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

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

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

The purpose of this funding opportunity announcement (FOA) is to invite applications for the Clinical Coordinating Center (CCC) of the Early Phase Pain Investigation Clinical Network (EPPIC-Net). EPPIC-Net will serve as the cornerstone of the NIH s Helping to End Addiction Long-term (HEAL) Partnership. EPPIC-Net will provide a robust and readily accessible infrastructure for the rapid implementation and performance of high-quality, comprehensive studies of patients with well-defined pain conditions, and the rapid design and performance of high-quality Phase 2 clinical trials to test promising novel therapeutics for pain. Studies will bring intense focus to relatively small numbers of patients with clinically well-defined pain conditions and high unmet therapeutic needs. Studies may be performed in either adult or pediatric populations. The network will be charged with testing novel, efficient study designs including adaptive and platform designs, validation studies of biomarkers, and biomarker-informed proof of principle or target engagement studies in phase 2 trials of interventions from academic and industry partners. EPPIC-Net will make clinical, neuroimaging, biomarker, and preclinical data, as well as biosamples, available through public access data and biospecimen repositories. It is anticipated that EPPIC-Net will be able to run at least five Phase 2 trials concurrently, in addition to deep clinical phenotyping and biomarker validation studies.

EPPIC-Net will consist of one CCC, one Data Coordinating Center (DCC), and approximately 10 specialized clinical centers (hubs). The CCC will both design and facilitate the implementation of clinical research protocols, including clinical trials. It will promote high quality and efficient timeliness in study execution using, among other tools, master trial agreements and a single Institutional Review Board (IRB), and will coordinate the selection and training of investigators across the network.

Clinical studies may come to the network from two sources:

(1) Clinical trials to test the efficacy of therapeutic candidates ( assets ) such as small molecules, biologics, and medical devices as contributed by academic or industry partners. More details on this are outlined in the Network Projects and Significant responsibilities of the CCC sections below.

(2) Clinical research studies aimed at understanding the biological basis of different pain states or validation of biomarkers for their utility in phase 2 studies. These studies would result from forthcoming FOAs from NIH.

Clinical studies may not be limited to these two sources, so EPPIC-Net must be flexible enough to incorporate studies from other sources as directed by the NIH.

Background

This program is part of the NIH Helping End Addiction Long-term (HEAL) Initiative, an effort to speed scientific solutions to stem the national opioid public health crisis. Opioid overdose deaths reached more than 42,000 annually in 2016 and more than 2 million Americans are addicted to opioids. There are also 25 million people, or 11% of the U.S. population, who experience daily chronic pain, many of whom are prescribed opioids for pain management. New treatment options for pain are needed to reduce the number of people exposed to the risks of opioids.

There is a clear public health imperative to stimulate and support research that improves the care and outcomes of patients with severe acute and chronic pain. The Federal Pain Research Strategy, published in 2017, identified the development of safer non-opioid analgesics as a top priority and specifically noted the need for the discovery and validation of new pharmacologic and non-pharmacologic targets for the treatment of pain. This was also identified as a priority in a series of cross-cutting meetings that convened experts from across government, industry, and academia to determine the high priority areas that could be addressed by a partnership across all sectors. There is a critical need for development of non-opioid pharmacologic and non-pharmacologic treatments for pain. It is also essential to study treatments that reduce the psychosocial and existential burden of pain associated with chronic medical illnesses such as cancer, complex regional pain syndrome, pancreatitis, polycystic kidney disease, headache and other craniofacial pain disorders, pelvic pain disorders, fibromyalgia, diabetic and chemotherapy related neuropathy, and sickle cell disease.

Low back pain represents an area of special interest for this FOA. According to National Health Interview Survey data, 20% of adults in the United States reported frequent back pain and 28% of adults experienced low back pain that lasted a whole day or more during the previous three months. Out of all 291 conditions included in the Global Burden of Disease 2010 Study, low back pain ranked highest in terms of years lived with disability. It is a tremendous public health and economic burden as well as a major contributor to the use of opioids in the US. Some non-opioid treatments appear to have mild to moderate effects on chronic back pain and function in some patients, and combination therapies are, in general, more effective than monotherapies. Currently there is no effective treatment that provides long term, sustained relief of back pain and disability for all patients.

In addition, there is an urgent need to optimize, and validate objective mechanistic biomarkers associated with pain conditions. It is also necessary to better understand the different biologic mechanisms that underly different pain conditions, as well as the mechanisms that tie common overlapping pain conditions together, through the intense clinical phenotyping of patients with specific pain conditions. This will enrich clinical study populations by allowing or improving cohort stratification, providing predictors of treatment responses, and demonstrating engagement of the therapeutic target.

To address these needs, EPPIC-Net will incorporate innovative designs to accelerate therapy development in well-phenotyped subpopulations of patients with well-characterized pain conditions. EPPIC-Net will perform comprehensive studies of the biologic basis of specific pain conditions, biomarker validation studies, and Phase 2 clinical trials to test interventions for their potential as efficacious, non-addicting treatments for acute and chronic pain.

Research Objectives

EPPIC-Net will harness multidisciplinary clinical, statistical, and data management expertise to provide the scientific leadership and infrastructure required to design and conduct multi-site Phase 2 clinical trials, biomarker validation studies, and deep phenotyping of patient populations to understand the biologic basis of a specific pain condition and its response to treatment. The overall goal is to accelerate development of non-addictive therapies for adult or pediatric patients with acute and/or chronic pain. Due to the enormous disease burden of low back pain (as outlined in the background), one further research objective of EPPIC-Net is to dissect the structures and mechanisms involved in chronic low back pain as well as to identify, prioritize and test new therapies targeted to these specific mechanisms.

The CCC will contribute to these objectives by providing scientific and organizational leadership for implementation of clinical studies in EPPIC-Net. The CCC will promote high quality and efficiency in trial execution, and efficient timeliness through such methods as pre-negotiated master trial agreements and a single Institutional Review Board (IRB). The CCC additionally organizes the EPPIC-Net governance committees and oversees training and quality assurance for study performance. The CCC is encouraged to be innovative and establish an iterative process of improving clinical trial efficiency and quality.

The CCC will also work with investigators from the NIH HEAL Partnership to develop and execute clinical trials based on meritorious assets, as described elsewhere in this FOA. The CCC will solicit appropriate expertise from the various hubs to develop biomarker-informed phase 2 clinical trial protocols matched to the specific asset. The clinical protocols will be targeted to defined pain conditions and designed with optimal go/no-go criteria as the primary trial outcome. For any particular asset, the CCC will work closely with the hub whose clinical population and PD/PI expertise is most closely aligned with the target patient population to develop a clinical protocol. Protocols deemed meritorious by NIH scientific peer review will be executed by the CCC in coordination with the hubs and DCC. In addition, the CCC may be tasked with facilitating and overseeing the execution of investigator-initiated clinical studies that result from forthcoming FOAs. It is anticipated that EPPIC-Net will be able to run as many as five Phase 2 trials concurrently, in addition to deep phenotyping and biomarker validation studies.

EPPIC-Net Organization

The EPPIC-Net will be funded by NIH, with NINDS as the lead institute. As described above, EPPIC-Net will consist of one CCC, one DCC, and up to 10 hubs with affiliated satellite spokes, with the capability to coordinate clinical research across different pain conditions in a large number of clinical centers across the United States.

As described below in more detail (see Clinical Coordinating Center: Roles and Responsibilities), the Clinical Coordinating Center (CCC) will provide scientific and organizational leadership to EPPIC-Net to achieve both efficiency and excellence in its implementation and performance of clinical trials. Responsibilities of the CCC will specifically include coordinating and managing the EPPIC-Net central IRB, establishing and managing master contract agreements with the clinical sites for trial performance, developing recruitment plans, coordinating investigator and coordinator training, tracking enrollment and overseeing quality improvement. In addition to coordinating clinical trials, the CCC will coordinate deep phenotyping and biomarker validation studies.

The Data Coordinating Center (DCC) will provide scientific and organizational leadership to EPPIC-Net in all aspects of data management, data quality, statistical design, statistical analysis, and through managing repositories for biosamples, clinical, neuroimaging, biomarker, and omics data. Responsibilities of the DCC particularly include management and support of the Data and Safety Monitoring Board (DSMB), and reporting to regulatory authorities (e.g., central IRB, FDA). The role and responsibilities of the DCC are described in RFA-NS-19-024.

The Specialized Clinical Centers (hubs) will provide scientific leadership and conduct clinical trials, prospective observational studies, and biomarker validation studies in the clinical centers. A Hub is envisioned as a regional academic medical center that will enroll patients directly and provide clinical and organizational leadership to a regional network of 2-10 satellite spokes that will also enroll patients. Each Hub must be capable of recruiting physicians and investigators for studies in a variety of pain conditions. Each Hub must be capable of recruiting physicians and investigators for studies in a variety of pain conditions. This will require broad pain expertise within the hub and spokes (e.g., neurology, rheumatology, obstetrics/gynecology, oncology, pediatrics, orthopedics, gastroenterology, or other subspecialty) and access to clinical populations from a wide variety of pain conditions. The roles and responsibilities of the Hubs and Spokes are described more fully in RFA-NS-19-025. In order to include the appropriate expertise on a given study or trial, EPPIC-Net will have the ability to include additional ad hoc hubs or spokes.

The CCC, DCC, hubs and spokes are each integral components of the network. The success of the network will require close, active cooperation and collaboration to assimilate these elements into a highly effective clinical research structure. Participants at all levels in EPPIC-Net are strongly encouraged to promote innovative methods to improve efficiency and quality in performance of clinical research. Additionally, the HEAL Partnership will enable consultation with representatives from industry, academia and pain-related non-profit organizations aimed at accelerating the goals of advancing NIH-funded pain research and accelerating the development of non-addictive pain treatments to reduce reliance on addictive opioids.

The FOAs for the CCC, DCC, and hubs will support cooperative agreements, under which the awardees will be expected to achieve previously agreed-upon milestones and metrics, as described in each of the FOAs.

Network Projects

Generally, appropriate clinical trials will be phase 2 trials to test novel drugs, biologics, and devices. It is possible that this could expand to natural products, surgical, or non-pharmacological interventions. EPPIC-Net will also incorporate studies including biomarker discovery and validation, and clinical studies to uncover underlying biologic mechanisms in specific pain conditions. In the planning phases of these studies, the CCC may be directed by NIH to work with the hub and satellite spokes to collate information about patients with pain conditions and perform deep phenotyping and clinical characterization.

More specifically, it is envisioned that clinical studies may come to the network in two ways:

(1) Academic or industry partners within the HEAL Partnership may propose clinical trials to test the efficacy of therapeutic candidates (e.g., novel drugs, biologics, and devices; assets ). These assets and trial protocols will be submitted to and reviewed under a different FOA. Expertise from the hubs will be critical in designing clinical trials around the highly prioritized assets. More details on this process are outlined below in Significant responsibilities of the CCC.

(2) Applications for clinical research studies aimed at understanding the underlying biologic mechanisms of different pain states or validation of biomarkers for their utility in phase 2 studies will be solicited through forthcoming FOA(s). NIH support of such studies will include additional funding for the CCC and other network components to coordinate the research with the study PI.*

*Note that NIH anticipates that the first examples of these kinds of studies will be focused on a patient-centric translational research program in low back pain. The goal of these studies will be to probe the biomedical mechanisms of low back pain in a biopsychosocial context using interdisciplinary methods and innovative technologies, so that novel treatments can be developed, tested and combined for a targeted, integrated and individualized approach to treatment.

Clinical studies may not be limited to these two sources, so EPPIC-Net must be flexible enough to incorporate studies from other sources in forthcoming FOAs as directed by the NIH. EPPIC-Net is intended as a multidisciplinary network reflective of the spectrum of clinical challenges confronted in pain management. Candidate therapies tested through clinical trials may come from academic investigators, investigators in military medical facilities, small business, industry, or other eligible institutions. The network may also be called upon to join or engage in other, on-going clinical trials in pain medicine. EPPIC-Net should be prepared to work collaboratively with other programs or networks, as a lead, partner or participant, as appropriate.

CCC: Roles and Responsibilities

The CCC provides scientific and organizational leadership to facilitate the conduct of clinical trials within EPPIC-Net. The CCC is the administrative center of EPPIC-Net, with responsibilities for contracts with sites for performance of clinical trials (master trial agreements with the clinical centers, other entities), planning budgets for proposed clinical trials, and disbursing payments to sites.

The CCC leads and manages the key EPPIC-Net governance committees:

The EPPIC-Net Steering Committee (ENSC)

The EPPIC-Net Management Committee (ENMC)

The EPPIC-Net Operations Committee (ENOC) (all described below).

The CCC has primary responsibility for establishing and communicating with the central IRB. The CCC is responsible for oversight of all aspects of trial enrollment and recruitment, from feasibility assessment, to planning, tracking and, if necessary, improvement plans. The CCC also is responsible for quality assurance related to clinical trials and to the overall performance of EPPIC-Net. The CCC will collaborate closely with the DCC, the hubs and spokes, the protocol PIs, and NIH.

The goal of EPPIC-Net is to implement each awarded clinical study efficiently and to the highest scientific standards. Since each clinical study will be unique, the CCC must be flexible in providing tailored solutions. Some examples are below:

- The CCC, together with the outside investigator from academia or industry ( asset owner ), will produce study-specific clinical protocols that will be submitted to a different FOA.

- Studies will require the CCC to engage expertise at the hubs or, in some cases, outside the network for trials in specific pain conditions. For certain studies such expertise could include orthopedics, anesthesia, neurology, physiatry, emergency medicine, oncology, diabetology, etc.

- The number and identity of clinical sites may be different in each clinical study, depending on the sample size and other considerations. Hubs and spokes will be selected based on the needs of the individual clinical trial.

- Some clinical studies may include out-of-network ad hoc clinical sites; in some rare circumstances some of these could be international.

- Some clinical studies may be performed in collaboration with other clinical networks.

- Some clinical studies may include such clinical venues as intensive care units, hospital wards, or outpatient clinics.

- EPPIC-Net is intended for adult and pediatric clinical studies.

Milestones will be determined at the time of award. Failure to meet the agreed upon milestones may result in reduced or restricted funding or early termination of the cooperative agreement (see Cooperative Agreement Terms and Conditions of Award).

Significant responsibilities of the CCC include the following:

a) Coordination of clinical trial protocol development on therapeutic assets.

Assets will be prioritized prior to being tested in the network. Of those that are deemed meritorious, the CCC will receive information on the assets and work with the asset-owner to solicit expertise from the various hubs (or ad hoc sites, if needed) to develop phase 2 clinical trial protocols matched to the specific asset. The CCC will receive information on the asset in the form of a dossier that will contain information on preclinical, clinical, and pharmacological data. The CCC will identify a PD/PI with expertise closely aligned with the target patient population for the asset to serve as the PI for the trial; this individual may be an EPPIC-Net hub PD/PI, or if appropriate expertise is not available within the network, the CCC may have to recruit expertise from an ad hoc site to serve as protocol PI for a given clinical trial. The CCC will provide guidance and serve as the coordinator between the asset-owner and the protocol PI.

The clinical protocols will be targeted to defined pain conditions in deeply phenotyped cohorts and will be designed to ascertain whether the intervention meets pre-specified go/no-go criteria for progressing to later stage development (i.e., Phase 3 industry-supported trials). The CCC will coordinate with the protocol PI to submit the asset-matched clinical protocol to a different FOA. This clinical trial protocol should be in the form of the standard template as outlined in NOT-OD-17-064. Of the clinical studies that are deemed highly meritorious by peer review, the CCC will then coordinate execution of the studies as outlined below.

b) Coordinating execution of clinical trials. When a clinical trial has approval from NIH, the CCC, along with the protocol PI, will be responsible for leading and coordinating the trial amongst the hubs and spokes as developed in the protocol. This includes working with the DCC to coordinate acquisition, storage, and dissemination of any asset that is being tested to distribute to the appropriate hubs and spokes. Further details of execution are outlined by topic area below.

c) Studies on low back pain. As NIH anticipates a forthcoming set of studies as part of the Back Pain Consortium (BACPAC) Research program. BACPAC is focused on chronic low back pain research using novel, inter and multidisciplinary integrated approaches and novel analytics for discovery of disease mechanisms and features for deep patient phenotyping and identification of new targets for intervention. More information can be found in the following notices: NOT-AR-19-022, NOT-AR-19-023, NOT-AR-19-024, and NOT-AR-19-025.

The CCC will be expected to have the expertise to coordinate the following kinds of studies:

Phase 2 trials of new drugs, biologics, devices, and physical interventions, particularly those that arise from new understandings of mechanisms of back pain;

Longitudinal cohort studies of patients with chronic low back pain, and;

Adaptive clinical trials based on the results of the longitudinal studies.

Further, the CCC will interact with an external data integration core specifically designed for these studies that will develop, deploy, and refine new algorithms for integrating patient phenotype, symptoms, and biomarkers (including newly developed modalities) to predict which patients will respond best to which interventions. The EPPIC-Net CCC will work closely with this group, but not be responsible for algorithm development or testing.

d) Master trial agreements. The CCC is charged with creating, negotiating, and maintaining master trial agreements and subcontracts for performance of clinical trials directly with each clinical site (hubs, spokes, ad hoc sites) for all clinical trials conducted in EPPIC-Net.

e) Centralized Budgets and Payments. For each clinical trial, the CCC will determine a budget with each clinical site (hubs, spokes, ad hoc sites). The CCC will distribute funds directly to each participating clinical center. All payments will be on a per-patient basis, according to protocol budgets and the master trial agreement. The CCC is encouraged to create or adopt appropriate technology to facilitate and simplify these procedures.

f) Central IRB of Record. The CCC will be responsible for identifying or establishing the central IRB of record for all studies conducted in EPPIC-Net, and managing communications between that IRB and EPPIC-NET. The central IRB must include physicians and other health care providers with expertise in neurology and pain medicine; ad hoc members with appropriate expertise may be added for individual clinical trials. The central IRB must be capable of executing all requirements for review, approval and oversight of standard clinical trials. The CCC is responsible for completion of reliance agreements with the clinical center institutions (hubs, spokes, ad hoc sites), coordination of a central IRB of record, and management of all required IRB communication and documentation. This includes but is not limited to maintaining documentation of IRB initial approvals, amendment approvals, site regulatory documents, communication with local IRBs or community organizations, adverse event reports, and annual reports.

The CCC may elect to establish and communicate with the central IRB in collaboration with their institutional IRB or a duly constituted independent IRB.

g) Recruitment Plans and Patient Enrollment. The CCC is charged with oversight of patient enrollment for each clinical trial and in aggregate for each hub and for the entire network. Each clinical trial is required to have a detailed recruitment plan, with attention to adequate gender, race, and ethnicity inclusion to assure that a valid analysis may be conducted at the conclusion of the trial. The CCC, working with the protocol PI, should implement corrective actions if a clinical trial is not meeting enrollment expectations. The CCC should also implement a corrective plan if a hub is failing to meet its overall patient recruitment commitments to EPPIC-Net. The CCC will also provide enrollment feasibility assessments for each clinical trial.

h) Quality Assurance. The CCC has specific responsibility for quality assurance in EPPIC-Net through creation and monitoring of specific, quantifiable performance metrics for itself, the DCC and the clinical sites. These metrics should include, at minimum, start-up time, patient recruitment and retention, time from last patient's last visit to database lock, and number and aging of data queries. The CCC should perform quality reviews at least annually on itself, the DCC and the hubs/spokes, the results of which will be shared with the EPPIC-Net Steering Committee and the EPPIC-Net Federal Committee. Innovative approaches to quality assessment and improvement are encouraged.

i) Other Clinical Trial Application Submissions. It is anticipated that there may be forthcoming funding opportunities from NIH or other federal agencies for clinical studies in patient populations with specific chronic or acute pain conditions. In that event, the CCC should encourage and support submission of clinical trial applications from colleagues at their institution or elsewhere within the pain medicine community.

CCC Roles and Responsibilities in terms of leadership and EPPIC-Net organization include, but are not limited to:

- Providing scientific leadership, particularly in relationship to clinical trial conduct and recognition of unmet needs in pain care research.

- Working with the DCC and hub PD/PIs to provide updates at regular meetings of the NIH Helping End Addiction Long-term (HEAL) Partnership program and to NIH Leadership as needed.

Promoting visibility and awareness of EPPIC-Net.

- Coordinating and supporting all EPPIC-Net Steering Committee (ENSC) (see EPPIC-Net Governance Committees below) (and any resulting working group) activities including, but not limited to, scheduling teleconferences and in-person meetings; arranging accommodations, transportation, facilities for in-person meetings; creating and maintaining documentation such as agendas and minutes; financial management including reimbursements.

- Coordinating all EPPIC-Net Management Committee (ENMC) and EPPIC-Net Operations Committee (ENOC) meetings (see EPPIC-Net Governance Committees below), including but not limited to scheduling, creating and maintaining documentation such as agendas and minutes, communicating decisions to external parties.

- Developing EPPIC-Net Standard Operating Procedures (SOPs) that address all aspects of clinical trial implementation, recruitment and enrollment, quality assurance, including joint Standard Operating Procedures (SOPs) with the EPPIC-Net DCC.

- Overseeing from final protocol design to analysis/publication the implementation of EPPIC-Net clinical trials and studies.

- Providing instruction and training to clinical sites regarding Good Clinical Practices (GCP) and EPPIC-Net processes, procedures and metrics;

- Clinical sites will include up to 10 Hubs that may participate in every clinical trial, 2-10 spokes per hub that may vary by trial, and potential ad hoc non-network clinical sites (number will vary from trial to trial).

- Providing a mechanism (e.g., call-in center, hot line, web chat) for promptly addressing procedural queries from sites, both for general EPPIC-Net processes and for processes specific to each clinical trial.

- Monitoring human subjects' protection among participants enrolled at all EPPIC-Net clinical sites.

Providing general logistical support (e.g., facilities, travel reimbursements) to the DCC for Data and Safety Monitoring Board (DSMB) meetings.

- Coordinating study drug management, including but not limited to drug/device and placebo acquisition, delivery plan for bulk drug or device, secondary packaging/labeling/distribution/storage, coordinating stability testing and accommodating expiration timelines, and drug/device accountability, if required to do so, in a specific clinical trial.

- Proposing innovative methods and leveraging existing local research resources to enhance programmatic efficiency. Applicants are specifically encouraged to interact with Clinical and Translational Science Awards (CTSAs), if present at their institution, to identify resources.

The CCC and DCC, once selected for potential funding, will jointly submit their SOPs for EPPIC-Net to NINDS and EPPIC-Net Federal Committee (defined further below). These will be revised from the individual versions originally submitted as part of their applications and will present a collaboratively developed plan. They will also submit a scope of work document that details the division of tasks and responsibilities. It is essential that the tasks required in planning and executing a complex, multi-center trial be clearly defined, and that the responsibilities of the collaborators (including CCC and DCC) be clearly delineated. It is therefore required that the joint DCC and CCC SOPs and scope of work document show excellent and seamless communication and coordination and reflect an in-depth understanding of the overall operational conduct of a complex, multi-center trial network.

The Responsibilities of the EPPIC-Net CCC in relation to clinical trials include, but are not limited to:

- Clinical trial protocol development;

- Rapid initiation of clinical trials;

- Supervision of all aspects of patient recruitment, enrollment, retention, and disposition;

- Financial management.

More specific detail follows, broken down by activities relevant to the progressive stages of clinical trial execution.

Prior to clinical trial protocol development/application submission, during the pre-application phase of a clinical trial, the CCC is responsible for:

- Coordinating investigators from companies (asset owners) and protocol PI to develop a draft clinical trial protocol tailored to a specific asset based on information provided in the asset dossier and input from the asset owner, including coordination of input from the ENSC, ENMC, and ENOC, as appropriate (see EPPIC-Net Governance Committees, below).

- Submitting asset-matched clinical trial protocols to NIH under a different FOA, using the standard template as outlined in NOT-OD-17-064.

- Providing information and guidance to potential investigators as they apply for NIH funding for a clinical trial to be performed in EPPIC-Net (e.g., review protocol synopsis and schedule of activities, estimate need for additional trial-specific ancillary sites).

- Performing feasibility studies for enrollment and performance of proposed clinical trials in EPPIC-Net.

- Developing a clinical trial budget that includes both per-patient site costs and funds required to support EPPIC-Net infrastructure.

After approval and award of a clinical trial, during the planning phase of approved clinical trials, the CCC is responsible for:

- Supporting the protocol PI and site investigators in finalization of the protocol.

- Supporting the protocol PI and site investigators in preparation of consent forms.

- Supporting the protocol PI and site investigators through central IRB review and approval.

- Developing a written, detailed patient recruitment plan, with attention to adequate gender and minority representation.

- Facilitating and monitoring the central IRB approval process.

- Collecting regulatory documents (1572 forms, curricula vitae, Good Clinical Practice [GCP] certifications, etc.) from all clinical sites.

- Finalizing details of per-patient payments to sites within approved budgets, developing site payment schedule, and finalizing contracts or subcontracts with sites per master trial agreements.

- Obtaining, storing, and disseminating candidate therapeutics and devices.

- Finalizing study drug packaging and labeling (if required for a particular clinical trial).

- Holding investigator meetings and ensuring initial study personnel training for GCP and protocol adherence.

- Supervising trial registrations on clinicaltrials.gov.

- Ensuring that any required FDA approvals or documents (e.g., IND, IDE, IND exemption) are in place prior to submission of the protocol to a different FOA.

During the enrollment and data collection phase of approved clinical trials, the CCC is responsible for:

- Overseeing the enrollment of eligible subjects.

- Tracking enrollment and retention; intervening if planned targets are not being achieved.

- Tracking gender, minority, and inclusion across the lifespan enrollment; intervening if these targets are not being achieved.

- Distributing study drug/device to centers as needed.

- Ensuring appropriate protocol implementation, protocol adherence and Good Clinical Practices (GCP) compliance.

- Answering queries from the centers (e.g., application of inclusion and exclusion criteria, drug dose adjustments, handling adverse events, procedures for premature withdrawals).

- Conducting site visits, as needed.

- Coordination activities with other networks or institutions, if applicable.

- Distributing the approved per-patient payments to the hubs, spokes and ad hoc clinical sites based on appropriate documentation received from each clinical center.

During the analysis and publication phase of each clinical trial, the CCC is responsible for:

- Coordinating the communication of the trial results to the investigators, patients, and public.

- Coordinating with the DCC to maintain data and biosamples from the clinical trial in the appropriate repositories.

- Publishing the primary and, if applicable, secondary manuscripts, in collaboration with the clinical trial PI and DCC.

EPPIC-Net Governance Committees

The success of EPPIC-Net requires collaboration and cooperation among its component parts and members. Therefore, participation in the EPPIC-Net governance committees is an important responsibility. The final governance structure will be determined with the participants after awards are made for the CCC, DCC, and hubs. The following proposed structure, based on that of other clinical trial networks, is provided as a guide for applicants to use in composing the research plan and budget of their application submission.

The EPPIC-Net Steering Committee (ENSC) is proposed as the main governing body. The responsibilities of the ENSC include: 1) to provide scientific leadership for EPPIC-Net; 2) to promote awareness of EPPIC-Net throughout the clinical pain research community; and 3) to systematically assess clinical needs and goals for pain care research. Membership and meeting frequency are outlined in the table entitled "EPPIC-Net Governance Committees." ENSC meetings may include other ad hoc participants, such as research team members from the CCC, hubs, spokes, or clinical trials.

The ENSC may establish working groups or subcommittees on an as-needed basis for specific functions, such as: 1) Support of CCC or DCC functions (e.g., developing per-patient budgets; assuring quality control; monitoring conflicts of interest; developing data sharing policies; developing and standardizing per-patient budgets); 2) Development of core competencies and technologies (e.g., imaging, sensor data analysis); 3) Subject area working groups (e.g., neurology, rheumatology, orthopedics); and 4) Working groups for allied health professionals (e.g. study coordinators); 5) Advisory committees (e.g., patients and advocates, external experts); 6) Special topics (e.g., publication plans, training/education materials).

The EPPIC-Net Management Committee (ENMC) and the EPPIC-Net Operations Committee (ENOC) oversee the day-to-day administration and operations of EPPIC-Net. The first is more oriented towards strategic and administrative functions, the second towards operational and executional functions. Each clinical trial will have a Trial Committee, responsible for conduct of that particular trial.

Table: EPPIC-Net Governance Committees

Committee	Membership	Meetings
EPPIC-Net Steering Committee	CCC PD/PI (chair), DCC PD/PI, PD/PI or designee from each Hub	Monthly by phone or webinar, adjusted by EPPIC-Net activity and needs Biannual face to face meetings in Washington, DC metro area
EPPIC-Net Management Committee	CCC PD/PI (chair), DCC PD/PI, selected Hub PIs*	Weekly or biweekly by phone or webinar
EPPIC-Net Operations Committee	CCC PD/PI (chair), DCC PD/PI, selected CCC and/or DCC research team members, selected Hub PDs/PIs*	Weekly or biweekly by phone or webinar
Trial Committee	Clinical trial PD/PI (chair), CCC and DCC research team members (one of which should be either the CCC PD/PI or DCC PD/PI)	Monthly by phone or webinar, adjusted by activity and needs of trial
* Hub PDs/PIs or designees will serve on a rotating basis, with attention to balance across specialties (e.g., neurology, rheumatology, orthopedics)

As part of the HEAL Initiative, federal oversight will be provided by the HEAL EPPIC-Net Federal Committee, which will consist of leadership and staff from the NIH HEAL Initiative Institutes. NINDS is the lead institute for the EPPIC-Net infrastructure of CCC, DCC, and clinical Hubs, but there will be substantial involvement from other NIH Institutes and Centers. NIH will provide at least one member to participate on the ENSC, ENMC, and ENOC. Independent of the governance above, the NINDS Director retains oversight for all funded research from individual institutes or programs. The Directors authority overrides all ENSC, ENMC, and ENOC decisions.

It is also anticipated that the governance committees of EPPIC-Net will have significant interaction with other HEAL Initiative coordinating committees made up of representatives from academia, industry, government, and the patient advocacy community.

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:

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• 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 not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are not allowed.

Applicant Organizations

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

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

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

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

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

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

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

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).

Only one application per institution (normally identified by having a unique DUNS number or NIH IPF number) is allowed. The NIH will make a single award.

Awards for the CCC and the DCC will not be made to the same PD/PI or institution to ensure that data analyses and data acquisition are performed independently.

Investigators at the CCC institution may apply for a Hub award (see FOA NS-19-025). A CCC and a Hub at the same institution should be led by separate PDs/PIs.

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

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

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

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:

Jeremy Brown
Telephone: 301-827-8375
Fax: 301-420-1080
Email: [email protected]

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed. for this specific FOA, the Research Strategy section is limited to 30 pages.

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

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

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

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

In addition:

Facilities and Other Resources:

Resources include not only equipment (e.g. computers, software), but also people and knowledge resources, such as, general support (e.g., administrative staff); colleagues or organizations with research and/or clinical trial expertise.

- Specifically describe facilities and resources for the central IRB and reliance agreements.

- Specifically describe facilities and resources available to support master contracts with Hubs, Spokes and other clinical sites.

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

The PD/PI for the Clinical Coordinating Center will be a clinical trials expert who has successfully coordinated and implemented multicenter clinical trials. As support, applicants should provide evidence to demonstrate experience in:

- Successfully coordinating, implementing, and executing multi-center clinical trials

- Experience in neurology and pain clinical trials is most relevant.

- Successfully designing multicenter clinical trials;

- Successfully working in a highly collaborative setting;

- Encouraging and implementing innovative methods to reduce clinical trial duration and cost and to increase trial quality at their site;

- Significantly contributing to Steering Committees or comparable governance committees;

- Submitting clinical trial grant applications;

- Experience with establishment and maintenance of central IRBs, if applicable.

Since the CCC PD/PI is the chair of the ENSC, ENMC, and ENOC, it is important that the PD/PI have sufficient time to attend and actively contribute to these EPPIC-Net governance committee meetings (see EPPIC-Net Governance).

Applicants are strongly encouraged to name an experienced research team. The applicants are encouraged to assemble a diverse team that includes women and minorities. The applicants are also encouraged to include young investigators or junior faculty, if appropriate. Members of the CCC research team are determined by the applicant, but typically might include:

- Experienced study coordinators and/or project managers, potentially with areas of subspecialty such as recruitment or interactions with IRBs;

- Experienced financial coordinator or manager;

- Site Support Manager or comparable staff for training of all Hubs, Spokes and ad hoc clinical sites;

- Components of the central IRB, such as IRB chair, members, director; and

- Liaisons to the IRB and clinical sites.

- The PD/PI and members of the CCC team are encouraged to include references to their publications that highlight recently coordinated trials.

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

- The budget submitted for this FOA should reflect baseline operations costs needed to initiate, organize and maintain the CCC in a state capable of performing timely pre-application concept assessments and ready for rapid implementation of clinical trials. Salary support for the PD/PI and research team members should only include time spent on EPPIC-Net activities, which may include organizational/administrative tasks, support of individual clinical trials, and participation in the EPPIC-Net governance and committee activities.

- The budget should include travel costs for one PD/PI and two CCC team members to attend in person ENSC meeting annually and other travel related to EPPIC-Net operations.

- The budget should also include travel costs for at least two CCC team members to attend in-person DSMB meetings

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

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

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

Research Strategy: The Research Strategy must consist of the following Sections A I.

A) Background and Experience

Without duplicating information submitted elsewhere such as biographical sketches or the Human Subjects-Clinical Trials Form, the applicant should include a description of current and up to 10 recently completed multicenter clinical trials. It is not necessary for the applicant to have led the trial or to have been a member of the CCC, though the applicant must clearly describe their role and contributions. The most informative and relevant examples would be multi-site clinical trials involving pain or other neurological disorders. The summary may however include clinical trials on any disease supported by any funding source, if judged relevant by the applicant. Provide clear specific trial identification information (e.g., name, funding source, IND sponsor, NCT number in clinicaltrials.gov) along with disease/disorder and/or intervention under study. Present specific performance metrics, including though not limited to:

- the number and location of sites (US and/or other countries);

- the number of patients;

- the length of follow-up;

- time to first contract/subcontract executed (starting from award date);

- time to last contract/subcontract executed;

- type of IRB (s) and relationship to Clinical Coordinating Center site;

- time to IRB at Clinical Coordinating Center site;

- time to first IRB approval at any consortium site;

- time to last IRB approval at a consortium site;

- time to first patient screened;

- time to first patient randomized;

- overall recruitment rate;

- proportion of patients lost to follow-up;

- proportion of patients missing data on primary or secondary efficacy measures;

- type and frequency of protocol deviations;

- time from last patient last visit to database lock;

- time from database lock to completion of statistical analyses; and

- time from statistical analyses available until final draft of primary manuscript

In addition to clinical trial expertise, the applicant should also include relevant information on how they might translate an asset dossier with valid preclinical, clinical, and pharmacological information into a clinical trial protocol.

B) Leadership Plan

Demonstration of leadership capability is required for the CCC PD(s)/PI(s), without duplicating information submitted elsewhere such as biographical sketches or the Human Subjects-Clinical Trials Form, It is also expected that, in order to successfully lead EPPIC-Net, the PD/PI already plays a leadership role in some capacity in the pain care research community, which should be described in the application.

- Demonstrated familiarity and leadership within the pain care research community.

- Leadership derives not only from the CCC PD/PI, but also from members of the CCC research team. A brief leadership plan should be presented which identifies and describes the roles of CCC personnel, along with how they will contribute to the success of EPPIC-Net. A brief leadership plan should be presented, including a succession plan with identification of a substitute/back-up PD/PI candidate, if possible, to assure programmatic continuity.

- Applicants should indicate their capability and willingness to attend and contribute to EPPIC-Net governance committees (see EPPIC-Net Governance Committee section) and provide examples of leadership and/or substantial contributions in comparable venues.

-Applicants should state their general support of collaborative research and their willingness to participate in a collaborative and interactive manner in all aspects of EPPIC-Net.

-Applicants should comment on any special expertise or unique strengths they can offer for leadership or collaboration within EPPIC-Net.

C) Administration and Organization

- The PD/PI should describe the duties of proposed personnel responsible for day to day administration and operations at the CCC. The organizational structure should be described with attention to how the structure will support optimal execution of the tasks in Clinical Coordinating Center: Roles and Responsibilities. If there is prior experience operating as a team, this should be described.

- The applicant should indicate how potential clinical trial investigators (from academia, military or industry) will be supported to work with EPPIC-Net in the feasibility phase and integrated into the network in the planning and implementation phases.

- Success of EPPIC-Net will require strong communication and close collaboration. The application should include a communication plan, which discusses:

- communication with the DCC, and any experience with working in a CCC/DCC structure;

- clinical sites (hubs, spokes, ad hoc sites), with attention to 1) general site training on EPPIC-Net processes; 2) clinical trial specific training; and 3) mechanism for answering questions from sites.

The applicant is encouraged to be specific. For example, a plan for clinical site training might include, though not be limited to, some of the following: 1) face to face and virtual venues for training (e.g., investigator meetings, ENSC meetings, site visits, webinars, teleconferences, newsletters); 2) planned target audiences (e.g., study coordinators, prehospital providers); 3) potential topics of general importance (e.g., GCP, recruitment strategies); 4) when or how certification or other means of training verification might be used; 5) training new site personnel when there is staff turnover; 6) whether and how training should be repeated periodically during long duration clinical trials.

- The EPPIC-Net Committees are key venues for organization and communication. The CCC PD/PI chairs the EPPIC-Net Management and EPPIC-Net Operations Committees, and the CCC organizes and facilitates all EPPIC-Net meetings. The application should discuss how the applicant proposes to optimally use these committees to generate a coherent network to identity, stimulate enthusiasm and ideas for pain care research, provide a forum for communication and education, and to execute tasks related to EPPIC-Net management and clinical trial execution.

- The applicant may propose changes to the committee membership or meeting frequency from that outlined in this FOA, with explanation of why these would be more effective.

- More mundane aspects of meeting management, such as logistics, selection of topics, and preparation and distribution of minutes, should be covered.

- The personnel responsible and existing support materials (e.g., templates, SOPs) should be identified. Relevant SOPs may be included in an appendix.

D) Operations and Communications:

- The application should describe the proposed CCC's standard operating procedures (SOPs) for clinical trial conduct and for administering and coordinating a network.

The ability of the proposed CCC research team to work in a collaborative and interactive manner with the Hubs, the DCC, the clinical trial PIs, and the EPPIC-Net Federal Committee should be discussed.

- Applicants should describe a communications plan with outside institutions that may include academia, private companies, other clinical trials networks, and PDs/PIs from other studies within the NIH HEAL Initiative.

- Administration of EPPIC-Net and implementation of clinical trials will require close collaboration between the CCC, DCC, and hubs. Applicants should describe their communications plan for the CCC, and any experience they have previously had working with a DCC and in a hub and spoke model.

- Successful implementation of clinical trials will require close collaboration between the CCC and the clinical sites. Applicants should describe the communication plan, including 1) general site training on EPPIC-Net processes; 2) clinical trial specific training; 3) aspects of instruction and training and the mechanism for answering questions from sites; and 4) mechanism(s) (e.g., call in center, hot line, web chat) for promptly addressing questions from sites. Prior experience with specific mechanisms, such as call in centers or hot lines, should be provided.

- Applicants should describe the communication plan with protocol PIs from the hubs.

E) EPPIC-Net Financial Management: Master trial agreements, Per Patient Billing and Payments

- The application should provide a summary of relevant prior experience (without duplicating information in the biosketch) and a plan for managing the financial aspects of EPPIC-Net.

- Master trial agreement: Plans for negotiating, establishing and maintaining master trial agreements with each clinical site (hub, spoke, or ad hoc site). Specific topics may include 1) use of subcontracts for sites participating in multiple clinical trials (e.g., Hubs), 2) possible means for expediting or streamlining contracts for new sites participating in a clinical trial (e.g., new Spokes, or out of network sites), 3) experience of approaches with federal institutions (e.g., VA hospitals, military hospitals), 4) experiences or approaches with international institutions.

- Per patient budgets: Plans for negotiating and maintaining for each clinical site. Specific topics may include: 1) extent of standardization or harmonization across sites; 2) use for estimating clinical trial budgets; 3) incorporation of new sites.

- Site payments: Procedures and mechanisms for site payments, including, but not limited to, 1) frequency, 2) mechanisms for triggering payments, 3) transfer of funds, 4) verification of receipt and 5) reporting to NIH.

- Consideration should be given to tools that may simplify procedures involving interaction with the sites, such as dedicated portals on the EPPIC-Net website or online budget calculators.

- The financial plan should also include CCC central management approaches, such as tracking and archiving, reconciliation, error checks and planned audits, if any.

- Challenges of managing Hubs and Spokes that are participating concurrently in multiple EPPIC-Net clinical trials should be addressed.

- The applicant should discuss their existing approach to financial management, including software, SOPs, templates or other tools.

- Applicants must document how they will obtain or access the legal and financial expertise for exemplary execution of the contracts, budgeting and payments. Any planned use of institutional resources (e.g., legal department, contract specialists, financial offices, IT support) should be clearly explained in the financial plan and must be documented in a letter of support from the institution.

F) EPPIC-Net Central IRB

Applicants should present any prior experience with establishment and management of central IRBs. Applicants should discuss their (and, if appropriate, their institution's) willingness and ability to establish and maintain a central IRB for EPPIC-Net, consistent with specifics presented in CC: Roles and Responsibilities. The plan for the central IRB should include:

- Establishing the central IRB;

- Negotiating and maintaining reliance agreements with each clinical site (Hub, Spoke, ad hoc);

- Mechanisms and procedures for serving as an IRB of record for routine clinical trials in EPPIC-Net;

- Identification of potential IRB chairs, IRB members or key support personnel.

- If the applicant plans to collaborate with an institutional IRB or independent IRB, the application should include: 1) the IRB roster; and 2) any special modifications or accommodations for EPPIC-Net, such as addition of members with pain care expertise or addition of administrative staff.

G) Recruitment and Patient Enrollment

The PD/PI should review prior experience without duplicating information submitted elsewhere such as biographical sketches, with and present a plan which addresses specifics such as: 1) mechanisms for performance of recruitment feasibility assessments; 2) creation of clinical trial specific recruitment plans; 3) centralized support for materials (e.g., brochures, posters), media (e.g., print, radio, TV, internet) and/or social media; 4) tracking enrollment accurately in real time during trial conduct; 5) creating corrective action plans, if needed. Tracking and corrective action plans for minority and gender enrollment should specifically be addressed.

- Plans should be described for recruiting patients with specific pain conditions and their phenotypes.

- Plans should be described for interaction with the clinical sites (hubs, spokes, ad hoc sites) in terms of data collection, and identification and intervention at sites lagging in enrollment.

- Plans for collaboration and incorporation of the clinical trial PI should be outlined.

- Describe the data resources that will be used for recruitment feasibility estimation (e.g., physician experience, hospital or clinic charts, electronic records, specialized registry or data base).

- Describe any particular tools or software that will be used or developed for recruitment, enrollment and/or feasibility.

- Describe the personnel responsible for recruitment and how their unique experiences and skills will increase successful patient enrollment in clinical trials conducted in EPPIC-Net.

- Present examples of corrective actions for inadequate enrollment in aggregate or for subpopulations.

H) EPPIC-Net Quality Assurance

- The applicant should review experience with quality assurance and improvement, including design and implementation of quality improvement programs. The application should identify CCC personnel responsible for quality assurance and the means by which DCC, Hub and/or clinical trial PIs or personnel will be integrated into the quality process. Additional resources for quality assurance expertise should be identified.

- The application should include a quality assurance plan, which has identifiable portions for the CCC alone and for EPPIC-Net overall (CCC, DCC, hubs). This plan should include, though not be limited to: 1) specific, quantifiable metrics; 2) means of collecting this data, particularly from the DCC and Hubs; 3) performance and communication of findings of annual quality review (communication to the EPPIC-Net Federal Committee as well as to DCC and Hubs); 4) proposed quality assurance besides the annual review (e.g., for cause site audits, on-going quality monitoring); 5) creation, communication, performance and verification of improvement plans; 6) creating incentives and enthusiasm for participation and compliance with quality assurance activities.

- If the applicant has ever undergone a clinical or regulatory audit as a CCC or clinical site, the results should be presented, along with implementation of any responsive improvement plan. Relevant audits relate to clinical research and may have been conducted by NIH, FDA or industry.

I) Innovations to Increase the Efficiency and Quality of the Clinical Research Enterprise

The CCC has the potential to promote the science and technology of the clinical trial process in general, as opposed to disease or indication specific interventions. Creative and innovative approaches to increasing the efficiency and quality of clinical research are welcomed. The applicant is invited to bring special attention to their constructive, innovative proposals and ideas and to describe how these would benefit EPPIC-Net itself or clinical research more generally.

Letters of Support

Letters of Support: A statement of commitment from each participating institution or organization must be provided. At least one letter of support from the applicant's institution must be included in the application. This letter should address how the general institutional commitment will be established and sustained, how the institution will maintain accountability for promoting scientific excellence, and how the EPPIC-Net effort will be given a high priority within the institution (relative to other research efforts and non-NIH supported programs.) The institutional commitment may be in the form of support for recruitment of scientific talent, provision of discretionary resources to the CCC director, assignment of specialized research space, cost sharing of resources, and/or other ways proposed by the applicant institution. Institutions should document their willingness to commit to use of a master trial agreement and a central IRB, as described. If the Institution is committing facilities or resources to create, maintain or support the central IRB and/or master contracts, these should be presented in detail. There may be multiple letters of support from the institution or its components, particularly if the institution is providing support of collaboration for specific CCC responsibilities, such as the central IRB or master contracting. At least one letter confirming institutional support should come from a high-level institution official(s) (e.g., Dean of the School of Medicine, Hospital President, and Vice President for Research).

If the central IRB will be in collaboration with the institutional IRB or a duly constituted independent IRB, the application should include a letter of support from the IRB chair. The letter should include any specific commitments of facilities or resources by the IRB (e.g., regulatory consultants, record storage space, computer software). If the proposed central IRB is an institutional IRB, senior institutional leadership should include the central IRB in their letter of support.

For those institutions with a CTSA, the applicants are encouraged to include documentation from the CTSA PD/PI regarding any support which will be provided to the CCC.

Additional letters of support are encouraged from key personnel and consultants, such as the proposed IRB chair, physician investigators, experts in recruitment or other CCC responsibilities or pain care experts.

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

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

Appendix:

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

The following items are recommended for inclusion in the Appendix:

- Sample documents that illustrate the CCC's expertise, such as policies, SOPs, etc.

- One sample protocol and set of Case Report Forms (CRFs).

- One sample study SOP describing regulatory document collection, IRB approvals, study drug management, procedures to minimize bias and maintain blinding, recruitment plans, retention plans, data sharing plans, safety monitoring plans, etc.

- Examples of current SOPs for management of a clinical trial network

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

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

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

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

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

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

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

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

Important reminders:

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

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

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by 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. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

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

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

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

How will the proposed CCC contribute to the advancement of clinical research and clinical trials within the framework of EPPIC-Net?

How will the CCC work with the hubs to translate an asset dossier into a clinical trial protocol?

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

Do the PD(s)/PI(s), collaborators, and other researchers demonstrate a successful track record of clinical pain research?

Does the application indicate that the PD/PI and research team have the appropriate experience to successfully lead, design and implement multicenter trials in EPPIC-Net? To what extent does the application show evidence of relevant experience the management of pain care? To what extent does the application show evidence of relevant expertise in pharmacology, toxicology, clinical trial design including endpoints and outcomes, and other expertise that be relevant in coordinating trial protocol design based on asset dossiers?

Is there evidence to suggest that the PD/PI can build on an existing leadership role in the pain research community to contribute to the success of EPPIC-Net? Is there evidence to suggest that the PD/PI and research team have appropriate experience to prepare them to form and manage a central IRB? Is there evidence to suggest that the PD/PI and research team have appropriate experience to prepare them for EPPIC-Net financial management responsibilities (e.g., master trial agreements, budgets)?

In what ways does the application suggest that the PD/PI can lead and contribute substantially to the EPPIC-Net governance committees (e.g., EPPIC-Net Steering Committee and subcommittees, EPPIC-Net Management committee, EPPIC-Net Operations committee)? Does the application demonstrate that the PD/PI will have time to attend the meetings and teleconferences?

Is there evidence to suggest that the applicant will be effective and successful in promoting and encouraging the submission of meritorious clinical trial grants for EPPIC-Net?
In what way does the PD/PI's experience prepare him/her for leading and working in highly collaborative settings?

Is there assurance that the proposed research team and administrative personnel are qualified, capable and experienced? In what ways will they increase the likelihood that performance will be exemplary at the proposed CCC?

To what extent do the performance metrics from past clinical trials (see Research Plan, Section A) support that the applicant would form an exemplary CCC? Does the evidence support the ability to carry out the tasks enumerated under CCC: Roles and Responsibilities?

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 application provide evidence to suggest that the PD/PI or other members of the proposed research team could institute novel and innovative procedures that would increase efficiency and/or quality of clinical trials conducted in EPPIC-Net?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the 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?

Does the application provide assurance that the proposed CCC will provide strong organizational focus for the CCC itself and for EPPIC-Net overall?

Does the application present a communication plan that promotes collaboration and information sharing: 1) with the DCC; 2) with clinical sites (hubs, spokes, ad hoc sites); 3) with protocol PIs? In what ways does the communication plan provide assurance that the CCC will provide sufficient procedural training and will provide rapid, accurate resolution of questions/issues?

Does the application present a financial management plan that will efficiently execute master trial agreements, per patient billing, and centralized site payments? How appropriate are the expertise and personnel incorporated into the CCC and/or provided by the institution?

Does the application present a thoughtful and thorough plan for performance of the IRB tasks outlined in "CCC: Roles and Responsibilities" and Research Plan, Section F? How appropriate are the expertise and personnel incorporated into the CCC and/or provided by the institution?

Does the application present a strategy for planning future patient recruitment and enrollment, including feasibility assessments, recruitment plans and other components outlined in Research Plan, Section G, which will contribute to the success of EPPIC-Net? Does the application demonstrate awareness and realistic planning for achievement of minority and gender enrollment?

Does the application evince strong concern for and adherence to high quality standards? Does the application propose a plan for quality assurance and quality improvement for the CCC itself and for the EPPIC-Net infrastructure (DCC, hubs) which will produce an exemplary and successful network?

To what extent does the application demonstrate that the proposed CCC will meet the challenges of flexibility and scalability required to meet the needs of the different clinical trials to be conducted in EPPIC-Net?

How will the CCC solicit additional content matter expertise when needed?

Does this application demonstrate that the proposed CCC will successfully manage master trial agreements, centralized trial budgeting and per patient payments, as planned in EPPIC-Net?

Does this application demonstrate that the proposed CCC will successfully form and manage an exemplary central IRB?

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

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

In the letters of support and commitment, what level and extent of commitment does the institution demonstrate for the PD/PI (may be expressed as additional protected time, departmental research leadership position, facilities, space, or resources)?

If the proposed CCC intends to use or collaborate with the institutional IRB or with an independent IRB, how strongly does the institution/independent IRB support the success of the EPPIC-Net central IRB? To what extent is support expressed in terms of access to personnel and resources?

If the proposed CCC intends to use or collaborate with the institution on financial management (e.g., master trial agreements, centralized budgets, centralized payments), how strongly does the institution support the success of this aspect of EPPIC-Net? How well is this support expressed in terms of access to personnel and resources?

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

For research that involves human subjects but does not involve one of the 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 project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of 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.

N/A

N/A

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

N/A

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

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

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

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

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NINDS, 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.
• Clinical trial expertise, track record, and resources.
• Strong track record of successful collaboration and participation in large, multi-center research teams and willingness to work collaboratively, including with other components of the EPPIC-Net.
• Willingness and evidence of ability to participate in all aspects of the EPPIC-Net program, including the ENSC, ENMC, ENOC, Trial Committees, ENSC working groups, and participation in teleconferences and in person meetings.
• Current and/or successfully completed NIH-funded clinical trial/study projects at the applicant’s institution.
• Ability to begin operations on the "Earliest Start Date" listed in this FOA (Section II.1).

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

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

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

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

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

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

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

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

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

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

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75(Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies. The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

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

- Organizing and managing the EPPIC-Net infrastructure including establishment of a central IRB and mechanisms for master trial agreements and centralized budgets and payments, managing the EPPIC-Net governance committees, implementing EPPIC-Net clinical trials (including GCP and other regulatory requirements, overseeing recruitment and retention, overseeing quality), reporting to the EPPIC-Net Federal Partners, and working collaboratively working with the DCC and hubs.

- The CCC PI is expected to chair the ENSC, ENMC and ENOC, and to participate in other EPPIC-Net committee meetings and clinical trial investigator meetings.

- 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. The owners of candidate therapeutics ( assets ) that undergo clinical testing through EPPIC-Net will retain the intellectual property rights to their asset.

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

- The NIH staff in collaboration with the EPPIC-Net Federal Committee will work with the EPPIC-Net investigators to develop performance milestones for the CCC. Failure to meet the agreed upon milestones may result in reduced funding or early termination of the cooperative agreement

- An NIH Project Scientist will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards:

- Cooperation or coordination with, or assistance to, awardees in performing project activities, e.g., development of research protocols; data collection, analyses, and interpretations; re-establishment of objectives during the course of a project;

- Providing for an option to halt a project activity if technical performance requirements are not met or if program objectives have already been met;

- Assistance with the selection of contractors or sub-awardees and in the selection of key project personnel other than PD/PI;

- Technical monitoring to permit specific direction of the project, including recommending approval of changes in technical approaches;

- Participation on committees as a voting member or in other functions responsible for helping to guide the course of EPPIC-Net; and

- Participation in the presentation of research results, including publications from the project.

- In addition to the Project Scientist, an NIH Program Official will be responsible for the normal programmatic stewardship of the award and will be named in the award notice.

Areas of Joint Responsibility include:

Participation on EPPIC-Net committees, specifically the EPPIC-Net Steering Committee (ENSC), and its working groups and subcommittees, EPPIC-Net Management Committee (ENMC), EPPIC-Net Operations Committee, (ENOC) and Trial Committees (see the EPPIC-Net Governance Committees).

Clarifying, negotiating and finalizing the milestones and timelines.

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 on-time submission, 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 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]

Jeremy Brown
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-827-8375
Email: [email protected]

Inna Belfer, MD, PhD
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-435-1573
Email: [email protected]

Diane St. Germain, RN, MS, CRNP
National Cancer Institute (NCI)
Telephone: 240-276-7050
Email: [email protected]

Houmam Araj
National Eye Institute (NEI)
301-451-2020
[email protected]

Sangeeta Bhargava, PhD
National Eye Institute (NEI)
301-451-2020
[email protected]

Yan Wang, M.D., Ph.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Telephone: (301) 594-5032
Email: [email protected]

Tanya Ramey, M.D., Ph.D.
National Institute on Drug Abuse (NIDA)
Telephone: 301-827-5944
Email: [email protected]

Dena Fischer, DDS, MSD, MS
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-4876
Email: [email protected]

Teresa L.Z. Jones, MD
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-435-2996
Email: [email protected]

Michelle R.J. Hamlet, Ph.D.
National Institute of Nursing Research (NINR)
Telephone: 301-496-9623
Email: [email protected]

Michelle R.J. Hamlet, Ph.D.
National Institute of Nursing Research (NINR)
Telephone: 301-496-9623
Email: [email protected]

Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9223
Email: [email protected]

Tijuanna DeCoster, PhD, MBA
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9231
Email: [email protected]

Erik Edgerton
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Telephone: (301) 594-7760
Email: [email protected]

Pam Fleming
National Institute on Drug Abuse (NIDA)
Telephone: 301-253-8729
Email: [email protected]

Diana Rutberg, M.B.A.
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-4798
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.