HEAL KIDS (Knowledge, Innovation and Discovery Studies) Pain Program: Frequently Asked Questions

What are the roles of the various NIH institute program staff in this initiative?

NICHD is the administrative lead for these two Notices of Funding Opportunities (NOFOs). Our institute partners will serve as Project Scientists and experts for programmatic review, as needed, and as Project Scientists for awards where relevant applications are assigned.

Can you please explain a cooperative agreement and the mechanisms according to the NIH?

A cooperative agreement is a grant mechanism that usually supports large-scale clinical research and projects. NIH staff are usually substantially involved in cooperative agreements, including a Project Scientist, who is involved in the scientific aspects of the program, and a Program Officer, who oversees the administrative and financial functions of the project. The “U” in the mechanism denotes a cooperative agreement. Details on different grant mechanisms are available at Types of Grant Programs.

Can NICHD Project Scientists for the cooperative agreements be contacted prior to submission to assist with preparation of the application?

No. The role of the Project Scientist does not begin until the grant has been awarded. NICHD program staff may answer questions and provide general guidance to applicants prior to submission but may not participate in the actual development of specific applications.

Can one institution apply to be a U01 clinical trial site as well as the U24 RDC?

A single institution may apply for both the U01 clinical trial award and the U24 RDC award. However, the Principal Investigator (PI) and team for each application must be separate and distinct. For example, the PI for the U24 application cannot be listed as a PI or Senior/Key Personnel for the U01 application. This restriction attempts to mitigate conflict of interest between the RDC and individual clinical trial teams.

Is a Letter of Intent required? If yes, when is it due?

No, a Letter of Intent is not required, is not binding, and does not enter into the review of a subsequent application. However, the information contained in the Letter of Intent allows NICHD staff to estimate the potential review workload and plan the review. The Letter of Intent is due by October 20, 2023, to Tammara Jenkins ([email protected]).

What are the best times to reach out to an NIH Program Officer to discuss a grant application – before or after the Letter of Intent?

NIH staff are committed to supporting investigators in identifying research priorities and helping to clarify funding opportunity goals. While the research design is solely the decision of the investigator, NICHD program staff can help investigators align with priorities of the NOFO. It is in the investigator’s best interest to contact program staff as early as possible in the development of proposals.

Can the Multiple PI (MPI) option be used for this application?

Yes, the MPI option may be used. We recommend that applicants follow the MPI instructions in the SF424 (R&R) Application Guide in conjunction with NOFO-specific language. Additional information on the implementation plans, policies, and procedures to allow more than one PI on individual research projects are available at https://grants.nih.gov/grants/multi_pi.

Can the same PI be an MPI on both a U01 application and a U24 application?

No, a single individual (PI) may not be listed as a PI/MPI or Senior/Key Personnel on both a U01 and a U24 application. 

Why is the total funding period 5 years for the U01 Clinical Trials, but 6 years for the RDC?

As outlined in the RFAs, the maximum project period for the U01 APCT awards is 5 years, while the maximum project period for the U24 RDC award is 6 years. This difference allows for additional time after the completion of the clinical trials for activities such as data curation, submission to the requisite HEAL data repository, and other program requirements specific to HEAL that fall under the responsibility of the RDC.

Can you describe the HEAL Common Data Elements (CDE) requirements?

Use of CDEs make it easier to consistently code and harmonize data across studies in a way that is cost-effective and efficient and provides rapid access to data. Information regarding the use of CDEs in HEAL-funded projects and requirements for applicants are outlined both in the RFA as well as at the HEAL Initiative webpage at https://heal.nih.gov/data/common-data-elements.

I am an appointed study section member with continuous submission privileges. Does that apply to this RFA?

No. Continuous submission only applies to R01s, R21s, and R34s submitted to NOFOs using standard due dates. This RFA does not use any of these mechanisms and does not use standard due dates; therefore, applications are not eligible for continuous submission.

Will the Technical Assistance webinar be recorded and available online after completion?

Yes, the complete session will be recorded and posted on the NIH Videocast website (https://videocast.nih.gov) a few days after the webinar. In addition, the HEAL KIDS Pain RFA information, slides, and FAQs will be posted on the HEAL KIDS Pain technical assistance webinar page.

Will the applications be reviewed in a standing NIH study section?

No. This RFA will be reviewed in a Special Emphasis Panel (SEP) convened by the review staff of the NIH Center for Scientific Review.

Please clarify: if the data should be submitted into HEAL-approved repositories, is there some expectation that the RDC will also be responsible for storing clinical data?

There is no expectation that the RDC will store clinical data. A Clinical Trial Data Coordinating Center (DCC) will be responsible for collecting and storing data during the trials, as well as working with the RDC to ensure data harmonization. At the completion of a clinical trial, the DCC will collaborate with the RDC to prepare the public-use datasets, ensuring the data are de-identified and have all necessary documentation, and will then submit the data to the approved HEAL repository. The RDC will provide support to the DCC and ensure the de-identified data are accessible to researchers.

What is the purpose of this Notice of Funding Opportunity (NOFO)?

The purpose of this funding announcement is to invite applications support innovative, groundbreaking, large-scale, multisite clinical trials.  The clinical trials should seek to establish or implement systematic and/or multimodal approaches for the diagnosis, assessment, and effective treatment of acute pain, including acute flares of chronic pain, for pediatric patients across the continuum of care (including pre-hospital settings, outpatient clinic or urgent care, emergency departments, neonatal and pediatric intensive care units, dental care settings and acute care/hospital facilities).

The RFA states “Applicants from institutions that have a CTSA funded by NIH should plan to access a National Center for Advancing Translational Sciences' Trial Innovation Network (TIN) (https://trialinnovationnetwork.org),” Please explain how CTSAs should “plan to access” NCATS’ TIN.

There are several references to the Clinical and Translational Science Awards (CTSAs) and the NCATS Trial Innovation Network (TIN). The references to these programs in the Notice of Funding Opportunity were intended only to provide a suggestion for applicants with CTSAs to seek SCIENTIFIC resources to assist in the design and implementation of clinical trials. The references were NOT meant to suggest, nor do they obligate, any financial resources from a CTSA or TIN to an applicant of this NOFO. A CTSA or TIN may help a funded investigator find additional clinical sites interested in participating, but they are not required to work with any specific trial. The burden is on the applicant to include all funding to pay sites for participating in a clinical trial, and to pay for all data and clinical coordination. The CTSAs and TINs are under no obligation to provide financial resources to applicants. If a CTSA and/or TIN does agree to provide resources to a trial, the PD/PI of the CTSA and/or TIN should provide a letter stating what will be provided if the application is funded.

Eligibility, Investigators, Sites

Is more than one (1) U01 application allowed by a PI?

Yes, as stated in the RFA Section III.3 Additional Information on Eligibility: “Applicant organizations may submit more than one application, provided that each application is scientifically distinct.”

I recently submitted an R01 on the same topic as our application. Can I include any part of that project in the U01 application?

No. NIH policy states that you cannot have duplicate or highly overlapping applications under review at the same time. An application is considered “under review” until the summary statement is issued.

What is the role and function of the U01 DCC? How will DCCs collaborate with the U24 RDC?

The U01 DCC will function as the primary center for day-to-day operations and for overall study coordination and quality assurance for a proposed trial within a single U01 clinical trial award. Functions may include:

• Developing data forms, protocol tools, and data management systems for study coordination, protocol development, data integrity, data quality assurance, and study safety reporting
• Providing biostatistical expertise for sample size calculations and other statistical advice and support, and computer programming for electronic data capture and other protocol tools
• Performing data analysis for monitoring, regulatory submissions, and study publications
• Developing a Data and Safety Monitoring (DSM) Plan including designating a DSM Board (DSMB), single Institutional Review Board (sIRB) activities, and Food and Drug Administration (FDA) Investigational New Drug (IND) or Investigational Device Exemption (IDE) management
• Initiating and implementing subcontracts for participating clinical sites for management of capitation funds

U01 DCCs will work collaboratively with the U24 RDC in several ways. First, the RDC will be responsible for organizing an Executive Committee (EC) to determine prioritization activities across the HEAL KIDS Pain Program. Members of the U01 DCCs will participate in this EC, as well as other HEAL KIDS Pain program meetings, workshops, etc. Additionally, each U01 clinical trial must budget for a Program Manager (for applications proposing two or more subawards), who shall coordinate between sites, between the NIH and the lead site, and between the project team sites, DCC, and the RDC. Similarly, the U24 applicants must also budget for a Project Manager to serve as a liaison to the APCT clinical trial teams.

How do applicants confirm that their application goes to the correct NIH Institute?  Do applicants need to request a specific study section?

The Division of Receipt and Referral (DRR), Center for Scientific Review (CSR) is responsible for assigning applications to NIH Institutes and Centers. The PHS Assignment Request Form is optional and may be used to communicate specific application assignment and review preferences to the DRR.  Preferences regarding Institute/Center assignment should be based on (1) the Institutes and Centers listed on the NOFO, and (2) the scientific focus of the application. This information will not be part of your assembled application, and it will neither be made available to program staff nor provided to reviewers.

DRR also assigns applications to NIH Scientific Review Groups (SRGs) and Special Emphasis Panels (SEPs). For applications submitted in response to this NOFO, a Special Emphasis Panel will be convened by the Center for Scientific Review (CSR) to conduct the review. As such, the applicant does not need to request a specific review panel.

Do all the members of the steering committee need to be identified and have committed to participating by the time the grant is submitted on November 20?

No, specific members do not need to be named in the Steering Committee (SC) plan, but rather a description of the general membership of the proposed SC, along with a plan for how the SC will function.  Of course, specific individuals may be named, if available.

Please explain who the “representative from the government” will be for the Steering Committee.

The “representative from the government” will be the Project Scientist and/or Project Officer for the grant as discussed in the Cooperative Agreement guidelines.

The NOFO states that the SC should be comprised of at least 3 people.  Please explain how many people should be in a SC of this nature.

The NOFO provides a minimum required membership, but applicants are expected to delineate the number of people and roles necessary to satisfactorily complete the business of the clinical trial. Typically, a PI from each clinical site will participate in the SC, as well as the DCC PI, SC Chair, NIH Project Scientist/Program Officer, and others.

There is another statement in the NOFO referring to a “Clinical Trial Protocol Steering Committee.”  Is this the same as the Steering Committee already mentioned?

Yes, there is only a need for 1 (one) Steering Committee per clinical trial. The “Clinical Trial Protocol” part of the name was capitalized in error in the NOFO. It refers to the SC for the clinical trial protocol.

Award Information

How many clinical trial awards will be made?

The NIH expects to award between 3 and 5 U01 awards in response to this NOFO.

The NOFO says that the NIH HEAL Initiative “intends to commit an estimated total cost of $11,000,000 to fund up to 3 to 5 awards in FY 2024.” Is that the amount for the entire funding cycle or per year? Does the amount span the entire 5 years of the award? Does the amount include indirect (F&A) costs? How does the funding get divided amongst the clinical sites and DCC?

The dollar amount indicated is the committed funds for fiscal year 2024, intended to cover all awards, including direct plus indirect costs. Because future budget years have yet to be approved by Congress, the amounts only represent funds for the initial award year. However, as with other NIH NOFOs, the expectation is that comparable funding will be available for the non-competing years of each award.

An applicant for a U01 clinical trial may request a budget for direct costs up to $2,100,000/year. Each U01 applicant will be responsible for developing a budget and subcontracting system to allow for adequate funding for each clinical site and the DCC.

Can the whole project be less than five (5) years?

Yes, the maximum project time is 5 years, but there are no other time limits delineated in the RFA. However, applicants will be required to include a timeline for pertinent study milestones and demonstrate how they will be able to meet the milestones within the expected time period (e.g., demonstrate how a large-scale multisite clinical trial will be completed in less than 5 years).

For this grant, what is meant by multisite?

A multisite clinical trial involves implementation of the same clinical protocol at two or more independent investigational sites, where participants are enrolled for an intervention and/or outcomes assessment. Multiple sites are generally required for large-scale clinical trials, especially pediatric clinical trials, because single center/site trials often are unable to enroll enough subjects to allow for extrapolation of data or generalizability of study results. Additionally, the use of multiple sites enhances the ability to recruit more diverse study populations, and in a shorter time due to the heterogeneity of pediatric populations at most clinical sites.

How many multicenter trials are allowed per U01?

Technically, an applicant may submit as many clinical trials within a single application as the $2.1 M direct cost will allow. However, applicants should be mindful of the overall intent of the NOFO to address large-scale, multisite clinical trials that have the potential to provide impactful outcomes.

Is there a minimum or maximum number of clinical sites required for the multi-site trial?

The minimum number of clinical sites required is two (2); single site trials are not allowed. There is no maximum number of clinical sites required or designated in the RFA. The number of clinical sites should be determined by the necessary sample size, the population available at each site, etc. Remember that the RFA is seeking large-scale, multisite clinical trials that, when completed, will provide the necessary data to move the field of pediatric acute pain research forward.

Can an individual site be part of a main hospital network, but geographically different with separate administrations?

Yes, individual sites that are geographically and administratively distinct may be considered separate clinical sites for the purposes of multisite.  

Please define how “independent” the DCC should be? Can a DCC at the primary U01 clinical site lead the DCC?

The DCC must be at a separate institution from the institutions participating as clinical sites in the clinical trial. As the NOFO states, existing networks with experienced clinical trial investigators and DCCs potentially positioned for this research are encouraged to apply. A DCC that is part of an established clinical research network is acceptable, as long as it is a separate entity and is not a site that is recruiting research participants.

Research Plan/Application

If more than one clinical trial is allowed, is the Research Strategy page limit of 12 pages just for 1 clinical trial or for all clinical trials within the U01 application?

The page limit for the entire Research Strategy section of the application is 12 pages, regardless of the number of clinical trials incorporated into the application. Applicants are reminded that all limitations described in the SF424 Application Guide, and that the Table of Page Limits must be followed. Failure to follow page limits or attempting to circumvent page limits will be grounds for rejecting an application.

What is the definition of “large-scale” studies for this RFA (i.e., effect size, sample size, etc.)?

There is no specific definition of what constitutes a “large-scale” study for this RFA. Typically, a large-scale clinical trial recruits a few hundred to a few thousand participants and is often at the level of a Phase III clinical trial to measure efficacy and effectiveness. The study should be robust and well-powered, so that, when concluded, it can provide data to strongly influence changes in clinical practice and inform clinical practice guidelines.

Are clinical trials that are observational in nature, such as looking at standard of care interventions for a pediatric cohort, acceptable?

According to the NIH definition of a clinical trial, a purely observational study would not be considered a clinical trial and, therefore, would not acceptable for the U01 RFA, which is clinical trial required. At least one study record in the application (e.g., one aim, etc.) must meet the definition of a clinical trial for an application to be acceptable.  

What is the page limit for the DCC part of the application? Is this a separate document from the Strategy section? Is it not in the instructions?

The instructions for discussing the DCC capabilities are in Section IV. Application and Submission Information>2.Content and Form of Application Submission>SF424(R&R) Other Project Information>Other Attachments>2. Data Coordinating Center (DCC) Capabilities. Documents requested in the “Other Attachments” section of the grant applications are not subject to page limitations. As instructed, the filename for the “DCC Capabilities.pdf” should be used in the application, and all other attachments should use the filename delineated in the instructions.

Can you clarify the following: “Research testing behavioral interventions to manage pain as the primary outcome will not be considered as high priority”?

Research testing that solely tests behavioral interventions to manage pain as the primary outcome will not be considered high priority for this RFA. Trials that test behavioral interventions for pain management already exist. For information on currently funded trials, please refer to the HEAL Initiative Funded Projects webpage and/or ClinicalTrials.gov.

NOTE: Trials that include behavioral interventions as standard of care and trials that include behavioral interventions studied in conjunction with other pharmacological or physical interventions may be of interest.

What is the purpose of this RFA?

The purpose of this NOFO is to invite applications for a single HEAL KIDS Pain RDC to provide the following: (1) leadership in data collection and management, data curation, data harmonization, and development and/or leveraging of relevant data standards; (2) administrative and logistical support including oversight of NIH HEAL-related requirements; (3) coordination of shared research-related resources for all HEAL KIDS Pain research activities; and (4) facilitating submission of data to HEAL-compliant data repositories and registering study level metadata with the HEAL Data Platform.

Functionally, the RDC will:

• Foster communication and collaboration across the APCT Program via the administrative coordination infrastructure
• Ensure high-quality data capture and exploration
• Maximize data comparability and harmonization
• Develop research skills in data science innovation

What is the most important part of the RDC’s scope?

The most important parts of the RDC scope are: (1) curating and harmonizing data elements across the research projects; (2) working with the DCCs to further develop their research projects; and (3) managing data sharing plans.

Eligibility, Investigators, Sites

Does the U24 allow/prefer the clinician scientist to be co-MPI to provide clinical perspectives?

The RFA does not indicate the need for a clinician scientist.  However, it does specify that experience and/or expertise in large scale, multisite pediatric clinical trials and the unique aspects of conducting research in the pediatric population is preferred. Of course, the addition of a clinical scientist as an MPI would be allowed.

Award Information

The NOFO says that the NIH HEAL Initiative “intends to commit an estimated total cost of $1,000,000 to fund up one award in FY 2024.” Is that the amount for the entire funding cycle or per year? Does the amount span the entire 6 years of the award? Does the amount include indirect (F&A) costs?

The dollar amount indicated is the total committed funds for fiscal year 2024, intended to cover all the RDC award, including direct plus indirect costs. Because future budget years have yet to be approved by Congress, the amounts only represent funds for the initial award year. However, as with other NIH NOFOs, the expectation is that comparable funding will be available for the non-competing years of each award.

An applicant for the U24 RDC may request a budget for direct costs up to $600,000 per year. The maximum project period for the U24 is 6 years, which differs from the U01 APCT program. The difference allows for additional time at the completion of the clinical trials for activities such as data curation and submission to the requisite HEAL data repository, etc.

Research Plan/Application

Is there a page limit on the RDC Experience Attachment?

As stated earlier, attachments included under the “Other Attachments” section of the application (Section IV. Application and Submission Information>2.Content and Form of Application Submission>SF424(R&R) Other Project Information>Other Attachments) are not subject to page limits.

Is the HEAL Public Access and Data Sharing Policy (Attachment 3 in “Other Attachments,” Section 4.2 Other Project Information) a separate document from a Data Management and Sharing (DMS) Plan (addressed in “Other Research Plan Section” in Section IV?

Yes, they are separate areas to be addressed in the application. Attachment 3: HEAL Public Access and Data Sharing Policy requires the applicant to address the specifics of the HEAL policy. Guidelines for complying with the HEAL Public Access and Data Sharing Policy are available at https://heal.nih.gov/data/complying-heal-data-sharing-policy. Resources and tools to assist with data related activities can be found at https://www.healdatafair.org/.  The HEAL Public Access and Data Sharing Policy applies to all NIH-supported NIH HEAL Initiative research projects with resulting publications and underlying primary data, to the extent feasible. The requirements of this Policy are in addition to those requirements and expectations specified under other applicable NIH public access and data sharing policies, including but not limited to the NIH Public Access Policy, the NIH Data Sharing Policy, and the Genomic Data Sharing Policy.

The NIH DMS Plan is not included in peer review and is therefore a separate document. Completion of both plans as instructed in the NOFOs is required. If additional clarification becomes available before the application due date, this question will be updated accordingly in the FAQs.

What is the role of the RDC in developing CDEs for the clinical trials? And is using a questionnaire outside the core CDEs permitted?

The RDC will be responsible for developing and/or recommending CDEs, providing specifications for the use of CDEs across all HEAL KIDS Pain program studies, facilitating harmonization of CDEs across the program studies, and facilitating coordination with HEAL CDE Program Managers as needed (http://www.heal.nih.gov/data/common-data-elements).

As delineated on the HEAL CDE webpage:

If the NIH HEAL Initiative determines that a new supplemental questionnaire should be added, the program managers will create the CDE files containing standardized variable names, responses, coding, and other information. The program will also format the case-report forms in a standardized way that is compliant with accessibility standards under Section 508 of the Rehabilitation Act of 1973 (29 U.S.C § 794 (d)), which “require[s] Federal agencies to make their electronic and information technology (EIT) accessible to people with disabilities.”

The HEAL CDE Program will also ask for 1) a reference for the Case Report Form (CRF), 2) if applicable, instructions about how to score the questionnaire, and 3) a copy of the questionnaire.