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

Purpose

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

EPPIC-Net will consist of one Clinical Coordinating Center (CCC), one Data Coordinating Center (DCC) and approximately 10 specialized clinical centers (hubs). As the main data manager for pain research in the HEAL Initiative, the EPPIC-Net DCC will host and manage clinical, neuroimaging, biomarker, and preclinical data from EPPIC-Net and other components of the HEAL Initiative’s pain research program, including the NIH Acute to Chronic Pain Signatures Program. The DCC will be responsible for making these data and clinical biosamples available to the research community to advance the science of pain. Lastly, the DCC will provide leadership in the statistical design and analysis of EPPIC-Net studies, and the systems and processes for data collection, management, quality assurance and reporting.

Clinical studies may come to the network from two sources:

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 DCC sections below.

Peer-reviewed 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 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, new 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 that 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. Further, it is necessary to better understand the different biologic mechanisms that underly different pain conditions, as well as the mechanisms that tie together common overlapping pain conditions, through 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 and to identify, prioritize and test new therapies targeted to these specific mechanisms.

The DCC will support these objectives by performing clinical trial data management, data quality control, study monitoring, and statistical analyses for EPPIC-Net. The DCC is responsible for preparing reports for the EPPIC-Net Data and Safety Monitoring Board (DSMB) and external regulatory and oversight groups. Moreover, the DCC is expected to be innovative in improving clinical trial efficiency and quality through study design and data management.

The DCC will further contribute to these objectives by hosting and managing repositories for biosamples, clinical, neuroimaging, biomarker, and omics data from EPPIC-Net trials, the Acute to Chronic Pain Common Fund program, and potentially other clinical components of the NIH HEAL Initiative. Further, as part of the NIH HEAL Partnership, the DCC will also serve as a hub for sharing previously collected preclinical, clinical, and pharmacological data across different sectors to include academia, industry, government, and non-profit entities.

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.

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

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

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

Network Projects

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

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 like novel drugs, biologics, and devices, which are referred to as assets . These assets and trial protocols will be submitted to a different FOA. Expertise from the hubs will be critical in designing clinical trials around the highly prioritized assets. More details on this process are outlined below in Significant responsibilities of the DCC.

(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, ongoing 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.

DCC: Roles and Responsibilities

The DCC will provide scientific and organizational leadership and will facilitate the conduct of clinical trials within EPPIC-Net. Its role includes web-based data collection, data management, data quality assurance, study monitoring, statistical analysis, provision of data summaries to external groups, and website implementation and maintenance. The DCC is encouraged to be innovative and support EPPIC-Net goals of rapid implementation and high quality through techniques such as modular Case Report Form (CRF) design, risk-based monitoring and web-based data capture. It should strive to collect complete, accurate and precise data while minimizing the burden on the participating clinical sites. The DCC has the primary responsibility for providing data reports and interim analyses for the Data and Safety Monitoring Board (DSMB), and for reporting to external regulatory and oversight groups such as the central IRB, FDA, the EPPIC-Net Federal Committee (defined under the EPPIC-Net Governance Committees) and any other appropriate groups convened as part of the HEAL Partnership. The DCC will collaborate closely with the CCC, the clinical research hubs and spokes, and the clinical trial Program Director/Principal Investigator (PD/PI). The DCC will also manage repositories for biosamples, clinical, neuroimaging, biomarker, and omics from the EPPIC-Net trials as well as previously collected data as part of the NIH HEAL Partnership.

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 DCC include the following:

a) Data management and storage related to EPPIC-Net clinical trials

Clinical trials in EPPIC-Net will test the efficacy of therapeutic candidates (e.g., novel drugs, biologics, and medical devices; assets ) as contributed by academic or industry partners within the HEAL Partnership. The DCC will be responsible for web-based data collection, data management, data storage, data quality assurance, study monitoring, and statistical analysis of these clinical trials. To ensure the uncompromised completion of ongoing clinical studies and trials, these data will be kept secure until it is cleaned, locked, analyzed, and published. The DCC will be responsible for ensuring the confidentiality, security, and privacy of personal identifiable data. NIH anticipates that collected data from the EPPIC-Net trials could also include image files and omics data (e.g., metabolomic, lipidomic, proteomic, extracellular RNA).

b) Data management, storage, and sharing related to pain research more broadly

As part of the NIH HEAL Partnership, the DCC will serve as a central hub for data sharing more broadly. It will manage previously collected preclinical, clinical, imaging, omics, and pharmacological data as it relates broadly to pain research and analgesics from the NIH HEAL Partnership and will encompass different sectors to include academia, industry, government, and non-profit entities. Further, the DCC will also play a role in storing and managing clinical, imaging, and omics data from several other NIH clinical programs focused on pain, including but not limited to the Acute to Chronic Pain Signatures program and the Back Pain Consortium (BACPAC) Research program (detailed further below). NIH anticipates a portion of these data will be made publicly available in close to real time for broad research use, and the DCC will be responsible for ensuring the accessibility of these data.

c) Data management related to low back pain

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 DCC will be expected to manage and store data related to these efforts, including phase 2 trials, longitudinal cohort studies, and adaptive clinical trials. The DCC will also collaborate with an external data integration core in this effort that will develop, deploy, and refine new algorithms for integrating patient phenotype, symptoms, and biomarkers (including newly developed modalities) to predict which patients will respond best to which interventions. The EPPIC-Net DCC and CCC will work closely with this group, but not be responsible for algorithm development or testing. Though the DCC will need to have the ability to manage and store these data and collaborate with this group, additional funds will be made available and thus do not need to be considered in the budget.

d) Biosample repositories. The DCC will establish and execute secure repositories for biosamples (e.g., blood, tissue, urine) produced as a result of clinical trials executed through EPPIC-Net. While it is difficult to specify the volume of biosamples, the DCC will need to be flexible enough to accommodate expansion of these needs as the number of trials increases. These repositories may also expand to include biosamples, from the associated NIH HEAL Initiative clinical programs mentioned above and potentially, other clinical trials networks. For example, in later years of the network (2022 and beyond), NIH anticipates that the DCC will be responsible for storing roughly 11,000 biosamples of blood and urine collected from the Acute to Chronic Pain Signatures program. The DCC will not be responsible for the costs of transferring these samples, but will only be responsible for the storage, management and distribution of these biosamples. Further, the biosample repository will also be responsible for managing and storing specimens obtained from the clinical trials on chronic low back pain and other EPPIC-net trials as described above.

e) EPPIC-Net DSMB members will be selected and appointed by the EPPIC-Net Federal Committee (see EPPIC-Net Governance, below). There will be one central DSMB, with addition of ad hoc members to provide expertise required for oversight of each individual clinical trial. The DCC will work with the DSMB members to create and finalize the DSMB charter and analysis plans, and provide data and analyses for the open and closed portions of DSMB meetings. The DCC will provide staff, including a dedicated statistician, to participate in both open and closed DSMB meetings. In some cases, it may be appropriate to devote two statisticians to each protocol; one would be blinded to interim results and would participate on the Trial Committee, while the second would be unblinded to interim results, would generate the DSMB data reports, and would report to the DSMB in closed sessions. An NINDS Liaison will be assigned; this staff member will not otherwise be involved in the trials and will coordinate the DSMB meetings, circulate the minutes, and verify that the recommendations of the DSMB are conveyed to the EPPIC-Net Federal Committee and/or participating NIH signing official for concurrence. It is anticipated that routine DSMB meetings will occur semi-annually, although the DSMB will meet (by teleconference or in person) more often if needed. The NIH will provide logistical support (e.g., travel arrangements. expense reimbursement, honoraria) for the DSMB members. The DCC and CCC should each plan to support the travel of 2 or 3 of their staff to these meetings through their grants.

f) Regulatory and other External Reporting. The DCC is responsible for any and all reports required by external regulatory authorities, because it holds the clinical trial database. However, preparation of the reports should be performed collaboratively with the CCC and Hub PDs/PIs.

Anticipated reports include:

1) ongoing expedited reporting of serious, unexpected, related adverse events to the FDA and central IRB;

2) periodic reporting of clinical trial status and safety events to the central IRB, the EPPIC-Net Federal Committee, and other groups convened as part of the NIH HEAL Partnership, as needed;

3) reporting trial status and final results on clinicaltrials.gov; and

4) annual IND update or IDE progress report, for trials conducted under IND or IDE.

In addition, the DCC will respond in a timely manner to all requests for ad hoc status and/or safety event reports from appropriate authorities. If there are instances where the hub PD/PIs or site PDs/PIs are required to submit additional reports (e.g., US regulatory authorities if multinational trial, institutional IRB), the DCC is responsible for supporting preparation of these reports and verifying that submission occurs in a timely manner. The DCC supports NIH-encouraged data sharing by preparing the final, limited personal health information or de-identified data set in an appropriate format and submitting this to a secure data repository after publication of the primary study results or after 18 months, whichever comes first. Inclusion of digital data such as ECG tracings or MRI images in the shared dataset is encouraged.

In addition to regulatory reporting, the DCC is responsible for providing requested data-related updates at meetings of the NIH Helping End Addiction Long-term (HEAL) Partnership program and to NIH Leadership as needed.

g) Risk Based Monitoring (Oversight of Clinical Investigations -- a Risk-based approach to monitoring, FDA, 2013) entails determination of the most efficient means of monitoring and review required to ensure highest accuracy of pre-identified key data fields and acceptable levels of accuracy in remaining data fields. The plan should stipulate technical approaches, such as on-site monitoring and/or various levels of stringency in off-site monitoring. It is suggested that the DCC create a general template for EPPIC-Net Risk Based Monitoring in parallel with development of its data capture systems during Year 1 of the EPPIC-Net DCC award. This template should address anticipated approaches to data fields common to all clinical trials (e.g., demographics, patient disposition) and should serve as a basis for subsequent trial specific Risk Based Monitoring plans.

h) Quality Assurance In addition to oversight of data quality in clinical trials, the DCC should continuously assess and strive to improve the quality of its own performance. The CCC has broader responsibility for quality assessment and improvement across EPPIC-Net. The CCC review will be performed at least annually and may include metrics such as 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. The DCC is expected to cooperate with and provide support to the CCC for these quality reviews. The DCC is further encouraged to propose innovative approaches to quality assessment and improvement.

i) The EPPIC-Net Website will be an important tool for increasing awareness of EPPIC-Net and managing communication about and within EPPIC-Net. The website should have a public section describing EPPIC-Net, give instructions to the clinical research community regarding any clinical research opportunities through EPPIC-Net, and provide ready access to public information such as on-going clinical trials, press releases, and publications. The website should also have a private section accessible only to EPPIC-Net and clinical trial personnel to facilitate communication about, though not limited to, EPPIC-Net committee meetings, metrics, and procedures. The DCC is responsible for design implementation and maintenance of the EPPIC-Net Website. The EPPIC-Net website will also be used for disseminating data from other NIH HEAL Initiative programs, the HEAL Partnership, and pain research more broadly (outlined above) to be made widely available to the research community.

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

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

- Providing scientific leadership, particularly in relationship to data and statistical issues;

Actively participating in all EPPIC-Net Steering Committee (ENSC), EPPIC-Net Management Committee (ENMC) and EPPIC-Net Operations Committee (ENOC) activities (see the EPPIC-Net Governance Committees);

- Promoting visibility and awareness of EPPIC-Net;

- Organization and support of the EPPIC-Net DSMB (as detailed above);

- Developing EPPIC-Net Standard Operating Procedures (SOPs) which address all aspects of data management and statistical analysis;

- Assessing status of existing resources for clinical trials in pain research and medicine, such as NIH Common Data Elements (CDEs) and Case Report Forms (CRFs), and creating and submitting new CDEs and CRFs if required;

- Creating, maintaining, and updating the EPPIC-Net website with input from the CCC;

- Establishing web capabilities for trial randomization, trial data collection and DSMB communications and data storage (which may be independent or incorporated into the EPPIC-Net website);

- Developing a Risk Based Monitoring Plan (RBM) template for EPPIC-Net;

- Providing instruction and training to clinical sites regarding EPPIC-Net data management processes, procedures, and metrics

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

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

- Providing leadership and guidance to hub PD/PIs and to spoke and other clinical site PDs/PIs on required regulatory reporting (e.g., annual central IRB safety reports, annual IND updates, clinicaltrials.gov reporting);

- Implementing procedures for backing up the program s clinical and administrative data, including regular back-up of the database with storage at a remote facility; and

- 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.

- Working with participants from the HEAL Partnership on organizing, managing and sharing preclinical and clinical data from industry research that will advance pain science and accelerate the development of non-addictive pain treatments.

- Working with other leaders of the NIH HEAL Initiative on centralizing data, data management, biosample storage, and biosample/data dissemination for research purposes.

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

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

- Responsibility for all aspects of data management, including quality control, for the multi-center clinical trials and studies;

- Overseeing statistical conduct from final protocol design to analysis/publication.

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

Prior to clinical trial application submission, during the pre-application concept assessment phase of a clinical trial, the DCC is responsible for:

- Providing information and guidance, particularly regarding statistical design, to the CCC, hub PD/PIs ( protocol PIs ), asset owners, and other potential investigators as they design a clinical trial protocol based on the standard template in NOT-OD-17-064 (e.g., assess protocol synopsis and schedule of activities);

- Performing a feasibility study of the proposed clinical trial, particularly in relation to any challenges in data management;

- Developing the components of the clinical trial budget that will be necessary to support DCC infrastructure and functions.

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

- Coordinating with investigators to transfer and store any previously produced data on assets to be tested as part of EPPIC-Net;

- Working with the protocol PI (and any other trial statisticians) to finalize data management aspects of the protocol;

- Working with the protocol PI (and any other trial statisticians) to finalize the trial sample size and the Statistical Analysis Plan;

- Working with the protocol PI and CCC to create a database for each clinical trial in a timely manner;

- Promptly developing Case Report Forms (CRFs).

- Creating and implementing a web-based or equally/more user-friendly randomization scheme and process;

- Developing a clinical trial specific data quality assurance plan; and

- Developing a clinical trial Risk Based Monitoring plan.

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

- Ensuring smooth transfer and providing secure repositories for any data (e.g., imaging, omics) associated with the clinical trial;

- Ensuring smooth transfer and providing secure repositories for any biosamples (e.g., blood, tissue, urine) associated with the clinical trial;

- Supporting all data management aspects of each clinical trial conducted in EPPIC-Net;

- Establishing a web-based, user-friendly database for each trial;

- Verifying that database meets required criteria for security features, such as

secure, password protected database access, and audit trails, consistent with the guidelines of the U.S. DHHS; and patient confidentiality features consistent with HIPAA and other regulations;

- Providing web-based or other user-friendly, rapid mode of central randomization;

- Performing central and on-site monitoring consistent with the Risk Based Monitoring Plan;

- Generating and promptly resolving data queries;

- Establishing and implementing quality assurance procedures for data quality and completeness;

- Providing data to the CCC to support therapeutics supply and distribution;

- Working with the CCC, hubs, spokes, and ad hoc clinical sites to report and track trial status in terms of enrollment, retention, protocol deviations, CRF completion, data query aging and other metrics;

- Providing true copies of data files and supporting documentation for each EPPIC-Net clinical trial in a timely manner;

- Providing a statistician to participate in open and closed portions of DSMB meetings;

- Providing data analyses for and attending DSMB meetings; and

- Performing required regulatory reporting.

During the Analysis and Publication Phase of each clinical trial, the DCC is responsible for:

- In collaboration with the hub clinical trial PD/PI overseeing or performing final study analyses per protocol;

- In collaboration with the hub clinical trial PD/PI overseeing or performing preparation of presentations and publications;

- In collaboration with the hub clinical trial PD/PI and the CCC, compiling and presenting final study reports to central IRB, DSMB, FDA, EPPIC-Net Federal Committee and other regulatory bodies;

- Coordinating with the CCC to maintain the data and biosample repositories after a clinical trial is complete and providing access to these resources to other researchers at NIH’s request; and

- Supporting data sharing via the NIH data repositories and clinicaltrials.gov.

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.

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

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

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

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

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

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

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

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

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

The letter of intent should be sent to:

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

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

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

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

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

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

In addition:

Facilities and Other Resources:

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

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

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

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

The PD/PI for the Data Coordinating Center should be an experienced statistician and expert in data management and analysis for clinical trials. Without duplicating information in the biosketch, the applicant should present evidence to demonstrate the following experience:

- Successfully implementing and coordinating data management in multi-center clinical trials;

- Successfully implementing and coordinating statistical analyses in multi-center clinical trials;

- Successfully managing projects conducted in a highly collaborative setting;

- Generating interim analysis reports and reporting to DSMBs;

- Designing clinical trials;

- Introducing innovative methods to rapidly implement clinical trials, minimize burden of data collection on sites, rapidly achieve data base lock, implement risk-based monitoring, and increase trial data quality;

- Experience may be particularly relevant when the trial was in a disorder related to clinical management of pain; and

- Experience or familiarity with drug or medical device development may also be particularly relevant.

It is important that the PD/PI be available to attend and actively contribute to all required EPPIC-Net governance committee meetings (see the EPPIC-Net Governance Committees in Part 2. Section I. of this FOA).

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 DCC research team are determined by the applicant, but typically would include:

- An experienced data management team including an experienced programmer and project manager;

- An experienced logistical coordinator for transfer and storage of biosamples and previously collected data;

- Experienced clinical monitor(s), particularly for execution of on-site monitoring;

- At least one experienced statistician, with a documented track record in supporting Phase 2 and 3 clinical trials (experience with adaptive or innovative statistical methodology is desirable); and

- The DCC must be able to support at least five concurrent Phase 2 clinical trials, including providing unblinded data for the DSMB and regulatory reporting while not endangering blinding of staff conducting the trials.

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

- The budget submitted for this FOA should reflect baseline costs needed to initiate, organize and maintain the DCC in a state capable of performing timely pre-application concept assessment and ready for rapid implementation of clinical trials.

- Salary support for the PD/PI and research team members should only include time spent on EPPIC-Net activities, which may include organizational/administrative tasks, support of individual clinical trials, and participation in EPPIC-Net governance and committee activities.

- The budget should reflect the costs of establishing and maintaining data and biosample repositories outlined above.

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

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

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

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

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

A) Background and Experience

Without duplicating information submitted elsewhere such as biographical sketches or the Human Subjects-Clinical Trials Form, the applicant should include a description of current and up to 10 recently completed multicenter clinical trials where the applicant held significant responsibility for data management and/or statistical analysis. The most informative and relevant examples would be multi-site clinical trials involving treatment for pain or other neurological disorders. The summary may however include clinical trials on any disease in any clinical setting, if judged informative by the applicant. The following metrics should be presented in tabular form for each clinical trial:

- Identification information: title, funding source, PD/PI, disease or disorder;

CRF: time required from start of CRF production until data collection system operational at first clinical site;

- Randomization scheme: time required from start of designs until system operational at first clinical site;

- Time from finalization of clinical trial protocol to finalization of Statistical Analysis Plan (SAP);

- Number of DSMB interim analyses performed and for each 1) data included (e.g., safety only, interim efficacy analysis) 2) time from date of last included patient visit until data provided to DSMB;

- Time from last patient's visit to database lock;

- Time from database lock to final analysis of primary outcome;

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

- Number and percentage of missing data cells (in final locked data base).

Published manuscripts that highlight recently coordinated trials should be referenced in the application in the Bibliography and References Cited section of the application. The applicant should summarize experience with 1) preparing and submitting data to NIH or other shared data repositories; and 2) performing analyses and posting results to clinicaltrials.gov.

B) Leadership

Demonstration of leadership capability is required for the DCC PD/PI(s) and should cover the specific points outlined in the Senior/Key Person Profile.

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

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

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

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

C) Organization and Project Management

- The PD/PI should describe the duties of the proposed additional DCC research staff.

- 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.

- The organization of the research team for performance of day-to-day administration and operation of the DCC should be described.

- See DCC: Roles and Responsibilities regarding specific tasks.

- Applicants should describe the standard operating procedure (SOPs) they have in place and the processes they currently apply when implementing multi-center clinical trials.

- Applicants are encouraged to provide examples of SOPs used for implementation of multi-center clinical trials, including, but not limited to SOPs describing database access, data quality control, data queries with audit trails, etc., as an appendix in the application.

- Applicants should discuss how they will accommodate variability in site identity and number from trial to trial.

D) Communication Plan

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

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

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

- Applicants should describe the communication plan with the protocol PIs from the hubs. Some projects may include a trial-specific statistician, independent of the DCC. The plan for delineating roles and responsibilities and for collaboration with a trial-specific statistician should be included.

- Applicants are encouraged to describe any special expertise or unique strengths they can offer to enhance communication and collaboration (e.g., established database tools, hardware, software, quality control tools, monitoring expertise, team leadership and training, communications platforms, website design and management).

- The EPPIC-Net website may be an integral component of the communication plan and means for organizational management. The applicant should discuss a plan for creation, maintenance and optimal use of the EPPIC-Net website, along with other communication and organizational tools. The website plan should include design, contents, capabilities and integration into the larger organizational management plan. The plan should also include logistical basics relevant to creation and maintenance of the website, such as availability and access to individuals with appropriate IT expertise and required computer equipment.

E) Repositories; Data Management; and Data Quality Assurance

Based on the tasks outlined in "DCC: Roles and Responsibilities", the applicant should describe plans for data management, data quality assurance, and repository structure. It is suggested that the presentation be organized using the clinical trial stages used in "DCC: Roles and Responsibilities." The plan should build on existing strengths and capabilities, which should be clearly described. The applicant is encouraged to address the following desirable attributes:

- Repositories for previously produced data associated with an asset, data from pain research more broadly, newly collected data from clinical trials (e.g., imaging, omics), and new or previously produced biosamples, as described above;

- Ability to ensure appropriate access to data determined to be publicly available in an expedient manner;

- Ability to ensure confidentiality, security, and privacy of personal identifiable data from trials performed in EPPIC-Net;

- User-friendly interface directed at the experience and knowledge of users such as physicians and nurses (rather than that of programmers, data managers or statisticians);

- Convenience for the location of the users;

- Ability to directly import digital data from electronic sources (e.g., laboratory, ECG, imaging data, electronic health records) into the trial database;

- Minimal burden of data collection on clinical personnel and sites;

- Seamless integration of data from disparate sources into a single central database, which facilitates reporting, and eventual data sharing and dissemination;

- Data validation performed as thoroughly as possible on collection and/or entry and completed promptly on an ongoing basis;

- Rapid and convenient generation and resolution of queries with minimal burden on clinical personnel;

- Support and integration with a risk-based monitoring approach to early recognition of signals for problems at specific clinical sites or across the clinical trial;

- Easy and prompt dissemination of data to statisticians and other analysts, in a variety of tab delimited formats;

- Easy and prompt production of regular and ad hoc reports on trial status, progress, safety and, when needed, outcomes;

- Graduated, role-based security, which permits varying degrees of access to data based on an individual’s role in the study;

- Protection for personal health information (PHI) consistent with applicable federal regulations; and

- A log of all authorized access.

F) Risk Based Monitoring

The applicant should summarize experience with and plans for use of Risk Based Monitoring (RBM) for data quality assessment and for clinical trial or program quality improvement. The plan may include, but is not limited to the following: 1) likely criteria to be included in a EPPIC-Net program RBM and clinical trial RBMs, 2) balance between central and on-site monitoring, 3) background and training of staff performing central and on-site monitoring, 4) whether or how to include clinical or medical reviews as an RBM component, 5) algorithms for identification of quality issues by RBM, 6) communication of identified issues, 7) triggers for on-site monitoring, 8) creation and implementation of quality improvement plans for identified deficiencies.

G) Statistical Support Plan

- Some clinical trials will ask the DCC to provide full statistical support. In other cases, the DCC staff may need work collaboratively with external statistical experts. The application should clearly address statistical support in each of these two situations.

- Based on the tasks outlined in "DCC: Roles and Responsibilities," the applicant should describe plans for statistical support and analysis. It is suggested that the presentation be organized using the clinical trial stages used in "DCC: Roles and Responsibilities." The plan should build on existing strengths and capabilities, which should be clearly described.

- The applicant should outline the expertise of the DCC in clinical trial design including simple, pragmatic trial designs, comparative effectiveness designs, and adaptive trial designs.

- The DCC may be called upon to provide rapid analyses in response to inquiries from the EPPIC-Net Federal Committee or regulatory authorities. Experience and plans for rapid provision of accurate analyses should be described. Examples should provide specific descriptive detail, for example the number of days from request to analysis available, or the number of tables and figures provided.

H) DSMB and Regulatory Reporting

The applicant should describe the experience of the DCC with support and facilitation of DSMBs, including but not limited to experience in:

- Serving on and facilitating DSMBs;

- Rapid collection of data for interim analyses;

- Preferred formats for reports on study status (e.g., enrollment, disposition), protocol deviation (include detection as well as reporting), safety data;

- Design, conduct, and interpretation of futility analyses for effectiveness or enrollment;

maintaining study blinding while providing unblinded data to the DSMB (failures should be included as well as successes);

- Provision, distribution and collection of data for DSMB meetings, particularly including retrieving unblinded data from DSMB members; and

- Rapid provision of requested additional analyses.

The applicant should describe the plan for DSMB support for EPPIC-Net, including though not limited to the points above. The DCC will be responsible for data compilation, analysis, report preparation and report submission to other regulatory oversight bodies, such as the central IRB, FDA or EPPIC-Net Federal Committee. These responsibilities include expedited safety reports, periodic annual reports, final reports and ad hoc reports. Applicants should discuss their prior experience with each of these types of reports.

- If there is experience with expedited safety reporting, indicate the number of reports filed and the proportion that were successfully filed within required regulatory timeframes.

- Explain how narrative composition and medical review were incorporated;

- If there is experience with annual reports, include specific metrics such as the number completed, recipient (e.g., FDA, institutional IRB), method used for planning and tracking, data base preparation including determination of stop date, interval from last data base entry to analysis available, interval from last data base entry to report ready, proportion filed within regulatory timeframe.

- Indicate what materials have been developed, particularly if available for use in EPPIC-Net. Relevant materials include SOPs, tracking data bases, templates, and standard report formats.

- Examples of existing SOPs or templates may be included in an appendix.

- Indicate how interactions with hub clinical trial PDs/PIs and other clinical sites will be incorporated to support preparation of each of the above types of reports.

- The applicant should provide a plan which addresses preparation, tracking and filing of each of the above types of reports for clinical trials in EPPIC-Net. The points mentioned above should be addressed in the plan.

I) Data Standardization

- The PD/PI should describe how standardization of data collection and data collection instruments will be promoted, including the use of existing or creation of new NIH common data elements.

- The applicant should mention experience and plans for performing additional analyses for and posting data on clinicaltrials.gov.

J) Quality Assurance

A specific plan for quality assurance and improvement should be provided for the DCC, including metrics, responsible personnel, and mechanisms for collecting data and for implementing improvement plans. Focus on actions undertaken at the DCC and indicate how these will be integrated with the CCC quality effort. Results of any prior audits conducted should be provided, along with any executed responsive improvement plan.

Letters of Support

A statement of commitment from each participating institution or organization must be provided. At least one letter of support from the applicant's institution must be included in the application. This letter should address how the general institutional commitment will be established and sustained, how the institution will maintain accountability for promoting scientific excellence, and how the EPPIC-Net effort will be given a high priority within the institution (relative to other research efforts and non-NIH supported programs.) The institutional commitment may be in the form of support for recruitment of scientific talent, provision of discretionary resources to the DCC director, assignment of specialized research space, cost sharing of resources, and/or other ways proposed by the applicant institution. There may be multiple letters of support from the institution or its components, particularly if the institution is providing support of collaboration for specific DCC responsibilities. At least one letter confirming institutional support should come from a high-level institution official(s) (e.g., Dean of the School of Medicine, Hospital President, and Vice President for Research).

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.
• Describe de-identification and protection of the privacy of the research participants.

Appendix:

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

The following items are recommended for inclusion in the Appendix:

- Sample documents that illustrate the DCC's expertise, such as CRFs, data dictionaries, user manuals, database training instruments etc.

- Sample study data quality plan describing the DMC's database access, data quality control, data queries with audit trails, etc.

- Sample Risk Based Monitoring Plan

- Sample SOPs

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 DCC contribute to the advancement of clinical research, particularly data and statistical components, within 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?

Does the application indicate that the PD/PI and research team have the appropriate experience to successfully lead, design and implement the data management and statistical components of multicenter clinical trials to be performed in EPPIC-Net? Is there evidence to suggest that the PD/PI and research team have appropriate experience to prepare them to facilitate and manage the EPPIC-Net DSMB(s)? For regulatory reporting?

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 DCC?

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

Does the application present evidence that the DCC will apply innovative methods to statistical and data management related aspects of clinical trials that would increase efficiency and/or quality of clinical trial conduct in EPPIC-Net?

Does the application contain innovative proposals for addressing some of the particular challenges facing the DCC, such as randomization and data collection in a busy clinical center, or collecting accurate, high quality data in a manner that minimizes burden on the clinical research team?

Does the application contain innovative proposals for incorporating complex digitized data (e.g., CT or MRI images) into the shared data repository?

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 the performance metrics from past clinical trials (see Research Plan, A) support the ability of the applicant institution to carry out key tasks (see DCC: Roles and Responsibilities) in a timely manner? To preserve the integrity of trial data and provide an accurate data base and high-quality analyses?

Does the application support that the proposed DCC will provide exemplary oversight and support to the EPPIC-Net DSMB(s), including meeting facilitation, data compilation and report generation?

Does the application demonstrate that the proposed DCC will be capable of providing unblinded data for closed DSMB sessions without jeopardizing blinding of other clinical trial personnel?

Does the application suggest that external reporting obligations, including to the central IRB, FDA, the EPPIC-Net Federal Committee, and clinicaltrials.gov will be performed reliably and accurately? In what ways does the proposed plan lend assurance that all regulatory reporting will be performed in timely manner with thorough, accurate and readily comprehendible reports suited to the requirements of the recipient?

In what ways does the proposed data management system achieve the characteristics of a desirable system as described in Research Plan, Item C? How well does the plan achieve the goals of making a user-friendly system that minimizes burden on clinical trial sites (e.g., can digital data be imported from laboratory data bases and/or machines)? How robust are the data validation and query systems?

Does the application provide evidence that the proposed DCC will provide exemplary statistical support and consultation, including contributions to clinical trial design, creating statistical analysis plans and performance of analyses? Does the application provide evidence that external trial-specific statisticians will be fully integrated with the DCC?

Does the application demonstrate that Risk Based Monitoring will be used to optimize generation of clean accurate, high quality clinical trial data while minimizing monitoring time, particularly on-site monitoring time? Does the application propose approaches for the particular needs or challenges of clinical trials conducted pain research?

Does the application demonstrate that the DCC has the required knowledge, experience and an appropriate plan for submitting de-identified, widely useable data bases to the data repository in a timely fashion at the conclusion of each clinical trial?

In what ways does the communication plan promote collaboration and information sharing: 1) with the CCC; 2) with hub and spoke PDs/PIs; 3) with other clinical sites? In what ways does the communication plan provide assurance that the DCC will provide sufficient procedural training and will provide rapid, accurate resolution of questions/issues?

How does the application provide assurance that the planned administration and organization of the DCC itself, and the DCC quality assurance program will lead to exemplary DCC performance and contribute to the success of the EPPIC-Net?

How does the application demonstrate the ability of the DCC to store clinical data and biosamples? Is the repository structure flexible enough to accommodate a databank and biosample repository of various sizes? Has the application demonstrated an ability to share this data in both a public and privately secure context?

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

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

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

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.

Additional DCC Responsibilities

Does the application demonstrate that the DCC will be able to incorporate the use of existing common data elements or work with NIH to create new common data elements for pain research?

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

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

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

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

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

Not Applicable.

Not Applicable.

Not Applicable.

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

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.
• 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:

- Coordinating all aspects of clinical trial data management, data quality control, and data monitoring for the EPPIC-Net. In collaboration with the clinical trial PD/PI and their specific project statistician (if included in the clinical trial grant), the DCC is responsible for clinical trial statistics from finalization of the Statistical Analysis Plan through performance of the final analyses. The DCC provides support for the Data and Safety Monitoring Boards (DSMBs), particularly including preparation and provision on interim analyses. The DCC is responsible for data provision and reporting to regulatory agencies such as the central IRB and FDA.

- 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 DCC. 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:

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

Terms and Conditions of Award The release of funds will be milestone-driven, according to milestones to be determined jointly by the awardee, NINDS and the EPPIC-Net Federal Committee and specified in the Notice of Award. The following are illustrative potential milestones for the first year of the award:

- Completion of EPPIC-Net SOPs, including 1) plans to ensure data quality; 2) plans for data analysis and manuscript submission for publication within one year of trial completion; 3) data sharing.

- Creation of EPPIC-Net website for data capture;

- Completion of DSMB charter; and

- Completion of template Risk Based Management plan.

In subsequent years, milestones will likely be more reflective of clinical trial support activities. If the DCC does not meet agreed milestones for the first or any subsequent year of the grant term, funding may be terminated, if necessary. In addition, the award may be restricted if the DCC is unable to achieve acceptable ratings on quality metrics for its responsibilities to EPPIC-Net clinical trials, or is unsupportive of broader EPPIC-Net functions (e.g., failure to participate in EPPIC-Net governance committees).

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]

Hua-Chuan Sim, MD
National Library of Medicine (NLM)
Telephone: 301-594-4882
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.