NCI Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Optional)

NCI Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Optional) is sponsored by National Cancer Institute (NCI). Intended to encourage exploratory or developmental research projects by supporting the development of pilot projects or feasibility studies to support creative, novel, and high-risk/high-payoff research in cancer.

Expired PAR-25-139: NCI Clinical and Translational Exploratory/Developmental Studies (R21 Clinical Trial Optional) This notice has expired. For NIH, in limited situations, applications may be accepted on a case-by-case basis for a short period after expiration to accommodate NIH late or continuous submission policies . Contact the eRA Service Desk for any submission issues.

Check the NIH Guide for active opportunities and notices. Department of Health and Human Services Part 1.

Overview Information Participating Organization(s) National Institutes of Health ( NIH ) Components of Participating Organizations National Cancer Institute ( NCI ) Funding Opportunity Title NCI Clinical and Translational Exploratory/Developmental Studies (R21 Clinical Trial Optional) R21 Exploratory/Developmental Research Grant Notices of Special Interest associated with this funding opportunity May 14, 2025 - Notice of Change to PAR-25-139 NCI Clinical and Translational Exploratory/Developmental Studies (R21 Clinical Trial Optional).

See Notice NOT-CA-25-045 . March 31, 2025 - This funding opportunity was updated to align with agency priorities. Carefully reread the full funding opportunity and make any needed adjustments to your application prior to submission.

April 4, 2024 - Overview of Grant Application and Review Changes for Due Dates on or after January 25, 2025. See Notice NOT-OD-24-084 . August 31, 2022 - Implementation Changes for Genomic Data Sharing Plans Included with Applications Due on or after January 25, 2023.

See Notice NOT-OD-22-198 . August 5, 2022 - Implementation Details for the NIH Data Management and Sharing Policy. See Notice NOT-OD-22-189 .

Funding Opportunity Number (FON) Companion Funding Opportunity See Section III. 3. Additional Information on Eligibility .

Assistance Listing Number(s) 93. 393, 93. 394, 93.

395, 93. 396, 93. 399 Funding Opportunity Purpose Through this Notice of Funding Opportunity (NOFO), the National Cancer Institute (NCI) intends to support preclinical and early phase clinical research, as well as correlative studies, directly related to advancements in cancer treatment, diagnosis, prevention, comparative oncology, symptom management, or reduction of cancer disparities.

This includes (but is not limited to) development and testing of the following: new molecular agents or biologics for cancer treatment; management strategies for cancer-related symptoms or treatment-related toxicity; cancer screening or diagnostic tools, such as imaging techniques; cancer preventive agents or approaches; predictive and prognostic biomarkers for patient selection or stratification; clinically relevant in vivo or in vitro tumor models (including genetically engineered mouse models, patient-derived xenograft models, organoids, and cell lines); and strategies to address therapeutic outcome disparities among underserved populations.

In addition to novel agents, new treatment strategies may involve repurposed agents or novel combinations of interventions (including radiation), based on established mechanisms of action. Comparative correlative studies in cancer patients with age, sex, racial/ethnic, or health disparities are encouraged to explore mechanisms underlying their differential responses (efficacy and toxicity) and resistance to therapeutic interventions.

Comparative oncology studies in dogs investigating strategies for treatment and diagnosis of human disease are supported as well. This NOFO does not support research that focuses on basic cancer biology (such as studies of cancer-related pathways, molecular mechanisms, or mechanisms of metastasis), late-stage clinical trials, risk assessment studies, epidemiological studies, or studies of behavioral interventions.

These applications will be deemed not responsive to this NOFO and will not be reviewed (see below for a more detailed description of studies that are not responsive for this NOFO). The R21 mechanism is intended to encourage exploratory and developmental research projects by providing support for the early and conceptual stages of these projects.

These studies may involve considerable risk but may lead to breakthroughs in particular areas, or to the development of novel techniques, agents, methodologies, models, or applications that could have a major impact on cancer research (preclinical or clinical). Open Date (Earliest Submission Date) Letter of Intent Due Date(s) Dates in bold and italics reflect changes per NOT-CA-25-045 .

Application Due Dates Review and Award Cycles New Renewal / Resubmission / Revision (as allowed) AIDS - New/Renewal/Resubmission/Revision, as allowed Scientific Merit Review Advisory Council Review Earliest Start Date February 13, 2025 February 13, 2025 March 01, 2025 July 2025 October 2025 December 2025 June 16, 2025* July 16, 2025* September 07, 2025* November 2025 January 2026 April 2026 All applications are due by 5:00 PM local time of applicant organization.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date. New Date September 08, 2025 per NOT-CA-25-045 (Prior Date July 02, 2025).

Required Application Instructions It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide , except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts ). Conformance to all requirements (both in the Application Guide and the NOFO) 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 Announcement Section I.

Notice of 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 Part 2. Full Text of Announcement Section I.

Notice of Funding Opportunity Description The purpose of this Notice of Funding Opportunity (NOFO) is to promote innovative preclinical, early phase clinical, and correlative studies that are hypothesis-driven and based upon established basic cancer research discoveries.

By using the R21 mechanism, this NOFO will support exploratory/developmental projects in the advancement of novel anti-cancer agents, diagnostic tools, correlative biomarker identification, clinical approaches in treatment, symptom management, and prevention of common or rare tumors, as well as research on cancer disparities.

These studies may involve considerable risk, but they would have the potential to lead to breakthroughs in particular areas, and/or to the development of novel techniques, agents, methodologies, models, or applications that could have a major impact on cancer research (preclinical or clinical).

This NOFO accepts only applications proposing research directly related to the development of novel approaches for cancer treatment, diagnosis, prevention, symptom management, or reduction of cancer disparities.

Studies that focus on basic cancer biology, such as studies of cancer-related pathways or molecular mechanisms, are not responsive to this NOFO (see below for a more detailed description of studies that are not responsive to this NOFO). Applicants are strongly advised to contact an appropriate NCI Scientific/Research Contact (see Section VII.

Agency Contacts) prior to submission of their applications with questions regarding the responsiveness of their applications. Applications for R21 awards should describe projects distinct from those supported through the traditional R01 mechanism.

For example, such projects could assess, through preclinical or early phase clinical studies, the feasibility of a novel area of investigation or a new experimental system that has the potential to enhance patient-oriented research. Another example could include the unique and innovative use of an existing methodology to explore a new scientific area.

Conversely, long-term projects, or projects designed to increase knowledge incrementally in a well-established area, will not be considered for R21 awards. Applications submitted under this mechanism should break new ground or extend previous discoveries toward new directions or applications in the areas discussed below.

Projects of limited cost or scope that use widely accepted approaches and methods within well-established fields are better suited for the R03 small grant mechanism, which is presently supported by the NCI Omnibus R03 FOA, PAR-20-052 .

Specific Research Objectives All areas of cancer research relevant to the mission of the Division of Cancer Treatment and Diagnosis (DCTD), the Division of Cancer Prevention (DCP), and the Center to Reduce Cancer Health Disparities (CRCHD), such as preclinical and clinical studies that focus on the development and testing of anti-cancer, symptom management, and cancer prevention interventions (drugs, biologics, natural products, dietary compounds or constituents, or complementary/alternative medicine), including combinations of agents; diagnostic and treatment methodologies; validation of predictive biomarkers for clinical use; and clinical and translational studies that seek to reduce the unequal burden of cancer in our society via research from underserved populations are appropriate for projects submitted to this NOFO.

Testing (in prevention, symptom management, and/or treatment studies) of new models that closely parallel the development and progression of human cancers or the development of disease and treatment-related morbidities are also appropriate for this NOFO.

In addition, comparative oncology studies of prevention, symptom management, and/or treatment of pet dogs with spontaneous cancers that serve as excellent models for human malignancies are acceptable for this NOFO.

Examples of the types of studies appropriate for this NOFO include, but are not limited to: Exploratory, Phase I, or small Phase II trials of new agents, repurposed agents, or combinations of interventions (including radiation) for treatment of common or rare cancers, based on established mechanisms of action, demonstrable pre-clinical activity in relevant animal models, and pharmacological and toxicological data; Window-of-opportunity clinical trials to assess the effects of therapeutic doses of interventions on the patients tumors and their systemic effects, as well as associated correlative studies; Pilot trials of anti-cancer combination therapies to explore less toxic and more efficacious routes of administration, doses, dosing schedules, and sequences of individual interventions; Exploratory, Phase I, or small Phase II trials of new preventive agents or approaches (including medical devices, cancer preventive surgery, risk-reducing surgery, and non-surgical ablative techniques) to block, reverse, or delay of precancer or cancer, based on rational target selection and pharmacological and toxicological data; Exploratory, Phase I, or small Phase II trials of new agents, repurposed agents, or combinations of interventions (including radiation) for the prevention or treatment of acute and chronic symptoms and morbidities related to cancer and its treatment, based on established mechanisms of action, and pharmacological and toxicological data; Treatment of additional eligible cancer patients with age, racial/ethnic or health disparities during ongoing or prospective clinical trials to evaluate their differential responses (efficacy and toxicity) and resistance to the investigational regimens; Clinical studies for preliminary evaluation of the safety and efficacy of new cancer screening or imaging tools and techniques (devices, instrumentation, methods, and agents) designed to improve upon current technologies, practices, and interventions; Pilot trials of new radiation treatment modalities, and development of novel tools and approaches for radiation dosimetry and treatment planning/toxicity modulation.

Correlative Studies/Biomarker Development: Development and/or validation of novel assays to support the characterization and efficacy of cancer therapies or cancer prevention interventions; Early validation of biomarkers, such as (but not limited to) the following: Predictive biomarkers that may lead to better cancer diagnosis and patient stratification, including imaging biomarkers or genetic/epigenetic signatures, using direct patient measurements or patient specimens from drug, biologic, radiation, or combination trials where the outcome is known; Biomarkers elucidating molecular targets of interventions aimed at preventing or treating symptoms and/or toxicities resulting from disease or its treatment; Biomarkers that may be used to predict or determine individual susceptibilities to symptoms and/or toxicities; Biomarkers elucidating molecular targets of cancer preventive interventions; Intermediate endpoint biomarkers for cancer prevention clinical trials; Biomarkers or genetic signatures that may be used to detect or predict early recurrence; Integration of biomarker measurements with imaging studies for the detection of early-stage cancers or to distinguish indolent from aggressive cancers; Biomarkers or genetic/epigenetic signatures that may improve cancer diagnosis, patient stratification, and/or prediction of treatment response among diverse age, racial/ethnic, and/or underserved groups to better elucidate and decrease cancer disparities.

Studies of particles, microvesicles, nucleic acids from tumor cells, and/or circulating tumor cells, for the purpose of cancer diagnosis, prognosis, detection of metastases, and cancer recurrence; Studies that correlate pathology image data with cancer diagnosis and prognosis; Studies that use high dimensional data (e.g., proteomic, genomic, or radiomic information) for cancer early detection, diagnosis, and disease stratification; Pharmacogenomic studies aimed at the identification of genomic profiles associated with increased/decreased efficacy or toxicity during clinical interventions; Correlation of the activation of specific signaling pathways with outcomes in immunotherapy clinical trials; Studies that use AI/machine learning models for the purpose of investigating cancer prevention, screening, or cancer symptom/toxicity modulation; Proton/image-guided radiation therapy dosimetry analysis of patient data; Dose-effect analysis of image-guided intervention (IGI) methods.

Target and Agent Development: Development of new molecular targeting agents or biologics for cancer treatment based on specific signaling pathways activated, or specific proteins expressed or amplified, during the process of tumorigenesis or tumor progression (including invasion and metastasis); Development of molecular targeting agents or biologics to reduce cancer therapy-related toxicity; Development of agents, biologics, or immunoprevention for cancer prevention or the treatment of pre-neoplasia; Development of molecular targeting agents, biologics, or novel strategies to enhance the effectiveness of immune therapies, including those that modulate the immunosuppressive tumor microenvironment; Evaluation of new combination treatment strategies and development of new agents to enhance the effectiveness of chemotherapy and other standard-of-care therapies; Development and preclinical evaluation of novel molecular agents and strategies to overcome therapeutic resistance; Performance of high-throughput screens for discovery of chemical probes and molecular targeting agents for cancer treatment; Development of theranostic agents.

Model Development and Analysis: Development and early validation of clinically relevant in vivo or in vitro (including 3D/organoid) models of common or rare tumors, when the purpose is to investigate diagnosis, treatment, and prevention strategies for human cancer (including efficacy of targeted therapies and treatment-related toxicity); Development and early validation of in vivo or in vitro models for the assessment, prevention, or treatment of cancer treatment-related toxicities; Development and early validation of in vivo or in vitro models for the assessment of immunoprevention or immunotherapy efficacy; Analysis of biological differences by race, age, and/or sex for the development of symptoms and/or toxicities; Analysis of clinical and genetic factors that may increase the incidence of symptoms and/or toxicities; Novel imaging approaches to characterize disease anatomy, physiology (including metabolism), and molecular biology (of the tumor and/or the microenvironment/vasculature) in order to guide the administration of targeted therapies in a clinical trial; Development of data acquisition methods and/or computational, mathematical, and animal models that can be used to assess imaging systems, including systems for IGI, and to improve image processing; Development of in vivo and in vitro models for the purpose of investigating cancer risk, when the purpose is to develop prevention strategies for human cancer; Development of in vivo and in vitro models for the purpose of investigating therapeutic outcome disparities among diverse racial/ethnic populations, including genetically engineered mouse models, patient-derived xenograft models, organoids, and cell lines; Comparative oncology studies to investigate diagnosis and treatment strategies for human disease.

Co-clinical trials in dogs and humans are appropriate. Applications Not Responsive to this NOFO The following types of studies are not responsive to this NOFO. Applications proposing such studies will be considered non-responsive and will not be reviewed.

Studies of basic science aspects of cancer biology, such as (but not limited to) studies of the following: Basic cellular pathways, mechanisms, and oncogenic events that drive the development of tumors and behavior of cancer cells.

Studies using therapeutic or preventive agents as tools/probes to interrogate basic cancer-related pathways and cellular mechanisms are not responsive to this FOA (although studies using agents for the purpose of studying therapeutic/preventive activity, mechanisms of drug action, or mechanisms of drug resistance are appropriate and responsive); The role of tumor-initiating and cancer stem cells in tumorigenesis; Epigenetic or transcriptional differences in tumor cells compared to normal cells; Metabolic alterations in tumors and/or the tumor microenvironment (TME); Features of the tumor microenvironment (TME) that contribute to cancer cell growth and survival; Mechanisms of tumor progression, invasion, and metastasis; Development of in vivo or in vitro models of tumors, when the purpose is to interrogate basic oncogenic pathways or mechanisms; Phase III clinical trials (although studies using specimens from these trials are appropriate); Early-stage biomarker identification and validation using cell lines and in vitro model systems (although in vitro studies on methods of biomarker measurement -- for example, studies involving validated microphysiological systems or tissue chips -- are acceptable provided they are matched with human patient samples where outcomes are known or prospectively obtained); Studies of behavioral interventions (although studies using specimens from these trials are appropriate); Studies that support epidemiological, behavioral, social, applied, and surveillance cancer research.

See Section VIII. Other Information for award authorities and regulations. Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs.

Section II. Award Information Grant: A financial assistance mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity. Application Types Allowed Resubmission - Resubmission of applications to PAR-19-356 , PAR-20-292 and this NOFO.

The OER Glossary and the How to Apply Application Guide provide details on these application types. Only those application types listed here are allowed for this NOFO. Optional: Accepting applications that either propose or do not propose clinical trial(s).

Need help determining whether you are doing a clinical trial? Funds Available and Anticipated Number of Awards The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications. The combined budget for direct costs for the two-year project period may not exceed $275,000.

No more than $200,000 may be requested in any single year. The maximum project period is 2 years. NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this NOFO.

Section III.

Eligibility Information Higher Education Institutions Public/State Controlled Institutions of Higher Education Private Institutions of Higher Education 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 (Other than Small Businesses) 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 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 Non-domestic (non-U.S.) Entities (Foreign Organizations) Non-domestic (non-U.S.) Entities (Foreign Organizations) 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 must complete and maintain the following registrations as described in the How to Apply- 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. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference the NIH Grants Policy Statement Section 2.

3. 9. 2 Electronically Submitted Applications for additional information.

System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually . The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.

NATO Commercial and Government Entity (NCAGE) Code – Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM. Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM. gov registration process.

The same UEI must be used for all registrations, as well as on the grant application. eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants. gov registrations; all registrations must be in place by time of submission.

eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application. Grants. gov – Applicants must have an active 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.

Eligible Individuals (Program Director/Principal Investigator) 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 their organization to develop an application for 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 How to Apply-Application Guide. This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1. 2 Definition of Terms .

3. Additional Information on Eligibility 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, per NIH Grants Policy Statement Section 2.

3. 7. 4 Submission of Resubmission Application .

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 NIH Grants Policy Statement 2. 3. 9.

4 Similar, Essentially Identical, or Identical Applications ). Section IV. Application and Submission Information 1.

Requesting an Application Package The application forms package specific to this opportunity must be accessed through ASSIST, Grants. gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.

gov Workspace are available in Part 1 of this NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution. 2.

Content and Form of Application Submission It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity 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. All page limitations described in the How to Apply- Application Guide and the Table of Page Limits must be followed. Instructions for Application Submission The following section supplements the instructions found in the How to Apply- Application Guide and should be used for preparing an application to this NOFO.

All instructions in the How to Apply - Application Guide must be followed. SF424(R&R) Project/Performance Site Locations All instructions in the How to Apply- Application Guide must be followed. SF424(R&R) Other Project Information All instructions in the How to Apply- Application Guide must be followed.

SF424(R&R) Senior/Key Person Profile All instructions in the How to Apply- Application Guide must be followed. All instructions in the How to Apply- Application Guide must be followed. All instructions in the How to Apply-Application Guide must be followed.

PHS 398 Cover Page Supplement All instructions in the How to Apply- Application Guide must be followed. All instructions in the How to Apply- 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 How to Apply- Application Guide.

All instructions in the How to Apply-Application Guide must be followed, with the following additional instructions: All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan.

All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan. Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply- Application Guide.

No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

PHS Human Subjects and Clinical Trials Information When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the How to Apply- Application Guide, with the following additional instructions: If you answered “Yes” to the question “Are Human Subjects Involved?

” on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record. Study Record: PHS Human Subjects and Clinical Trials Information All instructions in the How to Apply- Application Guide must be followed.

In addition, please include the following: If the study is an ancillary project to a Parent Clinical Trial, the study record should relate to the ancillary project and not the Parent Clinical Trial. Section 2 - Study Population Characteristics 2.

5 Recruitment and Retention Plan Recruitment and referral sources: include the number of potentially available participants per proposed site annually; Enrollment rate (e.g., number of participants meeting eligibility criteria for enrollment per month); Discussion of potential recruitment delays or challenges and alternative strategies that can be implemented if there are enrollment delays or shortfalls; Procedures to monitor enrollment and track/retain participants for follow-up assessments; Evidence to support the feasibility of enrollment, including prior experience and yield from research efforts using similar referral sources and/or strategies; Strategies to ensure the study population has scientifically appropriate diversity and representativeness; Decision points for terminating the trial.

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: Completion of the 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 individuals across the lifespan (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. Future year support is contingent on satisfactory achievement of performance milestones.

If milestones are not achieved fully, NCI may request development of a remedial plan and more frequent monitoring of progress, and/or take other remedial actions. Section 3 - Protection and Monitoring Plans 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 .

3. 5 Overall Structure of the Study Team In addition to the standard requirements for this item, provide a description of methods to identify additional collaborators, including enrollment/participation sites, if applicable.

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 a table.

Section 4 - Protocol Synopsis 4. 1. a Detailed Description It should summarize the necessary elements of the trial and supplement 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.

Applications submitted without the Clinical Protocol Synopsis are considered incomplete and will not be reviewed. Please include the dose and intensity of the intervention in the description, if applicable. 4.

3 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 for primary and secondary endpoints.

The power analysis should include a discussion of non-compliance, potential cross-over (if applicable), account for 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. Planned interim analyses for safety, efficacy, and/or futility should be described, if applicable.

For single-case design and other small-N study designs where traditional power analyses may not be applicable, provide a detailed description of the approach to sample size and analysis being used. Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the How