Part 1. Overview Information

Key Dates

All applications are due by 5:00 PM local time of applicant organization. 

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.

No late applications will be accepted for this Notice of Funding Opportunity (NOFO).

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide, except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts).

Conformance to all requirements (both in the Application Guide and the NOFO) 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 available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

1. Use the NIH ASSIST system to prepare, submit and track your application online.
2. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.
   
   
3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.



Table of Contents
Part 1. Overview Information
Key Dates
Part 2. Full Text of Announcement
Section I. Notice of 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. Notice of Funding Opportunity Description

The purpose of this notice of funding opportunity (NOFO) is to encourage cooperative agreement applications to the National Institute on Deafness and Other Communications Disorders (NIDCD) for investigator initiated high-risk clinical trials for in vivo imaging of the inner ear with high-resolution structural and functional imaging with the goal of advancing interventions into standard clinical care through well-designed and well-implemented clinical trials. This NOFO is specifically for clinical trials that meet ANY of the following criteria: requires FDA oversight, is intended to formally establish efficacy (phase III), or has potentially higher risks to participants. Clinical trials not meeting any of the criteria above are referred to the companion In Vivo High-Resolution Imaging for Inner Ear Visualization (R01 - Clinical Trial Optional) RFA-DC-25-005.  

Background: The inner ear is a complex and delicate sensory organ responsible for hearing and balance. The anatomy of the human inner ear, including the small size of the sensory structures and their deep location within the temporal bone, poses significant challenges for imaging this organ. While various imaging modalities exist, none currently provide sufficient resolution to fully visualize the inner ear structures, nor do technologies exist that produce images in sufficient detail for fine-grade distinctions of inner ear components in living human tissue. Such imaging is needed to improve the diagnosis and treatment of inner ear disorders.

While NIDCD has a significant investment in human post-mortem tissue to study the cochlea and vestibular system, detailed, non-invasive imaging in living humans has been severely impeded due to the limitations of current technology. These restrictions have seriously hampered progress in understanding pathology of the organs of hearing and balance in humans. The critical need to relate findings from animal models to human ear disorders, and for formulating specific diagnoses and treatment plans through the detailed visualization of the human inner ear has been emphasized in both a past NIDCD workshop “Visualizing the Human Inner Ear” (https://www.nidcd.nih.gov/research/workshops/visualizing-human-inner-ear-workshop/2019/summary) as well as the current NIDCD Strategic Plan for 2023-2027 (https://www.nidcd.nih.gov/about/strategic-plans). In addition, in 2023, NIDCD issued a Request for Information (RFI) inviting input regarding NIDCD’s support of non-invasive imaging in humans (https://grants.nih.gov/grants/guide/notice-files/NOT-DC-23-004.html). Throughout these activities, the need for high-quality, high-resolution imaging of the human inner ear was a strong and recurrent theme. For example, an improvement in imaging resolution of five- to tenfold may allow scientists and clinicians to see many structures—including endocochlear or endovestibular structures—in sufficient detail, to inform clinical decision-making. Visualizing the inner ear at a resolution necessary for unequivocal diagnoses in the clinician’s office, understanding the mechanisms underlying hearing and balance disorders, and developing and guiding treatments, including gene therapy, will directly support NIDCD’s scientific mission and improve human health.

Some examples of how advanced imaging could inform clinical management:

• Distinguishing between Ménière’s disease and vestibular migraines, which can present in similar ways, but require different treatments. In the case of the former, surgical ablation can help whereas that same procedure could exacerbate vestibular migraines.
• Identifying the correct patient cohort as candidates for future inner ear gene therapies.
• Determining the accuracy and targets of intracochlear treatments including the delivery of gene therapy.
• Measuring the location and realignment of otoconia during canal repositioning treatments, such as the Epley maneuver for treatment of Benign Paroxysmal Positional Vertigo (BPPV).
• Improving placement of cochlear and vestibular implants.
• Understanding blood vasculature changes and their relation to inner ear diseases.
• Understanding the underlying molecular basis of inner ear diseases.

Scope: Applications responsive to this announcement include, but are not limited to, the following general topics:

1. Development of new non-invasive imaging techniques: Projects may focus on developing new, in vivo imaging modalities or novel imaging technologies to provide high-resolution, three-dimensional in vivo imaging of inner ear structures.

2. Improvement of current imaging techniques: Projects may focus on developing new hardware or software tools to improve the spatial resolution, signal-to-noise ratio, or contrast of images from existing imaging techniques, such as micro-CT (computed tomography), OCT (optical computed tomography), super-resolution microscopy, photoacoustic imaging, and MRI (magnetic resonance imaging) including high-strength MRI, and fMRI (functional magnetic resonance imaging). Projects may also explore new methods for image reconstruction or image processing that can enhance the resolution of existing imaging techniques.

3. Development of novel imaging probes or contrast agents: Projects may focus on developing new imaging probes or contrast agents that can specifically target and visualize human inner ear structures for high-resolution spatial and functional imaging. Such probes may include, but are not limited to, new nanoparticle-based imaging agents, genetically encoded fluorescent probes, or contrast agents that can selectively bind to human inner ear tissues.

4. Translating technology to the clinic: Projects may focus on translating the developed imaging technologies to be used in a clinical setting. This may include developing new imaging devices that can be used in the clinic or performing clinical studies to evaluate the safety and efficacy of the imaging techniques in animals and humans.

Some specific targets of opportunities for applications could include, but are not limited to, those listed below:

• Differentiating soft tissue from bone in the inner ear
• Visualizing blood vasculature and blood flow in and around the inner ear, and changes to the blood flow patterns
• Imaging the inner ear at cellular and subcellular levels
• Distinguishing air from bone in the human inner ear
• Dynamic movements of inner ear components
• Physiology of inner ear functions
• Detailed images of features such as hair cells, otoliths, membranes, ions
• Determining the precise location of calcium carbonate crystals (otoconia)

The NIH defines a clinical trial as a research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes. This funding opportunity is specifically intended for clinical trials that meet ANY of the following criteria:

• Requires FDA oversight such as those requiring Investigational New Drug (IND) or Investigational Device Exemption (IDE) applications
• Have higher risks to participants, for example:
  • Involve a non-routine intervention
  • Involve utilization of unlicensed product/device
  • Involve utilization of a licensed product/device for an unapproved indication
• NIH defined Phase III Clinical Trial:
  • An NIH-defined Phase III clinical trial is a broadly based prospective Phase III clinical investigation, usually involving several hundred or more human subjects, for the purpose of evaluating an experimental intervention in comparison with a standard or controlled intervention or comparing two or more existing treatments. Often the aim of such investigation is to provide evidence leading to a scientific basis for consideration of a change in health policy or standard of care. The definition includes pharmacologic, non-pharmacologic, and behavioral interventions given for disease prevention, prophylaxis, diagnosis, or therapy. 

Only one clinical trial may be proposed per application. Drug, biologic, or device interventions require applicants to provide documentation from the FDA (see Section 4.5 of PHS Human Subjects and Clinical Trials Information).

Clinical trials that do not involve FDA oversight, are not intended to formally establish efficacy (may inform subsequent studies but are not aimed or sufficiently powered to directly change health policy or standard of care), and where the risks are no more than the potential risks encountered in routine medical care or procedures are referred to the companion In Vivo High-Resolution Imaging for Inner Ear Visualization (R01-Clinical Trial Optional) RFA-DC-25-005.

Applications Not Responsive to this NOFO:

Studies that are not responsive to this NOFO and will NOT be reviewed include the following:

• Applications that do not address scientific mission areas of the NIDCD
• Low-risk clinical trials not meeting any of the criteria above 
• Applications that propose more than one clinical trial
• Applications identified as a clinical trial that do not include a series of milestones for completion of the clinical trial and provide contingency plans should there be delays in attaining them
• Applications that do not address the required five points in the Research Strategy

Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs.

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

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Local 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).

Federal Governments

• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Organizations)

Non-domestic (non-U.S.) Entities (Foreign Organizations) are eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the How to Apply- 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. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications for additional information.

• System for Award Management (SAM) – 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.
  • Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registrations; all registrations must be in place by time of submission. 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 SAM registration in order to complete the Grants.gov registration.

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

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

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019 and Notice of NIH's Interest in Diversity, NOT-OD-20-031.

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 How to Apply-Application Guide.

2. Cost Sharing

This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1.2 Definition of Terms.

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, per NIH Grants Policy Statement Section 2.3.7.4 Submission of Resubmission Application. 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 NIH Grants Policy Statement 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

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

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:

Melissa Stick, Ph.D., MPH
National Institute on Deafness and Other Communication Disorders (NIDCD)
Telephone: 301-496-8683
Email: [email protected]

Page Limitations

All page limitations described in the How to Apply- Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the How to Apply- Application Guide and should be used for preparing an application to this NOFO.

SF424(R&R) Cover

All instructions in the How to Apply - Application Guide must be followed.

SF424(R&R) Project/Performance Site Locations

All instructions in the How to Apply- Application Guide must be followed.

SF424(R&R) Other Project Information

All instructions in the How to Apply- Application Guide must be followed.

SF424(R&R) Senior/Key Person Profile

All instructions in the How to Apply- Application Guide must be followed.

R&R or Modular Budget

All instructions in the How to Apply- Application Guide must be followed.

R&R Subaward Budget

All instructions in the How to Apply-Application Guide must be followed.

PHS 398 Cover Page Supplement

All instructions in the How to Apply- Application Guide must be followed.

PHS 398 Research Plan

All instructions in the How to Apply- Application Guide must be followed, with the following additional instructions:

Research Strategy: Applications must address the following five points in the application:

1. Discuss what type of imaging will be improved (spatial, temporal, or functional).
2. Specify the amount that image resolution will be increased compared to current techniques, and how this will impact the diagnosis and/or treatment of human inner ear pathology.
3. Include a timeline and detailed plan to take the proposed work into a clinical setting for non-invasive use with awake humans if that is not the end goal of the proposed clinical trial. 
4. Describe what clinical settings and under what conditions the technique could be used, how it would inform clinical care and management, and how it might guide clinical decision-making. If the technology can only be used invasively or with anesthetized humans, explain in detail the limitations and possible solutions for translation into a clinic setting.
5. Describe what inner ear pathologies (i.e., auditory, vestibular) may be better diagnosed and what, if any, treatments might be feasible if the increase in resolution is achieved.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the How to Apply- Application Guide.

Other Plan(s): 

All instructions in the How to Apply-Application Guide must be followed, with the following additional instructions:

• All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan
•  

Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply- Application Guide.

• No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

PHS Human Subjects and Clinical Trials Information

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the How to Apply- Application Guide must be followed.

Section 2 - Study Population Characteristics

Include the following additional information:

2.4 Inclusion of Women and Minorities

Applications in response to this funding opportunity must include a plan to conduct analyses to evaluate differences which may impact the intervention outcome(s) among sex/gender subgroups within the “Inclusion of Women and Minorities” attachment, as applicable. When there are no prior studies strongly supporting significant differences among the sex/gender subgroups, an exploratory subgroup analysis may be appropriate.
 

2.5 Recruitment and Retention Plan

Applications in response to this funding opportunity must propose innovative and proactive recruitment strategies for involving underrepresented populations such as underrepresented minority participants, as applicable and justified by the scientific goals. In addition to stating the demographic breakdown of the geographic area in which the science will be conducted and describing the planned distribution of subjects by sex/gender, race, and ethnicity, a recruitment plan focused specifically on engaging underrepresented populations must be included. The recruitment plan should include:

• an outline of operational measures that will be implemented to ensure diverse clinical trial participation
• a description of outreach, enrollment and retention strategies to reduce identified barriers and sustain the engagement of underrepresented participants.
• a detailed plan to increase community engagement that:
  • describes community partners and how they will be collaboratively engaged in the research project (e.g., activities, frequency and duration of involvement)
  • justifies how the planned partners and their level of involvement are relevant and will enhance the research project

The following racial and ethnic groups have been shown to be underrepresented in biomedical research: Blacks or African Americans, Hispanics or Latinos, American Indians or Alaska Natives, Asians, Native Hawaiians, and other Pacific Islanders.

2.7. Study Timeline

Basic elements of the study timeline must also include a Milestones Plan.

Milestones Plan

Applications must include a series of milestones for completion of the clinical trial and provide contingency plans should there be delays in attaining them. The milestones will undergo peer review and will be incorporated into the terms of award. Applicants are required to provide detailed project performance and timeline objectives. This plan must include a timeline for the following general milestones, as applicable:

• Completion of regulatory approvals;
• Listing in registry;
• Enrollment of the first subject;
• Enrollment of 25%, 50%, 75% and 100% of the projected recruitment time period for all study subjects, including women, minorities and children (as appropriate);
• Scheduled interim analyses;
• Completion of data collection time period;
• Completion of primary endpoint and secondary endpoint data analyses time period;
• Posting of primary outcome results in registry;
• Completion of final study report; and
• Detailed protocol-specific performance milestones and timeline.

These milestones will be negotiated at the time of the award, if appropriate.

Section 3 - Protection and Monitoring Plans            

3.1 Protection of Human Subjects

Include the following additional information:

3.1.1.b Study Procedures, Materials and Potential Risks

For risks identified from all sources and where feasible note the expected frequency, severity, and duration of the risk(s).

3.1.3 Potential Benefits of the Proposed Research to Research Participants and Others

State the problem or question (e.g., describe the population, disease, current standard of care, if one exists, and limitations of knowledge or available therapy) and the reason for conducting the clinical trial.

Provide a discussion of studies that led to the proposed clinical trial and information or data from preliminary studies which address the need for, safety and the feasibility of the trial as well as evidence of the potential efficacy for each proposed intervention including,

• A summary of findings from nonclinical in vitro or in vivo studies that have potential clinical significance and justify the safe administration of the intervention into humans
• A summary of relevant clinical research and any history of human use or exposure to the study intervention, including use in other countries, and clinical pharmacology studies
• Pertinent results for preliminary studies which justify the specific intervention dose selection, and administration method and schedule.
  • For a Phase III/pivotal clinical trial application, provide a summary of studies that led to the proposed clinical trial and data from Phase I and II clinical trials including trails including summaries of evidence for the potential safety and efficacy for each proposed intervention, dose selected and administration schedule.
• Discussion of important literature and data that are relevant to the trial and that provide background for the trial
• Applicable clinical, epidemiological, or public health background or context of the clinical trial
• Importance of the clinical trial and any relevant treatment issues or controversies

3.3 Data and Safety Monitoring Plan

The Data and Safety Monitoring Plan (DSMP) must address the following areas:

• Where the monitoring will occur;
• How site(s)/center(s), and participating facilities (labs, pharmacies) will be monitored.
• Also address the appropriate oversight over the conduct of the trial, including at a minimum the appropriate clinical monitoring independent of the study team, safety monitoring, regulatory submissions and compliance and quality management.
• Provide a data management plan addressing the following areas: (1) database system to be employed, (2) compliance with federal regulations, (3) security and emergency back-up, and (4) quality assurance and quality control of data from clinical sites and laboratories, as appropriate.

Applications that lack the DSMP are incomplete and will not be reviewed.

3.5. Overall Structure of the Study Team

An overview of the organizational structure including an organizational chart and details of the operations of the Study Chair, Clinical Coordinating Center, Data Coordinating Center, and Clinical Centers if applicable. The Clinical or Operational Coordinating Center and the Data Coordinating Center may be the same organization in some circumstances. The study team should include:

• A Clinical Operational Coordinating Center that provides overall project management and coordination for the clinical trial to ensure completion of pre-implementation requirements and enrollment meet timeline goals; data quality and integrity; conformance to implementing the Manual of Procedures (MOP); quality assurance and control;safety monitoring and reporting.
• Statistical support through the complete life cycle of the clinical trial including protocol development and study design, statistical analysis, and preparation of data/progress/safety monitoring reports and publications. It is expected that a statistician will be included as key personnel.
• Clinical Centers that are responsible for implementing the protocol, recruiting patients, providing the intervention/prevention required, conducting patient follow up, and submitting clinical trial data.
• Data management support (including a Data Coordinating Center for multi-site clinical trials) design and implementation of data forms, data entry accuracy and timeliness, data management, data quality assurance and control, and data storage/repository. It is expected that a data manager will be included as key personnel.
• Central resource centers such as a central laboratory, pharmacy or radiographic center, if appropriate.

Section 4 - Protocol Synopsis

4.1 Study Design

4.1.a Detailed Description:

In addition to providing a narrative description of the protocol and statistical methods as instructed for the PHS Human Subjects and Clinical Trials Information form, this section must also include:

• A clear definition of the protocol hypothesis
• Justification and support for selection of primary endpoint(s) as the most appropriate to inform future studies and to advance the intervention into clinical practice (clinical relevance, acceptance by regulatory authorities (e.g., FDA)) and clinical community (e.g., compared with gold standard), validity, and reliability of the measurement.
• For surveys and questionnaires, note for what populations the instrument was previously validated and specifically if the instrument was previously validated for the target study population.

Include the following additional information within the narrative study description: Identify each study group(s)/arm(s) including dose/duration of intervention for each, total number of participants and number of participants in each group/arm

• If applicable, describe the rationale for the type and selection of control (e.g., placebo, active drug, dose-response, historical). Discuss known or potential problems associated with the control group chosen in light of the specific disease and intervention(s) being studied
• Provide a justification for the route of administration, planned maximum dosage, and dosing regimen, including starting dose, of the study intervention(s) and control product(s)
• A description of the type/design of trial to be conducted (e.g., randomized, placebo-controlled, double-blinded, parallel design, open-label, dose escalation, dose-ranging, adaptive, cluster randomized, group sequential, multi-regional, superiority or non-inferiority design)
• A description of methods to be used to minimize bias
• Provide the plan for blinding and randomization (if applicable)
• Provide the plan for interim analysis
  • If applicable, include halting or stopping rules
  • If applicable, include an interim futility analysis with stopping rules to stop the trial if it is determined the trial is unable to achieve it's objective (e.g., statistical significance unlikely to be achieved)
• If stratification(s) is included, identify the stratification planned (e.g., sex, race/ethnicity, age, dose)

Provide the following information for drug, biologic and device interventions

• Name (brand name and generic if applicable)
• Name of manufacturer
• Procurement plan
• For devices, device support duration, expiration and battery life if applicable

4.3. Statistical Design and Power

In addition to the information requested in the PHS Human Subjects and Clinical Trials Information Instructions, provide detail on:

• Justification on the selection of the primary outcome and corresponding primary endpoint (measurement and window of observation), including
  • Clinical relevance
  • Acceptance by regulatory authorities (e.g., FDA) and clinical community
• Effect size that is clinically meaningful
• The sample size determination including information needed to validate your calculations and judge the feasibility of enrolling and following the necessary number of participants. In particular, specify all of the following:
  • Outcome measure used for Calculations Test statistic
  • Null and alternative Hypotheses Type I error rate (alpha)
  • Power level (e.g., 80% power)
  • Assumed event rate for dichotomous outcome (or mean and variance of continuous outcome) for each study arm, justified and referenced by historical data as much as possible. Also, provide information to support the clinical relevance of the selected effect size
  • Statistical method used to calculate the sample size, with a reference for it and for any software utilized
• Anticipated impact of dropout rates, withdrawal, cross-over to other study arms, missing data, etc. on study power
• Method for adjusting calculations for planned interim analyses, if any
• Discuss whether the sample size provides sufficient power for addressing secondary endpoints or exploratory analyses

4.5 Will the study use an FDA-regulated intervention?

In addition to the information requested in the PHS Human Subjects and Clinical Trials Information Instructions, if the intervention is a drug, biologic, or device, applicants must provide documentation from the FDA providing information on one of the following scenarios:

Format: Attach this information as a PDF file. The filename "FDA Documentation.pdf" should be used. See NIH’s Format Attachments page. Applications that lack this document are incomplete and will NOT be reviewed.

Content:

1. The protocol has been submitted under an open IND and the IND is not under full or partial hold. Under this scenario, applicants must provide documentation such as a "may proceed" email or letter from the FDA.
2. The protocol has been submitted as an original IDE or as a new study under an open IDE, and FDA has fully approved the IDE or IDE supplement. Under this scenario, applicants must provide documentation of an IDE or IDE supplement full approval letter from the FDA. The IDE or IDE supplement is required to be specific for the clinical trial protocol proposed (e.g., design, sample size, population, device model, etc.) and correspond with the FDA approval. Collation of multiple IDE supplement approvals for different components of the protocol is not adequate.
3. The protocol has been submitted under an IND and is on full or partial hold. Under this scenario applicants must provide full documentation from the FDA on the reasons for hold and the FDA recommendations. Applicants should discuss how they intend to address the hold issues and when they believe they will have FDA approval to proceed with trial implementation.
4. The protocol has been submitted as an original IDE or as a new study under an open IDE, and FDA has conditionally approved the IDE or IDE supplement. Under this scenario applicants must provide full documentation from the FDA on the conditions of approval. Applicants should discuss how they intend to address these conditions and when they believe they will have FDA approval to proceed with trial implementation.
5. The protocol is exempt from an IND. Under this scenario applicants must provide a copy of the exemption letter from the FDA.
6. The protocol is either exempt from the IDE regulations or does not require IDE approval because it is determined to be nonsignificant risk. Under this scenario applicants must provide either an IDE exemption letter or a copy of the risk determination letter from the FDA or IRB. NIDCD may request specifically for risk determination documentation from the FDA.

Note: Do not include the IND/IDE application, manufacturer’s product specifications, study protocol, or protocol amendments in this attachment

Section 5 - Other Clinical Trial-related Attachments

5.1 Other Clinical Trial-related Attachments

For this clinical trial funding opportunity, the following document must be submitted as an "Other Clinical Trial-related Attachment". Applications that lack these documents are incomplete and will NOT be reviewed.

Trial Management Plan: ONLY for multi-site clinical trials.

A description of how the proposed trial will be managed must be provided as an attachment using the filename "Trial Management Plan.pdf" and may not exceed 5 pages.

Describe the strategy that will be used throughout the project to ensure that management activities of the clinical trial are met including directly supporting the needs of scientific study leadership to identify barriers, make timely responses, and optimize the allocation of limited resources to meet pre-defined study objectives. This description should include:

• The role of study personnel responsible for trial management
• A risk assessment plan
• A risk management plan that addresses contingencies in the event that there is inadequate progress toward achieving the U01 milestones. The plan should identify a range of contingencies that could threaten study progress or feasibility and propose solutions using study resources.
• Key methodology and standard operating procedures governing resource management, study implementation, operations/execution, and study closure.
• How the clinical trial management team will resolve fiscal and logistical issues in a timely manner including plans to proactively evaluate and prioritize study risks and issue corrective responses.
• Processes required for orderly project closure including how the study will comply with the NIH Data Management and Sharing (DMS) Policy.

In summary, the trial management plan should provide sufficient detail to demonstrate the ability to achieve the goals of the clinical trial on-budget and on-time and to successfully manage and mitigate risks.

Independent Data Quality Auditing Plan: ONLY for clinical trials Phase II, III, or IV clinical trials

The file name "Data Quality Auditing Plan.pdf" should be used.

An Independent Data Quality Auditing Plan is a required attachment for clinical trials that are Phase II, III, or IV. The NIH requirements for monitoring clinical trials as described below are in addition to the application's Data and Safety Monitoring Plan (DSMP) attachment on the PHS Human Subjects and Clinical Trials Information form which describes how data and patient safety in the trial will be monitored.

The purpose of Independent Data Quality Auditing Plan is to verify that the clinical trial is being conducted, and documented in accordance with the Protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s).

Describe the person(s)/entity responsible for conducting the independent auditing (e.g., contracted Clinical Research Associate, Data Coordinating Center, Independent study monitor from the Clinical Coordinating Center) including qualifications and experience.

Describe the timing and frequency of planned auditing activities including:

• Study Initiation Visits
• Interim Monitoring Visits
• Study Close Out
• Locations where the monitoring will occur (e.g., participating clinical sites, data center, clinical coordinating center) and what data will be reviewed.

Provide an overall description of the auditing plan to ensure adherence to the protocol, study and implementation procedure deficiencies and deviations are identified, adequate documentation including the consenting process, and the quality and consistency of the study intervention(s), including fidelity monitoring for behavioral interventions. Include methods to monitor study intervention and systems to record and manage exceptions and deviations. If applicable, describe monitoring of participating facilities such as labs or pharmacies for adequate handling and storage of investigational product(s) and study specimens. Include a description to assure that the investigational product(s) accountability and reconciliation are performed adequately during and at the end of the trial per applicable regulatory requirements.

Describe plans for handling any deficiencies that are uncovered and in cases of serious deficiencies the appropriate reporting to relevant authorities, including but not limited to the IRB of record, DSMB if one is assigned, FDA if applicable, institutional officials, and the NIH.

Post-trial Transition Plan for Participants.  The file name “Post-trial Transition plan.pdf” should be used.

Applicants must describe the anticipated long-term care needs related to the clinical trial intervention for participants after a trial has ended (e.g., continued access to the intervention, and/or maintenance). Where relevant, it is recommended that applicants consider various post-trial scenarios, such as trial experimental intervention failure or success, regulatory approval options and decisions by manufacturers to commercialize or discontinue a product, and expiration date of the intervention. Next, applicants should describe a plan for the care of participants at the end of the trial and after the study period, if appropriate, related to the potential care needs. The plans may vary from project to project, depending on, for example, whether participants are likely to have other ways to access this care, insurance coverage, the anticipated risks and benefits of lacking this care, and the feasibility of facilitating this care. All plans should include information regarding post trial obligations of the applicant and when appropriate, manufacturer. In addition to these requirements, trials involving devices should have supplemental information to include but not limited to device post trial care and potential explanation. Applications that lack the Post-trial Transition Plan are incomplete and will NOT be reviewed.

Other Requirements:

• Clinical trials must be registered in ClinicalTrials.gov prior to the enrollment of the first participant.
• Any publications related to outcomes should be published in NIH PubMed Central.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the How to Apply- Application Guide must be followed.

NIDCD will not accept a delayed onset study under this funding opportunity. 

PHS Assignment Request Form

All instructions in the How to Apply- Application Guide must be followed.

Foreign Organizations

Foreign (non-U.S.) organizations must follow policies described in the NIH Grants Policy Statement, and procedures for foreign organizations described throughout the How to Apply- Application Guide.

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

See Part 2. 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. contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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 How to Apply-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 Section 7.9.1 Selected Items of Cost.

Applications must be submitted electronically following the instructions described in the How to Apply Application Guide. Paper applications will not be accepted.

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

For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply – Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

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

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the How to Apply Application Guide.

See more tips for avoiding common errors.

Prior Consultation with IC Staff 

Consultation with relevant IC staff at least 10 weeks prior to the application due date is strongly encouraged for all applications. IC staff will consider whether the proposed clinical trial meets the goals and mission of the Institute, whether it addresses one or more high priority research areas, and whether it is appropriate to conduct as an investigator initiated clinical trial. Scientific merit will be determined during peer review using the review criteria indicated in this NOFO. IC staff members are also available to work with potential applicants to determine the risk level of the proposed trial and delineate all documentation that will be needed at the time of application submission. During the consultation phase, if the proposed trial does not meet the IC's programmatic needs, applicants will be strongly encouraged to consider other Funding Opportunities. 

An initial resource is information found at https://www.nidcd.nih.gov/clinical-studies/concept-proposal-nidcd-clinical-trials. Written questions or requests for telephone consultation pertaining to clinical trial rules specifically may be submitted to Trinh Ly, MD ([email protected] (mailto:[email protected]). 

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

This funding opportunity supports a cooperative agreement between an NIDCD Project Scientist and an Investigator to support a clinical trial that meets ANY of the following criteria: requires FDA oversight, is intended to formally establish efficacy, or has potentially higher risks to participants. 

Applications containing more than one clinical trial or including other non-clinical trial research studies will be considered non-responsive and will not be reviewed.

In order to expedite review, applicants are requested to notify the NIDCD Referral Office by email at melissa_stick@ nih.gov  when the application has been submitted. Please include the NOFO number and title, PD/PI name, and title of the application.

Recipients or subrecipients must submit any information related to violations of federal criminal law involving fraud, bribery, or gratuity violations potentially affecting the federal award. See Mandatory Disclosures, 2 CFR 200.113 and NIH Grants Policy Statement Section 4.1.35.

Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at [email protected].

Post Submission Materials

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

Any instructions provided here are in addition to the instructions in the policy.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following scored review criteria and additional review criteria (as applicable for the project proposed). An application does not need to be strong in all categories to be judged likely to have a major scientific impact.

Reviewers will consider Factors 1, 2 and 3 in the determination of scientific merit, and in providing an overall impact score. In addition, Factors 1 and 2 will each receive a separate factor score. 

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

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

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NIDCD, in accordance with NIH peer review policies and practices, 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 will receive a written critique.

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.

Appeals of initial peer review will not be accepted for applications submitted in response to this NOFO.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this NOFO. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

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 Section 2.5.1. Just-in-Time Procedures. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding.

Prior to making an award, NIH reviews an applicant’s federal award history in SAM.gov to ensure sound business practices. An applicant can review and comment on any information in the Responsibility/Qualification records available in SAM.gov. NIH will consider any comments by the applicant in the Responsibility/Qualification records in SAM.gov to ascertain the applicant’s integrity, business ethics, and performance record of managing Federal awards per 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.

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 2.4.4 Disposition of Applications.

Section VI. Award Administration Information

1. Award Notices

A Notice of Award (NoA) is the official authorizing document notifying the applicant that an award has been made and that funds may be requested from the designated HHS payment system or office. The NoA is signed by the Grants Management Officer and emailed to the recipient’s business official.

In accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Any pre-award costs incurred before receipt of the NoA are at the applicant's own risk.  For more information on the Notice of Award, please refer to the NIH Grants Policy Statement Section 5. The Notice of Award and NIH Grants & Funding website, see Award Process.

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

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

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

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

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

2. Administrative and National Policy Requirements

The following Federal wide and HHS-specific policy requirements apply to awards funded through NIH:

• The rules listed at 2 CFR Part 200, Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards.
• All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the terms and conditions in the Notice of Award (NoA). The NoA includes the requirements of this NOFO. 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, Recipients, and Activities.
• If a recipient receives an award, the recipient must follow all applicable nondiscrimination laws. The recipient agrees to this when registering in SAM.gov. The recipient must also submit an Assurance of Compliance (HHS-690). To learn more, see the Laws and Regulations Enforced by the HHS Office for Civil Rights website.
  • HHS recognizes that NIH 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 NOFO.

All federal statutes and regulations relevant to federal financial assistance, including those highlighted in NIH Grants Policy Statement Section 4 Public Policy Requirements, Objectives and Other Appropriation Mandates.

Recipients are responsible for ensuring that their activities comply with all applicable federal regulations.  NIH may terminate awards under certain circumstances.  See 2 CFR Part 200.340 Termination and NIH Grants Policy Statement Section 8.5.2 Remedies for Noncompliance or Enforcement Actions: Suspension, Termination, and Withholding of Support. 

Successful recipients under this NOFO agree that:

Where the award funding involves implementing, acquiring, or upgrading health IT for activities by any funded entity, recipients and subrecipient(s) are required to: Use health IT that meets standards and implementation specifications adopted in 45 CFR part 170, Subpart B, if such standards and implementation specifications can support the activity.  Visit https://www.ecfr.gov/current/title-45/subtitle-A/subchapter-D/part-170/subpart-B to learn more.

Where the award funding involves implementing, acquiring, or upgrading health IT for activities by eligible clinicians in ambulatory settings, or hospitals, eligible under Sections 4101, 4102, and 4201 of the HITECH Act, use health IT certified under the ONC Health IT Certification Program if certified technology can support the activity. Visit https://www.healthit.gov/topic/certification-ehrs/certification-health-it to learn more.

Pursuant to the Cybersecurity Act of 2015, Div. N, § 405, Pub. Law 114-113, 6 USC § 1533(d), the HHS Secretary has established a common set of voluntary, consensus-based, and industry-led guidelines, best practices, methodologies, procedures, and processes.

Successful recipients under this NOFO agree that:

When recipients, subrecipients, or third-party entities have:

1. ongoing and consistent access to HHS owned or operated information or operational technology systems; and 
2. receive, maintain, transmit, store, access, exchange, process, or utilize personal identifiable information (PII) or personal health information (PHI) obtained from the awarding HHS agency for the purposes of executing the award.

Recipients shall develop plans and procedures, modeled after the NIST Cybersecurity framework, to protect HHS systems and data. Please refer to NIH Post-Award Monitoring and Reporting for additional information. 

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 (HHS) grant administration regulations at 2 CFR Part 200, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the recipients 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 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 recipients for the project as a whole, although specific tasks and activities may be shared among the recipients and NIH as defined below.

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

• Accepting and implementing the goals, priorities, protocols, procedures, and policies agreed upon, including methods and requirements recommended by a Data and Safety Monitoring Board (DSMB) (see below), and handling of data, including appropriate sharing of methods and data with the community
• Arranging appropriate approvals (when necessary) from the Food and Drug Administration (FDA) with respect to the use of investigational interventions
• Preparing the protocol and other study related documents for a clinical trial supported by NIDCD (only one clinical trial may be proposed per application)
• Using the Clinical Trial Protocol Template for Phase 2 and 3 IND/IDE Studies developed by the FDA and NIH (NOT-OD-17-064) to prepare the protocol
• Completing the full clinical trial protocol and informed consent which will be subject to review and acceptance by NIDCD
• Ensuring that activities not related to the scope of the NIDCD funded project are not included in the protocol
• Being aware that the clinical trial protocol and informed consent will also be subject to review by a DSMB, if one is established for the study, in an advisory capacity only
• Preparing, managing and ensuring all pre-implementation requirements are acceptable to NIDCD and completed in a timely manner prior to enrolling participants
• Providing to NIDCD the required pre-implementation documents including, but not limited to, the establishment of a DSMB & charter, development of quality management standard operating procedures, study staff training log, site initiation visits, development of trial case report forms, confirmation of study intervention procurement, preparation of the Statistical Analysis Plan detailing analysis methods necessary for the clinical trial as well as the Manual of Procedures (MOP)
• Ensuring upon implementation of the protocol, each field center (whether a single institution or a consortium of institutions), follows the procedures required by the protocol regarding study conduct and monitoring, patient management, data collection, and quality control
• Maintaining the recruitment progress (including recruitment of women, children, and specific minority groups), safety, indices of quality control, and related operational features and reporting at regular intervals to the NIDCD Project Scientist/Medical Officer
• Monitoring and maintaining appropriate records for protocols, informed consents, assurances, and annual certifications of Institutional Review Board (IRB) review and approvals for protection of human subjects and confidential information obtained by laboratories or data collected for the clinical trial
• Managing the clinical trial recruitment, assessment, data collection, and analysis functions
• Managing subsites including development of a contingency plan to evaluate performance and phase out of poor performing and/or unproductive subsites
• Assuming accountability to the applicant organization officials and to the NIDCD for the performance and proper conduct of the activities supported by the U01 in accordance with the terms and conditions of the award
• Assuming responsibility for implementing and reporting of the DSMB and the NIDCD recommendations to their Institutional Review Board.
• Managing involvement of industry or any other third party in the study. Except for licensing of patents or copyrights, support or involvement of any third party will occur only following notification of and concurrence by the NIDCD
• Making all study materials and procedure manuals available in the public domain. The awardee(s) is expected to publish and publicly disseminate results, data, and other products of the study, concordant with governance policies and protocols
• Ensuring that publications and oral presentations of work performed under this agreement acknowledge support by the NIDCD/NIH. The awardee(s) will register the clinical trial prior to enrollment of the first subject on the ClinicalTrials.gov protocol registration information website: https://clinicaltrials.gov/ (https://clinicaltrials.gov/)
• Recipients(s) will retain custody of and have primary rights to the data and software developed under these awards, subject to Government policies regarding rights of access consistent with current DHHS, PHS, and NIH policies.

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

• The NIDCD will designate staff, including a Program Officer (PO) and a Grants Management Specialist to provide normal stewardship and administrative oversight of the cooperative agreement; these two contacts will be named in the Notice of Grant Award
• An NIH Program Official within NIDCD will be designated as Project Scientist/Medical Officer for the clinical trial and will have substantial scientific programmatic involvement during conduct of this activity, through technical assistance, data sharing and analysis, composition of reports, and advice and coordination

The NIDCD Project Scientist/Medical Officer:

• Convenes an initial meeting with the PI and team, and the Program Officer as an observer
• Has shared responsibilities in managing and sharing the broad clinical trial issues of the clinical trials, although the awardee has lead responsibilities in specific tasks and activities
• Has access to data generated under this Cooperative Agreement and periodically may review the data and progress reports
• NIDCD staff including the project scientist may use information obtained from the data for preparation of internal reports of the activities of the study; serves as a resource to provide scientific/programmatic support by participating in the design of the activities, advising in management and technical performance, or participating in the preparation of publications
• Reviews, with the Program Officer, the annual or more frequent reports on progress of research activities
• Reviews the progress of the study, and of each participating facility, through consideration of the annual reports, routine reports, site visits, patient logs, etc.
• This review may include but is not limited to, compliance with the study protocol, meeting patient enrollment and milestones targets, adherence to uniform data collection procedures, the timeliness and quality of data reporting, and adequacy of adverse event management and reporting

The NIDCD reserves the right to adjust funding, withhold support, suspend, terminate or curtail a study or an award in the event of a failure to comply with the Terms and Conditions of Award; lack of adequate data reporting or quality control; other major breach of scientific conduct; or human subject ethical issues, whenever applicable.

Data Safety and Monitoring Board:

An independent Data and Safety Monitoring Board (DSMB) will be established jointly by the PI(s) and NIDCD. The DSMB will review interim results periodically as established in the data and safety monitoring plan and report to the NIDCD Project Scientist. The DSMB will report in writing the recommendations of the DSMB to the NIDCD Project Scientist. A summary report that does not contain confidential information will be prepared by the DSMB and distributed to the Principal Investigator (PI). NIDCD will determine concurrence/nonconcurrence of the DSMB recommendations. The PI(s) will assume responsibility for implementing and reporting of the DSMB and the NIDCD recommendations to their Institutional Review Board.

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 agreed upon by the PIs of the grant, 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 recipient. This special dispute resolution procedure does not alter the recipient's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16, other major breach of scientific conduct; or human subject ethical issues, whenever applicable.  

Publications and oral presentations of work performed under this agreement will require appropriate acknowledgment of support by the NIDCD/NIH. The recipient(s) will register the clinical trial prior to enrollment of the first subject on the ClinicalTrials.gov protocol registration information website: https://clinicaltrials.gov/ (https://clinicaltrials.gov/).

Consistent with the 2023 NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

4. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement Section 8.4.1 Reporting. To learn more about post-award monitoring and reporting, see the NIH Grants & Funding website, see Post-Award Monitoring and Reporting.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement Section 8.6 Closeout. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 2 CFR Part 200.301.

Section VII. Agency Contacts

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: https://www.era.nih.gov/need-help (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-480-7075

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

Amy Poremba, Ph.D.
National Institute on Deafness and Other Communication Disorders (NIDCD)
Telephone: 301-997-3152
Email: [email protected]

Melissa Stick, Ph.D., MPH
National Institute on Deafness and Other Communication Disorders (NIDCD)
Telephone: 301-496-8683
Email: [email protected]

Samantha Tempchin
National Institute on Deafness and Other Communication Disorders (NIDCD)
Telephone: 301-435-1404
Email: [email protected]

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.

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 2 CFR Part 200.