The Hemodialysis Opioid Prescription Effort (HOPE) Consortium, composed of five to seven Clinical Centers (CCs) and a Scientific and Data Research Center (SDRC) will develop an intervention to be tested in a randomized controlled trial to simultaneously address the problem of pain and opioid use in adult US in-center hemodialysis (HD) patients receiving chronic opioid prescriptions a) by initiating multipronged pain treatment tailored individually to each patient, without opioids, and b) by using buprenorphine and/or other novel agents to reduce dependence on opioids in affected patients. Multipronged interventions may include behavioral modification techniques such as Cognitive Behavioral/Group Therapy, which can be designed according to each participants psychosocial profile or alternative therapies, such as acupuncture, and can use social media platforms for implementation and evaluation. Interventions may also address treatment of depression and/or anxiety in affected patients as a strategy to ameliorate perception of pain. It is hypothesized that an intervention in hemodialysis patients receiving chronic opioid prescriptions focused on treating pain, taking into account individual patient characteristics, such as their psychosocial and mental health status, coexisting medical conditions, perception of pain, and coping mechanisms and strengths will reduce opioid medication prescription rates and/or morphine milligram equivalent (MME) doses compared with usual care. Whether a medical intervention, such as therapy with buprenorphine, can reduce the dose of opioid medication prescribed as well as the number of patients receiving chronic opioid prescriptions is unknown in this population. Such questions can be addressed in two- or three-arm trials. Analyses will consider comorbid illnesses (such as diabetes mellitus and mental health disorders), substance use (such as alcohol or benzodiazepines), and social determinants of health (such as socioeconomic status, social isolation, social support and racial discrimination) to identify novel risk factors for pain and opioid use in this population.

The primary endpoint is likely to be either a clinically meaningful reduction in the rate of opioid prescription and/or in participant MME dose. Other endpoints will be pain control, patient satisfaction with care, perception of quality of life, hospitalization rates and mortality.

Real time risk factor and outcome data may be captured via the electronic health record (EHR), by leveraging and expanding an existing pilot set of more than 200 standardized data elements identified and prioritized for comprehensive chronic kidney disease (CKD) care by the NIDDK CKD eCare Plan Working Group. The eCare Plan data element set includes new and existing data standards from widely used ontologies (such as ICD-10, SNOMED-CT, LOINC, RxNorm, etc) and is intended to enable interoperability of clinical data for research and care.

This Funding Opportunity Announcement (FOA) will establish CCs to work collaboratively with a SDRC in a Consortium assembled to design and conduct the trial. The CCs will be responsible for screening and recruiting study participants, conducting interventions, and collecting and electronically submitting data to the SDRC, which will accept and manage the data. Each CC will be required to enroll and follow 120 patients in the study. Each CC will submit a plan for screening HD patients to identify those receiving chronic opioid prescriptions and a proposed intervention designed to reduce the dose of opioid medication prescribed and/or the number of patients receiving chronic opioid prescriptions. Patients identified, who consent to participate in the study, will be evaluated to assess their psychosocial status, coexisting medical conditions, perception of pain, and coping mechanisms and strengths.

Applications including any home hemodialysis or peritoneal dialysis patients or children are not responsive to this FOA.

The Consortium is expected to comprise a wide range of expertise, including but not limited to nephrologists, experts in pain assessment and management and opioid medicine (including practitioners with certification in buprenorphine prescription), biostatisticians, ethicists, data scientists/informaticists and patient advisor participants.

Studies proposed by the successful applicants will be the starting point for discussions regarding the research to be undertaken by the Consortium. Investigators will devise studies that will be reviewed by a Data and Safety Monitoring Board (DSMB) and approved by the NIDDK. The final study protocol will be designed by the CC and SDRC Program Directors/Principal Investigators and approved by the Steering Committee, and then the DSMB and the NIDDK. Consortial study results are expected to provide evidence for management approaches to pain and minimizing opioid prescription in HD patients.

Research Objectives

The CCs will work in a collaborative, harmonious and efficient manner with the SDRC to comprehensively maximize the number of participants and collect initial and longitudinal data and information on clinical outcomes on all participants during the study period, within the purview of the HOPE Consortium. A CC can propose a set of dialysis units to work together under its direction to fulfill recruitment requirements.

It is envisioned that a successful applicant for a Clinical Center will have a large population of HD patients with complaints of pain and receiving chronic (more than 90 days/year) opioid medication prescriptions.

Applications for CCs should consider and submit:

1. A multiple PI plan including a nephrologist, a specialist in opioid medicine certified in burprenorphine prescription, a biostatistician clinical trialist, and a specialist in pain therapeutics.
2. A description of a clinical trial intervention (drugs, biologics, devices, or procedures) that specifies the trial population with specific inclusion and exclusion criteria, details regarding screening, the proposed multipronged pain intervention, which can be generalized across the CCs in the HOPE Consortium, the medical intervention proposed to reduce opioid medication prescription rates and/or participant MME dose, primary and secondary outcomes, and proposed manner and length of patient follow-up. The target population for the study should be carefully defined with respect to such variables as residual renal function, age, co-morbidities of diabetes, hypertension, autoimmune and infectious diseases, sex, race, and other factors deemed important. The intervention should consider how screening information regarding psychiatric conditions, substance use (such as alcohol or benzodiazepines) and social considerations will be addressed.
3. Plans for recruitment of study subjects, and backup plans, as appropriate, including the use of EHR as well as elements from the eCare Plan. The recruitment plan should demonstrate how the Clinical Center will recruit 120 patients as appropriate participants in the study.
4. Plans for data collection of outcomes.
5. A discussion of the unique role of Research Coordinators in the study.
6. Information regarding potential adverse effects associated with the interventions. Procedures designed to ensure patient safety, reduce perception of pain, and maintain participant perception of quality of life as well as patient satisfaction with life and with care, should be described in detail.
7. Statistical analytic issues.
8. If appropriate, one or more industry partners, who will submit letters of collaboration stipulating agreement to a) provide drug(s)/device(s) to be used in the study, b) allow access to HD patient recruitment, implementation of procedural changes, and/or drug therapeutic interventions for patients treated in specific dialysis units, and c) working collaboratively with the CC and other members of the HOPE Consortium on conference calls and during Steering Committee meetings, and in the dissemination of research findings through presentations at scientific meetings and in publications in the scientific literature.
9. A plan for expanding and testing use of the NIDDK CKD eCare Plan Working Group set of standardized data elements and associated data standards (https://www.niddk.nih.gov/health-information/communication-programs/nkdep/working-groups/health-information-technology/development-electronic-ckd-care-plan#draftSet) to improve capture of data relating to ESRD status, opioid medication prescriptions, opioid use disorder, opioid antagonist therapy, pain outcomes and other relevant data from EHRs and other health information technology systems using existing or novel data standards from common clinical ontologies (such as LOINC, ICD-10, SNOMED-CT, CPT, RxNorm). Resulting data captured from the EHR may be used to complement traditionally captured predictor or outcomes data for the trial.

Applicants for CCs are expected to demonstrate the relevance of the preliminary data for the implementation of a definitive randomized controlled trial of a potentially important intervention. How such a proposed intervention might impact the morbidity and mortality of HD patients should be justified in detail. Applicants should demonstrate their ability to recruit a diverse and appropriate population for the study, from a specific group of hemodialysis units. Letters from dialysis providers and large dialysis organizations (LDO) acknowledging the ability of CC investigators to recruit HD patients from their units are required. Applicants should demonstrate experience with regulatory agency procedures involved in bringing new therapies into clinical practice, as appropriate.

CC applications are expected to address common study issues such as:

a. Ability to work collaboratively to establish Consortium Agreements that address: (1) procedures for data sharing among Consortium members and data sharing with industry partners and qualified external investigators to provide opportunities to participate via ancillary studies and disseminated data analyses; (2) procedures for safeguarding confidential information, including without limitation, any data generated by the Consortium as well as data received from external collaborators; (3) procedures for addressing ownership of intellectual property that result from aggregate multi-party data; (4) procedures for sharing biological specimens; (5) procedures for sharing data with the research and clinical communities according to NIDDK policies; and (6) procedures for the HOPE Consortium for reviewing publications, determining authorship, and allowing industry access to manuscripts, as necessary.

b. Each industry collaboration will be governed by an appropriate Research Collaboration Agreement (e.g. Clinical Trial Agreement [CTA], Research Collaboration Agreement [RCA], etc) with terms that ensure collaboration is conducted in accordance with the terms of the Cooperative Agreement and all applicable NIH policies and procedures. Each industry/CC agreement will address ownership of intellectual property discovered from multi-party data generated by the HOPE Consortium, and the Consortium will develop intellectual property policies and procedures with terms that ensure collaboration and dissemination of research findings are conducted in accordance with the terms of the Cooperative Agreement and all applicable NIH policies and procedures. HOPE Consortium policies will require continued submission of data centrally to the SDRC and Consortium policies/procedures will address protection of personal medical records of individuals.

c. Awardees will meet to finalize the consortial study protocol(s). Both CC and SDRC awardees should be prepared to participate in conference calls immediately after funding, and should reserve September 23 and 24, 2019 in Bethesda, Maryland for the first Steering Committee meeting. Applicants should indicate their availability on these dates in their applications.

The HOPE Consortium Structure

The Consortium will consist of five to seven CCs and one SDRC. The CC and SDRC investigators will work collaboratively on the design, planning, execution and analysis of the intervention.

The CCs will be responsible, as a group, for recruiting patients, obtaining biological samples and clinical information from all participants at baseline and during follow-up, and transmission of those data and samples to the SDRC.

The SDRC will be primarily responsible for insuring the scientific integrity, comprehensiveness and robustness of the research design, biostatistics, data quality and storage, implementation, and data analysis of all study protocols. The SDRC investigators, including biostatisticians, will work with the CC investigators to develop the scientific design of the study.

The SDRC will have primary responsibility for ensuring that study data are obtained, stored and available for study both within and eventually outside the Consortium.

The HOPE Consortium PDs/PIs will have the primary responsibility for ensuring that the design of the study, including the primary outcome, is scientifically sound, comprehensive, with sufficient statistical power to study the primary outcomes. The SDRC will provide biostatistical and analytic expertise, and conduct analyses and interpretation of the data in conjunction with the investigators at the CCs. The SDRC and CCs will work closely together to achieve the goals of the HOPE Consortium.

The Steering Committee (SC) will serve as the governing body of the HOPE Consortium. Its actions and decisions will be determined by majority vote. The SC will be composed of the SDRC and CC Program Directors/Principal Investigators (PDs/PIs), other key investigators and the NIDDK Project Scientist, as well as patient participant representatives, appointed by the NIDDK. The SC will meet regularly in-person in the Bethesda MD / Washington DC metropolitan area, and by telephone or webinar, as necessary, as a full committee and in working groups to develop and implement study protocols. SC responsibilities include: providing input on and approval of all studies developed by the Consortium members prior to study implementation; review and approval of all data analyses, public presentations and publications of research conducted within the consortium; and development of policies and procedures for submission and approval of research applications using Consortium resources. The NIDDK will select a chair of the SC (Steering Committee Chair [SCC]) either from the PDs/PIs of the CC s, or outside the study group.

An Executive Committee (EC) will be comprised of the Steering Committee Chair, the SDRC PDs/PIs, and the NIDDK Project Scientist. Additional CC investigators, NIDDK Program Officers and other NIH officers, patient participant representatives and support personnel may participate in the EC as needed. The Executive Committee will make operational decisions for the HOPE Consortium between SC meetings by means of weekly telephone conference calls.

The NIDDK Project Scientist will assist the SC in the development of HOPE Consortium study protocols, will monitor the progress of projects and functioning of all consortial activities, will assist investigators in the analysis and interpretation of consortial data and will participate in all aspects of the research and in preparation and writing of all manuscripts from consortial studies for publication.

SDRC and CC investigators will devise studies that will be reviewed by a Data and Safety Monitoring Board (DSMB) and approved by the NIDDK. The final study protocol will be designed by the CC and SDRC Program Directors/Principal Investigators and approved by the Steering Committee, and then the DSMB and the NIDDK.

A DSMB will be appointed by the NIDDK at the beginning of the funding period, to provide input on the design of studies prior to their implementation. The DSMB will monitor the research efforts and the progress of the studies, and advise primarily the NIDDK as well as the Consortium investigators. The DSMB will include biostatisticians, pharmacologists, nephrologists, experts in pain management and opioid prescription, ethicists, and ESRD patients treated with maintenance hemodialysis. The DSMB will review study protocols prior to implementation, and will monitor progress and safety of the studies.

CC applicants should not suggest potential participants for the DSMB in their applications.

The CCs and SDRC will each identify two representatives of the population to be studied to serve on a Community Advisory Council, which will provide feedback to the Consortium regarding the design and conduct of the study.

Awardees will meet to finalize the HOPE Consortium study protocol(s). Both CC and SDRC awardees should be prepared to participate in conference calls immediately after funding and should reserve September 23 and 24, 2019 in the Bethesda, Maryland / Washington DC area for the first Steering Committee meeting.

Applicants should confirm their availability on these dates in their applications.

Subsequent 1-2 day in-person SC meetings will be conducted every 3-4 months for the first year and yearly or more often as needed thereafter in the Bethesda MD / Washington DC area. Applicants should budget accordingly.

Awardees must agree to abide by the Network Duality of Interests Policy and Procedures and may need to develop procedures to require study investigators and others associated with the study to identify financial and other conflicts of interest on a routine basis, at least annually, and to share this information with the NIDDK Program staff.

This study is part of the of the NIH’s Helping to End Addiction Long-term (HEAL) initiative to speed scientific solutions to the national opioid public health crisis. The NIH HEAL Initiative will bolster research across NIH to (1) improve treatment for opioid misuse and addiction and (2) enhance pain management. More information about the HEAL Initiative is available at: https://www.nih.gov/research-training/medical-research-initiatives/heal-initiative .

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

1. Eligible Applicants

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

• 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

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.

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.

Multiple PD/PI applications are required for this Funding Opportunity Announcement.

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101)

1. Requesting an Application Package

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.

2. Content and Form of Application Submission

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

Letter of Intent

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:

John Connaughton, Ph.D.

Telephone: 301-594-7797

Email:[email protected]

The multiple PD/PI plan should include a nephrologist, a specialist in opioid medicine certified in in burprenorphine prescription, a biostatistician clinical trialist, and a specialist in pain therapeutics.

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

Research Strategy: The Research Strategy section for the CC should include:

• A discussion of the significance of the problem being studied, the need for the studies, and the potential impact of the results of the studies, as well as how the studies will test the hypothesis(es) proposed.
• A concise description of the overall strategy, methodology and analyses to be used to accomplish the goals and specific aims of the study.
• A description of and rationale for the proposed study designs. Applicants should consider the advantages and disadvantages of two arm and three arm designs to inform clinical practice. For example, a two arm design could consider differences in outcomes between a multipronged pain intervention and a pain intervention combined with a drug to decrease opioid dependence. A three arm design could consider differences in outcomes between a usual care condition, a multipronged pain intervention and a pain intervention combined with a drug to decrease opioid dependence. Applicants can consider adaptive trial designs that may increase efficiency.
• A description of the participants to be included, the data to be collected and the protocols to be followed, including a discussion of potential biases or challenges in the protocols and how they will be addressed.
• Statistical methods that are appropriate for the study designs, including the underlying assumptions (and data) used to link these calculations to the endpoints and to the hypothesis(es) being tested.
• A consideration of how the most comprehensive and all-encompassing initial evaluation and enrollment of HD patients with complaints of pain and receiving chronic (more than 90 days/year) opioid medication prescriptions in a clinical trial will be performed by the Clinical Center, in collaboration with the other Clinical Centers and the SDRC.
• Discussion of the role of Research Coordinators in recruiting participants and implementing the intervention and maintaining participant followup.
• Discussion of how the data will be collated and analyzed by the Consortium, and how data will be transferred to the SDRC and the NIDDK Central Repository at the appropriate time.
• Discussion of how the data will be collated and analyzed by the Consortium, and how data will be transferred to the SDRC and the NIDDK Central Repository at the appropriate time.
• Discussion of the tools to be used in the study to measure participant perception of pain.
• Discussion of how data on important baseline and longitudinal clinical information and outcomes of participants will be collected by the Clinical Center, and how the data will be analyzed by the Consortium.
• Discussion of how analyses of medication use, perception of pain and quality of life and clinical findings will be analyzed together.
• Demonstration of the ability of the Clinical Center to work seamlessly with the SDRC so data on all participants can be accessed and analyzed.
• Discussion of studies that led to the proposed clinical trial and information or data from preliminary studies that address the need for and the feasibility of the studies; and
• An acknowledgement and discussion of the responsibilities of the Center as part of a multi-center collaborative project.
• Discussion of how the data will be collated and analyzed by the Consortium, and how data will be transferred to the SDRC and the NIDDK Central Repository at the appropriate time.
• Discussion of the tools to be used in the study to measure participant perception of pain.
• Discussion of how data on important baseline and longitudinal clinical information and outcomes of participants will be collected by the Clinical Center, and how the data will be analyzed by the Consortium.
• Discussion of how analyses of medication use, perception of pain and quality of life and clinical findings will be analyzed together.
• Demonstration of the ability of the Clinical Center to work seamlessly with the SDRC so data on all participants can be accessed and analyzed.
• Discussion of studies that led to the proposed clinical trial and information or data from preliminary studies that address the need for and the feasibility of the studies; and
• An acknowledgement and discussion of the responsibilities of the Center as part of a multi-center collaborative project.

Clinical Center applicants should describe how they will carry out major scientific responsibilities, including:

• Providing research study design and implementation expertise for all consortial studies.
• Ensuring the scientific integrity and robustness of the research design, implementation, adherence, and data quality of all study protocols.
• Handling participant confidentiality and safety.
• Participating in and conducting training and certification of study staff.
• Monitoring the implementation of the studies including adherence and data quality.
• Obtaining clinical information, including information on all participants.
• Working collaboratively with the Consortium SDRC PDs/PIs and conducting the various research efforts undertaken by the Consortium.
• Staffing the CC with clinicians, including nephrologists, clinical trialists, experts in pain assessment and management and opioid prescription, including certification in
  buprenorphine prescription, and ethicists and advisors from the relevant community patient population, in a meaningful way.

An application for a Clinical Center must:

• Propose study designs incorporating innovative strategies, and analytical approaches to accomplish the goals of the FOA, including obtaining comprehensive inclusion of data on outcomes.
• Present experience of the team as a whole with a wide range of clinical trials pertinent to this FOA.
• Present a plan for coordination of biosample (e.g. serum, plasma, DNA, tissue, stool and urine, as applicable) collection, storage, quality control and distribution of data and clinical samples.
• Present a plan to work collaboratively with the SDRC investigators in the planning, implementation and analysis of all major studies
• Describe the roles, responsibilities and interactions of the CC investigators with the SDRC and provide a leadership plan.

The following modifications also apply:

• Clinical Center applications should provide a Data and Resource (Biological Sample) Sharing Plan .
• Consortium investigators are expected to share their findings with the scientific community through scientific presentations and publications, and through sample and data sharing, according to NIDDK policies.
• All Consortial-derived data and biological samples are expected to be provided to the NIDDK Data and Sample Biorepositories in accordance with Institute guidelines, consistent with achieving the goals of the program.

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.

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

3. Unique Entity Identifier and System for Award Management (SAM)

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

4. Submission Dates and Times

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.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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.

7. Other Submission Requirements and Information

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.

Use of Common Data Elements in NIH-funded Research

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

1. Criteria

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.

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

Significance

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?

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

Specific to this FOA: Is the study proposed in the application an important and feasible intervention which is likely to favorably affect the opioid prescription rate, the dose prescribed, the perception of pain and quality of life, and morbidity and mortality of HD patients?

Investigator(s)

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?

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

Specific to this FOA: Do the CC key investigators have documented expertise in pain management and in opioid prescription, including certification in buprenorphine prescription?

Does the CC have expertise in psychosocial aspects of medical care, including expertise in mental health disorders?

Does the CC have expertise in ensuring scientific integrity and robustness of the proposed clinical research studies?

Does the applicant have experience with EHR methodologies to enhance screening, recruitment and follow-up and data capture?

Does the application describe the roles and responsibilities of the key investigators with a leadership plan?

Does the CC have expertise in design, performance and analysis of clinical trials?

Does the CC have expertise in implementation, adherence, and data quality?

Do CC key investigators have a track-record of research productivity and cooperation within a broad, multi-site research effort?

Is sufficient expertise in place for the collection, coordination and transfer of biosamples and their storage, quality control and distribution (e.g. serum, plasma, DNA, tissue, stool and urine, as applicable)?

Have the investigators demonstrated that they can work collaboratively to achieve comprehensive identification and followup of outcomes related to the goals of the FOA? Have the investigators demonstrated that they can work collaboratively with other CCs and the SDRC?

Innovation

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

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

Specific to this FOA: Does the CC propose innovative approaches to the scientific question(s), research design, data quality, implementation, and data analysis efforts?

Has the applicant proposed efficient approaches to screening for eligibility for the trial, employing human resources as well as the EHR?

Does the CC propose innovative approaches to the multipronged pain intervention, ensuring it will be generalizable across the CCs in the Consortium?

Does the CC propose innovative approaches to the medical intervention to reduce opioid prescription?

Does the CC propose innovative approaches to achieving comprehensive identification and follow-up of outcomes?

Does the CC propose innovative approaches to a Cognitive Behavioral Therapy intervention for pain, tailored to individual patients psychosocial characteristics, that can be deployed in a standardized fashion throughout the consortium?

Does the CC propose innovative approaches to Research Coordinators facilitation of recruitment of participants, ensuring participant adherence to interventions and maintaining followup?

Does the CC propose innovative approaches to achieving comprehensive identification and follow-up of participant outcomes?

Has the CC included representatives of the HD patient community and of patients with pain and users of opioid medications to provide advice on the planning and conduct of the studies?

Has the CC proposed innovative ways of interacting and partnering with patients to achieve the goals of the FOA?

Has the CC proposed innovative ways of interacting and partnering with Consortium members to maximally use, in a comprehensive, synergistic fashion, the data collected by the Consortium, to achieve the goals of the FOA?

Approach

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

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

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

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

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

Specific to this FOA: Has the applicant for a CC proposed an important, well-designed trial focused on amelioration of pain, and limiting opioid prescription rates and doses, in the context of potentially mediating or moderating psychosocial factors?

Is the proposed study likely to be feasible and generalizable?

Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed?

Has the applicant provided back-up plans for recruitment of 120 appropriate participants?

Does the CC propose research study designs and analytical approaches to achieve the goals of this FOA?

Are the safety considerations and follow-up plans designed to ensure patient well-being during and after the studies?

Does the CC propose integrated analyses of the clinical and treatment data in participants?

Does the CC propose comprehensive plans for collection and analysis of information, including quality control and assurance efforts and assessments?

Are appropriate biomarkers and alternative/surrogate outcomes proposed in the design of the study?

Does the research plan provide relevant materials to the NIDDK Central Repository?

Has the CC proposed feasible ways of interacting and partnering with the Consortium to maximally use, in a comprehensive, synergistic fashion, the data collected by the Consortium, to achieve the goals of the FOA?

Have the CC investigators presented a plan for efficient evaluation of potential participants with pain receiving chronic opioid prescriptions for study participation?

Have the investigators presented a feasible trial of medications such as buprenorphine to decrease opioid prescription rates and/or dose?

Have the CC investigators considered pitfalls in attempts to screen and recruit potential participants comprehensively, in addition to using data provided by the EHR?

Has the applicant presented a multipronged pain intervention that can be uniformly protocolized and applied across the Clinical Centers?

Have the investigators presented letters from dialysis providers and large dialysis organizations (LDO) acknowledging the ability of CC investigators to recruit HD patients from the units required?

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

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?

Environment

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

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

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

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

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

?Study Timeline

Specific to applications involving clinical trials

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

Protections for Human Subjects

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.

Vertebrate Animals

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.

Biohazards

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.

Resubmissions

Not applicable.

Renewals

Not applicable.

Revisions

Not applicable.

Applications from Foreign Organizations

Not applicable.

Select Agent Research

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).

Resource Sharing Plans

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).

Authentication of Key Biological and/or Chemical Resources:

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.

Budget and Period of Support

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

2. Review and Selection Process

• 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.

• 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.

3. Anticipated Announcement and Award Dates

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

1. Award Notices

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

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

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

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

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

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

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

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

2. Administrative and National Policy Requirements

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.

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.

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.

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, 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:

1. Developing the research design and study protocol, including definition of objectives and approaches, sample size and power calculations, and establishing procedures for participant recruitment and follow-up, data collection, quality control, interim data and safety monitoring, final data analysis and interpretation, and publication of results.

2. Establishing a Steering Committee to implement, coordinate and manage the project(s). Awardee(s) will name investigators to serve as members on a Steering Committee and other subcommittees, as appropriate, meeting periodically. Awardees will be required to accept and implement the common protocol(s) and procedures approved by the Steering Committee.

3. Designating Protocol Chairs. The Program Directors/Principal Investigators (for studies involving multiple protocols) shall designate a single Protocol Chairperson (if the Program Director/Principal Investigator does not assume this role) for each protocol to be carried out by the study group. The Protocol Chairperson shall function as the scientific coordinator for the protocol and shall assume responsibility for obtaining approval to implement the protocol from the Steering Committee and for developing and monitoring the protocol. Significant modifications to approved protocols must be approved by the Steering Committee.

4. Implementing collection of data specified by the study protocol. For a multi-center study, each awardee/site is required to ensure that data will be submitted expeditiously to the Data Coordinating Center. Additionally, individual investigators/sites must demonstrate the ability to implement the strategy specifically designed for their individual study population.

5. Establishing procedures for data quality and completeness. Awardees are responsible for ensuring accurate and timely assessment of the progress of each study, including development of procedures to ensure that data collection and management are: (1) adequate for quality control and analysis; (2) for clinical trials, as simple as appropriate in order to facilitate cooperation/referral of study participants by physicians to avoid unnecessary expense; and (3) sufficiently staffed across the participating institutions. For research involving multiple sites, a plan for analysis of pooled data will be developed by the Steering Committee.

6. Submitting interim progress reports, when requested or agreed upon by both parties, to the NIDDK Program Official including as a minimum, summary data on protocol performance. For coordinated multiple awards or a multi-site single award, the NIDDK Program Official may require additional information from individual awardees/sites. Such reports are in addition to the required annual noncompeting continuation progress report.

7. Reporting of the study findings. 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 awardee must also be adherent to Study Publication and Presentation Policy. The NIDDK will have access to and may periodically review all data generated under an award. NIDDK staff may co-author publications of findings with awardees consistent with NIH and study policies.

8. Agree that any third-party (including both industry and academia) collaboration should be governed by a research collaboration agreement (e.g. Clinical Trial Agreement, Research Collaborative Agreement, Memorandum of Understanding, etc.) with terms that ensure the collaboration is conducted in accordance with the Cooperative Agreement, applicable NIH/NIDDK policies and procedures. The NIDDK Program Official may consult with others at NIH, including the NIDDK Technology Advancement Office.

9. Any involvement of a third party (including both industry and academia) in the study, including access to any study data; study results; using the name of the study; or the name of the NIH or NIDDK, is permitted only after written concurrence by the NIDDK Program Official who may consult with others at NIH including the NIDDK Technology Advancement Office.

10. Study investigators are required to publish and to release publicly and disseminate results and other products of the study, in accordance with study protocols and steering committee policies on publications.

11. Maintaining confidentiality of information: The awardee(s) will maintain the confidentiality of the information developed by the investigators (i.e., protocols, data analysis, conclusions, etc.) as well as proprietary information of a company collaborating with the study.

12. The NIDDK has established Central Biosample, Genetic, and Data Repositories for the archiving and storage of data and biosamples collected in large, multi-site studies funded by NIDDK. Prior to enrolling participants, the PI or his/her designee will coordinate with the NIDDK Central Repository to develop a Data Sharing Plan and prepare the collected data for eventual archiving and distribution. In addition, if applicable, the PI or his/her designee will work with the NIDDK Biosample Repository to coordinate procedures for coding, shipping, processing, receipt, storage and sharing of study samples that are to be maintained in the Repository. All samples and data transferred to the Repositories will be under the custodianship of the NIDDK, although the study’s Steering Committee will have proprietary control of and exclusive access to the samples and data for an agreed-upon period of time. Subsequently samples and data will be available to the wider scientific community in accordance with the NIH policy on Data Sharing ( http://grants.nih.gov/grants/policy/data_sharing/ and,

http://grants.nih.gov/grants/policy/data_sharing/data_sharing_guidance.htm#goals, and http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm), as well as the NIDDK policy for data sharing in multi-center and large single-center clinical studies http://www.niddk.nih.gov/research-funding/process/human-subjects-research/Documents/PublicversionNIDDKdatasharingpolicy2013July2013.pdf.

13. The Food and Drug Administration Amendments Act of 2007 (FDAAA or US Public Law 110-85) was passed on September 27, 2007. The law requires mandatory registration and results reporting for certain clinical trials of drugs, biologics, and devices. If trials conducted under this grant are applicable clinical trials subject to FDAAA, the sponsor or his/her designee will perform the mandatory study registration and reporting of study results to ClinicalTrials.gov. For more information about this law and requirements for sponsors and/or investigators, visit the PRS and U.S. Public Law 110-85 Information Page at http://prsinfo.clinicaltrials.gov/fdaaa.html. In addition, grantees should be aware that clinical trials not covered by FDAAA may still require registration in an approved registry in order to be published, according to the guidelines issued by the International Committee of Medical Journal Editors (http://icmje.org/recommendations/browse/publishing-and-editorial-issues/clinical-trial-registration.html).

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

An NIDDK Project Scientist with substantial involvement will:

1. Serve as the contact point for all facets of the scientific interaction with the awardee (s). As required for the coordination of activities and to expedite progress, NIDDK may designate additional NIDDK staff to provide advice to the awardee on specific scientific and/or analytic issues. Such staff may include another Project Scientist or Project Coordinator, who will provide direct technical assistance to the awardees to optimize the conduct and/or analysis of the study; or who may assist in the coordination of activities across multiple sites.

2. For multi-center studies, participate in the Steering Committee that oversees study conduct. The NIDDK Project Scientist or Project Coordinator will be a full participant and voting member of the Steering Committee and, if applicable, subcommittees.

3. Serve as a resource to study investigators with respect to other ongoing NIDDK activities that may be relevant to the study to facilitate compatibility with the NIDDK missions and avoid unnecessary duplication of effort.

4. Have substantial involvement assisting in the design and coordination of research activities for awardees as elaborated below:

a. Assisting by providing advice in the management and technical performance of the investigations, coordinating required regulatory clearances for investigational agents used in the study, which are held by NIDDK. The NIDDK may reserve the right to cross file or independently file an Investigational New Drug Application or an Investigational Device Exemption form with the FDA.

b. The NIDDK Project Scientist or Project Coordinator may coordinate activities among awardees by assisting in the design, development, and coordination of a common research or clinical protocol and statistical evaluations of data; in the preparation of questionnaires and other data recording forms; and in the publication of results.

c. Reviewing procedures for assessing data quality and study performance monitoring.

d. The NIDDK Project Scientist or Project Coordinator may be co-authors on study publications. In general, to warrant co-authorship, NIDDK staff must have contributed to the following areas: (a) design of the concepts or experiments being tested; (b) performance of significant portions of the activity; (c) participation in analysis and interpretation of study results and (d) preparation and authorship of pertinent manuscripts.

The NIDDK Program Official identified in the Notice of Award will:

1. Interact with the Program Director(s)/Principal Investigator(s) on a regular basis to monitor study progress. Monitoring may include: regular communications with the Program Director/Principal Investigator and staff, periodic site visits, observation of field data collection and management techniques, quality control, fiscal review, and other relevant matters; as well as attendance at Steering Committee, data safety and monitoring board, and related meetings. The NIDDK retains, as an option, periodic review of progress by researchers not involved with the study.

2. Review and approve protocols prior to implementation to insure they are within the scope of peer review, for safety considerations, as required by Federal regulations.

3. The NIDDK Program Official will monitor protocol progress, and may request that a protocol study be closed to accrual for reasons including: (a) accrual rate insufficient to complete study in a timely fashion; (b) accrual goals met early; (c) poor protocol performance; (d) patient safety and regulatory concerns; (e) study results that are already conclusive; (f) low likelihood of showing a benefit of the intervention (futility); and (g) emergence of new information that diminishes the scientific importance of the study question. The NIDDK will not permit further expenditures of NIDDK funds for a study after requesting closure except as specifically approved by the NIDDK.

4. Make recommendations for continued funding based on: a) overall study progress, including sufficient patient and/or data accrual; b) cooperation in carrying out the research (e.g., attendance at Steering Committee meetings, implementation of group decisions, compliance with the terms of award and reporting requirements); and/or c) maintenance of a high quality of research, which will allow pooling of data and comparisons across multiple cooperative agreement awards for common data elements.

5. Appoint an independent Data and Safety Monitoring Board (DSMB) as appropriate for Phase III clinical trials or other high risk studies, or an Observational Study Monitoring Board (OSMB) for observational/epidemiologic studies; these Boards will review study progress, safety data, and interim results, as appropriate, and provide guidance to the NIDDK. The NIDDK Program Official or their Project Coordinator will serve as the Executive Secretary and/or NIDDK program representative on the DSMB/OSMB.

Areas of Joint Responsibility include:

In addition to the interactions defined above, NIDDK Project Scientist and Awardees shall share responsibility for the following activities:

Steering Committee

A Steering Committee organized by the study investigator(s) will be the main governing body of the study.

The Steering Committee has primary responsibility to design research activities, establish priorities, develop common protocols and manuals, questionnaires and other data recording forms, establish and maintain quality control among awardees, review progress, monitor patient accrual, coordinate and standardize data management, and cooperate on the publication of results. Major scientific decisions regarding the core data will be determined by the Steering Committee. The Steering Committee will document progress in written reports to the NIDDK Program Official, and will provide periodic supplementary reports upon request.

The Steering Committee will be composed of all Program Director(s)/Principal Investigator(s), (including those of data coordinating /statistical centers, if any) and co-investigators as deemed necessary, and the NIDDK Project Scientist. The final structure of the Steering Committee and voting procedures will be established at the first meeting. The NIDDK Project Scientist will have voting membership on the Steering Committee, and as appropriate, its subcommittees. The frequency of Steering Committee meetings will be dictated by a vote of the members of the Steering Committee.

A Chairperson of the Steering Committee, other than the NIDDK Project Scientist, will be selected by the NIDDK, in consultation with the Steering Committee. The Chairperson provides leadership to the Committee by conducting the Steering Committee meetings, representing the study group to the External Oversight Committee established by the NIDDK and by interacting closely with the awardees during protocol development and implementation.

Dispute Resolution

Any disagreement that may arise on scientific/programmatic matters (within the scope of the award), between award recipients and the NIDDK may be brought to dispute resolution. A dispute resolution panel will be composed of three members --one selected by the awardee (or the Steering Committee, with the NIDDK member not voting), a second member selected by NIDDK, and the third member elected by the two prior selected members. These special dispute resolution procedures in no way affect the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations at 42 CFR Part 50, Subpart D, and HHS regulations at 45 CR Part 16.

3. Reporting

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.

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]

Paul L Kimmel MD
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-1409
Email:[email protected]

Ryan Morris PhD
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-480-1296
Email:[email protected]

Norma Deguzman
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-480-1810
Email:[email protected]