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 as five Phase 2 trials concurrently, in addition to deep clinical phenotyping and biomarker validation studies.

EPPIC-Net will consist of one Clinical Coordinating Center (CCC), one Data Coordinating Center (DCC) and approximately 10 specialized clinical centers ( hubs ). The purpose of this funding opportunity announcement (FOA) is to invite applications for the hubs within the network. A hub will typically be a regional medical center that will actively enroll subjects into clinical trials and studies performed in EPPIC-Net. Each hub should have ready access to patient populations with specific pain conditions and have expertise in their characterization. A hub will additionally provide scientific leadership and administrative oversight to its multiple (2-10) satellite sites ( spokes ).

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 hubs will contribute to these objectives by conducting clinical trials and biomarker validation studies. The hubs will also work with the EPPIC-Net CCC and investigators from the NIH HEAL Partnership to develop and execute clinical trials based on meritorious assets, as described elsewhere in this FOA. PDs/PIs at the hubs will serve as experts to develop biomarker-informed phase 2 clinical trial protocols matched to the specific asset. The clinical protocols will be targeted to defined pain conditions 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 work closely with the PD/PI from the hub with expertise most closely aligned with the target patient population for the asset, to develop a clinical protocol matched to that asset (or an ad hoc hub if need be). If deemed meritorious by NIH peer review, the PDs/PIs at the hubs will work with the CCC to execute the clinical trial.

Due to the vast 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.

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.

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. The roles and responsibilities of the CCC are described more fully in RFA-NS-19-023.

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 its 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 therefore requiring broad pain expertise within the hub and spokes (e.g., neurology, rheumatology, obstetrics/gynecology, oncology, pediatrics, orthopedics, gastroenterology, or other subspecialty) and have access to clinical populations from a wide variety of pain conditions. The roles and responsibilities of the hubs and spokes are described more fully below. 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.

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 scientifically reviewed and prioritized prior to entering the network by NIH peer review. 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.

Hubs: Characteristics, Roles and Responsibilities

A typical EPPIC-Net Clinical hub is envisioned as a medical center with full multidisciplinary coverage (24/7) such as 1) a major pain referral center or 2) a tertiary care facility or health care system that cares for patients with a wide variety of pain conditions. A hub must function as an exemplary clinical research site itself, while concurrently providing leadership, organizational oversight and research support of its spokes.

Each hub must be able to:
1) Execute Phase 2 trials;
2) provide and coordinate the multiple specialties that may participate in the trials, such as neurology, anesthesiology, rheumatology, obstetrics/gynecology, oncology, pediatrics, orthopedics, physical medicine, gastroenterology, or other subspecialties providing care to patients with pain; and
3) propose and oversee a network of spokes.

Each hub must have a flexible network of spokes. The principal function of the spokes is to provide access to a larger patient population for trial enrollment. Spokes also increase access to patients with a particular pain condition, to patients from underserved communities to enhance diversity, or complement the hub by providing access to specific research or clinical expertise. For each clinical trial, the hub would be expected to construct a network of 2-10 spokes specifically tailored to the needs of that particular trial. Since the requirements of each clinical trial will be somewhat different, the identity and configuration of spokes will be unique for each trial. Therefore, a hub should have relationships with a number of potential spokes, and the ability to add spokes as appropriate. To demonstrate the ability to attract spokes, the applicant is requested to identify in the grant submission potential spoke sites committed to participation in at least one clinical trial. The hub may need to have plans and mechanisms for recruiting and adding other spokes, when needed.

The hub and spokes together must be able to 1) support recruitment of at least 100 well-phenotyped subjects with specific pain conditions per year into concurrent phase 2 trials (exact subject numbers may be different per the milestones in any specific trial), and; 2) provide physicians who are experts in the fields of neurology, anesthesiology, rheumatology, obstetrics/gynecology, oncology, pediatrics, orthopedics, physical medicine, gastroenterology, or other subspecialties providing care to patients with pain. Additional expertise may also be required. Spokes may range from academic pain treatment centers to community hospitals, or other applicable health care settings and networks to expand patient access and representation of minority, rural and other segments of the population. The spokes may be geographically related partnering medical centers or geographically distant centers where productive collaboration have been well established. Spokes should be located in North America. Spokes may enroll and treat patients on-site or may identify patients to transfer to the hub for enrollment. There is no ideal or preferred arrangement.

Since the design and requirements will be unique for each meritorious clinical trial, EPPIC-Net must be flexible. Hubs should be resourceful and innovative in approaching the challenges of each study. Examples of some variations that may occur include, but are not limited to:

- Participant age (adult only studies as well as with children or adolescents, if appropriate for the pain condition);

- Requiring patients with relatively infrequent causes of pain;

- Management that involves multi-specialty clinics;

- Outcome measures collected well beyond the clinical encounter, i.e., 30 days, 90 days, or longer after the intervention

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 hubs include the following:

a) Clinical trial protocol development and execution on therapeutic assets.

A separate FOA will be used to allow prioritization of assets 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 biomarker-informed 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. A hub PD/PI will be identified by the CCC whose expertise is closely aligned with the target patient population for the asset. This hub PD/PI will serve as the PI for the trial. (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 from the hub.

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 hub PD/PI who designed the protocol will work with the CCC to submit the asset-matched clinical protocol back to NIH for peer review. 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 hubs and spokes will carry out the clinical trial as designed in the protocol.

b) 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 hubs will be expected to recruit patients for 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.

While the hubs will be expected to have access to patient populations with chronic low back pain, further information on this research program will be available in forthcoming FOAs.

c) Master Contracts and Payments will be used to speed implementation of clinical trials in the EPPIC-Net. The CCC will negotiate and maintain a master contract with each hub and each spoke. Payments will be on a per-patient basis, according to clinical trial budgets and the master trial agreement, and will be directly distributed by the CCC to each hub and spoke. All clinical centers, both hubs and spokes, are expected to work cooperatively with the CCC and to accept the master contract and payment system. Applicants are encouraged to consult with their institutions regarding acceptability of master contracts. Applicants who cannot accept master contracts and payments will be considered non-responsive to this FOA.

d) Central Institutional Review Board (IRB). The CCC will implement and manage a central IRB for the EPPIC-Net and will create reliance agreements with each hub and spoke. All the clinical centers must use the central IRB for standard clinical trials. The hubs will use the central IRB for EFIC studies, though fulfillment of community-based requirements may entail collaboration with local IRBs, local community liaisons, local community representatives or other means.

e) Patient Enrollment In cooperation with the CCC, the hubs are responsible for creating and executing clinical trial-specific patient recruitment plans for itself and its spokes. Achievement of recruitment goals for diverse and underserved populations (i.e., ethnic groups, racial groups, gender, rural populations) is particularly important. If recruitment is not meeting expectations, the hub, in cooperation with the CCC, must create and successfully execute a corrective action plan(s) to continue participation in EPPIC-net.

f) Quality Assurance The hub is responsible for quality control and improvement for itself and its group of spokes. The CCC has broader responsibility for creation and monitoring of specific, quantifiable performance metrics for the EPPIC-Net, which will likely include start-up time, patient recruitment and retention, time from last patient last visit to database lock, and number and aging of data queries. Quality reviews will be performed at least annually. Hubs and spokes are expected to cooperate with the CCC in quality reviews and are further encouraged to propose innovative approaches to quality assessment and improvement.

g) EPPIC-Net Governance Committees. The hub PD/PI or designee is expected to actively participate in the EPPIC-Net Steering Committee (ENSC) and to serve on a rotating basis on the EPPIC-Net Management Committee (ENMC) and the EPPIC-Net Operations Committee (ENOC). The governance committees and anticipated meeting frequency are described at the end of this section.

The responsibilities of the EPPIC-Net hubs include but are not limited to:

- Accepting and implementing policies and procedures approved by the EPPIC-Net Steering Committee (see EPPIC-Net Governance Committees);

- Participating in select trials conducted in EPPIC-Net;

- Identifying and recruiting spokes, including altering or adapting its spoke network to the particular needs of each clinical trial;

- Providing the spokes with clinical leadership, research support, guidance and oversight for the EPPIC-Net processes and procedures and regular communication regarding status of the EPPIC-Net and individual clinical trials;

- Providing required data for feasibility assessments of trial applications (e.g., enrollment estimates, budget estimates) to the CCC;

- Implementing trials at the hub and spoke sites, involving, but not limited to: 1) assembling local research team(s), 2) training the spokes on EPPIC-Net and trial procedures, 3) assuring protocol adherence, 4) recruiting, treating, and following patients according to the study protocols, and 5) collecting and entering accurate, high quality data and biosamples into the central data management system and repositories as run by the DCC.

- Accurately identifying and recruiting eligible subjects for clinical trials, with attention to adequate gender and minority representation;

- Retaining participants throughout the follow-up period as required by protocol;

- Ensuring adequacy of human subjects' protections;

- Tracking and reporting trial and performance data to the CCC and/or DCC on a regular and frequent basis, including recruitment, retention, and adverse events, as required per protocol and by the IRB;

- Providing complete, accurate, and timely data entry, as well as rapid and complete resolution of any data queries, and a high level of data quality and completeness to the DCC.

- Cooperating with monitoring visits;

- Providing data to the DCC in a timely fashion for DSMB meetings;

- Actively participating in quality assessment and improvement;

- Actively participating in all EPPIC-Net Steering Committee (ENSC), and, as appropriate, SC subcommittees, EPPIC-Net Executive Committee (ENMC) or EPPIC-Net Operations Committee (ENOC) meetings and activities (see EPPIC-Net Governance Committees);

- Specifically, hub PD/PIs or designees are expected to provide scientific viewpoints and expertise on the breadth of issues discussed in the above venues, especially in the design of phase 2 trials for novel treatments in specific pain conditions.

- Participating in authorship of manuscripts and public dissemination of project results, as appropriate;

- Proposing innovative methods and leveraging existing local research resources to enhance programmatic efficiency;

- Applicants are specifically encouraged to interact with the Clinical and Translational Science Award (CTSA), if present at their institution, to identify resources. This may include access to or assistance from Recruitment (RIC) and Trial (TIC) liaisons at the CTSA.

- Promoting visibility and awareness of the EPPIC-Net within the Institution and the larger pain research community;

- Increasing and disseminating knowledge about pain research at the hub and spokes to medical students, residents, fellows, allied health professionals and nurses when feasible. Helping new investigators develop skills and experience to progress to more senior or experienced status, when appropriate.

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 a hub and a Clinical Coordinating Center (CCC, RFA-NS-19-023 ) or Data Coordinating Center (DCC, RFA NS-19-024) may be made to the same institution. There must be different PDs/PIs leading the hub and the CCC or DCC to ensure that each activity receives full attention.

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
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.

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

The PD/PI for the hub will be a clinical trials expert with a track record of successfully implementing clinical trials. The PD/PI for the hub will have knowledge of and familiarity with a specific pain condition. As support, applicants should provide evidence to demonstrate experience in:

- Working with clinicians who have access and expertise in characterizing patients with specific pain = conditions;

- Conducting clinical trials or biomarker validation studies;

- Contributing to leadership of a multicenter clinical trial;

- Establishing and/or contributing to leadership of or a network of satellite or affiliated clinical centers;

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

- Contributing to Steering Committees or comparable governance committees; and

- Working in a highly collaborative setting.

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 research team are determined by the applicant, but often may include:

- Experienced study coordinator (s) and/or study nurses(s). At least one of these individuals should be sufficiently experienced to serve as a resource and guide for the spokes;

- Other research physicians;

- Experienced recruitment coordinator or specialist; and

- Experienced data management coordinator or specialist.

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

Budget requests may include the following allowable items:

- The budget submitted for this FOA should reflect baseline costs needed to initiate, organize and maintain the hub in readiness for rapid implementation of clinical trials.

- Partial support for the PD/PI(s) salary but ONLY for time spent on site organizational/administrative tasks or the EPPIC-Net governance activities;

- Salary support for full or part-time research nurses, administrative personnel, and study assistants;

- Travel directly related to the EPPIC-Net (e.g., Steering Committee meetings, spoke site visits).

The following items are NOT allowed in the budget requests:

- Costs of clinical care provided to patients (e.g., for patient care reimbursement, transportation costs);

- Clinical and Data Coordinating Center costs; and

- Any physician, nurse or personnel compensation beyond that described above. Funds for tasks specific to conduct of a specific clinical trial, since these will be awarded separately in the grant for that individual clinical trial.

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 E. Information should be presented in a manner which clearly delineates experience and capabilities for the hub itself and the hub with its proposed spoke network.

A) Background and Experience

The applicant should include a description of current and up to 10 recently completed clinical trials, without duplicating information in the biosketches. The most informative and relevant examples would be multisite phase 2 clinical trials, or clinical trials focused on the pain treatments. The summary may however include clinical trials on any disease from any funding source, if judged informative by the applicant. The following metrics should be presented in tabular form for each clinical trial:

- Identification information: title, funding source, PI, disease or disorder, intervention

- Enrollment: total number, enrollment over time, demographic breakdown and relative ranking or contribution in the context of other participating sites;

- Time from IRB approval to first patient enrolled;

- Number and percent of patients lost to follow up;

- Number and percent of patients who successfully completed the clinical trial;

- Protocol deviations: number, type

- Time for query resolution, number/percentage >30 days, >60 days, >90 days, >120 days (for final locked data base).

The role of the hub and proposed research team should be clear. Published manuscripts that highlight recently coordinated trials should be referenced in the application in the in the Bibliography and References Cited section of the application.

B) Leadership

Demonstration of leadership capability is required for the hub PI(s), and should cover the specific points outlined in the Senior/Key Person Profile. It is also expected that, in order to successfully lead a group of spokes and pre-hospital providers, the PD/PI already plays a leadership role in some capacity to the pain medicine community or local medical community, which should also be described in the application.

- Leadership derives not only from the hub PD/PI, but also from members of the hub research team. - - A brief leadership plan should be presented which identifies and describes the roles of hub personnel, along with how they will contribute to the success of EPPIC-Net including in the design of phase 2 trials of drugs and devices in deeply phenotyped cohorts with specific pain conditions.

- 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 to the collaborative effort.

C) Research Program

The application should:

- Present evidence of their experience in designing clinical trial protocols, especially those focused on pain;

- Present the data demonstrating the capability of the hub and any identified spokes to recruit, maintain, and characterize ( phenotype ) a patient population with a specific pain condition.

- Present their concept for a hub and spoke network, and discuss its capabilities and merits, along with attaining the flexibility and scalability for the range of clinical trial challenges presented in hubs: Characteristics, Roles and Responsibilities.

- Describe how the hub PD(s)/PI(s) will identify, recruit and manage spokes. The application should include: 1) identity of 2-10 spokes committed to participation in at least one clinical trial; 2) approaches to optimizing the spoke network for individual trials; 3) plans for identifying, recruiting and selecting additional spokes, as needed; 4) procedures for adding a spoke. The applicant should discuss how they plan to make the spoke network flexible and scalable to meet potential challenges.

- Describe how the hub PD/PI will identify, recruit and manage spoke sites. The application should include: 1) identity of at least one spoke site committed to participate in EPPIC-Net; 2) plans for identifying, recruiting and selecting additional spoke sites, as needed; 3) procedures for adding a spoke site.

- Present data demonstrating the capability of the hub and spokes to achieve an enrollment commitment of up to 100 patients per year (assuming five on-going studies).

- Identify a committed group of multidisciplinary professionals at the hub and committed spokes appropriate for performance of phase II clinical trials in pain conditions.

- Specific clinical trials may require participation of other disease experts and/or subspecialists, including but not limited to experts in neurology, anesthesiology, rheumatology, obstetrics/gynecology, pediatrics, orthopedics, physical medicine, gastroenterology, or other subspecialties providing care to patients with pain. Applicants should describe 1) the potential pool of disease experts and subspecialists; 2) plans for outreach, recruitment, collaboration and integration of disease experts/subspecialists; 3) plans to motivate disease experts to support recruitment and engage in hub activities. 4) collaborative infrastructure that would enable multidisciplinary involvement in EPPIC-net.

- Include any particular experience with or proposals for innovative methods to reduce clinical trial duration and cost, and to increase trial quality. Proposals for utilization of novel methods in EPPIC-Net are encouraged.

- Present evidence that their hub and spoke configuration contains the appropriate expertise and clinical population to execute clinical trials related to low back pain.

D. Organization and Operations.

- The duties of proposed personnel responsible for day to day administration and operations at the hub and committed spokes should be described.

- If there is prior experience operating as a team, this should be described.

- See Senior/Key Person Profile, for additional descriptions of the research team.

- EPPIC-Net intends to use master contracts, centralized trial budget estimation and payment on a per-patient basis. Institutional acceptability and experience with these approaches should be addressed for the hub and committed spokes.

- Responsible personnel and procedures for negotiation and maintenance of master contracts should be identified.

- EPPIC-Net plans to establish a central IRB at the CCC, and requires hubs and spokes to use this central IRB to facilitate clinical trial initiation. Institutional acceptability and experience with central IRBs should be addressed for the hub and committed spokes,

- Responsible personnel and procedures for negotiation and maintenance of reliance agreements should be identified.

- The application should delineate the organization and operations of the hub itself as a clinical center. The applicant should be specific. Examples of relevant information include though are not limited to:

- Standard operating procedures for clinical trial activation and conduct;

- Personnel responsible for and data resources used for enrollment feasibility estimates and patient recruitment (e.g., hospital or clinic charts, specialized registry or data base).

- Personnel responsible for and methods/mechanisms used for specific tasks during conduct of a clinical trial, such as: 1) management of investigational drug/device supply; 2) minimization of protocol deviations due to enrollment of inappropriate subjects; 3) patient retention; 4) actual data entry into patient records and study forms; 5) verification of accuracy of entered data; 6) timely resolution of data queries;

- Ability to perform and experience with data transfer, particularly including direct transfers of electronic data from ECG, clinical laboratories (e.g., hematology, chemistry), imaging (e.g., X-ray, MRI) and/or electronic health records into clinical trial data bases.

- The application should present the organization and operations of the hub/spoke complex. Examples of topics include: 1) communication with the spoke PDs/PIs and research staff; 2) training spoke PDs/PIs and research staff on EPPIC-Net processes; 3) harmonizing or qualifying standard operating procedures; 4) motivation and incentives for participation and enrollment; 5) mechanisms for oversight of spoke performance; 6) mechanisms for improving spoke performance, if needed.

E. Quality Assurance

- A specific plan for quality assurance and improvement should be provided for the hub, including metrics, responsible personnel, and mechanisms for collecting data and for implementing improvement plans.

- Describe how the spokes will be integrated into quality assurance.

- The applicant should discuss results of prior site audits at the hub or committed spokes, if available, and implementation of any responsive improvement plan. Relevant audits relate to clinical research and may have been conducted by NIH, FDA or industry

Letters of Support

A statement of commitment from each participating institution or organization must be provided. In addition, an institutional letter of support from the applicant's departmental and/or institutional leadership must be included in the application. It should address how the 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 network site director, assignment of specialized research space, cost sharing of resources, and/or other ways proposed by the applicant institution. Letters from a high-level institution official(s) (e.g., Dean of the School of Medicine, Hospital President, and Vice President for Research) should be included confirming this commitment.

A statement of commitment to participate in EPPIC-Net should be provided from the spoke sites. These letters should include description of particular resources to be committed, relevant prior experience, planned organizational and/or administrative structure in conjunction with the hub, and willingness to participate collaboratively in the broader EPPIC-Net structure (e.g., central IRB, master contracts).

For those institutions with a Clinical Translational Science Award (CTSA), the applicants are encouraged to include documentation from the CTSA principal investigator regarding any support which will be provided to the hub. This may include access to or assistance from Recruitment (RIC) and Trial (TIC) liaisons at the CTSA.

Additional letters of support may be included from key personnel, such as disease experts and physician subspecialists.

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.

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 hub contribute to the advancement of clinical research in pain and clinical trials with the framework of EPPIC-Net?

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 familiarity with clinical pain research?

Does the application indicate that the PD/PI has the appropriate experience to prepare him/her for designing, leading and performing clinical trials? Which components of the PD/PI's experience prepare him/her for designing and performing early phase clinical trials in pain medicine?

Does the application indicate that the PD/PI has prior or existing leadership roles in the pain medicine community and/or local medical community which will contribute to the success of EPPIC-Net?

How do the PD/PI's past experiences prepare him/her for establishing and/or leading a network of affiliated clinical sites?

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

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 hub and spokes?

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 this application demonstrate that the proposed hub will participate in master contracts, centralized trial budgeting and per patient payments, as planned in EPPIC-Net? Does this application demonstrate that the proposed spokes will participate in master contracts, centralized trial budgeting and per patient payments, as planned in EPPIC-Net?

Does this application demonstrate that the proposed hub/spokes will perform clinical trials under approval by a central IRB, as planned for EPPIC-Net?

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 trial conduct in the network, at the hub and/or its affiliated spokes? Does the application provide evidence to suggest that the PD/PI, through participation in the EPPIC-Net governance committees, could provide innovative ideas to increase efficiency and/or quality of clinical trial conduct throughout 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?

To what extent do data in the application (e.g., prior clinical trial performance; catchment area) support the ability of this hub and its spokes to enroll a substantial number of subjects per year? To contribute to enrollment goals for minorities, gender, or other underserved groups (e.g., rural patients)? Does this application lend assurance that the proposed hub/spoke group will be able to contribute to clinical trials in the planned range of pain disorders and associated conditions, especially chronic low back pain? How strong are the letters of support and commitment?

To what extent does the resultant hub/committed spoke network fulfill the characteristics outlined in "Clinical hubs: Characteristics, Roles and Responsibilities"?

In what ways does the application lend assurance that the applicant can tailor spokes to the needs of each trial, which include:
1) execute phase 2 trials in various settings, including out-patient clinics in several specialties;
2) provide and coordinate the multiple medical specialties which may participate in the trials; and
3) propose and oversee a network of spokes. (see examples above in "Clinical hubs: Characteristics, Roles and Responsibilities")?

In what ways does the organization plan promote communication and collaboration:
1) among research personnel at the hub;
2) with disease experts; and
3) between the hub and spokes?

Does the application support that the operational procedures and quality assurance program will lead to exemplary trial execution? To what extent does the evidence in the application demonstrate that the hub and committed spokes can and will consistently deliver high quality clinical trial performance? Were findings from prior audits (if any) appropriately resolved?

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?

How will the hubs and spokes solicit additional content matter expertise when needed?

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, does the institution demonstrate appropriate commitment for the PD/PI (may be expressed as additional protected time, departmental research leadership position, facilities, space, or resources)?

Does the institution(s) provide evidence of willingness to accept the EPPIC-Net procedures specifically including: 1) standardized master trial agreements; 2) per-patient payments: 3) centralized trial budgeting; 4) central IRB; 5) provide an environment conducive to multidisciplinary engagement in early phase pain trials?

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.

N/A

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:

- Trial participant safety, implementation of network protocols in accordance with GCP and other regulatory requirements, participant recruitment and retention, reporting to the CCC, DCC, central IRB and DSMB.

- 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).

The release of funds will be milestone-driven. Milestones will be determined jointly by the awardee, NINDS and the EPPIC-Net Federal Committee after the grant has been awarded and will be specified in the Notice of Award. The following are illustrative potential milestones for the first year of the award:

- Formation of a network of spokes;

- Completion of reliance agreements for central IRB;

- Completion of master contracts.

When phase 2 trials are being conducted in EPPIC-Net, milestones will be reflective of enrollment and timely provision of high-quality trial data.

The hubs must achieve their agreed milestones during the first year in order to be eligible for future years of funding. hubs that do not meet agreed milestones for any year of the grant term may be terminated, if necessary. In addition, awards may be restricted at sites unable to successfully participate in the EPPIC-Net clinical trials (e.g., inadequate patient enrollment, unacceptable ratings on quality metrics) or unsupportive of broader EPPIC-Net functions (e.g., failure to participate in governance).

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]

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.