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

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

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

The purpose of this funding opportunity announcement (FOA) is to stimulate the development of methods for better understanding tolerability (see definition below) by analyzing the clinical trials adverse event data through the use of the Common Terminology Criteria for Adverse Events (CTCAE) and the Patient-Reported Outcomes version of the CTCAE (PRO-CTCAE ), as well as other clinically relevant data, e.g., stage of disease, laboratory findings, co-morbidities, concurrent medications, including patient-reported outcomes (PROs) from cancer clinical trials. An additional purpose is to create a consortium of the funded research teams comprised of principal investigators, biostatisticians, data scientists, investigators with patient-reported outcome (PRO) measurement expertise, and cancer clinical trialists to share analytic approaches to determine tolerability and develop a menu of methods for public use.

Key Definitions for the context of this FOA:

• Adverse event (AE): denotes any unfavorable and unintended sign, symptom, or disease temporarily associated with the use of a medical treatment or procedure that may or may not be considered related to the medical treatment or procedure.
• NCI Common Terminology Criteria for Adverse Events (CTCAE): refers to the set of criteria for the standardized classification of adverse event (AE) reporting. A grading (severity) scale from 1 (mild) - 5 (death) is provided for each AE term. The more than 800 AE items in CTCAE can be categorized as 1) laboratory events, e.g., hemoglobin or potassium levels; 2) observable events, e.g., atrial fibrillation or retinal tear; or 3) symptomatic events, e.g., pain or nausea.
• Patient-Reported Outcomes (PROs): A type of clinical outcome assessment. A measurement based on a report that comes directly from the patient (i.e., study subject) about the status of a patient’s health condition without amendment or interpretation of the patient’s response by a clinician or anyone else. A PRO can be measured by self-report or by interview provided that the interviewer records only the patient’s response. Symptoms or other unobservable concepts known only to the patient can only be measured by PRO measures. PROs can also assess the patient perspective on functioning or activities that may also be observable by others. PRO measures include:
• Rating scales (e.g., numeric rating scale of pain intensity or Minnesota Living with Heart Failure Questionnaire for assessing heart failure)
• Counts of events (e.g., patient-completed log of emesis episodes or micturition episodes)
• Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE ): refers to the patient-reported outcome measure developed to evaluate symptomatic AEs in patients on cancer clinical trials and was designed to be used as a companion to the CTCAE, the standard lexicon for adverse event reporting in cancer trials. PRO-CTCAE includes an item library of 124 items representing 78 symptomatic toxicities from the CTCAE. PRO-CTCAE responses are scored from 0 (none) - 4 (very severe). (https://healthcaredelivery.cancer.gov/pro-ctcae).
• Tolerability: refers to the degree to which adverse effects of a drug and other aspects of a drug can be tolerated by a patient, usually measured by the rate of "dropouts," number of hospitalizations, drug adjustments, or patients that forfeit participation in a study due to moderate to severe adverse effects.

NCI convened the Blue Ribbon Panel (BRP) in 2016 to provide recommendations for achieving the Cancer Moonshot's ambitious goal of making a decade's worth of progress in cancer prevention, diagnosis, and treatment in just 5 years, now called the Beau Biden Cancer Moonshot Initiative. The BRP (https://www.cancer.gov/research/key-initiatives/moonshot-cancer-initiative/blue-ribbon-panel/members) was charged with assessing the state of the science in specific areas and identifying major research opportunities that could uniquely benefit from the support of the Cancer Moonshot and could lead to significant advances in our understanding of cancer and in how to intervene in its initiation and progression. The recommendations focused on areas in which a coordinated effort could profoundly accelerate the pace of progress in the fight against cancer and were not intended to replace existing cancer programs, initiatives, and policies already underway. The BRP final report was approved by the National Cancer Advisory Board and included a recommendation for Symptom Management Research. The 21st Century Cures Act was signed into law in December 2016 dedicating new funds to support efforts associated with the Beau Biden Cancer Moonshot Initiative, including support for this FOA.

The spectrum of cancer treatment interventions has changed in recent years from cytotoxic agents to those that target signaling pathways or modify the patient’s immune response. The typical adverse events (AEs) seen with cytotoxic agents are moderate to severe, often occur acutely in the first cycle of a patient's treatment and at predictable time points within a treatment cycle. The AE profiles of the targeted agents, which are often given orally over prolonged periods of time, result in chronic, persistent, low-grade AEs that can be cumulative and lead to elective patient discontinuation.

As more targeted anticancer agents are approved for use, there is a need to better understand tolerability over time to ensure that patients benefit from the use of these novel treatment interventions. The traditional methods (dose reductions, dose holds, hospitalizations) for understanding tolerability of targeted and/or regimens intended for long-term use may not be sufficient. Frequently, these agents result in AEs that do not necessarily occur with the first cycle of treatment, but may develop at later timepoints, worsen over time, and/or become cumulative.

AEs are prospectively captured, reviewed, and acted upon in real time for patient safety. The standard lexicon for collecting and reporting AEs on cancer clinical trials is CTCAE reporting. The data generated from the use of CTCAE reporting is typically presented with the clinical trial results in a table summarizing the proportion of the study participants experiencing the most severe AEs during any cycle of treatment. This approach does not account for the trajectory of toxicity over time, i.e., onset, fluctuation, persistence, or the resolution of the AEs, and, thus, misses an important and highly relevant aspect of tolerability.

Studies have reported that when clinician-reported AEs are compared to similar patient-reported items in health-related quality-of-life (HRQOL) instruments, clinicians under-report the incidence and severity of symptomatic events. The differences have been attributed to patients reflecting upon their day-to-day functioning whereas clinicians are reporting AEs and intervening specifically for medical safety. These different perspectives can provide important and complementary information and highlight the current need to identify and understand low-grade symptomatic AEs, which may be persistent and bothersome prompting elective treatment discontinuations.

The systematic assessment of patient-reported symptomatic AEs, using contemporary PRO measures and informative methods to analyze and represent the trajectory of those symptomatic AEs will provide a more comprehensive understanding of tolerability.

Currently, the data generated from PRO-CTCAE in clinical trials are analyzed descriptively limiting its interpretation and use. To date, there has been limited evaluation of optimal methods to analyze and interpret patient-reported symptomatic AEs in the context of other clinical trial data, e.g., clinician-rated adverse events, which are crucial for a variety of stakeholders, including trialists, drug regulators, clinicians, and patients.

Overall Research Focus. Research activities proposed under this FOA must be focused on applying analytic methods that incorporate CTCAE, PRO-CTCAE, and other clinically relevant data (e.g., stage of disease, laboratory findings, co-morbidities, concurrent medications) to provide better insights into patient tolerability of agents and regimens undergoing testing in cancer clinical trials. Complementary expertise of biostatisticians, data scientists (or combined expertise of both), clinical trialists, and PRO experts are needed to develop these analytic methods to enhance our understanding of tolerability in the context of targeted anticancer agents and novel cancer treatment regimens.

Multi-disciplinary Teams. To realize this goal, the team is expected to be comprised of biostatistician(s) and data scientists (or combined expertise of both), clinical trialist(s), and PRO measurement expert(s) who have had a history of past collaborations.

Longitudinal analytic approaches may include (but are not limited to) the following:

• Analyzing clinician reporting of CTCAE grades grading, patient-reported symptomatic AEs, and dose modifications longitudinally;
• Employing pharmacokinetic data in conjunction with PRO-CTCAE scores and CTCAE grading;
• Examining the association between patient-reported low-severity symptomatic AEs over time and the development of clinically severe and actionable AEs;
• Addressing missing data, particularly in the setting of the development and resolution of AEs;
• Gauging the extent of bias because of different kinds of missing data;
• Representing the data using different graphical techniques; and
• Analyzing baseline symptoms to facilitate attribution of emerging symptomatic AEs over time.

The following types of activities remain outside of the scope of this FOA and non-responsive to this FOA. Applications proposing such activities will not be reviewed.

• Projects lacking currently available datasets and proposing to prospectively collect data. Funding cannot be used for prospective collection of data.
• Data that were collected outside of the setting of a clinical trial, i.e., routine collection during standard cancer care.
• Data that were collected in disease settings other than cancer.
• Datasets lacking PRO-CTCAE data and/or CTCAE data.
• Projects comparing data between (or among) arms when the primary endpoint has not been reported.

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 in response to this FOA.

Higher Education Institutions

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

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

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

• State Governments
• 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)
• 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) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

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

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

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

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

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

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

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

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

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

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

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

The letter of intent should be sent (e-mailed) to:

Ann O'Mara, Ph.D., R.N.
National Cancer Institute (NCI)
Telephone: 240-276-7050
Email: [email protected]

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:

Specific Aims:

In addition to addressing the specific aims and approach(es), applicants must describe the relevance of the research to the objectives of this FOA.

Research Strategy:

The Research Strategy must include the following:

• Health Disparities: BRP recommendations outline a set of opportunities that, if implemented, will transform our understanding of cancer and result in new opportunities to more effectively prevent and treat the disease, which can reduce the burden of cancer in all Americans and ameliorate the health disparities that currently exist. Minority health and health disparity populations (which include individuals from urban and rural areas who are poor and medically underserved) continue to suffer disproportionately from certain cancers and have higher morbidity and mortality rates. If applicable to the type of research project being proposed, the Research Strategy must address how minority health and/or health disparity populations or data will be integrated into the proposed studies.

The Research Strategy must consist of Subsections A-D as defined below:

Subsection A. Data Sources

• The investigators need to have at least one clinical trial dataset with CTCAE and PRO-CTCAE data, but can also use clinical trial datasets with CTCAE and other PRO data to generate proof-of-principle analyses to use in future trials using PRO-CTCAE.
• The trials need not have fully matured. The datasets for these applications may be a subset of the larger trial, but need to include relevant clinical event data.
• Applicants must use existing data sources rather than collect new data.
• For refinement and validation, applicants may propose to use trial data from newly initiated trials in years 3-5.
• Include a description of the clinical trial(s) in which the data were collected.
• Include a description of the dataset, including sample size, demographics of the patient population, frequency of data collection, and types of data collected.
• Applicants may propose analyses based on their own trial data sets, or propose proof-of-principle analysis of their own data with replication and validation of the analytic approach in another data set available within the consortium.

Subsection B. Describe Analysis Strategy

Research teams will leverage secondary analysis of data from existing trials, and will seek to establish proof-of-principle for a range of methodologies for analysis and interpretation of PRO-CTCAE data including descriptive approaches, those based on inferential statistics and graphical analysis of data, and simulation studies. The methods and analytic approaches should consider the PRO-CTCAE data in conjunction with other relevant clinical trial data (e.g., CTCAE grading, pharmacokinetic, laboratory, dose modifications, concurrent medications, co-morbidities, and other PRO data). PRO-CTCAE data may be analyzed with other clinical trial data to evaluate tolerability, to identify actionable AEs and earlier timepoints for supportive care interventions, and to improve patient outcomes.

• An operational definition(s) of tolerability will be developed as it relates to the patient- and clinician-reported data that will be used in the analyses.
• Describe analytic methods to evaluate PRO-CTCAE data collected in one or more clinical trials.

Subsection C. Describe the Research Team and Members' Roles/Responsibilities (without duplicating information already requested/provided in the biosketches)

• Each funded research team will be comprised of at least one of each of the following: biostatistician, data scientist (combined expertise of biostatistician and data scientist is acceptable), clinical trialist, and PRO measurement expert.
• Describe research team’s experience with analysis of PRO data and with the analysis of adverse event data.
• Describe the leadership structure, decision-making processes, and communication among research team members.
• Describe the research team members' past collaborations.

Subsection D. Collaborations with Consortium

This initiative will create a consortium of the funded research teams, academic investigators, industry sponsors, NCI and regulatory staff and patient advocates to collaborate in the comparative testing of analytic methods and approaches to interpreting the data generated from PRO-CTCAE in cancer clinical trials. In addition, a Steering Committee will be established to facilitate and promote collaboration within the consortium.

Investigators will be required to share their analytic approaches and methods with members of the consortium and the Steering Committee. The investigators are encouraged, but not required to share datasets.

• Describe the approach to collaboration across the consortium to achieve the objectives of this initiative.
• Describe past experiences working within a consortium or network.

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:

• Addressing the Cancer Moonshot Public Access Pilot Program: Utilizing the provision outlined in the 21st Century Cures Act, NCI has established a data sharing strategy that requires public access immediately upon publication of all research results and underlying data for projects that are funded as part of the Beau Biden Cancer MoonshotSM Initiative. NCI will give competitive preference and funding priority to applications with a data sharing plan that complies with the strategy described here. The data sharing plan will become a term and condition of award.

Appendix:

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

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

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

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 and responsiveness by the NCI, NIH. Applications that are incomplete, non-compliant, and/or nonresponsive will not be reviewed.

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

For NCI-relevant CDEs, please visit CDE (Common Data Element) Browser.

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

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.

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?

Specific for this FOA: Does the application propose a clinically significant definition or set of definitions for tolerability? Will the results accelerate research to better understand tolerability?

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?

Specific for this FOA: Do the PDs/PIs represent an optimal mix of a biostatistician, a data scientist (combined expertise is acceptable), a clinical trial investigator, and a PRO expert? Have the PD/PIs demonstrated a history of collaboration? Has the biostatistician/data scientist demonstrated a history of analyzing and reporting patient reported outcome and/or adverse event data? Has the clinical trial investigator demonstrated a history of conducting and reporting clinical trials?

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

Specific for this FOA: To what degree will the analysis plan result in novel and feasible methods to evaluate patient- and clinician-reported data from clinical trials to better understand tolerability?

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?

Specific for this FOA: Does the application contain acceptable plans for addressing the Cancer Moonshot Public Access Strategy? Does the application address missing data?

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

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

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

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

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

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

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

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

Not applicable

Not applicable

Not applicable

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

Not applicable

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 NCI, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
• Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

Applications will be assigned 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 submitted in response to this FOA. 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.

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 http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.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 http://www.hhs.gov/ocr/civilrights/understanding/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 http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

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

Cooperative Agreement Terms and Conditions of Award

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

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

This program will be organized as a consortium and awardees will be expected to contribute to the collective effort by sharing preliminary findings and resources with the other Consortium participants. To achieve this goal, as well as ensuring the sharing of expertise among multiple disciplines, a Steering Committee will be formed that will be comprised of PIs, NCI staff, and the Food and Drug Administration (FDA) staff. NCI and the FDA, specifically the Center for Drug Evaluation and Research and Patient Outcomes Oncology Center of Excellence have been collaborating and consulting on issues related to tolerability and adverse event reporting. The Steering Committee will meet once every year, at locations selected by the Steering Committee in consultation with the NCI. The first meeting will focus on defining the process and procedures for the coordination of awardee activities.

Steering Committee responsibilities will include the following aspects:

• Identifying areas of opportunity that can best be exploited with a group effort of the awardees;
• Encouraging the development of new methodologies and approaches to be shared among the awardees;
• Optimizing the information flow among the awardees and the NCI.

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

• Defining objectives and approaches, analyzing, and interpreting results, and publishing reports of results conducted under this award.
• Assuming responsibility for submission of all abstracts, manuscripts, and reviews (co)authored by members of the grant and supported in part or in total under this Agreement. The PD/PI is requested to submit manuscripts accepted for publication to the Project Scientist so that an up-to-date summary of progress accomplished can be maintained and joint press conferences and press releases prepared. Publications or oral presentations of work performed under this Agreement are the responsibility of the PD/PI and will require appropriate acknowledgement of NCI support.
• Assuming responsibility and accountability to the applicant organization for the performance and proper conduct of the research in accordance with the terms and conditions of the award.
• Serving as voting members of the Steering Committee (the PD/PI and another senior investigator from each award [U01] will be required to attend Steering Committee meetings once a year).
• Accepting and implementing the goals, priorities, procedures, and policies agreed upon by the Steering Committee to the extent consistent with applicable grant regulations.
• Overseeing the implementation of the approved data sharing plan.
• The PDs/PIs and their awardee institutions will be accountable for implementing the approved research resource sharing plan.
• All institutions/organizations will be expected to share with each other their analytic approaches and the knowledge gained from these activities.
• Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

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

The NIH/NCI Project Scientists/Coordinators will be involved in assisting and coordinating interactions and collaborations among the various investigators and will ensure access to other NIH relevant programs.

Specific activities of substantially involved NCI staff members will include:

• Facilitating access to NCI resources, biostatistician/data scientist, clinical trialist, PRO measurement expertise, etc.;
• Advising on the development of approaches and methods for the analyses of incorporating PRO-CTCAE data for the use of understanding tolerability;
• Participating in the activities of the Steering Committee;
• Serving as a liaison between the Steering Committee, the awardees, regulatory agencies, and the NIH;
• Ensure common access to awardee-generated resources for the broader cancer research community and facilitating access to NCI resources, biostatistician/data scientist, clinical trialist, PRO measurement expertise, etc.;
• Assisting the investigators in avoiding unwarranted duplications of effort across awardees;
• Co-organizing and participating in the Steering Committee meetings;
• Reviewing the compliance of awardees with the recommendations developed by the Steering Committee; and
• Coordinating external evaluation of the entire programmatic initiative.

Areas of Joint Responsibility

Areas of joint responsibility will occur within the Steering Committee. NCI Project Scientists will assist the Steering Committee in developing and drafting operating policies and policies for dealing with recurring situations that require coordinated action(s).

The Steering Committee will consist of the following voting members:

• Three representatives from each award; and
• One NCI Project Scientist/Coordinator.

The chair of the Steering Committee will be selected from among the representatives of all awardees (i.e., the voting members).

Additional NIH staff members, including representatives from NCI extramural divisions and the FDA's Center for Drug Evaluation and Research and Patient Outcomes Oncology Center of Excellence may participate in Steering Committee meetings as non-voting members as needed (for example to provide additional expertise), as well as a patient advocate. Additional non-voting members to serve in an advisory capacity may be added to the Steering Committee as needed by a decision of the existing voting committee members.

The Steering Committee may decide to establish sub-committees for specific purposes. The NCI Project Scientists/Coordinators will serve on such sub-committees, as they deem appropriate.

Dispute Resolution

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

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: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-945-7573

Ann O'Mara, Ph.D., R.N.
National Cancer Institute (NCI)
Telephone: 240-276-7050
Email: [email protected]

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

Crystal Wolfrey
National Cancer Institute (NCI)
Telephone: 240-276-6277
Email: [email protected]

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

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