It is critical that applicants follow the Multi-Project (M) 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 overall goal of this funding opportunity announcement (FOA) is to improve the treatment of adult glioblastoma (GBM) by developing novel effective agents that can cross the blood brain barrier (BBB) and testing them in the clinic. To implement this initiative, multi-institutional teams are invited to participate in the Glioblastoma Therapeutics Network (GTN). Each GTN team is expected to drive therapeutic agent(s) from pre-clinical development, through IND studies, into pilot clinical studies in humans.

The mechanism for this grant will be the NIH U19 cooperative agreement.

Limited progress has been made in the treatment of adult GBM despite enormous public and private investments into basic, translational, and clinical research. The standard of care (i.e., maximal surgical resection followed by adjuvant radiation and temozolomide chemotherapy) has not changed in 15 years, and yields a median survival of about 15 months and a 5-year survival of less than 5%. Distinct pathophysiologic challenges at least partially explain the lack of progress in GBM therapies. First, GBM is a locally infiltrative brain malignancy without a well-defined border; surgical resection cannot be extended to obtain a tumor free margin. Therefore, adjuvant chemotherapy and radiation therapy (RT) are required after surgery, and the clinical efficacy of these two modalities is critical to treatment success. Second, chemotherapy for brain tumors must cross the blood-brain-barrier (BBB) to have a therapeutic effect; poor BBB penetration can lead to limited anticancer activity despite systemic toxicities. Third, in the setting of RT, the dose is limited by RT tolerance of the normal brain parenchyma. Finally, the efficacy of other therapies, including targeted agents and immunotherapy, is impeded by GBM's intratumoral genetic heterogeneity and its immunosuppressive tumor microenvironment, which is marked by scant effector T-cell infiltration, preventing the antitumor efficacy of immune checkpoint inhibitors. Clearly, the development and selection of specific agents for GBM need to break new ground if effective treatments are to be found for this disease.

Definitions and Acronyms for this FOA:

• Adult Glioblastoma (GBM): primary or secondary grade IV glioma in a patient over the age of 18 years
• BBB: Blood-brain-barrier
• Development Candidate: a drug-like small molecule or biological therapeutic, the end-product of the lead optimization stage.
• GTN: Glioblastoma Therapeutics Network
• Internal Advisory Board: panel of experts within the institution(s) of the U19, not to include U19 personnel.
• Lead Optimization stage: The Lead Optimization stage begins with one or more lead compounds; the goal of the Lead Optimization stage is to identify a compound for further development. Activities in the Lead Optimization stage include medicinal chemistry [structure-activity relationships (SAR) for improved potency and selectivity]; in vivo testing in rodents; exploratory pharmacokinetics (PK), metabolism and toxicology; and compound selection based on the outcome of these activities and on the defined compound profile. Development Candidate(s) is/are the end-product(s) of the lead optimization stage. The Lead Optimization stage is followed by the Preclinical Development stage. For a diagrammatic representation of drug development stages, see slide 5 of the GTN slide set.
• NCC: Network Coordination Center
• Preclinical Development stage: The Preclinical Development stage bridges the Lead Optimization stage and Phase I clinical trials. Activities in Preclinical Development focus on the Development Candidate and include scale-up and formulation; PK, ADME and GLP toxicology; efficacy studies using the clinically intended route of delivery; and IND filing. Agents being developed for GBM should demonstrate transit through the BBB as part of the PK studies.

To implement this initiative, a GBM therapeutics network (GTN) of highly collaborative U19 teams will be established, with each team capable of driving therapeutic agent(s) from pre-clinical development, through IND studies, into pilot clinical studies in humans. Appropriate development candidates include: (1) novel agents or (2) agents or combinations approved for other indications and repurposed for treatment of GBM following relevant preclinical studies. As developing drugs from the discovery phase is a long and expensive process that often encounters obstacles and failures, this FOA will focus on a cooperative effort in drug development, rather than on discovery. A unique aspect of the GTN will be the ability of members to leverage models and methodologies for cross-validation of promising agents across the network.

NCI’s current research infrastructure (notwithstanding its extensive clinical trials capabilities) needs to expand critical drug development capabilities that are required for a comprehensive, full scale effort to develop and test effective GBM therapeutic strategies. This would include the qualification of new BBB-penetrating drugs and combinations of therapeutic modalities (including other small molecule and biological agents, and radiation therapy), and the development of functional biomarkers to demonstrate that drugs and/or combinations reach their tumor or microenvironment targets. Successful evaluation of these novel agents and combinations in clinically relevant preclinical models and early-phase proof-of-mechanism clinical trials (that include pharmacokinetics [PK], molecular pharmacodynamic [PD] assays, and imaging) could lead to the translation of new agents into later-stage GBM clinical trials.

Overall:

• Each multi-institutional team in the GTN will propose, using the U19 mechanism, a minimum of two scientific projects focused on agent(s) that have completed or are solidly in lead optimization status and are new to the treatment of GBM.
• Each U19 team must be composed of investigators from two or more institutions, two of which are capable of independently accruing patients to GTN clinical trials, and may be led by multiple PD/PIs, to accelerate the development of the candidate agent(s) proposed.
• Required components of each U19 are an Administrative Core; two Research Projects; and one Shared Resources Core that serves at least one Research Project. Additional Research Project(s) and Shared Resources Core(s) may be included. Projects and cores within each team should demonstrate synergy that could not be accomplished without extensive intra-U19 collaborations among components. Each U19 should propose integrated clinical activities to move agents from pre-clinic to the clinic including the preparation of an IND.
• U19 applicants have the option to apply for the Network Coordination Center.
• Although components of each multi-disciplinary U19 team will vary with the development stage and type of the proposed agent(s), it is anticipated that successful U19 teams will include outstanding expertise and experience in small molecule or biologics development, such as medicinal chemistry, pre-IND in vivo modeling, drug development (drug formulation, scale-up, ADMET, PK/PD assays and imaging), and clinical trial development and execution; it is imperative that each team include all the necessary expertise to advance the agent(s) to the clinic.
• There should be cooperation between teams so that reagents, assay protocols, animal models, patient samples, technologies, and development of clinical protocols are shared. As some teams will be further along in the process than others, when any one of the teams is ready to test their agent(s) in a pilot clinical trial, all other U19 sites are highly encouraged to participate as secondary sites as guided by the GTN Steering Committee and the NCI.
• As a cooperative agreement, a high level of programmatic guidance on trans-U19 coordination is expected.

Refer to the NCI BSA meeting videocast (May 12, 2020) and the associated GTN slide set for further details on the GTN. Information specific to biopharmaceutical development may be found here.

Research Projects and Shared Resources Cores:

• Projects focusing on small molecules are preferred; biologic agents that target either the tumor or the immunosuppressive microenvironment and that meet the criteria for this concept may be proposed.
• Research Projects may be hypothesis-driven or hypothesis-generating. Specific Aims of a Research Project may encompass preclinical and/or clinical studies.
• Each Research Project must be led by a minimum of two co-leaders: one laboratory scientist and one clinical researcher.
• Agent(s) should have completed, or be solidly in, the lead optimization stage of drug discovery and must be new to the treatment of GBM. If an agent has shown promise in preclinical studies but is still at the lead identification stage of drug discovery, the investigators will have to state how they will reach lead optimization within one year.
• Published or preliminary data demonstrating success in discovery of one or more Development Candidates is necessary for FOA responsiveness. Specifically, data demonstrating the following for new or repurposed agents are required: validation of the proposed target(s) for GBM; process of lead selection, including preliminary structure-activity relationship data if the agent is a small molecule; potent target activity (IC50 in primary assay); selectivity for tumor versus normal cells, and selectivity for the proposed target versus analogous targets; preliminary chemical solubility; exploratory PK, metabolism and toxicology; and in vivo testing in at least one model of GBM.
• Successful development of agents for GBM will depend on the use of preclinical models that closely mimic human adult GBM including assessment of passage through the BBB and ideally allow for repeated assessment of tumors over the course of disease treatment.
• Availability of primary human GBM samples and PDX models will also be important for efficacy testing in vitro and in vivo and, possibly, development of predictive biomarkers to guide early-stage clinical studies.
• In the preclinical phases of the studies, inclusion of existing NCI resources is encouraged, when available and appropriate for the proposed study. These resources may include but are not limited to those in the NCI Developmental Therapeutics Program, the PDX Models Repository, the NCI Formulary, the DCTD Clinical Pharmacodynamic Biomarkers Program, and the Cancer Immune Monitoring and Analysis Centers (CIMACs). Applicants to this FOA may include expertise from contract research laboratories or through public-private partnerships.

Network Coordination Center (NCC):

• The GTN will require one independent Network Coordination Center (NCC) to provide network harmonization on scientific and clinical activities. U19 teams may propose the NCC as one component of the U19 application; the NCC must be located at the U19 primary institution.
• Applications for the NCC component should provide a detailed work scope including administrative coordination of the GTN; coordination and standardization of biospecimen procurement, biobanking, and transport practices; coordination of model sharing; development of standard operating procedures for the functioning of the network and data management; support of meetings and communications among members of the GTN; and formation and maintenance of a GTN website. Because the onset of funding of the NCC will coincide with that of the U19s, the detailed scope of research resources and functions that the NCC will provide remains to be determined. Therefore, the NCC applicant's organization needs to demonstrate broad expertise and flexible capabilities in the functions listed above.
• Additional funds ($300,000 in direct costs per year) will be allowed for the Network Coordination Center component. Only one NCC will be chosen by the NCI for the GTN and will be guided by peer review.

Steering Committee (SC):

A Steering Committee (SC) will be formed during the first year of the GTN.

• Composition of the SC will include representatives from (i) each of the U19 teams including the Coordination Center, (ii) NCI staff including intramural GBM investigators and Program Officials, and (iii) possibly other funded GBM investigators including Brain Tumor SPORE awardees, radiation oncologists with GBM expertise, and industrial partners.
• The SC will be responsible for establishing criteria required to move an agent into clinical trials and will determine the readiness of GBM therapeutic candidates from the GTN or from other NIH programs (such as NExT or NINDS) to enter clinical studies.

The following non-exhaustive list of examples, in support of a focused drug development effort, if included, would be responsive to this RFA. Studies that:

• Investigate small molecules or biological agents that have not been tested in GBM clinical trials. Included are studies of agents at or beyond the lead optimization stage of drug development that:
• address a target or process that is new to GBM;
• target a challenging aspect of GBM biology such as infiltration into brain parenchyma or passage through the BBB;
• address a known GBM target in a novel way (for example an allosteric inhibitor rather than one that inhibits an enzyme’s active site or an alternate up- or downstream protein in a molecular pathway);
• are repurposed and approved for other indications and have shown strong preclinical data in GBM.
• Assess combination(s) of new agents with standard-of-care chemotherapy and/or radiation therapy.
• Assess combination(s) of new agents with non-standard-of-care treatments.
• Assess whether single agent(s) and combinations reach their molecular target(s) at the concentration(s) required for adequate drug effect, in preclinical model(s) and/or proof-of-mechanism clinical studies.
• Investigate novel immunotherapies for GBM that are at advanced stages of pre-clinical development. Studies of immunosuppression, use of syngeneic or humanized animal models, and development of predictive and prognostic biomarkers of response and resistance are responsive.
• Investigate novel RT approaches and GBM radio-sensitizing agents that are at advanced stages of pre-clinical drug development.
• Investigate RT effects on the BBB and the impact of barrier disruption on entry of the proposed novel agent across BBB.
• Employ existing GBM preclinical animal models with demonstrated relevance to human GBM. It is likely that projects will require a panel of in vivo models to reflect heterogeneity of tumor cells and the complex microenvironment of GBM.
• Use human pre- and post-surgical specimens for preclinical studies to assess proof-of-mechanism or resistance mechanisms.
• Further develop and test molecular and functional imaging capabilities in preclinical and clinical settings. As only a subset of GBM patients qualify for surgical resection, developing advanced functional imaging capabilities that could study drug effect non-invasively is a critical necessity.
• Leverage industry support, when possible, to expand the portfolio of drugs available for preclinical testing.

The following applications will be considered non-responsive to this FOA and will not be reviewed:

• Applications that are not multi-institutional or where at least two institutions are not capable of independently accruing patients to clinical trials.
• Applications that focus on cancers other than adult GBM.
• Studies that focus solely on the biology of GBM and its tumor microenvironment and not on the development of novel therapeutics for GBM.
• Applications proposing extensive model development.
• Applications proposing early drug discovery projects.
• Applications that lack GBM-specific preclinical data on the candidate drug(s).
• Applications that cannot or will not work together with either the NCC or the Steering Committee.

IMPORTANT NOTE: Applicants uncertain as to whether their intended project meets the requirements of this FOA are encouraged to contact the Scientific/Research Contact listed below in Section VII.

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

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

Higher Education Institutions

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

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

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

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

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) 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.
• o NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

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

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

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

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

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).

The application forms package specific to this opportunity must be accessed through ASSIST or an institutional system-to-system solution. A button to apply using ASSIST is 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 Multi-Project (M) Instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise and where instructions in the Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

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

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

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

The letter of intent should be sent to:

Suzanne Forry, PhD
National Cancer Institute (NCI)
Telephone: 240-276-5922
Fax: 240-276-7897
Email: [email protected]

Available Component Types	Research Strategy/Program Plan Page Limits
Overall	12
Admin Core	12
Core(s) (use for Shared Resources Core)	12
Project (use for Research Projects)	12
GTN Network Coordination Center Component (optional)	12

Additional page limits 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 a multi-component application.

The application should consist of the following components:

• Overall: required
• Administrative Core: required, maximum of 1
• Shared Resources Core(s): minimum of 1, maximum of 4
• Projects: minimum of 2, maximum of 4
• Network Coordination Center Component: optional

When preparing your application, use Component Type Overall .

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

Complete entire form.

Note: Human Embryonic Stem Cell lines from other components should be repeated in cell line table in Overall component.

Follow standard instructions.

Facilities and Other Resources:

• In addition to standard items, describe existing facilities and/or other resources (such as existing institutional shared resource cores) available to the proposed U19.
• As applicable and pertinent to the proposed research, describe partnerships (e.g., with industrial entities) that will provide relevant capabilities.

Enter primary site only.

A summary of Project/Performance Sites in the Overall section of the assembled application image in eRA Commons compiled from data collected in the other components will be generated upon submission.

Include only the Project Director/Principal Investigator (PD/PI) and any multi-PDs/PIs (if applicable to this FOA) for the entire application.

A summary of Senior/Key Persons followed by their Biographical Sketches in the Overall section of the assembled application image in eRA Commons will be generated upon submission.

The only budget information included in the Overall component is the Estimated Project Funding section of the SF424 (R&R) Cover.

A minimum total effort for each Overall PD/PI or MPI of the U19 is 2.4 person months (PM) in aggregate for all functions served on the U19; effort cannot be reduced below this level during the entire project period.

A budget summary in the Overall section of the assembled application image in eRA Commons compiled from detailed budget data collected in the other components will be generated upon submission.

Specific Aims: List the aims of the proposed U19. Summarize the expected outcome(s) of the U19 as a whole, including the impact that the results of the proposed translational research will have on GBM treatment. Briefly describe how the U19 is structured and how the Research Projects and Shared Resources Core(s) alone and together fit into the overall goals.

Research Strategy: This section should summarize the structure and the overall research strategy for the multi-component, multi-institutional application. The overall concept of the U19 should be conveyed by describing how the development and testing of novel therapies for GBM will be approached. Summarize the special features in the environment and/or resources that make this U19 strong or unique to the overarching goals of the GTN. The Research Strategy should be organized into sections that address the following: Overall Significance; Overall Innovation; Overall Approach; Overall Investigators; and Overall Environment. Specifics of Research Projects and Cores should be described separately.

Overall Significance

• Describe why the proposed U19 is important in the context of the known challenges to treatment of GBM.
• Explain how successful development and testing of the novel therapeutic agent(s) proposed could change clinical treatment of GBM.

Overall Innovation

• Describe the therapeutic agent(s) and/or combinations that are new to the treatment of GBM. If similar agents and/or combinations have been tested in preclinical or clinical studies of GBM, explain how those in the U19 are novel, with increased likelihood to succeed.
• Summarize the novel theoretical concepts approaches/methodologies, instrumentation, or intervention(s) to be developed or used in the Research Projects and/or Shared Research Cores.
• Describe innovative approaches in proposed clinical trials that are likely to provide results that will move the study along the translational continuum.

Overall Approach

• Include an overview schematic of the structure of the U19 and the interactions and collaborations among the U19 components. Include outside resources (e.g., contracts, industry) that will provide resources or expertise, even if funding is not requested through the U19.
• Provide a narrative description of the overall structure that clearly outlines all resources and expertise to move the novel therapeutic agent(s) and/or combination(s) from drug development to preclinical testing and into Phase I clinical trials. Provide a rationale for the selection of Research Projects and Shared Resources Core(s).
• Provide preliminary data that led to proposing the U19 application. Detailed preliminary studies sections should be included in the individual Research Projects and Shared Resources Cores. Cross-reference information when applicable.
• Explain how the proposed Research Projects and Shared Resources Core(s) will, together, address the overall goals of the U19.
• State the overall milestones of the U19 that are anticipated in the funding period.
• For foreign components of the U19, describe how these components present special opportunities for furthering research advancements using talent, resources, populations, or environmental conditions that exist in other countries and are not readily available in the United States or augment existing U.S. resources.

Overall Investigators

• Succinctly describe specific expertise of the Overall PDs/PIs and Project Leaders that makes them appropriate for their associated roles on the U19 team, without duplicating information in biosketches. For the Overall PD(s)/PI(s), describe prior experience leading multi-institutional, multi-disciplinary research endeavors.
• Describe how this selected team has collaborated and published together in the past.
• Describe how the scientific, clinical and/or technical expertise of the U19 team is complementary and will strengthen the GTN.

Overall Environment

• Summarize the unique aspects of the participating organizations that are important to the success of the U19.

Describe how the scientific, clinical and/or technical resources of the U19 team will strengthen the GTN, without duplicating information in the facilities and resources sections.

PHS Human Subjects and Clinical Trials Information (Overall)

When involving human subjects research, clinical research, and/or NIH-defined clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, there must be at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record within the application. The study record(s) must be included in the component(s) where the work is being done, unless the same study spans multiple components. To avoid the creation of duplicate study records, a single study record with sufficient information for all involved components must be included in the Overall component when the same study spans multiple components.

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

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

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

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

When preparing your application, use Component Type Admin Core.

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

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

Enter Human Embryonic Stem Cells in each relevant component.

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Core Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget forms appropriate for the specific component will be included in the application package.

The U19 overall PD/PI(s) is/are expected to serve as Core Lead of the Administrative Core with a minimum effort of 0.6 person months. If multiple PD/PIs serve as co-leads of the Administrative Core, each is expected to devote at least 0.6 person months. The minimum total effort for each PD/PI or MPI of the U19 is 2.4 person months in aggregate for all functions served on the U19.

Restricted Funds for trans-GTN Projects

• Each U19 must have a special restricted Pilot Project Fund of $50,000 direct costs for supporting the U19's trans-GTN pilot projects. For years 1-5 of the U19, these funds must be allocated in the "Other Expenses" category on the Budget form as "Restricted Funds for Pilot Projects."
• Approval of the NCC and NCI staff is required for the release of restricted funds for proposed pilot projects.
• The funds to support approved pilot projects will be allocated to the U19 awardee institution.

Travel

Travel funds must be included in the proposed budget to support travel for at least one U19 PD/PI to participate in face-to-face Steering Committee Meetings, if appropriate.

If an NCC component is included, budgets and activities for the proposed NCC and the U19 Administrative Core should not overlap.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

Specific Aims: Succinctly describe the specific objectives and goals of the Administrative Core.

Research Strategy: The following aspects should be addressed:

Leadership

• For U19 leadership, describe prior experience leading large research endeavors with complex budgets.
• Describe and/or diagram the chain of responsibility for decision-making and administration.
• Provide a succession plan which describes the process by which new leadership will be selected if the U19 PD(s)/PI(s) is no longer willing or able to lead the U19 Program.

Administrative management

• Describe the plans for the fiscal management, clerical support, manuscript preparation, and compliance to NIH public access policy (PMCID), and meeting organizations.
• Discuss how quality control in U19 Research Projects, Core(s), and associated institutions will be administered.
• Indicate the relationship of the Administrative Core to the administrative structure of the applicant institution and partnering institutions

Planning and evaluation

• Describe the function and intended areas of expertise of a required internal advisory board
• Describe how progress of the U19 will be internally evaluated during the project period, how milestones will be assessed, and how decisions to initiate changes will be made.
• Address how the U19 team will handle potential problems and provide alternative strategies in case of milestone delay or failure.

Integration of U19 components

• Explain how coordination and communication among the Research Projects, Shared Resources Core(s), and participating institutions will be achieved at the overall program level.

Interactions with other U19s

• Address how decisions on the use of yearly trans-U19 Pilot Project Funds will be made. Explain the process for soliciting, reviewing and selecting pilot collaborative projects. Examples of pilot collaborative projects could include model sharing; high-risk, high-reward projects; assay development; technology development.

Communication with Network Coordination Center

• Provide a statement of commitment with specific plans to collaborate with the designated NCC for (1) trans-GTN sharing of resources, and (2) participation in clinical trials as therapeutic agents are approved by the GTN Steering Committee.
• If an NCC component is proposed, describe how independence of the two administrative groups will be assured.

Letters of Support: Provide letters of support from the Institution(s) and members of the Internal Advisory Board.

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

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
• Sharing of genomic data should be consistent with respective NIH and NCI policies (see https://datascience.cancer.gov/data-sharing/genomic-data-sharing).

Appendix:

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

When involving human subjects research, clinical research, and/or NIH-defined clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the SF424 (R&R) Application Guide must be followed

When preparing your application, use Component Type Core.

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

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

Enter Human Embryonic Stem Cells in each relevant component.

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

ASSIST will default to Project Lead . If you would like to use a different category, then replace Project Lead below with a different Category (e.g., Core Lead).

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Core Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget forms appropriate for the specific component will be included in the application package.

Budgets are also required for each consortium (subcontract) if they are part of any Core.

Core Lead (s) must commit to a minimum of 0.6 person months of effort.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

Specific Aims: List in priority order, the broad activities and services of the proposed Core. In addition, state the Core's relationship to the U19's goals and how the Core relates to one or more of the Research Projects in the application.

Research Strategy: Shared Resources Cores may be proposed as distinct components that support non-hypothesis-driven research activities for one or more of the Research Projects of the U19. Shared Resources Cores may include but are not limited to Clinical, Biospecimen, Biostatistics/Informatics, Medicinal Chemistry, Preclinical Drug Development, or Animal Studies Cores.

• Describe the facilities and/or services that will be provided, how the facilities and/services will meet the specific needs of each project, a prioritization plan for providing the services, and plans for quality control. State the rationale for centralizing activities in a Core rather than including them in individual projects.
• Indicate why the Shared Resources Core is an essential part of the U19, and how the proposed services will facilitate accomplishment of the proposed goals and milestones of the U19.
• If the Core is at a different geographic location than the Research Projects it serves, describe plans for data/sample transfer and communication.
• Describe the role(s) of the Core Lead and key participants, and do not duplicate information provided in the Biosketches or the Budget Justification.
• Shared Resources Cores should not duplicate resources already available at the institution. If the Core augments an existing shared resource supported by an NCI Cancer Center Support Grant (P30), describe how this Core augments or complements the existing resource. The activities of Shared Resources Cores must not overlap with each other or with the activities of a Research Project.

Letters of Support: Provide letters of support from collaborators detailing nature and extent of participation.

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

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
• Sharing of genomic data should be consistent with respective NIH and NCI policies (see https://datascience.cancer.gov/data-sharing/genomic-data-sharing).

Appendix:

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

When involving human subjects research, clinical research, and/or NIH-defined clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the SF424 (R&R) Application Guide must be followed

When preparing your application, use Component Type Project.

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

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

Enter Human Embryonic Stem Cells in each relevant component.

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

ASSIST will default to Project Lead . If you would like to use a different category, then replace Project Lead below with a different Category (e.g., Core Lead).

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Project Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget forms appropriate for the specific component will be included in the application package.

Each Research Project must be led by a minimum of two co-leaders: one laboratory scientist and one clinical researcher. Each Project Leader should devote at least 1.8 person months effort (15%).

If the Research Project involves a clinical trial, the Applicant is responsible for including the costs of all support for statistical design, data collection, analysis and management, data deposition into NCI or other portals and ClinicalTrials.gov, as well as costs for clinical site monitoring, project management and quality assurance. If clinical trial costs will be covered by sources other than the U19, applicants should indicate the source of funds and provide letters of support. Alternatively, these costs can be incorporated into the budget of relevant Shared Resource Cores. Specific cross-references should be made to clarify how these necessary functions will be supported.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

A U19 Research Project may focus on preclinical research and/or clinical trial(s). Projects may include hypothesis-driven, hypothesis-generating and/or milestone-driven Aims. Aspects of the research that are covered by Shared Resources Cores should be clearly cross-referenced in the Research Plan.

Specific Aims: List the Aims of the proposed Research Project. Concisely describe the hypothesis or hypotheses to be tested and/or milestones to be achieved. A timeline of specific tasks over the project period is encouraged. In addition, state the individual Research Project's relationship to the U19's overall goals and milestones and how it relates to other Research Projects or Cores.

Research Strategy:

Significance

• Explain the critical barrier(s) to GBM treatment that the proposed Research Project addresses, and how the GBM research field and clinical care will be changed if the proposed aims are achieved.
• Describe the scientific premise for the proposed Project, including consideration of the strengths and weaknesses of published research or preliminary data crucial to the support of the Project.
• Discuss how the proposed project relates to therapeutic development efforts underway in academia and industry.
• For Projects focused on agent drug development, explain the importance of the target, the novel agent and/or the therapeutic combination for improved treatment of GBM.
• Explain how the proposed Project will improve scientific knowledge, technical capability, and/or clinical practice in GBM.

Innovation

• Explain how the Project challenges and seeks to shift current translational research or clinical practice paradigms.
• For projects focused on development of a lead compound or agent, repurposed agent, or combination, describe the novelty of the proposed therapeutic agent(s) and/or combination(s) for treatment of GBM. If similar agent(s) or combinations were previously tested in GBM, provide a rationale for pursuing the agents and/or combinations proposed in the U19.
• Describe any novel theoretical concepts, approaches or methodologies, instrumentation or intervention(s) to be developed or used, and any advantage over existing methodologies, instrumentation or intervention(s).

Approach

• Describe the overall strategy, methodology, and analyses to be used to accomplish the specific aims of the project. Include how the data will be collected, analyzed, and interpreted. Emphasize how the experimental design and methods proposed will achieve robust and unbiased results.
• Discuss potential problems, alternative strategies, benchmarks, and milestones for success anticipated to achieve the specific stated aims and the overall aim of testing in clinical trials in the 5-year grant period.
• Discuss plans for collaborations with Research Project(s) in the U19, Shared Research Cores, contractors, and/or industry.

Non-clinical Research: Applicants should refer to slide 5 of the GTN slide set for description of drug discovery and development activities necessary to reach IND filing and entry into Phase I clinical trials. Development Candidates, i.e., drug-like small molecules or biological therapeutics at or beyond the "preclinical development" stage, are preferred for this FOA.

• For Projects pursuing agents that have not completed activities of the "lead optimization" stage,
• describe how an optimal Development Candidate will be identified within one year of the start of the U19.
• For all proposed Development Candidates (novel or repurposed agents), provide published or preliminary data demonstrating:
• validation of the target/pathway addressed by the agent(s) for GBM pathogenesis;
• process of Development Candidate selection: e.g., structure-activity relationship (SAR) data and chemical structure (small molecules only);
• exploratory PK, metabolism and toxicology;
• in vivo testing in at least one model of GBM
• for small molecules only: potency, selectivity (vs. normal cells and analogous targets), solubility;
• for biologics only: qualification of assays for identity, purity, potency; genetic optimization; production of adequate material to support product characterization and animal efficacy studies from a single batch or from batches shown to be equivalent.
• For all proposed Development Candidates (novel or repurposed agents), provide preliminary data and/or a plan to address the following:
• scale-up and formulation;
• PK, particularly penetration of the BBB;
• ADME and GLP toxicology (testing of effects on cognition is encouraged);
• efficacy studies with agent delivered by the clinically intended route;
• a feasible path to the clinic; and
• generation and filing of the IND.
• In addition, for biologics provide data or plans for the following as appropriate for the type of agent: generation of master cell and/or virus banks; generation of reference standard material; accelerated stability studies; range finding studies; and tissue cross-reactivity studies.
• If preclinical model(s) are included, present the rationale for the models that are chosen, and the relevance of the proposed model(s) to human adult GBM. For animal models, address methods for measuring adequate delivery through the blood-brain-barrier. Describe how the design of the animal studies may lead to design of clinical studies in human adult GBM.
• Describe how potential chemical, biological, or drug development pitfalls will be addressed, and effects of these obstacles on timely achievement of U19 milestones.

Clinical Trials:

Provide a clinical study synopsis keeping the relevant review criteria in mind, but do not duplicate information in the required clinical trial documents (e.g., PHS Human Subjects and Clinical Trials Information Form or IRB-approved clinical trial protocol):

• Describe the scientific rationale/premise of the study(ies) that is/are based on previously well-designed preclinical and/or clinical research.
• Describe the planned analyses, PK and PD assessments and statistical approach for the proposed study design.
• Demonstrate that the eligible population of patients is available within the institutions for study.
• Address potential ethical issues.
• Describe how the recruitment timelines are feasible for adequate accrual.
• Address the differences, if applicable, in the intervention effect due to sex/gender and race/ethnicity.
• Describe the plans to standardize, assure quality of, and monitor adherence to, the clinical protocol and data collection or distribution guidelines.
• Describe the plan to obtain required study agent(s), if not within one or more of the applicant institutions.
• Describe how existing available resources, as applicable, will be used.
• Describe the procedures for data management and quality control of data at clinical site(s) or at U19 laboratories, as applicable.
• Describe the methods for standardization of procedures for data management to assess the effect of the intervention and quality control.
• Describe the plan to complete data analysis within the proposed period of the award.
• Include information on preliminary studies, data, and/or experience of the co-leaders of the Project that are pertinent to the Project.

Letters of Support: Provide letters of support from collaborators detailing nature and extent of participation including letters for functions not supported by the U19 budget.

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

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
• Sharing of genomic data should be consistent with respective NIH and NCI policies (see https://datascience.cancer.gov/data-sharing/genomic-data-sharing).

Appendix:

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

• Draft or IRB approved protocols can be attached to the appendix

When involving human subjects research, clinical research, and/or NIH-defined clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the SF424 (R&R) Application Guide must be followed

When preparing your application, use Component Type Network Coord Ctr.

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

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

Enter Human Embryonic Stem Cells in each relevant component.

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

ASSIST will default to Project Lead . If you would like to use a different category, then replace Project Lead below with a different Category (e.g., Core Lead).

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of NCC Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget forms appropriate for the specific component will be included in the application package.

The maximum budget per year for the NCC is $300,000 direct costs.

The NCC Lead(s) must commit a minimum of 0.6 person months effort each. Overall U19 PD/PI(s) are restricted from also serving as NCC Leads.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

The overarching function of the Network Coordination Center (NCC) is to provide harmonization of scientific and clinical activities of the U19 teams comprising the GTN. Applicants who wish to apply for this role should provide a detailed work scope including:

• Administrative coordination of the GTN;
• Coordination and standardization of biospecimen procurement, biobanking, and transport practices;
• Coordination of model sharing;
• Development of standard operating procedures for the functioning of the network and data management;
• Support of meetings and communications among members of the GTN and with the GTN Steering Committee; and
• Creation and maintenance of a GTN website.

Because the onset of funding of the Coordination Center will coincide with that of the U19's, the detailed scope of research resources and functions that the NCC will provide remain to be determined. Therefore, the NCC applicant needs to demonstrate broad expertise and flexible capabilities in bioinformatics, biostatistics, data management, and GBM modeling approaches relevant to the support of GBM research and clinical trials.

The design of the GTN website should allow for public accessibility for the broadest audience including patients, advocacy groups, and the general public. Initially, the website should include basic information about the GTN such as goals, Principal Investigator's contact information, and the scope of the U19s. In the future, it is expected that the public facing GTN website will include GTN achievements (e.g., publications, clinical trials). The website should also feature a restricted access site for U19 grantees to serve as a location for sharing of privileged and sensitive information, preliminary data, and information not ready for public release.

Specific Aims: List the specific aims of the Network Coordination Center.

Research Strategy:

• State the features of the institution and the NCC team that are uniquely suited for leadership of the NCC.
• Address the necessary functions of the NCC and describe optional capabilities available at the NCC institution.
• Address flexibility to realign resources and expertise based on the needs of the GTN.
• Describe the process for fair and unbiased decision-making and dispute mediation between U19s.
• Discuss how quality control and communication across the U19s will be administered.
• Provide a timeline for the key functions of the NCC
• Describe the clinical trials management system that will be used for all network trials.

Letters of Support: Provide letters of support relevant to the Network Coordination Center component.

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

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
• Sharing of genomic data should be consistent with respective NIH and NCI policies (see https://datascience.cancer.gov/data-sharing/genomic-data-sharing).

Appendix:

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

When involving human subjects research, clinical research, and/or NIH-defined clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the SF424 (R&R) Application Guide must be followed

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) using ASSIST or other electronic submission systems. 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.

For information on how your application will be automatically assembled for review and funding consideration after submission go to: http://grants.nih.gov/grants/ElectronicReceipt/files/Electronic_Multi-project_Application_Image_Assembly.pdf.

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

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

Important reminders:

All PD(s)/PI(s) and component Project Leads 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.

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 (SAM). 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 components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

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

Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

For this FOA, note the following:

A meritorious GTN U19 application is expected to be well-balanced in interdisciplinary science that spans expertise in both GBM drug development and research implementation in early phase GBM trials. The overarching goal of the GTN is to increase treatment options for patients diagnosed with GBM and have transformative potential to impact disease progression or recurrence. Exemplary applications should articulate how the proposed drug development will produce new and effective treatment strategies for patients with GBM.

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

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the U19 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 U19 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 U19 component that by its nature is not innovative may be essential to advance a field.

Does the U19 address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the U19 are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

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

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the U19? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

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

Specific to this FOA: Do the Overall PD/PI(s) have experience leading multi-institutional, multi-disciplinary research program(s), which may predict success of the U19?

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

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

Specific to this FOA: Are the proposed therapeutic agent(s), repurposed drugs, and/or drug combinations new to the treatment of GBM? If similar agent(s) or combinations were previously tested in GBM, is there a clear rationale for pursuing the agents and/or combinations proposed in the U19? Does this U19 uniquely combine preclinical drug development, GBM modeling, and allied technologies with clinical trial principles in a manner that may produce a novel therapeutic strategy for patients with GBM?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the U19? Have investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the U19 involves human subjects and/or NIH-defined clinical research, are the plans to address:

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

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

Does the application adequately address the following, if applicable:

Study Design

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

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

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

Data Management and Statistical Analysis

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

Specific to this FOA: Is the approach of the U19 adequate to move the novel therapeutic agent(s) and/or combination(s) from drug development to preclinical testing and into Phase I clinical trials? Assess the likelihood that the U19 will, as an integrated effort, achieve the stated Overall Aims and meet proposed milestones.

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

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

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

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

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

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the Research 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 Research Project proposed).

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

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

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

Specific to this FOA: If the project includes in vitro and/or in vivo models, are the models relevant to the treatment of human GBM?

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

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

Specific to this FOA:

• Is there adequate evidence of co-leadership of the project by basic and applied/clinical investigators in the conception, design, and proposed implementation of the project?
• Will the investigators commit adequate effort to successfully execute and manage the proposed Research Project?
• If applicable, are there investigators on the Project with experience and expertise in regulatory activities, including IND submissions?

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

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

Specific to this FOA: If similar agent(s) or combinations were previously tested in GBM, is there a rationale for how the proposed agents and/or combinations are new to GBM?

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

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

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

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

Does the application adequately address the following, if applicable:

Study Design

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

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

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

Data Management and Statistical Analysis

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

Specific to this FOA:

If the lead drug candidate has not yet been selected, is a strategy proposed to reach the lead optimization stage within a year, and is the strategy feasible?

Are assays, advancement criteria and/or data presented that are appropriate to the stage(s) of drug development, toward the goal of IND filing and transition to the clinic?

• Are plans for scale-up, formulation, pharmacokinetics (including penetration of the blood-brain barrier), ADME, GLP toxicology, and efficacy by the clinically intended route presented?
• If preclinical model(s) is/are included, is/are the relevance of the proposed model(s) to human adult GBM sound and scientifically meritorious?

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

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

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

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

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

Specific to this FOA, for Projects proposing clinical trials:

• Is there an adequate plan for communication among investigators at the multiple clinical sites?
• Are collections of biospecimens included in the protocol and if so, are collection, processing, and distribution adequate?

Reviewers will assign one numerical score based on the following criteria (these criteria do not receive separate scores).

Leadership

Are the scientific qualifications, involvement, leadership and time commitment of the Leader(s) sufficient for requirements of the proposed U19?

Administrative Management

• Does the plan for the Administrative Core adequately address administrative management including fiscal and data operations?
• Is the administrative and organizational structure clearly defined, and is it appropriate?
• Is there evidence that clerical and administrative personnel and quality controls are in place for the smooth running and total integration of the U19?
• Is there an adequate succession plan for U19 leadership?
• Is there a sufficient plan for conflict management?

Planning and evaluation

• Are there clear descriptions of the functions and intended areas of expertise of a required internal advisory board?
• Are there suitable descriptions of how the U19 will be evaluated during the project period, how milestones will be assessed, and how decisions to initiate changes will be made?
• Does the Administrative Core section include plans for how the U19 team will handle potential problems and provide alternative strategies in case of milestone delay or failure? Are the plans reasonable?

Integration of U19 components

Does this Core adequately facilitate communication and integration across all Projects and Shared Resources Cores?

Communication with Network Coordination Center

Is there an appropriate statement of commitment with specific plans to collaborate with the designated Network Coordination Center and to participate in clinical trials as therapeutic agents are approved by the GTN Steering Committee?

Reviewers will assign one numerical score based on the following criteria (these criteria do not receive separate scores).

Investigators

Are the qualifications, experience, and commitment of the Shared Resources Core Director(s) and other key personnel adequate and appropriate for providing the proposed facilities or services?

Approach

• Does the proposed plan demonstrate that the activities of the Core are well-integrated with those of the projects and that the investigators within the projects are working closely with those of the Core to meet project objectives?
• What is the overall quality of the proposed Core services and are adequate quality control processes proposed for the facilities or services provided by the Shared Resources Core (including procedures, techniques, and quality control)?
• Evaluate the criteria for prioritization and usage of Shared Resources Core products and/or services.
• If the Core is at a different geographic location than the Research Projects it serves, is the plan for data and/or sample transfer and communication adequate?
• Are the plans to augment and/or complement existing shared resources supported by an NCI Cancer Center Support grant (P30) adequate, if applicable?

Environment

Is the environment for the Shared Resources Core appropriate to support the program as proposed?

Reviewers will assign one adjectival score based on the following criteria (these criteria do not receive separate scores), but will be included in the overall impact score for the application.

Investigators

• Are the NCC Leader(s) and other personnel well suited to their proposed roles? Have they demonstrated experience in managing translational research?
• Do the investigators demonstrate significant experience with coordinating collaborative basic or clinical research in the setting of a multi-component grant?
• Does the NCC team include broad expertise in bioinformatics, biostatistics, data management, and GBM modeling relevant to the support of GBM research and clinical trials?

Approach

• Does the Research Strategy include feasible plans for:
• Administrative coordination of the GTN;
• Coordination and standardization of biospecimen procurement, biobanking, and transport practices as well as coordination of model sharing;
• Development of standard operating procedures for the functioning of the network and data management;
• Support of meetings and communications among members of the GTN and with the GTN Steering Committee; and
• Creation and maintenance of a secure GTN website? Are the plans for both public-facing and GTN-specific features of the GTN website suitable?
• Does the NCC plan demonstrate flexible capabilities in bioinformatics, biostatistics, data management, and GBM modeling relevant to the support of GBM research and clinical trials?
• Is the process outlined for fair and unbiased decision-making and dispute mediation between U19s adequate?
• Is the plan for administration of quality control and communication across U19s adequate?
• Is the timeline for performing NCC functions well planned and feasible?

Environment

• Are the institutional support, equipment and other physical resources available to the investigators adequate for the NCC proposed?
• Are there unique features of the NCC institutional environment, infrastructure, or personnel that will contribute to the probability of success?
• Are resources available within the scientific environment to support electronic information handling?

As applicable for the U19, Research Project, Shared Resources Core, or NCC proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Study Timeline

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

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

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

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

When the proposed U19, Research Project, Shared Resources Core, or NCC involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

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

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

Not applicable.

Not applicable.

Not applicable.

As applicable for the U19, Research Project, Shared Resources Core, or NCC 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 .

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

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

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), convened by the NCI in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

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

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

Applications will be assigned 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.

Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.

ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain applicable clinical trials on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols. Data and Safety

Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

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

Awardee-selected projects that involve {clinical trials or studies involving greater than minimal risk to human subjects} require prior approval by NIH prior to initiation.

• The awardee institution will comply with the NIH Guidance on Changes That Involve Human Subjects in Active Awards and That Will Require Prior NIH Approval.
• The awardee institution will provide NIH with specific plans for data and safety monitoring, and will notify the IRB and NIH of serious adverse events and unanticipated problems, consistent with NIH DSMP policies.

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 laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex. This includes ensuring programs are accessible to persons with limited English proficiency. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html.

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.

• Recipients of FFA must ensure that their programs are accessible to persons with limited English proficiency. HHS provides guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.html and https://www.lep.gov. 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 https://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.
• 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.
• HHS funded health and education programs must be administered in an environment free of sexual harassment. Please see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html; https://www2.ed.gov/about/offices/list/ocr/docs/shguide.html; and https://www.eeoc.gov/eeoc/publications/upload/fs-sex.pdf. For information about NIH's commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what NIH's expectations are for institutions and the individuals supported on NIH-funded awards, please see https://grants.nih.gov/grants/policy/harassment.htm.
• Recipients of FFA must also administer their programs in compliance with applicable federal religious nondiscrimination laws and applicable federal conscience protection and associated anti-discrimination laws. Collectively, these laws prohibit exclusion, adverse treatment, coercion, or other discrimination against persons or entities on the basis of their consciences, religious beliefs, or moral convictions. Please see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/index.html.

Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697.

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

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) 2 CFR Part 200 Administrative Regulations, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75, NIH Grants Policy Statement (which implements the aforementioned HHS Regulations (45 CFR Part 75), and other HHS, PHS, and NIH grant administration policies.

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

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

The PD(s)/PI(s) will have primary authority and responsibility to define objectives and approaches, and to plan, conduct, analyze, and publish results, interpretations, and conclusions of studies conducted under this program. The PD(s)/PI(s) assume responsibility and accountability to the applicant organization officials and to the NCI for the performance and proper conduct of the research supported by the U19 award. Specific responsibilities and rights include:

• Developing novel drugs and/or combinations for testing in clinical trials;
• Working with the Network Coordination Center (NCC) to collaborate with other U19 teams to conduct clinical trials with appropriate target enrollment; and to share data, models, specimens, and agents;
• Participation in GTN meetings, working groups, and/or teleconferences as needed;
• Implementation of the data sharing plan; Institutions/organizations participating in the GTN will be expected to share knowledge, data, research materials, and any other resources necessary and relevant to the GTN;
• Serving as a voting member of the GTN Steering Committee;
• Adhering to the Steering Committee and NCC recommendations and policies (to the extent consistent with applicable grants regulation) to ensure that the preclinical and clinical goals of the network are accomplished.

In addition, Network Coordination Center Leader(s) will have responsibility for:

• Administrative management of the GTN;
• High quality, timely execution of all NCC services to the GTN;
• Overseeing efficient operations of the NCC;
• Ensuring compliance of the NCC with government regulations;
• Assuring security of all databases;
• Overseeing quality control in all data and materials collections;
• Assisting in establishing Standard Operating Procedures together with the Steering Committee.
• Communicating with the NCI-designated government representatives; and
• Ensuring that the tools developed within the NCC under this FOA are freely available to all GTN members.

Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

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

Designated NCI Program Staff member(s), acting as Project Scientist(s), will participate in the following activities:

• Assisting in avoiding unwarranted duplications of effort across the GTN;
• Helping to coordinate collaborative research efforts that involve multiple U19 awardees;
• Aiding in directing U19 awardees to NCI resources which may be helpful to the goals of the U19;
• Monitoring the operations of the U19s and making recommendations on overall project directions;
• Reviewing the progress of individual U19s and making recommendations on overall project directions;
• Participating in establishing Standard Operating Procedures, with the Steering Committee;
• Participating in the development and evaluation of trans-U19 activities; and
• Assisting the GTN awardees as a liaison in stimulating their broader interactions with other NCI and NIH programs to disseminate results and outcomes and effectively leverage existing NIH/NCI resources and infrastructures (e.g., databases).

In addition, an NCI Program Director acting as the Program Official will be responsible for the normal scientific and programmatic stewardship of the awards and will be named in the award notice. The Program Official may also have substantial programmatic involvement as a Project Scientist.

Areas of Joint Responsibility include:

Steering Committee

A Steering Committee will be the governing body of the GTN and will be formed during the first year of the GTN. The Steering Committee will be composed of the following members:

• One representative (an Overall PD/PI or a designated U19 senior investigator) from every U19 award;
• One representative from the NCC (an NCC PD/PI or a designated NCC senior investigator);
• NCI Project Scientist(s).

Additional members of the SC who will serve in an advisory capacity may include other NCI extramural staff; GBM investigators from the NCI intramural program; NCI SPORE or other NIH grant awardees not part of the GTN; radiation oncologists with GBM expertise; and industrial partners. Decisions on administration and leadership of the Steering Committee will be made at the initial meeting.

The Chair of the Steering Committee will be selected by a vote of the Steering Committee.

The Steering Committee will meet as needed by videoconference, teleconference, or in person (if warranted). The Steering Committee Chair will be responsible for scheduling SC meetings, in coordination with NCI Project Scientists.

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

Primary responsibilities of the Steering Committee include, but are not limited to, the following activities:

• Establishing criteria required to move an agent into clinical trials;
• Determining readiness of therapeutic candidates from the GTN or from other NIH programs (such as NCI NExT or NINDS) to enter clinical studies;
• Serving as a hub for a broader outreach to the entire extramural research community investigating GBM.

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 regulation 42 CFR Part 50, Subpart D and DHHS regulation 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, application errors and warnings, documenting system problems that threaten submission by the due date, and 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)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-945-7573

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

For general and preclinical inquiries:

Suzanne Forry, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-5922
Email: [email protected]

For inquiries on radiation therapy:

Michael Graham Espey, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-5690
Email: [email protected]

For clinical inquiries:

Bhupinder S. Mann, MBBS
National Cancer Institute (NCI)
Telephone: 240-276-6560
Email: [email protected]

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

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