Department of Health
and Human Services (HHS)
and Human Services (HHS)
National Institutes of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
UG1 Clinical Research Cooperative Agreements - Single Project
New
None
RFA-HD-21-032 - Data Coordinating Center for the Neonatal Opioid Withdrawal Syndrome Pharmacological Treatments Comparative Effectiveness Trial (U24 Clinical Trial Required)
93.865
This FOA invites applications for Clinical Centers to design and implement a multi-center, comparative effectiveness, randomized controlled trial (RCT) to assess the optimal pharmacological treatment for Neonatal Opioid Withdrawal Syndrome (NOWS).
A separate FOA (RFA-HD-21-032) will invite applications for Data Coordinating Center (DCC).
Information obtained from this study is expected to inform clinical practice guidelines and the care of infants with NOWS.
The funding for this initiative is provided from the Helping to End Addiction Long-term (HEAL) initiative (https://heal.nih.gov/).
30 days prior to application due date
March 30, 2021
All applications are due by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on the listed date(s).
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.
Not Applicable
July 2021
October 2021
December 2021
Not Applicable
It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from NIH Guide for Grants and Contracts).
Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.
Applications that do not comply with these instructions may be delayed or not accepted for review.
Purpose and Objectives
This FOA invites applications for Clinical Centers to conduct a multi-center, comparative effectiveness, randomized controlled trial (RCT) to assess the optimal pharmacological treatment for Neonatal Opioid Withdrawal Syndrome (NOWS) to inform clinical practice guidelines. Centers selected must agree to be part of a consortium that will collaboratively develop and implement a uniform protocol.
A separate FOA (RFA-HD-21-032) will invite applications for a Data Coordinating Center (DCC) to provide additional scientific input as well as coordinate study design and protocol development, protocol implementation, and data analysis.
It is anticipated that there may be a pilot or vanguard phase before the study is fully launched. If additional sites are needed to recruit adequate numbers of participants, subcontracts may be added to individual study sites or the DCC.
The funding for this project is provided from the Helping to End Addiction Long-term (HEAL) initiative (https://heal.nih.gov/).
Background
At the 2018 National Prescription Drug Abuse and Heroin Summit, National Institutes of Health Director Francis S. Collins, M.D., Ph.D., announced the launch of the HEAL (Helping to End Addiction Long-term) Initiative, an aggressive, trans-agency effort to speed scientific solutions to stem the national opioid public health crisis. Part of this initiative is to evaluate treatments and long-term consequences of Neonatal Opioid Withdrawal Syndrome (NOWS).
Women and children bear a substantial part of the burden of the current opioid crisis in the United States. Hospitalizations for opioid use disorder in pregnant women more than quadrupled during 1999 2014. This is a significant public health concern, given that opioid exposure is associated with adverse maternal and neonatal outcomes, including preterm labor, stillbirth, NOWS, and maternal mortality. Cases of NOWS have increased 5-fold since 2004 a baby is born suffering from opioid withdrawal approximately every 15 minutes, and recent data from the U.S. Pediatric Health Information System suggest an incidence of NOWS as high as 20 cases per 1000 live births (with a treatment cost of more than $560 million per year). In addition, not only can opioid use during pregnancy lead to NOWS, but both the mothers and babies may be at higher risk of opioid use and its consequences later in the life course, setting up intergenerational cycles of opioid overuse.
The Advancing Clinical Trials in Neonatal Opioid Withdrawal syndrome (ACT NOW) project's Current Experience study found a wide variation in NOWS care practices, including pharmacologic agents, with no consensus as to which medication regimen is better. Currently, the most common first-line medications for NOWS are morphine and methadone; phenobarbital and clonidine are the most commonly used adjunct agents.
A meta-analysis published in 2019 suggested that buprenorphine may be the optimal pharmacologic treatment for infants with NOWS. However, the primary findings of this meta-analysis need to be interpreted with caution and properly conducted direct comparative-effectiveness studies are needed to inform clinical practice.
Unfortunately, findings from previous studies that compared different treatment medications for NOWS have been limited:
To address these scientific gaps, a workshop supported by the HEAL initiative and addressing issues related to the treatment of infants with NOWS was held on August 24-25, 2020. Contents of the workshop are archived on the following website: https://heal.nih.gov/events/2020-buprenorphine-infants.
As such, this FOA invites applications for Clinical Centers to participate in a multi-center, large-scale RCT that directly compares morphine, methadone, and buprenorphine, and takes into account non-pharmacologic factors and adjunct therapies. The expected follow-up is at least 24 months. A separate FOA (RFA-HD-21-032) will provide support for a DCC to support these efforts. The goal is to generate results that can inform clinical practice guidelines.
Study Structure
NICHD anticipates making awards to multiple Clinical Centers and one DCC.
Governance and Oversight: Principal Investigators from these awards, plus NICHD Program Staff, will form a Steering Committee, which will be in charge of: designing a common protocol; implementing the study; analyzing and interpreting the data; reporting results; and depositing de-identified data in a public repository. The Director of NICHD will appoint an independent Steering Committee Chair.
NICHD will also appoint an independent Data and Safety Monitoring Committee (DSMC) for this trial.
Clinical Centers are not expected to submit a trial design at the time of the application.
Data Coordination Center: The DCC will provide needed statistical expertise and analysis for the trial and logistical support to the Steering Committee and DSMC. The DCC and the NIH will closely monitor participant accrual and retention. The DCC will be responsible for administering capitation and implementation costs to the Clinical Centers based on recruitment and retention. It will also be responsible for submitting and obtaining necessary approvals via a single Institutional Review Board (IRB). If required by the U.S. Food and Drug Administration, it will work with the Steering Committee and NIH staff to obtain Investigational New Drug (IND) waivers and/or approvals, and meeting the IND reporting requirements.
Clinical Centers: Each Clinical Center will support a team of a Principal Investigator, an Alternate Principal Investigator, and a Research Nurse Coordinator.
Clinical Centers may propose collaborations with other institutions as needed to enhance research expertise, recruitment capacity for the target population, and diversity of population.
Successful Clinical Centers must demonstrate (and grantees must continue to meet) the following requirements]:
Institutional applicants must clearly express their intent:
See Section VIII. Other Information for award authorities and regulations.
Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities. See Section VI.2 for additional information about the substantial involvement for this FOA.
The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types. Only those application types listed here are allowed for this FOA.
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NICHD intends to commit approximately $5,000,000 of HEAL funds in FY21 to fund an estimate of 15-20 awards.
The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.
HEAL has committed a total of $7,000,000 in FY21 to support this FOA as well as its accompanying FOA (RFA-HD-21-032).
Application budgets must reflect the actual needs of the proposed project. Applicants may request up to $150,000 in direct costs per year.
The maximum project period is five years.
NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this FOA.
Higher Education Institutions
The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:
Nonprofits Other Than Institutions of Higher Education
For-Profit Organizations
Local Governments
Federal Governments
Other
Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are not allowed.
Applicant organizations
Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.
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 his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.
For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.
PD(s)/PI(s) and the Alternate PI for the Clinical Centers should either be a neonatologist certified by the American Board of Pediatrics, Neonatal-Perinatal Medicine Sub-Board, or a pediatrician certified by the American Board of Pediatrics with experience in caring for infants with NOWS.
Each institution must designate a Principal Investigator (PD/PI) responsible for all aspects of the center's participation. The PI participates as a member of the Steering Committee.
The Principal Investigator has primary responsibility for:
This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.
Applicant organizations may submit more than one application, provided that each application is scientifically distinct.
The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:
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 FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.
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:
The letter of intent should be sent to:
Andrew A. Bremer, MD, PhD
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-402-7886
Email: andrew.bremer@nih.gov
All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.
The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed.
Facilities and Other Resources
Population Available for Clinical Trial
The application must contain information describing the available population for this trial as well as a willingness to enroll eligible patients. Applicant clinical centers must have at least 3 infants treated pharmacologically for NOWS per month (on average). In order to provide peer reviewers with the specific neonatal population available for this study at the clinical site(s), include information regarding admissions over the two previous calendar years (2019-2020) in tabular format; a sample format is provided below:
|
2019 |
2020 |
|
|
Number of births |
||
|
Number of NOWS admissions |
||
|
Number of infants with NOWS treated pharmacologically |
Centers with more than one clinical site, please include each site's information in separate tables or columns.
Applicant clinical centers should state whether their site(s) have implemented Eat, Sleep, and Console (ESC) as a treatment strategy for infants with NOWS.
If there is an anticipated increase or decrease in the birth rate or the number of NOWS admissions for 2021-2026, this should be indicated at the time of application.
Clinical Capabilities
The applicant clinical center is expected to have a full range of perinatal subspecialists, clinical capabilities and support staff, including an active research coordinator. A detailed description of the clinical attributes of the Neonatal-Perinatal Program must be provided. Availability of an institutional pharmacy with 24/7 capacity that can manage controlled substances is expected.
The application should describe the site's staffing and experience in clinical care and research.
Follow-up Program
The application should include a description of neonatal follow-up capabilities for the center.
Applicants should describe in detail mechanisms in place to insure compliance and assistance with neonatal follow-up, including: procedures for identifying infants for follow-up while in the nursery, maintaining contact with families, scheduling appointments, actions taken for missed appointments, number of home visit appointments including staff participating in home visits, and creative measures instituted at the center to insure excellence in follow-up rates and compliance with clinical research study protocols.
The follow-up portion of the clinical capabilities must include expertise in performing Bayley Scales of Infant and Toddler Development 4th Edition assessments, neurological examinations, and hearing and vision assessments.
The current system of follow-up assessment including data collection, population demographics, compliance rates, schedule of follow-up visits, funding sources, policies and procedures for conducting research in the follow-up setting and appropriate specialist involvement in the follow-up program should be delineated in the application.
A target goal of 80% follow-up is desirable; the application should include examples of achieving this level of follow-up in a high-risk infant population if possible.
Other Support
Applications should include a list of funded clinical research that has augmented other neonatal clinical research. This includes but is not limited to financial support from NIH, granting agencies, and institutional support.
Special Strengths
Applicants are encouraged to describe special or unique strengths that may be relevant to NOWS research.
In addition, special administrative strengths or experience as well as participation in administrative aspects of clinical research (institutional review board, data and safety monitoring committee, advisory board for clinical research, clinical research committees and so forth) should be highlighted.
All instructions in the SF424 (R&R) Application Guide must be followed.
The application should include the following personnel with accompanying Biosketches:
All instructions in the SF424 (R&R) Application Guide must be followed.
Each applicant should submit base budget estimates for all years. Each year's budget at the time of application will be limited to a BASE BUDGET with maximum allowances as follows:
Budgets are limited to $150,000 in direct costs per year and should reflect the actual needs of the trial protocol as it is completed over the project period. The overall provision of money is subject to the availability of NICHD funding.
The DCC will be responsible for issuing payments to the Clinical Centers for protocol-specific expenses, including a per patient capitation. The protocol budgets will consist of specific protocol-related allowances, capitated per subject enrolled in each study. Capitation funds can be utilized to fund key personnel. To receive reimbursements, a funded clinical center must set up an agreement with the DCC.
The clinical center PD/PI or his/her designee will be required to help the DCC manage protocol costs. The PD/PI or his/her designee should propose estimates of recruitment efforts for each protocol to the DCC and update these at least annually. The DCC may establish a recruitment limit. If a clinical center investigator believes that their site(s) is able to exceed the limit, then permission to do so must be obtained from the DCC.
The clinical centers' F&A rates on the initial competitive awards will not be adjusted in future years due to changes in their negotiated rate agreements.
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:
Specific Aims:
All applications should list Specific Aims for the proposed participation in the consortium. These should not be the same as the specific aims of the Clinical Trial Proposal (Subsection 5).
As noted above, the clinical site will participate in a multi-center, comparative effectiveness, randomized controlled trial (RCT) to assess the optimal pharmacological treatment for Neonatal Opioid Withdrawal Syndrome (NOWS). The final protocol will be developed in coordination with the other Clinical Sites and the DCC once they are selected.
The clinical trial will be delayed onset.
Research Strategy:
All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:
In lieu of traditional research strategy with the usual headings, the application should use the following subsections: Overall strategy and Readiness for the clinical trial.
Subsection 1: Overall strategy and Administrative Plan
The applicant should describe the applicant's overall strategy and administrative plans to oversee and monitor the clinical trial and study team.
Subsection 2: Readiness for the Clinical Trial
The applicant should describe the institution's readiness to engage in a multicenter clinical trial focused on the pharmacological management of NOWS.
Research Staffing:
The application should describe the respective roles of staff and a management plan for how staff interact with the neonatal-perinatal medicine subspecialists and other individuals listed under Senior/Key Persons.
This trial will require patient recruitment at nights and on weekends and holidays, so plans for availability for staff must be included in the application and budget.
For centers with more than 1 clinical site, please include management plan(s) for supervision, training, in-service, certification, data handling, quality assurance, cost effective management, and communication of these additional sites.
Patient Population:
Applications should describe the eligible subject populations and actual enrolled study subjects. Eligibility and enrollment in previous clinical trials should also be included in the application. Ability to recruit, retain, and follow up infants in clinical trials and observational studies is critical to being successful. Large eligible populations with low numbers enrolled in trials are considered less favorably than smaller populations that have higher enrollment rates.
The patient population must be characterized by demographics, obstetric parameters, and payment status. Indications must be given of the proportions of various subgroups, including minorities that have been eligible and actually have been randomized in previous or current clinical trials.
Centers with ongoing or pending studies/trials that will limit availability of patients for this trial must described these conflicts in the application. If there is to be a projected increase or decrease in subjects eligible for study, this should be described in the application.
Academic Productivity:
Without duplicating information in the Biosketches, provide evidence of research productivity by the clinical center in previous or ongoing clinical studies and trials, especially those of a cooperative or multicenter design. Contributions in key areas of research development and design, patient recruitment, retention and study completion, data collection and analysis, and track record of publications should be included in the application.
Letters of Support:
Include letters of support from partnering institutions or outside collaborators with statement of roles/responsibilities. The application must include a statement from the applicant institution (senior institutional official) describing the commitment to the planned program, senior and junior investigators, research staff and infrastructure needed.
A letter of assurance of cooperation with the policy for capitation of research costs as outlined below should be provided from the departmental and institutional offices of sponsored research programs.
Applications from institutions that have a Clinical and Translational Science Award (CTSA) funded by NIH or other funded perinatal research centers as resources for conducting the proposed research should provide a letter of agreement that identifies the types and levels of support from the PD/PI or the CTSA program director.
There must be a clearly expressed intent to participate in a cooperative manner with the other Clinical Centers, the DCC, the NIH, and the DSMC in all aspects of research in a manner consistent with the terms of the award
Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide.
The following modifications also apply:
Any proposed sharing plan mustbe consistent with the HEAL Public Access and Data Sharing Policies (https://heal.nih.gov/about/public-access-data).
Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.
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 SF424 (R&R) 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 SF424 (R&R) Application Guide must be followed.
Section 2 - Study Population Characteristics
Inclusion Enrollment Report(s)
The Data Coordinating Center will provide inclusion reports of Human Subjects for the final protocol and will report to ClinicalTrials.gov for the consortium.
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 SF424 (R&R) Application Guide must be followed.
Only delayed onset clinical trial applications should be submitted. All study details will be provided in HSS when the clinical trial is converted to a full study record.
All instructions in the SF424 (R&R) Application Guide must be followed.
See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov.
Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.
Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.
Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.
Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.
This initiative is not subject to intergovernmental review.
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.
Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.
Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.
For assistance with your electronic application or for more information on the electronic submission process, visit 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 Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.
The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.
See more tips for avoiding common errors.
Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by Program staff at NICHD, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.
Pre-Application Materials
A workshop supported by the HEAL initiative and addressing issues related to the treatment of infants with NOWS was held on August 24-25, 2020. Contents of the workshop are archived on the following website: https://heal.nih.gov/events/2020-buprenorphine-infants.
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.
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.
For this particular announcement, note the following:
The clinical site will participate in a multi-center, comparative effectiveness, randomized controlled trial (RCT) to assess the optimal pharmacological treatment for Neonatal Opioid Withdrawal Syndrome (NOWS). The protocol will be developed in coordination with the other clinical centers and the DCC.
The clinical trial will be delayed onset.
A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.
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 review criteria and additional review criteria (as applicable for the project proposed).
Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.
Significance
Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?
Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?
Investigator(s)
Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?
Is there a significant track record of productivity in clinical research by the investigators and the clinical team in the recent past? Do the investigators have the scientific, administrative, clinical, and academic qualifications to conduct successful clinical research? Does the research team at the center have the institutional support and capabilities including the patient population to participate fully in a trial focused on the pharmacological treatment of NOWS? Do the key personnel have the knowledge and experience in areas relevant to the conduct of collaborative clinical research, especially randomized clinical trials, including experience in research design? Is there commitment of staff time for the satisfactory conduct of the studies? Do the investigators have experience as well as qualified team members who would be responsible for data quality and management activities?
With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?
Innovation
Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?
In addition, for applications involving clinical trials
Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?
Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?
Does the application adequately address the following, if applicable:
Study Design
Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?
Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?
Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?
Data Management and Statistical Analysis
Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?
Specific for this FOA:
Does the applicant demonstrate an effective clinical trials skills development plan that is likely to positively impact the research team's ability to design and implement clinical trials in their institution?
Does the applicant demonstrate the ability to successfully implement multi-center clinical trials including the ability to recruit, retain, and follow up infants in high-risk families in clinical studies?
Is there evidence of a willingness to work and cooperate with other Clinical Sites, the DCC and the NIH in a manner summarized in this FOA?
Does the research team, with proposed partner institutions or collaborators, have the ability to design multicenter clinical trials?
Does the research team demonstrate the ability to successfully comply with the HEAL Data Sharing Policy and Resource Sharing Plan?
If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?
Environment
Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?
If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?
Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?
Specific for this FOA:
Does the institution demonstrate the commitment to support NOWS research and the proposed program? Are the research infrastructure and facilities that are available and accessible to this program described? Is there adequate institutional assurance to provide support to the program in areas of fiscal administration, personnel management, space allocation, procurement, planning, and budgeting?
Is there demonstrated adequacy of administrative, clinical, and data organizational management facilities?
Are there additional administrative strengths, such as affiliations or collaborations with other research units, institutions, or organizations that strengthen the environment of the applicant Clinical Site?
If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers of infants requiring pharmacological therapy for NOWS; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; (4) have access to a 24-hour 7-day-per-week pharmacy that can handle controlled substances; and, (5) operate within the proposed organizational structure?
As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.
Study Timeline
Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?
Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?
Protections for Human Subjects
For research that involves human subjects but does not involve one of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.
For research that involves human subjects and meets the criteria for one or more of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.
Inclusion of Women, Minorities, and Individuals Across the Lifespan
When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.
Vertebrate Animals
The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.
Biohazards
Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.
Resubmissions
Not Applicable
Renewals
Not Applicable
Revisions
Not Applicable
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.
Applications from Foreign Organizations
Not Applicable
Select Agent Research
Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).
Resource Sharing Plans
As noted above, does the research team demonstrate the ability to successfully comply with the HEAL Data Sharing Policy and Resource Sharing Plan?
Authentication of Key Biological and/or Chemical Resources:
For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.
Budget and Period of Support
Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.
Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NICHD, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.
As part of the scientific peer review, all applications 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 FOA.
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 FOA. 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:
Information regarding the disposition of applications is available in the NIH Grants Policy Statement.
A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.
Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.
Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.
Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.
ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain applicable clinical trials on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm
Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols.
Data 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).
All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.
Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex. This includes ensuring programs are accessible to persons with limited English proficiency. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html.
HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA.
Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697.
In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.
The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Parts 75, and other HHS, PHS, and NIH grant administration policies.
The administrative and funding instrument used for this program will be the cooperative agreement an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.
The PD(s)/PI(s) will have the primary responsibility for:
The NICHD Project Scientist or Project Coordinator will:
The NICHD Program Official will:
The Steering Committee will:
Areas of Joint Responsibility include:
The management of the consortium includes committees with the following functions:
Steering Committee
Data and Safety Monitoring Board:
In addition, the consortium will develop policies and procedures that govern its operations, including publications. These policies and procedures can be amended by the Steering Committee and the NICHD.
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 arbitration. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.
Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.
ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain applicable clinical trials on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm
Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols. Data 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).
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.
The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.
In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.
We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.
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: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573
Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov
Andrew A. Bremer, MD, PhD
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-402-7886
Email: andrew.bremer@nih.gov
Sherry Dupere, PhD
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-451-3415
Email: duperes@mail.nih.gov (mailto:duperes@mail.nih.gov)
Bryan S. Clark, MBA
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6975
Email: clarkb1@mail.nih.gov
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 45 CFR Part 75.
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