Department of Health and Human Services
Part 1. Overview Information

 

Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Institute of Neurological Disorders and Stroke (NINDS)
National Heart, Lung, and Blood Institute (NHLBI)
National Human Genome Research Institute (NHGRI)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
National Institute of Allergy and Infectious Diseases (NIAID)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
National Institute on Drug Abuse (NIDA)
National Institute of Mental Health (NIMH)
National Center for Complementary and Integrative Health (NCCIH)

Funding Opportunity Title

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Collaborative Research Centers (CRCs) (U54)

Activity Code

U54 Specialized Center- Cooperative Agreements

Announcement Type

New

Related Notices
Funding Opportunity Announcement (FOA) Number

RFA-NS-17-021

Companion Funding Opportunity

RFA-NS-17-022, U24 Resource-Related Research Projects – Cooperative Agreements

Catalog of Federal Domestic Assistance (CFDA) Number(s)

93.853; 93.279; 93.213; 93.242; 93.273; 93.856; 93.855; 93.172; 93.846; 93.840; 93.233; 93.839; 93.838; 93.837

Funding Opportunity Purpose

This Funding Opportunity Announcement (FOA) invites applications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Collaborative Research Centers (CRC). The overarching goal of this initiative is to establish a network of Centers that will work collaboratively to define the cause(s) of and discover improved treatments for ME/CFS.  A more immediate goal for each Center is to rapidly advance synergistic, interdisciplinary research programs while serving as local resources and national leaders in ME/CFS research.  Successful CRC research programs will facilitate research in ME/CFS through conducting of 1) collaborative basic and/or clinical research on ME/CFS; 2) longitudinal studies of individuals with ME/CFS within each ME/CFS CRC and across CRCs within the network; 3) access to information related to ME/CFS for basic and clinical researchers, academic and practicing physicians, healthcare professionals, patients, and the lay public. Clinical data management for efficient data collection as well as data mining and data sharing will be addressed through the separate data management and coordinating center (DMCC). Institutions must be committed to the establishment and continuation of the proposed ME/CFS CRC.  Funding decisions will focus on those applications most likely to make highly impactful contributions to ME/CFS research, as well as on those with the greatest potential to collaborate effectively across the ME/CFS CRC program.      

Key Dates

 

Posted Date

January 27, 2017

Open Date (Earliest Submission Date)

April 2, 2017

Letter of Intent Due Date(s)

30 days prior to the application due date

Application Due Date(s)

May 2, 2017, by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on this date.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

AIDS Application Due Date(s)

Not applicable 

Scientific Merit Review

July 2017

Advisory Council Review

August 2017  

Earliest Start Date

September 2017

Expiration Date

May 3, 2017

Due Dates for E.O. 12372

Not Applicable

** ELECTRONIC APPLICATION SUBMISSION REQUIRED**

NIH’s new Application Submission System & Interface for Submission Tracking (ASSIST) is available for the electronic preparation and submission of multi-project applications through Grants.gov to NIH. Applications to this FOA must be submitted electronically using ASSIST or an institutional system-to-system solution; paper applications will not be accepted. ASSIST replaces the Grants.gov downloadable forms currently used with most NIH opportunities and provides many features to enable electronic multi-project application submission and improve data quality, including: pre-population of organization and PD/PI data, pre-submission validation of many agency business rules and the generation of data summaries in the application image used for review.

Required Application Instructions

It is critical that applicants follow the Multi-Project (M) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts) and where instructions in the Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. 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.


There are several options to submit your application to the agency through Grants.gov. You can use the ASSIST system to prepare, submit and track your application online. Or, you can use other institutional system-to-system solutions to prepare and submit your application to Grants.gov and track your application in eRA Commons. Learn more.

Problems accessing or using ASSIST should be directed to the eRA Service Desk.
Table of Contents

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


Part 2. Full Text of Announcement
Section I. Funding Opportunity Description

This Funding Opportunity Announcement (FOA) invites applications for a ME/CFS Collaborative Research Center (CRC) that will participate in a network with other funded ME/CFS CRCs and a Data Management and Coordinating Center (DMCC), which will be supported by a separate FOA (RFA-NS-17-021). 

The ME/CFS CRCs will perform collaborative research on ME/CFS to inform the etiology, pathogenesis and/or treatment of ME/CFS. Each ME/CFS CRC may consist of a collaborative, multi-disciplinary group of basic and clinical investigators; investigators from the NIH-funded Clinical and Translational Science Awards sites (CTSAs), where applicable; institutions; and relevant organizations, including patient advocacy group organizations; and will focus on research on ME/CFS. The ME/CFS CRCs are expected to help provide the foundation and infrastructure for future clinical trials. Previous experience with similar consortia demonstrate that those that both engage and integrate patient advocacy groups into their research program have achieved greater success in enrollment in studies. ME/CFS CRC applicants at an institution with a CTSA are strongly encouraged to partner with and include the investigators and resources available at their CTSA.

The ME/CFS CRC should be on research to identify the etiology, pathogenesis and/or new treatments for ME/CFS, and may include studies on the various manifestations of the disease.   The DMCC will provide the data management and support necessary for the network of ME/CFS CRCs to function optimally. The DMCC will work with the ME/CFS CRCs to integrate protocols, forms, and research tools into the research.  The biostatistician from the DMCC will provide statistical support for protocol development and assist in study design and analysis.

The overall theme, proposed research projects, and associated cores must inform the etiology, pathogenesis and/or treatment of ME/CFS.  Requirements include 1) a minimum of two and a maximum of three research projects; 2) an Administrative Core; and 3) a plan for outreach and partnering with other ME/CFS stakeholders (patients, advocacy organizations, etc.).  Research core(s) may be included if they are essential to accomplish the aims of at least two proposed research projects. This program will prioritize innovative and integrative research with significant potential for discovery.  Significant synergy must be evident among a Center’s research projects and cores (if proposed), such that successful completion of the aims could not be accomplished without the Center structure. 

The ME/CFS CRC Director (PD/PI) must be an established leader in scientific research with visionary leadership skills and proven experience in the stewardship of large-scale research programs.

Although the  National Institutes of Health (NIH) Policy on the Use of a Single Institutional Review Board of Record for Multi-Site Research (NOT-OD-16-094 and NOT-OD-17-027) is pending implementation, it is expected that applicants will utilize a single IRB for multi-site clinical studies proposed in the application if possible. This policy enhances and streamlines the process of IRB review and reduce inefficiencies so that research can proceed as expeditiously as possible without compromising ethical principles and protections for human research participants.

Clinical trials are beyond the scope of ME/CFS CRC applications and must not be included in the applications. For the NIH definition of a clinical trial please see:

http://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-015.html.  However, it is anticipated that the CRCs will develop the science and clinical research infrastructure that herald a future interventional trial application. Applications proposing clinical trials will be considered non-responsive.

This FOA allows applications for ME/CFS research relevant to the mission of the participating NIH ICs (see below: Research Areas of Interest). Prospective applicants are urged to consult with the Scientific/Research Contacts of the NIH early in the preparation of the application (see Section VII. Agency Contacts).

ME/CFS CRC Steering Committee

The Steering Committee is led by a Chair and an Executive Committee, who works with the NIH program officers to achieve these goals.  The Chair's term is one year, to start and end at the annual Director's meeting.  The Steering Committee Executive Committee will consist of past, current and rising Chairs, for a total of three years of service per Chair; respective ME/CFS CRC grants must be actively funded during the term of service.  Each ME/CFS CRC Director will be expected to participate on the Steering Committee for the duration of her/his ME/CFS CRC.  The Steering Committee will also include two representatives from Non-Governmental Organizations (NGOs).  Additional outside members from the research community will be added on an ad hoc basis to address emergent issues within the program.  The NIH Project Scientists should be included as ex officio participants for all meetings and correspondence.

Annual meetings of the ME/CFS CRC Directors will be held.  Meeting planning duties will be shared between the Program Staff from the NIH ICs and the ME/CFS CRC Steering Committee.  The meeting is designed to provide dedicated time during which ME/CFS CRC investigators can discuss emergent issues and approaches in the research on ME/CFS.  By providing a focused and interactive Agenda, the annual meeting fosters the initiation and maintenance of collaborative efforts and resource sharing among the Centers.

Participation in the ME/CFS CRC Steering Committee Activities

Each ME/CFS CRC Director will participate in activities of the ME/CFS Research Center Steering Committee, which promotes collaboration and strengthens cooperation among the network of ME/CFS CRCs.  For example, the Steering Committee functions to:

Strengthen communication and data sharing among ME/CFS CRCs

Define and share best practices and resources

Identify novel collaborative research opportunities

Pursue mechanisms for translation of research findings toward clinical realization

Coordinate activities in areas of common interest, including investigator career enhancement and community outreach and partnership

Facilitate interdisciplinary collaboration in ME/CFS research among and beyond the ME/CFS CRCs

Develop, implement and monitor metrics for the evaluation of program progress.

Background

ME/CFS is a debilitating and complex disorder that severely impacts the lives of an estimated 800,000 to 2 million Americans, with 25% or more of the individuals either house- or bed-bound.  The underlying etiology and pathophysiology of ME/CFS are unknown and there is no diagnostic test for the disease.  Therefore, there is currently no gold standard for case definition of ME/CFS.  For studies proposed under this FOA, it is recommended that the investigators utilize the Canadian Consensus Criteria for ME/CFS as proposed by Carruther and colleagues in 2003 and revised by Jason and colleagues in 2010, and the recent case definition from the Institute of Medicine Report on ME/CFS.

The Revised Canadian Clinical Case (CCC) Definition for ME/CFS requires that symptoms be present from the following six symptom categories for 6 months or longer:

  • Fatigue, including substantial reduction in activity level;
  • Post-exertional malaise (PEM) and/or post-exertional fatigue;
  • Pain;
  • Neurologic/cognitive manifestations; and
  • Autonomic, neuroendocrine, or immune manifestations. 

In addition, the revised CCC recommends the use of a structured questionnaire (the DePaul Symptom Questionnaire) to gather standardized information on symptoms as well as the use of the scales of the Short Form 36-Item Questionnaire (SF-36) of the Medical Outcomes study to assess whether a patient has a substantial reduction in functioning. 

The Proposed Diagnostic Criteria for ME/CFS developed by the IOM panel require that the patient have the following 3 symptoms:

1. A substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social or personal activities that persists for more than 6 months and is accompanied by fatigue, which is often profound, is of new or definite onset (not lifelong), is not the result of ongoing excessive exertion, and is not substantially alleviated by rest,

2. Post-exertional malaise,* and

3. Unrefreshing sleep.

At least one of the two following manifestations is also required:

1. Cognitive impairment* or

2. Orthostatic intolerance.

*Frequency and severity of symptoms should be assessed.  The diagnosis of ME/CFS should be questioned if patients do not have these symptoms at least half of the time with moderate, substantial, or severe intensity.

It is expected that the investigators funded for the ME/CFS CRCs will reach consensus together on the specific instruments and measures to be utilized across all studies of individuals with ME/CFS supported by this FOA.

This FOA supports and will implement the recommendations from two recent expert panel reports that recommended a multidisciplinary approach to gain understanding of ME/CFS:

https://prevention.nih.gov/programs-events/pathways-to-prevention/workshops/me-cfs/workshop-resources#finalreport

http://www.nap.edu/catalog/19012/beyond-myalgic-encephalomyelitischronic-fatigue-syndrome-redefining-an-illness

Research Objectives

The ME/CFS CRCs will consist of the funded ME/CFS CRCs and a single Data Management and Coordinating Center (DMCC). This initiative will support a collaborative and coordinated network of sites comprised of investigators at multiple institutions/sites committed to investigation of ME/CFS working to enhance communication and sharing of resources and data in a multidisciplinary approach.  In addition, activities of community engagement and participation should be included in the plans for the ME/CFS CRC to ensure success.  The ME/CFS DMCC will support a comprehensive and integrated approach to data collection, storage, and management, and the integration of clinical data with other unique data, including genetic, imaging, pathologic, and laboratory data as well as assistance to organize and coordinate collaborative research projects. The DMCC will incorporate new approaches to distributed computing and federated databases.

It is expected that each ME/CFS CRC will consist of basic and/or clinical investigators from multiple institutions and relevant organizations, and will focus on areas of ME/CFS research that are relevant to the interests of the participating NIH Institutes and Centers (ICs).  Finally, successful applicants for each ME/CFS CRC will be expected to participate in collaborative project(s) with the other funded ME/CFS CRCs.  Collaborative projects selected by the CRC should have a thematic focus and rational basis and should be consistent with commonly accepted definitions of ME/CFS within the biomedical research community.   The Administrative Core will be responsible for soliciting, reviewing, and selecting collaborative projects which will each last not more than two years. The collaborative projects will utilize patient cohorts, biospecimens, and/or assays developed and used in the ME/CFS CRCs to carry out their research. 

Organization and Management of the ME/CFS Research Network (CRCs and DMCC)

A Steering Committee, composed at a minimum of the Program Director/Principal Investigator (PD/PI) of each ME/CFS CRC, the PD/PI of the DMCC, a representative(s) from the ME/CFS community, and the Project Scientists from the relevant NIH ICs, will establish the procedures for the function of the ME/CFS Research Network, as outlined in Section VI. Awards Administration Information under "Network Steering Committee."

The DMCC for the ME/CFS Research Network will be established under another FOA. The DMCC will serve as a resource, working with and providing expertise for all of the ME/CS CRCs.  The ME/CFS CRCs will be expected to work with the DMCC to assure compatibility of data collection systems and consistent data standards and to establish the collaborative project(s). It will provide a scalable coordinated clinical data integration of developed and publicly available datasets for data mining at all sites, web-based recruitment and referral, and a user-friendly resource site for the public. The DMCC will provide a management system for collection, storage, as well as a portal and tools for research scientists and clinicians. In addition, the DMCC, in conjunction with the NIH, will provide logistical and administrative assistance for Network activities; produce and/or maintain Network Operating Policy and Procedures, documents, worksheets, and data collection forms; and monitor Network compliance while addressing privacy and confidentiality issues related to database management, and multi-level data sharing. In order to participate in this Network, each Center is expected to use the DMCC for the above mentioned activities. All sites will be expected to collaborate with the DMCC throughout the course of their studies in order to assure compatibility and standardization of data management approaches. To enhance recruitment in clinical studies each site is expected to utilize the Contact Registry developed by DMCC, and the DMCC will resolve issues related to the use of any specific study participants in the proposed studies. The Contact Registry is a method by which patients with ME/CFS can register themselves with the ME/CFS Research Network in order to be contacted in the future about clinical research opportunities and updates on the progress of the research projects. The Contact Registry is anonymous and free of charge. The Contact Registry can also be used by the investigators to facilitate the rapid enrollment of subjects in survey protocols.

The ME/CFS Research Network will require cooperation among the participating NIH IC Project Scientists, Directors of the ME/CFS CRCs and their collaborators, and the Director of the DMCC to maximize their effectiveness.

Research Areas of Interest

Overall research areas of interest include, but are not limited to:

  • Determining the etiology and pathogenesis in ME/CFS;
  • Studies that help to identify subtypes of ME/CFS based on biological markers and/or symptom classifications;
  • Longitudinal studies to understand the course of disease over time to better characterize the manifestations of ME/CFS; and develop and validate outcome measures for future intervention trials.
  • Identification of potential treatment targets for ME/CFS.

Applicants may propose either basic or clinical studies.  Examples of basic research projects include, but are not limited to, the following:

  • Characterization of cellular and molecular mechanisms of disease processes.
  • Elucidation of the mechanism of action, including neural pathways and systems contexts, of identified ME/CFS risk genes/factors.
  • Identification and characterization of genetic and/or environmental risk factors that predict disease onset and progression.
  • Identification of novel therapeutic targets and pathways via hypothesis-driven, mechanistic studies.
  • Research in model systems designed to validate clinically identified biomarkers for disease onset, progression, and response to treatment.
  • Use of de-identified human biospecimens, including post-mortem tissues and other biospecimens, to elucidate idiopathic, immune, genetic, or other disease mechanisms.

Research areas of interest for the participating ICs include, but are not limited to:

  • Studies on the etiology and pathogenesis in ME/CFS, including the elucidation of infectious etiology of ME/CFS and physiological and genetic host determinants involved in ME/CFS manifestations including, but not limited to microbiome-related studies;
  • Identification of potential triggers or modifiers of immune responses or immune cell metabolism that contribute to ME/CFS;
  • Application of current methodologies (e.g., immune phenotyping) or computational modeling to better characterize human immune responses triggered in ME/CFS;
  • Identification of immune/inflammatory biomarkers in cerebrospinal fluid, blood, urine, etc. that can identify physiologically relevant subgroups of ME/CFS;
  • Evaluation of etiological basis for subjective experience of fatigue in transdiagnostic samples from individuals with ME/CFS, including role of disturbances in restorative properties of sleep examined employing a Research Domain Criteria (RDoC) approach;
  • Identification of modifiable targets for intervention to alleviate the symptom of fatigue in transdiagnostic samples, consistent with the experimental medicine approach to clinical trial design;
  • Characterizing etiological mechanisms underlying impairments in domains of cognitive function seen in individuals seeking care for ME/CFS, employing a Research Domain Criteria (RDoC) approach in transdiagnostic samples;
  • Elucidation of the mechanisms conferring increased risk for psychiatric comorbidities commonly seen in individuals seeking care for ME/CFS, including but not limited to major depression, somatization disorder, post-traumatic stress disorder, and personality disorders
  • Molecular and cellular neural mechanisms and CNS, peripheral nerve and autonomic circuitry involved in fatigue and post-exertional malaise in ME/CFS;
  • Characterization of the cognitive changes over time and following mental or physical exertion, including the mechanisms by which triggers cause exacerbation of cognitive symptoms in individuals with ME/CFS;
  • Mechanisms of co-morbid pain syndromes with ME/CFS;
  • Underlying causes of sleep architecture in ME/CFS leading to sleep abnormalities, including unrefreshing sleep, in ME/CFS;
  • Mechanisms underlying autonomic dysfunction and neuroendocrine abnormalities in ME/CFS.
  • Studies to understand how exposures to environmental insults industrial chemicals or manufacturing byproducts, e-waste, metals, pesticides, herbicides, and inhaled toxicants including indoor air pollutants from cooking and other sources) relate to the development of ME/CFS;
  • Alterations in cardiopulmonary or hemodynamic status, including POTS (Postural Orthostatic Tachycardia Syndrome) in individuals with ME/CFS;
  • Disturbances in sleep and circadian rhythm in individuals with ME/CFS;
  • Development of new brain and peripheral nervous system imaging technologies and the early stage validation and translation of these technologies for use in studying ME/CFS;
  • Symptom management, disease prevention and health promotion, including the neurobiological effects and mechanisms of complementary and integrative health interventions;
  • Symptom management, particularly the use of mind and body approaches for sleep disturbance, pain management, or mental health conditions such as those commonly managed in primary care (e.g. mild to moderate depression, anxiety, and post-traumatic stress);
  • Studies to examine the effects of probiotics and other natural products on gut microbiome-brain interactions. Of particular interest are studies of probiotics for depression, anxiety, or chronic pain in individuals with ME/CFS.

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

Section II. Award Information
Funding Instrument

Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities. See Section VI.2 for additional information about the substantial involvement for this FOA.  

Application Types Allowed

New

The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.

Funds Available and Anticipated Number of Awards

NINDS and participating ICs intends to commit $6 million in FY 2017 to fund 2-3 awards. Future year amounts will depend on annual appropriations

Award Budget

Application budgets are limited to $1,200,000 per year, and need to reflect the actual needs of the proposed project.

Award Project Period

The maximum project period is 5 years

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

Section III. Eligibility Information
1. Eligible Applicants
Eligible Organizations

Higher Education Institutions

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

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

o   Hispanic-serving Institutions

o   Historically Black Colleges and Universities (HBCUs)

o   Tribally Controlled Colleges and Universities (TCCUs)

o   Alaska Native and Native Hawaiian Serving Institutions

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

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

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  allowed.

Required Registrations

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.

Eligible Individuals (Program Director/Principal Investigator)

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.

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

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

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

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

A button to access the online ASSIST system is available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

Most applicants will use NIH’s ASSIST system to prepare and submit applications through Grants.gov to NIH. Applications prepared and submitted using applicant systems capable of submitting electronic multi-project applications to Grants.gov will also be accepted.

2. Content and Form of Application Submission

It is critical that applicants follow the Multi-Project (M) Instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions except where instructed in this funding opportunity announcement to do otherwise and where instructions in the Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

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:

Vicky Whittemore, PhD
Telephone: 301-496-1917
Fax: 301-402- 1501
Email: vicky.whittemore@mail.nih.gov

Page Limitations

Component Types Available in ASSIST

Research Strategy/Program Plan Page Limits

Overall

12

Admin Core

6

Core (Use for Research Core and Clinical Core)

6

Project (Use for each Basic Research Project and Clinical Research Project)

12

Additional page limits described in the SF424 Application Guide and the Table of Page Limits must be followed.

Instructions for the Submission of Multi-Component Applications

The following section supplements the instructions found in the SF424 (R&R) Application Guide, and should be used for preparing a multi-component application.

The application should consist of the following components:

  • Overall: 1 required
  • Administrative Core: 1 required; maximum of 1
  • Research Core: optional; maximum of 1
  • Clinical Core: optional; maximum of 1
  • Basic Research Project: minimum of 1; maximum of 2
  • Clinical Research Project: minimum of 1; maximum of 2
  • The sum of the number of Basic Research Project(s) and Clinical Research Project(s) must be no more than 3.
Overall Component

When preparing your application in ASSIST, use Component Type ‘Overall’.

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

SF424 (R&R) Cover (Overall)

Complete entire form.

PHS 398 Cover Page Supplement  (Overall)

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

Research & Related Other Project Information (Overall)

Follow standard instructions.

Project/Performance Site Location(s) (Overall)

Enter primary site only.

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

Research & Related Senior/Key Person Profile (Overall)

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

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

Budget (Overall)

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

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

PHS 398 Research Plan (Overall)

Specific Aims: Describe the overall aims of the proposed ME/CFS CRC.  

Research Strategy: The Overall section should state the vision and rationale for the proposed ME/CFS CRC, and provide an overview of planned synergistic activities within the ME/CFS CRC and a proposed concept for a collaborative study that could only be completed by collaborating with other ME/CFS CRCs.  Organize the Research Strategy into sections on Significance, Innovation and Approach.

Significance:  Provide a vision statement for the ME/CFS CRC, including expected contributions to the advancement of ME/CFS research and/or treatment.  Describe how the CRC addresses an important problem or a critical barrier to progress in ME/CFS research. Include the overall ME/CFS Center program objectives or the proposed grant period.  Describe the proposed interdisciplinary approach, including the potential contribution the ME/CFS CRC can make as a local resource for and national leader in ME/CFS research and to effectively and rapidly advance an innovative, interdisciplinary, highly impactful research program.  Describe and clearly justify the specific ME/CFS research need(s) to be addressed and the scientific premise for the proposed studies. Describe how successful completion of the aims will change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field..  A plan for outreach and partnering with other ME/CFS stakeholders (patients, advocacy organizations, etc.) should be described.

Describe the relevant group experience and expertise of the PD(s)/PI(s), collaborators and researchers as a whole without duplicating information in the biosketches.  Describe the complementary and integrated expertise of the PD(s)/PI(s) and other investigators, as well as their leadership approach and governance plan, as well as the organizational structure of the ME/CFS CRC.

Innovation:  Describe how novel approaches, investigator expertise, and collaborative activities will advance the goals of the ME/CFS CRC program, including unique contributions that will elucidate the causes of and result in potential therapeutic advances for ME/CFS. Describe how the proposed research will challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions.  Describe how the proposed research will utilize novel approaches to advance our understanding of ME/CFS and make major advances in the field, including leading to future development of novel and/or improved therapies for ME/CFS.

Approach:  Describe the general research framework of the ME/CFS CRC including the overall strategy, methodology, and analyses to be used to accomplish the aims of the projects.  Discuss the proposed research program, highlighting its central theme.  Describe the synergy among the ME/CFS CRC components, especially the scientific and collaborative approaches that will ensure thematic coherence of the ME/CFS CRC research and activities. Describe the strategies that will be utilized to ensure a robust and unbiased approach, including potential problems, alternative strategies, and benchmarks for success.  Identify the proposed research that may be in the early stages of development that may be risky, and how the risk will be managed. 

Detailed descriptions of preliminary data for new projects should be included within the relevant Research Project section, not in the Overview. 

Provide summary evidence for feasibility, including preliminary findings that support the formation of a ME/CFS CRC. Present compelling evidence that the assembled research team will work together effectively to accomplish the goals of the proposed ME/CFS CRC, and will collaborate with other ME/CFS CRCs and the DMCC to advance research in ME/CFS.  Describe potential to serve as a local resource for and national leader in ME/CFS research.

Letters of Support: Include a letter from a high-level institution official(s) (e.g., Dean of the School of Medicine, Vice President for Research) to confirm institutional commitment to the ME/CFS CRC program.  The letter should provide details on how institutional commitment will be established, examples of how the institution maintains and promotes scientific excellence in ME/CFS research, and how the ME/CFS CRC will be prioritized within the institution (relative to other NIH and non-NIH funded programs).  Examples of institutional commitment may include, but are not limited to: provision of discretionary resources to the ME/CFS CRC Director, funding for pilot projects, support for recruitment of scientific talent and career enhancement activities, access to institutional infrastructure assignment of specialized research space, funding and resources for community outreach and engagement activities, and or other means of support.  The letter should describe the role of the institution in conflict arbitration and resolution, should such arise among ME/CFS CRC investigators.

The letter should describe collaborative efforts and/or opportunities with other institutional programs.  For example, opportunities may exist for collaboration with the Clinical and Translational Science Awards (CTSA), a consortium of NIH-funded academic health centers that accelerate the process of translational laboratory discoveries into treatments for patients, train a new generation of clinical and translational researchers, and engage communities in clinical research efforts.  The letter should describe how the CRC may leverage additional institutional partnership opportunities to further program goals.

Applicant institutions receiving funding from other ME/CFS-related research, should detail the unique contributions of the ME/CFS CRC to the institutional ME/CFS research effort, how interaction among these projects will advance ME/CFS research, and provide commitment to the support of the ME/CFS CRC in this context.

Collaboration with Non-governmental Organizations (if applicable):  ME/CFS CRCs and non-governmental patient advocacy organizations have common goals for understanding the cause(s) of ME/CFS and to improve treatment.  Letters should detail planned or ongoing outreach and partnership activities between ME/CFS CRCs and these groups.

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. The applicant should provide a description of the data sharing plans, including broad sharing of biospecimens, data and protocols with other ME/CFS CRCs through the DMCC.

Appendix:

 Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.  Consent forms should be submitted as Appendix material and must make it clear that any biological samples and de-identified clinical data will be appropriately shared with academics or industry.    

PHS Assignment Request Form (Overall)

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

Administrative Core

When preparing your application in ASSIST, use Component Type ‘Admin Core.’

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

SF424 (R&R) Cover (Administrative Core)

Complete only the following fields:

  • Applicant Information
  • Type of Applicant (optional)
  • Descriptive Title of Applicant’s Project
  • Proposed Project Start/Ending Dates
PHS 398 Cover Page Supplement (Administrative Core)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Administrative Core)

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

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

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

Project /Performance Site Location(s) (Administrative Core)

List all performance sites that apply to the specific component.

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

Research & Related Senior/Key Person Profile (Administrative Core)
  • In the Project Director/Principal Investigator section of the form, use Project Role of ‘Other’ with Category of ‘Admin Core Lead’ and provide a valid eRA Commons ID in the Credential field.
  • In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
  • Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
  • If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
  • Each ME/CFS CRC must include a Center Administrator. This position must be filled by an expert administrator, not by the ME/CFS CRC Director or by Project or Core Leaders.  The Administrator must have proficiency in administrative oversight for large research projects.  Additional duties will include coordination of the annual progress report, including Center research discoveries, collaborations with other ME/CFS CRCs and the DMCC, publications, funding sources, and community outreach activities.  
Budget (Administrative Core)

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

Budget for the following ME/CFS CRC-specific activities should be included in the Administrative Core:

  • Annual ME/CFS CRC Directors' Meeting:  Include travel and lodging costs for the Center Director, Administrator, and Project and Core Leads to attend the annual ME/CFS CRC Steering Committee Meeting.
  • Outreach and Partnership Activities:  Include funds for planned ME/CFS CRC outreach and partnership activities. Overarching Career Enhancement Activities: Include funds for general career enhancement activities for ME/CFS CRC investigators.  Administrative Core funds may not be budgeted for support of individual investigators; associated costs should be included in the Research Project(s) in which they participate.
  • Collaborative Projects:  Include direct funds of $200,000 per year in all years of the grant award to be utilized for one collaborative project that will be done collaboratively with the other ME/CFS CRCs and the DMCC. These will be restricted upon award for use only to support the collaborative project. 

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

PHS 398 Research Plan (Administrative Core)

Specific Aims: Describe the goals and planned activities of the Administrative Core   

Research Strategy: Organize the Research Strategy into sections on Significance, Innovation and Approach.

Significance:  Describe how the Administrative Core will serve as the organizational foundation for research activities of the ME/CFS CRC, as well as how the Core will effectively support the ME/CFS CRC to serve as a local and national resource for ME/CFS research.

Innovation:  Describe how the Administrative Core will maximize synergy among ME/CFS CRC investigators, and fosters relationships with broader research and advocacy communities.

Approach:  Describe the proposed activities of the Core, including but not limited to the following:

Promote the integration and function of the ME/CFS CRC components and activities.

Provide support for the ME/CFS CRC Director in oversight of the CRC governance.

Organize regular meetings of the ME/CFS CRC Executive Committee (composed of the ME/CFS CRC Director, project and core Leads and the ME/CFS CRC Administrator).

Participate in timely meetings of the External Advisory Committee (organized by the DMCC)

Develop and execute timely community outreach and partnership activities.

Coordinate career enhancement activities within the ME/CFS CRC.

Coordinate participation of the investigators associated with the ME/CFS CRC in the annual ME/CFS CRC Directors' and the Steering Committee Meeting (organized by the DMCC).

Coordinate and maintain an accounting of resource generation, sharing of data and resources with the DMCC and related utilization, and steps taken to maximize the research utilization of these resources within and beyond the ME/CFS CRC.

Provide advance notice of manuscripts and publications to the NIH Project Scientist; work with the appropriate NIH Office of Communications on press releases highlighting the ME/CFS CRC accomplishments.

Work with the PD/PI to prepare and submit annual progress reports.

Work with the PD/PI to provide assurance for compliance with NIH policy requirements.

Provide timely updates to ME/CFS CRC information to the DMCC in order to keep the overall and specific ME/CFS CRC websites updated.

The Approach section should include plans for the following:

Administrative Structure: 

Describe the administrative structure of the ME/CFS CRC, including lines of communication, decision-making processes, and procedures for resolving conflicts.  Describe the administrative, technical, and scientific responsibilities for ME/CFS CRC personnel and collaborators.

ME/CFS CRC Governance:  Describe plans to convene an internal Executive Committee, consisting of the ME/CFS CRC Director, Administrator, Project Leaders and Core Leaders, to assist the Director with scientific and administrative decisions.  Describe Executive Committee activities, including regular meetings to discuss Center activities and research priorities.  Describe inclusion of institutional officials.  Describe conflict resolution strategies.

Collaborative Project

Describe the process by which proposals for the collaborative project will be solicited, reviewed, and selected. Potential projects should not be proposed.

Letters of Support:  Letters of support specific to the Administrative Core should be included if appropriate.

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

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

Appendix:

Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.   

PHS Inclusion Enrollment Report (Administrative Core)

When conducting clinical research, follow all instructions for completing PHS Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.  

Research Core

When preparing your application in ASSIST, use Component Type ‘Core’.

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

SF424 (R&R) Cover (Research Core)

Complete only the following fields:

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

PHS 398 Cover Page Supplement (Research Core)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Research Core)

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

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

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

Project /Performance Site Location(s) (Research Core)

List all performance sites that apply to the specific component.

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

Research & Related Senior/Key Person Profile (Research Core)

In the Project Director/Principal Investigator section of the form, use Project Role of ‘Other’ with Category of ‘Core Lead’ and provide a valid eRA Commons ID in the Credential field.

In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.

Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.

If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.  

Core personnel responsible for data management and data sharing should be identified in the application.    

Budget (Research Core)

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

Budgeting of funds to collect and store biospecimens from study participants, including postmortem tissues, for direct use in ME/CFS CRC research projects is permitted, but the NIH will not provide funds to support infrastructure for general brain or biospecimen banking.  All biospecimens should be stored and shared through the NeuroBioBank (NeuroBioBank), NINDS-supported Coriell Institute - NINDS Human Genetics Repository, or other existing biorepositories as approved by NIH.  For the NINDS Policy on support for related efforts, see:  Notice of Change in Funding Mechanisms for Brain Banks and Biospecimen repository policies (NOT-MH-12-020).

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

PHS 398 Research Plan (Research Core)

Specific Aims:   Describe the goals and planned activities of the Research Core, as well as its essential relationship to the Aims of at least two Research Projects.    

Research Strategy:  Organize the Research Strategy into sections on Significance, Innovation and Approach.

Significance:  Describe the essential relationship of the Research Core to at least two proposed research projects, the means through which this Core will advance the aims of each associated project, and what resources generated will support the ME/CFS CRC's status as a local and national resource for ME/CFS research.

Innovation:  Describe how the standardized approaches and facilities utilized will both address the theme of the ME/CFS CRC and advance ME/CFS research.

Approach:  Indicate percent usage by each proposed research project.

Research Core approaches may include, but are not limited to:

  • Shared, standardized assays
  • Neuropathology
  • Genetics/genomics
  • Computational modeling
  • Proteomics, metabolomics, microbiome

Research Core approaches cannot include the following:

Hypothesis- or discovery-driven aims

Method or tool development

Use of ME/CFS CRC Research Cores to establish and maintain institutional infrastructure and generalized resources is beyond the scope of this FOA; a companion FOA (RFA-NS-17-022) has been issued and should be utilized for those purposes. 

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. A Resource Sharing Plan is expected with plans for sharing resources with the ME/CFS DMCC (see companion RFA-NS-17-022).

Appendix:

Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.   

PHS Inclusion Enrollment Report (Research Core)

When conducting clinical research, follow all instructions for completing PHS Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.  

Clinical Core

When preparing your application in ASSIST, use Component Type ‘Core’.

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

SF424 (R&R) Cover (Clinical Core)

  • Complete only the following fields:
  • Applicant Information
  • Type of Applicant (optional)
  • Descriptive Title of Applicant’s Project
  • Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Clinical Core)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Clinical Core)

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

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

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

Project /Performance Site Location(s) (Clinical Core)

List all performance sites that apply to the specific component.

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

Research & Related Senior/Key Person Profile (Clinical Core)

In the Project Director/Principal Investigator section of the form, use Project Role of ‘Other’ with Category of ‘Core Lead’ and provide a valid eRA Commons ID in the Credential field.

In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.

Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.

If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Core personnel responsible for data management and data sharing should be identified in the application.  

Budget (Clinical Core)

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

ME/CFS CRC Clinical Core budget should include the following:

  • Adequate costs for proactive subject recruitment and retention plans should be included within the Clinical Core Budget.
  • Funds dedicated to this Core must be utilized only to support those specific clinical activities necessary to support the ME/CFS CRC Research Projects; the Core cannot be used to follow extended cohorts or populations or collect samples that are not directly related to activities of the proposed CRC.
  • Additional funds may be directed to the Clinical Core at a later time to support the collaborative project that all ME/CFS CRCs will participate in but should not be included in the requested budget.  These funds will be held until the details of the collaborative project are determined.  These funds will come from the $200,000 that each ME/CFS CRC is required to budget for the collaborative project.

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

PHS 398 Research Plan (Clinical Core)

Specific Aims:  Describe the subject population and related clinical data and biospecimens to be collected.  

Research Strategy: Organize the Research Strategy into sections on Significance, Innovation and Approach.

Significance:  Describe the contributions of the Clinical Core to the goals of the ME/CFS CRC and its essential relationship to the complementary Clinical Research Project(s).

Innovation:   Describe how the activities of the Clinical Core, including subjects chosen for study, will both address the theme of the ME/CFS CRC and advance ME/CFS research.

Approach:  Describe the proposed activities of the Clinical Core which may include, but are not limited to, the following:

  • Follow a defined cohort of patients and control study participants studied in ME/CFS CRC research projects.
  • Collect standardized clinical data that conforms to Common Data Elements for ME/CFS (in development).
  • Deposit eligible data in the ME/CFS DMCC.
  • Standardize collection and storage of biospecimens according to defined NIH ME/CFS biospecimen protocols (to be determined by the Steering Committee post-award).
  • Provide information and samples to other ME/CFS CRCs and researchers as requested.
  • Promote and community outreach and partnership activities, in collaboration with the Administrative Core.
  • Integrate new technologies (e.g. mobile technologies, wearable devices, telemedicine) to improve data collection and subject participation.
  • Partner with the CTSA to enhance and support activities of the Clinical Core, whenever possible.

Applicants should provide a timeline of Core activities planned within the project period of ME/CFS CRC funding, and describe any potential plans for the research cohort beyond this period of support.

Applicants are strongly encouraged to establish partnerships with patients groups and solicit their input on recruitment and the clinical meaningfulness and design of the question under study.

Recruitment and retention plans, including a discussion of the availability of study participants for the proposed study and the ability of enrolling centers to recruit and retain the proposed number of subjects, including women and minorities, should be included, without repeating information on the Inclusion of Women and Minorities attachment.  Recruitment and retention strategies should be tailored and targeted for specific populations as appropriate.  Strategies should be proven or creative/innovative.  Data supporting recruitment and retention estimates should be provided.  For multi-site studies, a site activation and management plan should be included.  Study timeline, including enrollment period, and completion stage, should be described.

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. To increase the impact of a proposed clinical aspect, applicants are also strongly encouraged to strengthen their proposed investigation through collaboration and sharing with and beyond the ME/CFS CRC program as appropriate.

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.  

PHS Inclusion Enrollment Report (Clinical Core)

When conducting clinical research, follow all instructions for completing PHS Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.  

Basic Research Project

When preparing your application in ASSIST, use Component Type ‘Project’.

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

SF424 (R&R) Cover (Basic Research Project)

  • Complete only the following fields:
  • Applicant Information
  • Type of Applicant (optional)
  • Descriptive Title of Applicant’s Project
  • Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Basic Research Project)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Basic Research Project)

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

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

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

Project /Performance Site Location(s) (Basic Research Project)

List all performance sites that apply to the specific component.

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

Research & Related Senior/Key Person Profile (Basic Research Project)

In the Project Director/Principal Investigator section of the form, use Project Role of ‘Other’ with Category of ‘Project Lead’ and provide a valid eRA Commons ID in the Credential field.

In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.

Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.

If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.   

Budget (Basic Research Project)

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

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

PHS 398 Research Plan (Basic Research Project)

Specific Aims:  State the aims of the basic research project and the hypothesis to be tested.

Research Strategy:  Organize the Research Strategy into sections on Significance, Innovation and Approach.

Significance:  Describe the contributions of the basic research project to the goals of the ME/CFS CRC.  Explain why the ME/CFS CRC structure is required to accomplish proposed aims.  Describe and justify the identified research need.  Address how successful completion of proposed studies would advance ME/CFS research. 

Innovation:  Provide evidence that use of novel concepts, models, and/or technologies will contribute to the advancement of ME/CFS research.

Approach:  Describe the experimental approaches and model system(s) utilized to address the specific aims. 

Requested support for the creation of model systems, including but not limited to in vivo models and induced pluripotent stem cells (iPSC), requires strong justification.  Applicants proposing to develop iPSC lines should review "NINDS Requirements for Induced Pluripotent Stem Cell Development and Resource Sharing (NOT-NS-14-032).

Provide a strong biological rationale for the intended approach.  Applicants should include the rationale for the chosen model(s) and endpoints, adequacy of controls, justification of sample size, statistical methods, blinding methods, strategies for randomization, and robustness and reproducibility of results when describing supporting data and designing the proposed studies.  Where appropriate, potential conflicts of interest should be noted when describing supporting data and designing the proposed studies (as appropriate).

If proposing a basic research project to fulfill the required collaboration project the applicant must describe how the participation and involvement of the other ME/CFS CRCs, and the DMCC, will enhance the goals and specific aims of the project. (E.g. The participation of the other ME/CFS CRCs may include sharing of biospecimens to increase the number available for research and/or analysis.)

Letters of Support: Letters of support from collaborators should be included as appropriate. 

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

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

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.   

PHS Inclusion Enrollment Report (Basic Research Project)

When conducting clinical research, follow all instructions for completing PHS Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.  

Clinical Research Project

When preparing your application in ASSIST, use Component Type ‘Project’.

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

SF424 (R&R) Cover (Clinical Research Project)

Complete only the following fields:

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

PHS 398 Cover Page Supplement (Clinical Research Project)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Clinical Research Project)

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

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

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

Project /Performance Site Location(s) (Clinical Research Project)

List all performance sites that apply to the specific component.

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

Research & Related Senior/Key Person Profile (Clinical Research Project)

In the Project Director/Principal Investigator section of the form, use Project Role of ‘Other’ with Category of ‘Project Lead’ and provide a valid eRA Commons ID in the Credential field.

In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.

Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.

If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.   

Budget (Clinical Research Project)

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

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

PHS 398 Research Plan (Clinical Research Project)

Specific Aims:  State the research goals of the clinical research project and expected contributions to the goals of the ME/CFS CRC.  Explain why the ME/CFS CRC structure is required to accomplish the proposed aims.  Address how successful completion of the proposed studies will inform and advance future ME/CFS research and clinical trials.      

Research Strategy:  Organize the Research Strategy into sections on Significance, Innovation and Approach.

Significance:  Describe the rationale for proposed clinical studies based on unmet medical need for ME/CFS.  Describe and clearly justify the identified research need.

Innovation:  Describe novel aspects of clinical studies and potential to inform disease mechanisms and advance state-of-the-art treatment strategies for ME/CFS.

Approach:  Describe how proposed clinical studies will improve understanding and treatment of ME/CFS.  State the biological rationale for the intended approach, including supporting data from rigorously designed preclinical experiments and clinical studies.  Indicate the methodological rigor of proposed studies.  Provide the rationale for the chosen study participants and endpoints, adequacy of controls, justification of sample size, statistical methods, and robustness and reproducibility of results.

Letters of Support:  Collaboration with NIH Intramural Researchers (if applicable):  Include a letter from the Scientific Director of the collaborating NIH Institute.  The letter must describe the role of intramural staff, and specify the nature and amount (funding) of NIH intramural resources to be allocated to the proposed project.  In addition, the letter should state that the conduct of the project will comply with the DHHS regulations for research involving human subjects (if applicable) and with the PHS policy on vertebrate animal research (if applicable). 

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

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

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

PHS Inclusion Enrollment Report (Clinical Research Project)

When conducting clinical research, follow all instructions for completing PHS Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.  

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

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

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

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.

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

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

For assistance with your electronic application or for more information on the electronic submission process, visit 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) and component Project Leads must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH.

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

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Common Data Elements (CDEs)

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. 

In order to maximize data standardization across studies, the NIH strongly encourages researchers to use the Common Data Elements  ME/CFS CRC clinical research projects and cores will be encouraged to include General CDEs and ME/CFS CDEs once they have been developed.  

General CDEs

All "core" general CDE items and forms will be required in the following domains for all study participants:

Participant/Subject Characteristics (Demographics)

Participant/Subject History (Medical History and Behavioral History)

Assessments and Examinations (Physical/Neurological Exam, Vital Signs, Laboratory Tests and Biospecimens/Biomarkers)

Treatment/Intervention Data (Prior and Concomitant Medications and Supplements)

Protocol Experience (Inclusion and Exclusion Criteria, Informed Consent and Enrollment)

Applicants may also employ supplementary assessment and measurement tools if relevant to addressing the specific hypotheses proposed in their application.  If other tools are proposed, applicants are strongly encouraged to use those suggested or provided by the CDE program.

As appropriate, applicants are encouraged to make use of the following resources for clinical research:

- NeuroQOL (http://www.neuroqol.org )

- NIH Toolbox (http://www.nihtoolbox.org )

- PROMIS (http://www.nihpromis.org )

Collaboration with NIH Intramural Scientists

NIH Intramural researchers may serve as collaborators or consultants on ME/CFS CRC projects.

During the application process, intramural researchers must provide their Scientific Director with copies of formal letters of collaboration, and in turn obtain written approval from the Scientific Director for inclusion within the ME/CFS CRC application.  All requests for substantial intramural involvement in extramural research activities must also be approved by the Ethics and Grants Management Offices from the respective NIH Institute or Center (IC).

Should an extramural application include the collaboration with an intramural scientist, no funds for the support of the intramural scientist may be requested in the application.  The intramural scientist may submit a separate request for intramural funding as described above.

Post Submission Materials

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

Section V. Application Review Information
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.

Overall Impact - Overall

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

Scored Review Criteria - Overall

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 Center that by its nature is not innovative may be essential to advance a field.

Significance

Does the ME/CFS CRC  address an important problem or a critical barrier to progress in the field? Is there a strong scientific premise for the project? If the aims of the ME/CFS CRC 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?

Does the proposed ME/CFS CRC identify and address a critical challenge in ME/CFS research? Is there strong evidence that the proposed ME/CFS CRC will advance research in ME/CFS, through both its scientific projects and cores? Will the proposed Center effectively and rapidly advance an innovative, interdisciplinary, highly impactful research program while serving as a national leader in ME/CFS research? Is the use of the Cooperative Agreement (U54) mechanism justified and will the proposed research benefit from the ME/CFS CRC structure?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the ME/CFS CRC? If Early Stage Investigators or New Investigators, or 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?

Reviewers will consider the following during evaluation of the ME/CFS CRC Director:

Will the ME/CFS CRC Director provide visionary scientific leadership?

Does the Director have appropriate leadership experience, including leading a large-scale research program that predicts success of the ME/CFS CRC? 

Is the Director an established leader in scientific research with a history of successful funding, as well as currently active funding?

Has the Director made an appropriate time commitment to the ME/CFS CRC, including leadership of the Administrative Core?

If the Director’s primary area of expertise is in an area other than ME/CFS research, is it clear that the Director’s skills can be applied in novel ways to the advancement of ME/CFS research and treatment?

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?

During evaluation of the proposed ME/CFS CRC applications, reviewers will consider the level of innovation specifically related to state-of-the-art ME/CFS research, including the following: Does the ME/CFS CRC take novel approaches to advancing the stated goals of the proposed ME/CFS CRC, i.e., will proposed research advance understanding of ME/CFS and have potential to lead to the development of novel and/or improved therapies? Are the proposed projects likely to make major rather than incremental advances toward this goal?  

Approach

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

If the ME/CFS CRC 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?   

Is the ME/CFS CRC organized around a clearly articulated central theme? Is the synergistic relationship among the ME/CFS CRC components, especially the scientific and collaborative approaches that will ensure thematic coherence of the research and activities, clearly described? Will successful completion of proposed objectives directly inform the pathology, progression and treatment of ME/CFS? Is there evidence that individual investigators will function as an effective collaborative team to achieve the goals of the ME/CFS CRC? Does the ME/CFS CRC have the capacity to mobilize local resources and contribute to ME/CFS research at a local and national level?

Are there appropriate plans for the ME/CFS CRC to collaborate and otherwise contribute to the overall ME/CFS CRC program (the Network), through participating in collaborative efforts, the ME/CFS CRC Steering Committee, the annual ME/CFS CRC Directors' meeting, and other program-wide activities?

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? 

In addition, reviewers will consider the following:

Is there reasonable evidence that the institution will provide support for the ME/CFS CRC, e.g. by provision of discretionary resources to the ME/CFS CRC Director, recruitment of scientific talent, funding for pilot projects, assignment of specialized research space, access to/use of resources, and/or by any other means?

Does the applicant institution support a strong research base on ME/CFS and/or similar diseases? If the applicant institution houses other large-scale, ME/CFS-related research efforts, is there adequate description of the relationship between the proposed ME/CFS CRC and those projects, and is potential overlap addressed appropriately?

If ME/CFS CRC investigators are located at more than one institution, are planned communication and collaboration strategies detailed and appropriate?  

Scored Review Criteria - Research Projects

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for each 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.

Significance

Does the project address an important problem or a critical barrier to progress in the field? Is there a strong scientific premise for the project?  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 project contribute to the overall success of the ME/CFS CRC? Will the proposed research result in major rather than incremental advances in ME/CFS research?

Investigator(s)

Is the expertise of the research project leader, collaborators, and other researchers well suited to the project? Does the project lead have a productive record of bringing novel and significant projects to fruition as an independent principal investigator? If the investigator does not have current NIH funding, does (s)he have active, independent funding that is the equivalent of an NIH R01? Is sufficient investigator effort dedicated to the research project and ME/CFS CRC activities?

Innovation

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

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the 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 project challenge existing paradigms or clinical standards, address an innovative hypothesis or critical barrier to progress in the field? Is the work proposed appropriate to the expertise of the Lead and other researchers?

Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well-reasoned, and appropriate to the aims of the project? Are the subject population and stated endpoints well-justified?

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?

Review Criteria - Cores

Reviewers will provide overall numeric scores; individual criterion scores are not provided. The review criteria for the individual cores are provided below.

Administrative Core

Does the Administrative Core Lead/ME/CFS CRC Director have appropriate expertise and dedicate sufficient time to administrative activities? If an Associate Director is named, does that person have required expertise to effectively assist the Center Director with scientific and administrative management? Does the ME/CFS CRC Administrator have sufficient expertise with NIH policies, practices and fiscal management to provide support for the program?

Is the line of communication clear between the ME/CFS Director and Administrator? Is there an appropriate plan for establishing and maintaining effective communications and cooperation among the ME/CFS CRC investigators and with investigators outside the CRC? Is the proposed management structure appropriate for scientific administration, coordination of resource generation and utilization, as well as fiscal administration, procurement, property and personnel management, planning and budgeting? Does the Core support the ME/CFS CRC's role as a national leader in ME/CFS research?

Are there internal and external procedures for monitoring and evaluating the proposed research projects and core facilities/resources? Are there appropriate plans for management of data, animal models and other resources?

Are proposed career enhancement activities well-integrated into the theme of the ME/CFS CRC? Are proposed career enhancement activities specifically designed for ME/CFS CRC investigators, i.e. are activities separate from and do they enhance/build upon existing institutional resources and programs? Is there a clear strategy for the organization of outreach activities? Are proposed outreach and partnership activities designed to inform and engage the public about research ongoing in the ME/CFS CRC, as well as how that research integrates into current advances in ME/CFS research? Do ME/CFS CRC investigators participate in community outreach efforts to increase awareness and convey the importance and implications of their research activities to the patient and advocacy communities?

Is the method for soliciting, reviewing, and selecting collaborative projects appropriately described?

Research Cores

Is the Research Core essential to advance the scientific aims of at least two proposed research projects? Does the Core address the central theme of the overall program? Will the facilities or services provided by the Core (including procedures, techniques, and quality control) be used effectively? Are the Core Lead and key personnel well-qualified to provide the Core service(s)? Does the Core have the potential to generate and share resources that support the Center's status as a national resource for ME/CFS research?

Clinical Core

Is the Clinical Core essential for the support of the proposed clinical research project(s)? Does the Core Leader have the appropriate expertise and seniority to direct the proposed Clinical Core facility? Are there appropriate plans for the rigorous management and quality control of any research data or materials to be obtained from human subjects?

Are plans in place for subject recruitment? Is there a specific and feasible plan for inclusion of diversity in subject recruitment? Is the proposed subject cohort well-defined and appropriately diverse? Are proposed plans for recruitment and retention of the population adequate?

Have standard operating procedures been established for collection and storage of biological samples and/or for genotype/phenotype information? Will clinical data be collected using the NINDS Common Data Elements (CDEs)? Do plans include standardized collection and transmission of data to the designated Data Management and Coordinating Center (DMCC)?

Additional Review Criteria - Overall

As applicable for the ME/CFS CRC 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.

Protections for Human Subjects

For research that involves human subjects but does not involve one of the six 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 six 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.

Inclusion of Women, Minorities, and Children 

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 children 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

Additional Review Considerations - Overall

As applicable for the NME/CFS CRC 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.

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 .


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

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), convened by the Center for Scientific Review 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 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 National Advisory Neurological Disorders and Stroke Council. 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.
  • Synergy between the proposed projects and cores (if any) and between the investigators.
3. Anticipated Announcement and Award Dates

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.

Section VI. Award Administration Information
1. Award Notices

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.

2. Administrative and National Policy Requirements

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.

The award will also include restricted funds that will be used to support a collaborative research project. 

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 Parts 74 and 92 (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 (U54), an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

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

The PD/PI of the Me/CFS CRC will have the primary responsibility for defining the details of the project within the guidelines of the RFA-NS-17-022 and for performing the scientific activity, and agrees to accept close coordination, cooperation, and participation of the NIH staff in those aspects of the scientific and technical management of the project described below. Specifically, awardees have primary responsibility as described below.

ME/CFS Research Center Directors and the DMCC Director

The ME/CFS CRC Directors, with the assistance of the Data Management and Coordinating Center Director (DMCC Director), are responsible for the overall management of the Network.  The relationship between the Centers and the Data Management and Coordinating Center (DMCC) should be one of equal partners.

Collaboration and Coordination

The collaboration of investigators in the Centers is highly encouraged based on shared interests and complementary talents and will be facilitated, when possible, by the DMCC.

Steering Committee Membership and Meeting Attendance

Each ME/CFS CRC Principal Investigator, including the Principal Investigator of the DMCC, will be a voting member of the Network Steering Committee and participate in all Committee activities and decisions including, but not limited to, conference calls and special subcommittees as may be necessary. The Steering Committee shall be responsible for determining the frequency of meetings and scheduling the time and location. The Steering committee will establish the procedures for the function of the network, as outlined in section "Steering Committee."

Data Coordination and Management and Sharing

The ME/CFS CRC awardees will have primary rights to all data developed under those awards, subject to Government rights of access consistent with HHS and NIH policies. The DMCC will develop a data management system with the input of the Steering Committee. The Centers will place their data at the DMCC. The intention of the NIH is that the data collected within this Network will become a resource for the ME/CFS community and be made available to the scientific community through an X-governed data repository. Criteria and mechanisms for data sharing among investigators within the Network and with the scientific community will be developed by the Steering Committee.

The DMCC will also coordinate with NIH program staff including registration with and data uploading of appropriate studies to the ME/CFS CRC and DMCC-governed data repository, as well as to dbGaP a database for genotypes and phenotypes, National Library of Medicine. Data transfer to dbGaP (or other designated NIH data resources), is expected to occur on regular basis according to the data sharing policy for the ME/CFS CRCs established by the Steering Committee and as approved by NIH staff.

Publication and Presentation of Study Findings

Timely publication of major findings is encouraged. Publications and oral presentations of work performed under this agreement will require appropriate acknowledgment of the ME/CFS CRCs and the DMCC, and NIH ICs support. The Steering Committee will establish unifying procedures and criteria for presentation and publication of data developed within the ME/CFS CRCs and DMCC so that these procedures and criteria are consistent.

Federally Mandated Regulatory Requirements

Each institution participating in the ME/CFS CRCs and DMCC is required to meet DHHS regulations for the protection of human subjects and FDA requirements for the conduct of research using investigational agents. At a minimum, these include:

1. methods for assuring that each institution at which ME/CFS CRC and DMCC investigators are conducting clinical studies has registered with the Office of Human Research Protections (OHRP; http://www.hhs.gov/ohrp/) and has a Federal wide Assurance; that study protocols are reviewed and approved by the responsible Institutional Review Board (IRB) prior to patient entry; that active protocols are reviewed at least annually by the IRB, and that amendments are approved by the IRB.

2. methods for assuring or documenting that each patient, or patient's parent/legal guardian, gives fully informed consent to participation in a research protocol prior to the initiation of the clinical study.

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 HHS, PHS, and NIH policies.

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

One representative from NINDS, will be designated to serve as the Program Coordinator for this cooperative agreement. The Program Coordinators for the DMCC and Project Scientists from the appropriate NIH ICs will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice and coordination above and beyond normal program stewardship for awards, as described below.

Steering Committee Membership and Meeting Attendance

The NIH Program Coordinator from NINDS and the Project Scientists from the appropriate NIH ICs will serve on the Steering Committee (see below) and will participate in all Committee activities, including, but not limited to, meetings, conference calls, subcommittees, and special committees. They will assist in development of operating policies, quality control procedures, and policies that require cooperative action. While the Program Coordinator and Project Scientists will attend Steering Committee Meetings along with the Project Scientists from the ME.CFS CRCs, their cumulative votes may never exceed 1/3 of the total committee votes.

Monitoring Performance

The Program Coordinator and IC Project Scientists will assist the Steering Committee in the development of procedures for monitoring the performance of the clinical studies. This includes participation in periodic on-site monitoring with respect to compliance with protocol specifications, quality control and accuracy of data recording, and accrual.

Publication and Presentation of Clinical Studies Findings

The NIH staff may contribute, through review, comment, analysis, and/or co-authorship, to reporting results of the clinical studies to the investigator community and other interested scientific and lay organizations. Co-authorship by the NIH staff will be subject to approval in accordance with the NIH policies regarding staff authorship of publications resulting from extramural awards.

The Government, via the NINDS Program Coordinator, IC Project Scientists and Program Officials, will have access to data generated under this Cooperative Agreement and may periodically review the data and progress reports. Information obtained from the data may be used by NIH staff for the preparation of internal reports on the activities of the clinical studies. However, awardees will retain custody of and have primary rights to all data developed under these awards.

Program Stewardship

The assigned Program Official from NINDS will be responsible for normal programmatic stewardship and monitoring of this award. The Program Official will not serve as the substantively involved IC Project Scientist. They may receive input and recommendations from other NIH staff in monitoring the awards.

Areas of Joint Responsibility include:

All investigators within theme/CFS CRCs and the DMCC must be willing to work cooperatively and collaboratively.  It is expected that there will be at least one annual meeting of the all of the ME/CFS CRC and DMCC investigators.

Steering Committee

A Steering Committee will be established to serve as the main governing body of the cooperative network. At a minimum, the Steering Committee will be composed of one representative from each of the ME/CFS CRCs, one representative from the DMCC, the NIH Program Coordinator from NINDS, at least one member of the community engagement groups (patient advocacy organizations) from each ME/CFS CRC, and other participating IC Project Scientists. All members are expected to actively participate in all Steering Committee activities. The combined vote of NIH membership may never exceed 40 percent.

The Chairperson of the Steering Committee will be selected by the Steering Committee from among the non-Federal members during one of the early meetings of the Committee to be convened by the NIH Program Coordinator. All major decisions will be made by the Steering Committee. The Committee will meet at least semi-annually.  As needed, the Steering Committee may establish subcommittees for special purposes. It is expected that most of the work of the Steering Committee will be performed in these subcommittees. The Centers and DMCC must abide by decisions of the Steering Committee.

The Steering Committee will have responsibility of facilitating the conduct of the clinical studies, promoting collaboration, establishing and updating the content of the web resource site, and establishing procedures for reporting results of studies. Each full member will have one vote. Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee.

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 regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

3. Reporting

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 progress report, 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.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

Application Submission Contacts

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, 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)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)

Telephone: 301-710-0267

Scientific/Research Contact(s)

Vicky Whittemore, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1917
Email: vicky.whittemore@mail.nih.gov

Peer Review Contact(s)

Nick Gaiano, PhD
Center for Scientific Review (CSR)
Telephone: 301-435-1033
Email: gaianonr@mail.nih.gov

Financial/Grants Management Contact(s)

Tijuanna Decoster, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9231  
Email: decostert@mail.nih.gov

Section VIII. Other Information

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.

Authority and Regulations

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.

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