ENRICH - Frequently Asked Questions
Slides from April 12th Webinar Available Here.
A1. These Funding Opportunity Announcements (FOAs) invite applications for: a) clinical or community sites under RFA-HL-22-007 and b) a Resource and Coordinating Center (RCC) under companion FOA RFA-HL-22-008, which together will work with NIH project office staff in conducting a large multi-center group- or cluster-randomized trial under the Early Intervention to Promote Cardiovascular Health of Mothers and Children (ENRICH) program. Awards made under RFA-HL-22-007 will test the effectiveness of an implementation-ready intervention at multiple sites within the United States to determine if a cardiovascular health (CVH) module delivered within the context of a home visiting program can enhance maternal and early childhood CVH. Clinical sites will work collaboratively with other awardees in the FOA, as well as with the RCC that is under companion FOA RFA-HL-22-008. The goal of ENRICH is to promote CVH and address CVH disparities in both mothers and children (0-5 years old) who are of low socio-economic status, live in low-resource rural or urban communities, or who are in diverse geographic regions of the United States with a high burden of cardiovascular disease (CVD) risk factors.
Q2. What is a "multi-site" (as opposed to a "single-site") clinical trial for the purpose of these FOAs?
A2. A multi-site clinical trial involves the implementation of the same clinical protocol at two or more independent investigational sites where participants are seen for an intervention and/or outcomes assessment. In a multi-site trial, investigational sites are typically administratively or corporately distinct from each other. More information can be found here: https://www.nhlbi.nih.gov/grants-and-training/funding-opportunities/foa-Investigator-Initiated-Multi-Site-Clinical-Trials-FAQ. In the ENRICH trial, participating mother-and-child dyads will receive a common intervention and/or outcomes assessment across these sites.
Q3. Must each submitting institution partner with a home visiting institution prior to submission?
A3. As stated in the FOA RFA-HL-22-007, "investigators must partner with at least one evidence-based home visiting program to gain access to evidence-based home delivery programs and must obtain approval for any adaptations or enhancement to an evidence-based home visiting model". Also as stated in the FOA, "applications must include letter(s) of support from collaborating home visiting organization or partners, and other relevant entities (e.g., Native American Tribal Organizations, Federally recognized tribal governments) and their relevant commitment to participate. Letters must specify the in-kind resources that will be used to compensate home delivery staff. Applications without the required letter(s) of support will not be reviewed. If partial funding is to be provided by sources other than NHLBI, provide letter(s) of support from the source(s) signed by an authorized representative."
Applicants are not required to show partnership with other applicant institutions (e.g., universities) who are applying to the RFAs.
RFA-HL-22-007 uses the UG3/UH3 mechanism, which is a bi-phasic, milestone-driven cooperative agreement mechanism. It is indeed also expected that multiple clinical/community sites that receive the UG3 awards will work together with the ENRICH Resource and Coordinating Center (RFA-HL-22-008) and NIH project office staff to develop one common protocol (including study design, analytic plan, sample size) to be used across multiple sites in the UH3 phase. Applicants will be expected to use information gathered in the UG3 phase, including findings from feasibility and pilot studies, and submit proposals to inform the common protocol, including the testing of intervention, for the UH3 phase.
Q5. Can applicants work with more than one evidence-based home visiting program in order to obtain the required sample size?
A5. Yes, applicants may work with more than one evidence-based home visiting program. At a minimum, applicants must partner with at least one evidence-based home visiting program.
RFA-HL 22-007 states the following under "Specific Areas of Research" (Part 2., Full Text of Announcement):
Investigators are expected to conduct research to accomplish the following:
- Identify clearly-defined study population(s) that include at-risk mother and child (e.g., low SES, low-resource rural or urban communities, or populations residing in diverse geographic regions of the U.S. (e.g., South Eastern, Stroke Belt, Mississippi Delta, Appalachia) or those with high burden of CVD risk factors (obesity, hypertension, diabetes); or those with risk of developing pre-eclampsia or gestational diabetes.
- Design and implement interventions which enhance ongoing evidence-based home visiting programs to test implementation-ready approaches and examine their impact on CVH measures in mother and child, including a focus on mediators and moderators of the intervention effect (e.g., social determinants of health indicator such as access to healthcare).
- Support skills development of home-visiting staff professionals and at least one ESI, particularly those underrepresented in biomedical research, in life-course approaches, intervention methods, adherence to prevention and treatment recommendations by team-based approaches involving the health care team, and implementation science focused on preserving and promoting ideal CVH.
- Leverage evidence-based home visiting models (https://homvee.acf.hhs.gov/HRSA-Models-Eligible-MIECHV-Grantees) that have been ascertained as meeting the HHS established criteria of evidence of effectiveness including the following:
- Evidence of HHS support of home visiting staff to implement interventions in the home.
- Assessed as moderate or high-quality impact using evidence-based criteria
- Favorable impact on primary and secondary health outcomes as defined by Home Visiting Evidence of Effectiveness (HomVEE) review (https://homvee.acf.hhs.gov/)
- Favorable sustained impacts >1-year post program inception on maternal or child health outcomes
- Favorable impacts on maternal or child health that have been replicated
Investigators must partner with at least one evidence-based home visiting program (i.e., local implementing agency) to gain access to evidence-based home delivery programs, and must obtain approval for any adaptations or enhancement to an evidence-based home visiting model. Investigators must leverage in-kind support already provided by HHS to local implementation sites for the home visiting program.
Q6. Are studies allowed to recruit from clinical settings or only through home visiting programs?
A6. It is strongly recommended that applicants work with evidence-based home visiting programs. However, applicants may work with home visiting models that have not yet been determined by HomVEE (https://homvee.acf.hhs.gov/) to meet HHS criteria for evidence of effectiveness as long as they adhere to the established evidence-based criteria in the FOA, provide compelling justification for their proposed inclusion, and obtain approval from supporting agencies along with a commitment of in-kind support for the home-based programs in the trial.
Q7. Is it a requirement in the UG3 phase that the awardees agree upon and then pilot test one common intervention across sites?
A7. There is not a requirement that awardees in the UG3 phase pilot test one common intervention across sites. Instead, several pilot tests are anticipated, as part of an overall iterative process to help inform the successful design of a common protocol for the UG3 phase. The pilot tests for the common protocol are expected to be developed collaboratively by the clinical/communities site awardees, the Resource and Coordinating Center (RCC) investigators that are awarded under RFA-HL-22-008, and the NIH project team, and approved by the ENRICH Steering Committee. These tests will address various aspects under consideration for inclusion in the common protocol in the UH3 phase such as recruitment strategies and intervention components. During the UG3 phase, strong partnerships with the evidence-base home visiting programs will be further enhanced. Training of the trial staff for the UH3 phase may also begin in the UG3 phase.
U24 RCC-related Questions:
Q8. My University will be submitting two applications (UG3/UH3 and U24 with different PIs). Would it be a problem if there are some key personnel on the UG3/UH3 also on the U24 or vice versa?
A8. With respect to overlapping personnel, make sure the levels of effort and actual duties on both applications do not show that someone is receiving funds twice for the same work to be completed.
Q9: What is expected of RCC during the UG3 phase vis-a-vis ENRICH Multisite Clinical Centers?
A9. Some highlights of Years 1-2, which are listed in the RFA HL-22-008 include (but not limited to the following):
- Develop a coordinating structure to support clinical center functions
- Convene clinical sites and foster collaboration and communication
- Facilitate development of a common protocol for the UH3 phase
- Intervention, study design, analytic plan, sample size, common data elements etc.
- Coordinate the approval of protocol by NHLBI-appointed DSMB
- Train staff on common protocol
- Facilitate pilot testing of components of the common protocol
- Develop and implement data collection procedures
- Skills development training for Early Stage Investigators (ESIs), home-visiting staff & Other study staff
Note these activities must be milestone driven. See Section I. Funding Opportunity Description in RFA HL 22-008.
Q10. Will the U24 application be an independent application that will not need to be accompanied by a UG3/UH3?
A10. Yes. An institution can submit one or the other or both but they have to be independent of each other.
Q11. How do roles of the proposed Resource Coordinating Center (RCC, U24) relate to roles for Clinical or Community Sites (CC, UG3/UH3)?
A11: The roles for the RCC are distinct from the roles of the clinical centers. Data analysis is by the RCC at the UH3. Statisticians from both the RCC and the CCs will provide input in the UG3 phase and in the design of the common protocol. Data analysis of common data will come from the RCC. Please also refer to A9 (answer to Q9) for some highlights of functions for the RCC relative to the CCs.
Q12: Is the common database implemented in the UH3 phase the only database the RCC is expected to implement?
A12. Yes. The RCC must be able to transfer data collected at clinical sites into a database that holds all data for ENRICH. It is possible other databases may be discussed during the first 1-2 years. During the UH3 phase, one database by RCC should manage data for the pilot studies as well. The CCs may also analyze data in coordination with the RCC and their own data if they have the resources.
Q13. Do you expect the common protocol will require an FDA compliant database?
A13. No, we do not expect the trials will use FDA regulated product that require IND or IDE application or FDA compliant database.
Q14. What are some examples of expected skills for ESIs and home visiting professional staff that should be fostered and that the RCC is expected to play a major role in development?
A14. We expect that skills training of ESIs and Home Visiting Professional staff would include aspects of the study protocol, for examples: data collection and measurement, and intervention. In particular for ESIs, we expect the RCC to provide skills development that would support their growth as independent researchers. Examples would include the ENRICH protocol and study design, clinical trial implementation, blinding of the study population, etc. We also expect the RCC to foster ESI career development. An example would be to encourage their first- or co-authorship of peer-reviewed publications in scientific journals.
Q15. Why is clinical trial required indicated in the U24?
A15. It is an infrastructure set-up (similar to the multi-site clinical trial FOAs) – PAR-19-329 and PAR-19-330 (collaborative U24 clinical trial required).
Q16: Please clarify if the ENRICH sites are expected to deliver the intervention prenatally, starting in early pregnancy.
A16: Yes, we expect the intervention to begin early in pregnancy and/or early postpartum. As stated in the RFA, "Many [evidence-based] home visiting models are designed to begin during pregnancy or shortly after birth and typically continue through early childhood, up to 5 years old." Thus, we expect applicants to target pregnant women early in the pregnancy to the extent possible within their localities. In some cases, applicants may have access to mothers and children during the postpartum and that is also acceptable
Q17: Will interventions beginning in the pre-conception period be permissible under this RFA?
A17: Interventions beginning at pre-conception are not permissible under this RFA. We expect applicants to target pregnant women early in their pregnancy. Applicants may use other FOAs such as the NHLBI PAR 19-328, Single-Site Investigator-Initiated Clinical Trials (R61/R33 Clinical Trial Required) https://grants.nih.gov/grants/guide/pa-files/PAR-19-328.html or the Multi-Site Investigator-Initiated Clinical Trials (Collaborative UG3/UH3 Clinical Trial Required) https://grants.nih.gov/grants/guide/pa-files/par-19-329.html.
Q18: Is it appropriate for clinical centers to have expertise in interventions to promote cardiovascular health in mothers or children or is expertise for interventions for both recommended?
A18: Clinical center applicants must have expertise in the research that is commensurate with their intervention approach. Because both mother and child are to be intervened on, we recommend that applicants include personnel that have expertise in interventions to promote cardiovascular health in both mother and child.
Q19: Is the purpose of the UG3 phase to conduct a feasibility test of an 'already developed' cardiovascular health (CVH) promotion module delivered within a home visiting program?
A19: To the best of our knowledge, there are no comprehensive evidence-based CVH modules currently being implemented as part of evidence-based home visiting models. The purpose of ENRICH is to develop and implement such modules and beginning in the UG3 with pilot testing of interventions that could inform the development of a common protocol. Several pilot tests are anticipated, as part of an overall iterative process to help inform the successful design of a common protocol for the UG3 phase. The pilot tests for the common protocol are expected to be developed collaboratively by the clinical/community awardees, the Resource and Coordinating Center (RCC) investigators that are awarded under RFA-HL-22-008, and the NIH project team, and approved by the ENRICH Steering Committee and DSMB. These pilot tests will address various aspects under consideration for inclusion in the common protocol in the UH3 phase such as recruitment strategies and intervention components. During the UG3 phase, strong partnerships with the evidence-based home visiting models and programs will be further enhanced. Training of the trial staff for the UH3 phase may also begin in the UG3 phase.
Q20: Will the awardees collaborate in the UG3/UH3 phase for a sole CVH module to test- or will multiple options exist?
A20: As stated in the FOA (Section 1. Funding Opportunity Description) "During the UG3/UH3 phase, multiple clinical/community awardees that receive the UG3 awards will work together with the RCC (RFA-HL-22-008) and project office staff to develop one common protocol (including study design, analytic plan, sample size) to be used across multiple awardee sites in the UH3 phase. Toward that end, community/clinical awardees may need to conduct pilot studies in Year 2 of this phase to refine the development of the common protocol. Applicants will be expected to submit proposals for the study design and analytic plan to be used in the UH3 to evaluate the intervention and use information gathered in the UG3 phase that would inform the analytic plan for the UH3 phase."
Q21. What is meant by "in-kind" support from HRSA in the RFA-HL-22-007?.
A21. "In-kind" support implies funding support already provided to evidence-based home visiting agencies by HHS (i.e., Maternal, Infant and Early Childhood Home Visiting (MIECHV), Temporary Assistance for Needy Families (TANF), Medicaid). Awardees are encouraged to include sites receiving other forms of federal funding, but should ensure that the activities covered under one type of federal award are distinct from activities covered under this grant. For example, programs receiving MIECHV funds to implement evidence-based home visiting services may not use grant funds under this announcement to support those services.
Q22. Are we allowed to budget effort for home visiting program staff at the State level for assistance with home visiting research expertise into the research budget and for local program staff to attend trainings and deliver intervention components?
A22. Yes. as long as these activities are not already covered with another form of federal funding (i.e., MIECHV, TANF, Medicaid) to avoid duplication of use of federal funds for the same activity.
Q23: Are we allowed to budget for local data management capability including support for a data coordinator, building of a local database, and a local statistician for the duration (UG3/UH3) of the proposal.
A23: Yes, if your budget allows, and a strong justification is provided. Please be aware that we expect the RCC will have a statistician and provide support for a common database that will hold all study data across the sites. We also expect to have data analysis and measurement subcommittee that would consist of statisticians from the Clinical sites and those from the RCC.
Q24. Please clarify "local implementing agency" in the FOA.
A24: A local implementing agency (LIA) is an organization that administers a home visiting program. LIAs are typically local non-profit social service organizations, local public health departments, hospitals, school districts, or Tribal health and human services agencies. Investigators are expected to partner with at least one home visiting program (i.e., local implementing agency) and an expert in CVH interventions. It may be difficult to reach the desired sample size if recruiting through just one local implementation agency; therefore, applicants are encouraged to partner with models, states, agencies, etc. that have more than one site that could participate in the effort. Applicants are expected to gain approval for any adaptations and/or enhancements to an evidence-based home visiting model from the home visiting model developer.
Q25: What sample size should each application power their studies on?
A25: NHLBI expects to have approximately 3,000 mother-child dyads across all six awardee sites in response to the RFA HL 22-007. We recommend that each applicant submit an analysis plan based on approximately 3,000 mother-child dyads for the UH3 phase. It is anticipated that group- or cluster-randomized trial (GRT) design will be used. Information on GRTs and related study designs may be found here: https://researchmethodsresources.nih.gov/methods/grt
The above response clarifies the question posed during the pre-application webinar on whether power calculations should be based on 500-600 mother-child dyads at each applicant site. NHLBI recommends that each applicant power their study on 3,000 mother-child dyads and NOT on 500-600 mother child dyads.
Q26. Are applicants allowed to include biological/survey measures of adversity? There is a prescribed list in the RFA but is there flexibility to think beyond the ones listed in the RFA?
A26. Yes, there is flexibility to think beyond those listed in the RFA. Cardiovascular health metrics are important and so are questionnaires or surveys (e.g., demographics and social determinants of health factors).
Q27. Can investigators be listed on multiple clinical sites if they have experience and relationships with home visiting programs in multiple states and multiple models?
A27. The levels of effort should not be duplicative in multiple applications, and should not exceed 100%. If the applications are selected for award, the investigator may be asked to withdraw from one.
Q28. What is the role of statisticians in the UG3/UH3 applications as against that of statisticians in the U24 application, especially for the common protocol to be conducted years 3-7?
A28. The statistician on the UG3/UH3 application would serve on a data analysis committee with other statisticians awarded under the U24 and be part of the team to collaboratively work with the RCC statistician to develop the common protocol paying attention to study design and power, adjudication of ancillary study designs, and processes for common data analysis. The role of the site statisticians in the UH3 phase will be defined in the analysis plan developed during the UG3 phase.
Q29. Will all clinical sites deliver the intervention to the same age groups, and does the intervention need to begin during pregnancy?
A29. The intervention is expected to be delivered during pregnancy and post pregnancy for the mother and from infancy through childhood. The decision on age groups will be considered during the common protocol development to be ready for implementation in the UH3 phase.
Q30. Do all participants need to receive a version of the cardiovascular health (CVH) component of the intervention? Or can some be in a control group receiving the standard home visiting model?
A30. We expect that group- or cluster-randomization will have some groups in the intervention to receive the CVH module and other groups to receive the usual home visiting model intervention.
Q31. Do sites collaborating with one awardee all have to use the same home visiting program?
A31. It is important to select home visiting programs in which you will have adequate sample size to conduct the study.
Q32. Does the study design/intervention need to include randomization of participants or groups in the UG3 phase or are quasi-experimental designs allowed?
A32. Selection of the study design you choose should be commensurate with the study goals in the UG3 phase.
Q33. Is there a recommended FTE for PIs for both the CCs and RCC?
A33.The FTEs for the PIs for both the CCs and RCC should be commensurate with their effort on the study.
Q34. Do evaluation assessments (e.g. CVH markers) need to be collected at home or can participants come to a clinical center for assessment of evaluation outcomes?
A34. Applicants are encouraged to consider the feasibility of data collection methods they choose and provide justification for their selection.
Q35. For U24, it would help to know what attachments are needed for PHS Human Subjects and Clinical Trials Information V2.0 since the U24 will not enroll participants.
A35. Although the RCC will not enroll subjects, they will be responsible for monitoring study participant accrual and retention at each of the clinical awardee sites. Also, see Section 5 - 5.1 Other Clinical Trial-related Attachments:
Applicants must provide a detailed table listing the characteristics of trials they have been involved in that demonstrate experience in trial coordination in the last 5 years. The table must be provided as an attachment called "Clinical Trial Research Experience.pdf" and may not exceed 3 pages. The table columns should include:
Column A: clinical study title
Column B: applicant's role in the study
Column C: a brief description of the study design
Column D: planned enrollment
Column E: actual enrollment
Column F: whether the studies completed on schedule or not
Column G: publication reference(s)
Q36. Do you expect each UG/UH3 recipient using their own clinical trials data management system possibly different from that deployed by the U24 recipient?
A36. UG3/UH3 applicants may have their own clinical trials management system. However, all common data across the study will be managed by the RCC and analyzed by the RCC.
Q37. Some maternal and child health indicators, services and referrals are already mandated under HRSA/MIECHV performance indicators and systems outcomes (aka benchmark areas). Can we leverage these benchmarks (e.g., smoking cessation, adherence to well child visits, safe sleep practices) to avoid overlap in content delivered?
A37. Yes, you can.