, DCTD); the Radiation Research Program (RRP, DCTD); the Office of Complementary and Alternative Medicine (OCCAM, DCTD); and also the Office of HIV and AIDS Malignancies (OHAM, Office of the Director). Applicants can learn more about the various program goals, research priorities, and strategies developed to diagnose and treat cancer by visiting the DCTD website (https://dctd.cancer.gov/) and the OHAM website (https://www.cancer.gov/about-nci/organization/oham). Applications submitted to this FOA must meet the NIH definition of a clinical trial (see NOT-OD-15-015) and provide specific clinical trial information as described in this FOA and the NIH application FORM E guidelines. To help determine if your study meets the NIH definition of a clinical trial, simply answer the questions listed on the NIH Grants & Funding website at https://grants.nih.gov/ct-decision/index.htm. Investigators who are involved in clinical trials supported through this FOA are expected to follow the NIH Policy on Good Clinical Practice (see NOT-OD-16-148). Investigators who are new to the conduct of clinical trials are welcome to apply to this FOA and participate in clinical trial research, but they are encouraged to identify appropriate mentors and to establish the right personnel compositions for the clinical trial teams.

This FOA is applicable to a broad range of clinical trial evaluations designed to improve the diagnosis and treatment of cancer in areas of common and unmet need. Each application should represent the applicant's or applicants' interest(s) and competencies, as well as the science related to diagnosis and treatment of cancer patients through well-designed and executed clinical trials. In addition, strategies to assess feasibility can include a novel area of investigation, new experimental systems, and/or existing technologies in a new area.

Although the rationale must be supported by preliminary data, the proposed clinical investigations may include study designs, methods, and interventions that are not themselves innovative but address important questions and/or unmet needs.

This FOA is applicable to a broad range of clinical trial evaluations that improve the diagnosis and treatment of cancer in areas of common and unmet need. Potential areas of research may include, but are not limited to, the clinical evaluation of new or improved anticancer drugs and biologics, including immunotherapies, new or improved imaging technologies and surgical interventions, novel approaches to radiation therapy, and incorporation of complementary medicine approaches to treatment. The research component may include the development of therapeutics, diagnostics, and devices in combination with standard of care therapies including chemotherapy, immunotherapy, surgery, radiotherapy, or any combination of these modalities.

Examples of projects appropriate to this FOA include applications with the primary intent of conducting early phase clinical trial(s) for testing the efficacy, safety, clinical management, and/or implementation of novel therapeutic or diagnostic interventions, such as drugs, biologics, vaccines, stem cells, imaging agents, imaging devices, or image-guided therapies. Applicants may, for example, propose to conduct an early phase clinical trial that:

• Evaluates the dosing, safety, tolerability, pharmacokinetics, pharmacodynamics, and effectiveness of novel anticancer drugs, biologics, immunotherapeutics (e.g., adoptive cell transfer therapies), and their combinations as well as of imaging agents or other interventions;
• Evaluates new or improved image-guided interventions, radiation modalities, means of delivery, or combinations with novel agents;
• Tests imaging probes or quantitative approaches incorporated into commercially available imaging instrumentation (e.g., positron emission tomography [PET], single photon-emission computed tomography [SPECT], magnetic resonance [MR] imaging, computed tomography [CT], ultrasound [US], optical imaging, and photoacoustic imaging [PAI]);
• Assesses imaging tools, methods, devices, and instruments that can perform at the molecular, cellular, and organ levels;
• Investigates multi-parametric imaging approaches and biomarker detection assays including radiomics, radiogenomics, genomics, proteomics, and metabolomics;
• Evaluates imaging or laboratory biomarker activity, pharmacodynamic response, target engagement, dose-response trends;
• Selects or ranks the best potential imaging interventions, technologies, and/or dosing regimens to be evaluated in a subsequent trial, based on tolerability, safety data, biological activity, or preliminary clinical efficacy (e.g., a futility trial);
• Tests approved agents and combinations for new indications;
• Conducts exploratory investigational new drug (IND) studies (see the FDA's website for information regarding FDA's Exploratory IND Guidance document); and
• Evaluates cancer treatments derived from traditional medicines or their plant sources.

Research approaches should focus on interventions with outcome measures that contribute to the improvement of knowledge regarding mechanism of action or resistance, therapeutic index, prediction of response, standard-of-care practices, and/or quality of life. Research that combines expertise in more than one clinical research area (e.g., the development of therapeutics, diagnostics, and devices) is also welcome.

Prior to submitting applications to this FOA, applicants are encouraged to consult with the Scientific/Research contacts for the area of science for which they are planning to develop an application. Early contact (at least 12 weeks prior to submission) is encouraged. This period provides an opportunity for NCI staff to discuss the scope and goals, and to provide information and guidance to the applicants.

Trials proposed must meet the NIH definition of a clinical trial (see NOT-OD-15-015) and should contribute to the advancement of evidence-based medicine/practice and the sciences that support it. Applicants may propose to conduct an early phase trial by itself, or in combination with other non-clinical trial research aims as appropriate. The FOA will support the conduct of investigator-initiated oncologic intervention research at all early stages, from early mechanistic research and intervention development (e.g., stage 0 and/or I) through implementation and cost-effectiveness research. NCI funds may be used to support single-site, multi-site, hypothesis-driven, pathway-related, exploratory/feasibility and pragmatic trials (as defined below) designed to improve the management of care for patients with cancer. The trial design should be appropriate for the hypothesis to be tested. This FOA also supports randomized phase II trials that can be performed within the temporal and fiscal limits of this program announcement. The National Institutes of Health (NIH) and Food and Drug Administration (FDA) developed a clinical trial protocol template with instructional and example text for NIH-funded investigators to use when writing protocols for phase II clinical trials that require Investigational New Drug application (IND) or Investigational Device Exemption (IDE) applications. The web-based e-Protocol Writing Tool and the template (which is optional for use here) can be found at NOT-OD-17-064. Note that phase III clinical trials are not sought by and will not be supported through this FOA (see below).

Description of the type of clinical trials that can be supported include:

• Single site clinical trial(s): Early phase trials where the protocol is implemented by one investigational site that conducts and coordinates the protocol. While a single site clinical trial may enroll participants from multiple locations/clinics within a geographic area, those participants will receive an intervention or undergo outcome assessments under the direction and oversight of one research team at one investigational site.
• Multi-site clinical trial(s): Early phase trials that recruit study subjects from two or more geographically distinct enrollment sites, or centers. The sites are usually distinct in other characteristics (e.g., demographic, socioeconomic, or clinical). Study protocols are followed at these sites.
• Mechanistic clinical trial(s): Hypothesis-driven interventional studies (i.e., early phase trials) focused on basic and/or translational discovery research on the biology and pathobiology of cancer.
• Feasibility clinical trial(s): Early phase trials that propose to break new ground and/or extend previous discoveries toward new directions and/or applications.
• Pragmatic trial(s): Early phase trials that test an intervention under the usual clinical conditions in which it will be applied, while explanatory trials do so under more idealized circumstances.
• Ancillary clinical trial(s): Early phase trials that address research questions related to ongoing NCI-funded studies supported through the NCI-designated Cancer Centers and/or other NCI network programs. In this case, the parent study can provide participants, infrastructure, and data. However, funds from this FOA cannot be used solely for infrastructure needs within a given trial.
• Pharmacodynamic trial(s): Early phase trials that link outcomes to measurements on pre- and post-treatment specimens to test hypotheses about therapeutic mechanisms based on pre-clinical data.
• Biomarker-driven trial(s): Early phase trials that test predictive or prognostic biomarker findings obtained from pilot trials.
• Co-clinical trial(s): Early phase trials that involve patients and in parallel (or sequentially) animal or human-in-animal models of cancer that mirror the genetics and biology of the patients' malignancies or pre-cancerous lesions. The co-clinical trial should include either a therapeutic goal (e.g., the prediction, staging, and/or measurement of tumor response to therapies) or an early diagnostic goal.

This FOA will not support:

• Investigator-initiated phase III cancer-related medical/oncologic intervention and/or investigational imaging clinical trials as specified in the NCI policy for R01 and P01 activity codes found in Notice NOT-CA-13-012.
• Applications involving only animal and/or in vitro studies that do not complement a trial are not appropriate; however, applications proposing both animal work and/or in vitro studies and a clinical trial are appropriate.
• Applications proposing only observational studies that do not meet the NIH definition of a clinical trial. These studies may be submitted as R01s to the NIH Parent R01 (currently PA-16-160) or another relevant NIH FOA.
• Clinical trials to investigate behavioral interventions are not supported under this announcement but should be submitted to the NCI investigator-initiated clinical trials FOA sponsored by DCP and DCCPS.
• NCI-supported networks and consortia that serve as an infrastructure support system for NCI clinical trials.

Applications proposing these kinds of studies will not be considered for funding.

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

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

Higher Education Institutions

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

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

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Institutions)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

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

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

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

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

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

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

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

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

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

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

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

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

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

Letter of Intent

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 NCI staff to estimate the potential review workload and plan the review.

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

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

The letter of intent should be sent via email to:

Lori A. Henderson, Ph.D.
Division of Cancer Treatment and Diagnosis
National Cancer Institute
Telephone: 240-276-5930
Email: hendersonlori@mail.nih.gov

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

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

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

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

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

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

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

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

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

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

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

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

Appendix:

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide. For applications that have the complete Clinical Trial Protocol available, combine all clinical documents in a single pdf file in the Appendix. Resubmission applications that have modified the clinical trial(s) should indicate the changes in the Clinical Trial Protocol.

Use only for applications with due dates on or after January 25, 2018. When involving NIH-defined human subjects research, clinical research, and/or clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the additional instructions provided below.

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

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed with additional instructions for specified sections as follows:

Section 2 - Study Population Characteristics

Section 2.5 Recruitment and Retention Plan

Please include a discussion of the availability of potential participants for the proposed study and anticipated yield from recruitment and screening efforts. If there is more than one site, please provide a table showing the expected number and demographics of the population to be recruited at each site and overall. The plan should also include a discussion of past experiences in recruiting and retaining similar populations, expected challenges to recruitment and retention, and possible contingency plans.

Section 2.7 Study Timeline

The study timeline should describe key milestones throughout the project and trial that need to be met to achieve the goals of the study. A milestone is defined as a scheduled event in the project timeline that signifies the completion of a project stage or activity. Applicants are required to provide detailed project performance and timeline objectives as outlined below. Investigators must indicate where within the Plan the clinical trial or trials are scheduled and when the required documents will be available if not included at the time of submission. Program staff will review the milestones and timelines which can be negotiated, as needed, at the time of the award.

This section should include an estimated timeline for the following general milestones, as applicable:

• Complete finalized Clinical Trial Protocol for submission to NCI
• Registration of clinical trial in ClinicalTrials.gov
• Completion of regulatory approvals
• Enrollment of the first subject
• Enrollment of 25%, 50%, 75%, and 100% of the projected recruitment for all study participants including women, minorities, and children (as appropriate)
• Completion of data collection time period
• Completion of primary endpoint and secondary endpoint data analyses
• Completion of final report of the primary outcome
• Reporting of results in ClinicalTrials.gov
• Status of the FDA-regulated product requiring IND or IDE if applicable

In addition to meeting the above recruitment and other targets, applicants should give contingency plans if they do not meet the milestones and address other implementation activities necessary such as start-up tasks to achieve trial completion.

Section 3 - Protection and Monitoring Plans

Section 3.3 Data and Safety Monitoring Plan

In addition to the description of safety monitoring, address plans to monitor trial performance, including plans to assure fidelity to the protocol and integrity of the data. Information about Data and Safety Monitoring Plans are available at https://humansubjects.nih.gov/data_safety.

Section 4 - Protocol Synopsis

Section 4.1 Brief Summary

It should summarize the necessary elements of the trial and supplements the Research Strategy, which includes an overview of the state-of-science and relevance of the trial and is meant to justify the need, its potential impact, and provide supporting preclinical and/or clinical evidence to justify the proposed trial, its design, and likelihood of successful completion. Resubmission applications that have modified the clinical trial(s) should indicate the changes in the Protocol Synopsis. Applications submitted without the Clinical Protocol Synopsis are considered incomplete and will not be supported through this FOA.

Section 4.4 Statistical Design and Power

The sample size and statistical power calculations should contain enough detail, including sufficient information on the assumptions made, so that a reviewer can readily duplicate the projected sample size. The power analysis should include a discussion of the anticipated level of adherence to the intervention and rates of follow-up (i.e., drop out/lost to follow-up) during key outcome collection contacts. A discussion of how missing data will be handled should be included. Any planned interim analyses should also be described.

Section 5 - Other Clinical Trial-related Attachments

Section 5.1 Other Clinical Trial-related Attachments

Applicants are asked to provide a list of clinical trials that demonstrate their experiences in trial coordination over the last 5 years, without duplicating information in biosketches. A table should be provided as an attachment using the filename "Clinical Trial Experience." The table should also include the following for each trial listed: start and completion date; percent of target accrued; whether the trials reached completion; and, if applicable, the date of first publication.

Investigators who are new to the conduct of clinical trials should identify an appropriate mentor and establish the right composition for the clinical trial team (e.g., trial manager, statistician, data manager, study coordinator(s), research assistants, institutional review board [IRB] and ethics coordinator, etc.). In this situation, only the names and titles of key team members should be listed in the table.

Applications that are submitted without appropriate required attachments will be considered incomplete and will not be supported through this FOA.

Delayed Onset Study

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

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

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

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

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

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

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

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

Important reminders:

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

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

See more tips for avoiding common errors.

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

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

Important Update: See NOT-OD-18-228 for updated review language for due dates on or after January 25, 2019.

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

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

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

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

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

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

Specific for this FOA:

Is the proposed Phase II clinical trial necessary for larger confirmatory studies?

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

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

Specific for this FOA:

Does the Clinical Trial Experience attachment demonstrate the ability of the PD/PI(s) and investigative team to conduct the proposed trial and meet the planned milestones? How well defined are their roles and responsibilities? Is the expertise of the mentor for new investigator application involving a clinical trial appropriate for the planned study?

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

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

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

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

Does the application adequately address the following, if applicable,

Study Design

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

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

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

Data Management and Statistical Analysis

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

Specific to this FOA:

If applicable, does the Protocol Synopsis for the Phase 0 or I clinical trial adequately describe the necessary elements of the clinical trial for implementation? If applicable, how likely can the Phase II clinical trial protocol be efficiently implemented and completed within the proposed timeframe? Does the Phase II clinical trial protocol indicate an appropriate mechanism to capture, track, and monitor adverse events? Does the Phase II clinical trial protocol outline appropriate stopping rules or clear go/no decisions to mitigate risks?

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

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

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

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

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

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

Study Timeline

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

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

Specific to this FOA:

Are the listed milestones achievable within the timeframe of the project?

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

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

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

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

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

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

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

For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

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

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

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

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

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

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

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NIH Center for Scientific Review (CSR), 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.

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

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

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

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

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

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

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

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

Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA. ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain "applicable clinical trials" on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration of all trials whether required under the law or not. For more information, see http://grants.nih.gov/ClinicalTrials_fdaaa/

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

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

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

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

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

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

Cooperative Agreement Terms and Conditions of Award

Not Applicable

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

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

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

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

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

For Therapeutic Studies:

Lori A. Henderson, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-5930
Email: hendersonlori@mail.nih.gov

For Imaging Studies:

Michael McDonald, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-6448
Email: mmcdonald@mail.nih.gov

For Radiation Research Studies:

Jeff Buchsbaum, MD, PhD, AM
National Cancer Institute (NCI)
Telephone: 240-276-5914
Email: jeff.buchsbaum@nih.gov

For Biomarker Studies:

Tracy G. Lively, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-5944
Email: livelyt@mail.nih.gov

For Alternative Medicine Studies:

Dan Xi, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-6143
Email: xida@mail.nih.gov

For HIV Studies:

Rebecca Liddell Huppi, Ph.D.
National Cancer Institute
Telephone: 240-781-3324
Email: liddellr@exchange.nih.gov

Syed Quadri, Ph.D.
Center for Scientific Review (CSR)
Telephone: 301-435-1211
Email: quadris@mail.nih.gov

Shane Woodward
National Cancer Institute (NCI)
Telephone: 301-276-6303
Email: woodwars@mail.nih.gov

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.