This FOA invites applications for Clinical Centers to carefully characterize the normal course of glycemia over the entire duration of pregnancy and understand the evolution of dysglycemia when it occurs. Clinical Centers will recruit and study pregnant women starting in the first trimester and continuing at least through delivery. A separate FOA (RFA-DK-18-019) will solicit a Biostatistics Research Center. Each Clinical Center applicant will propose a study design and provide detailed information about recruitment capacity. All awardees will form a cooperative research consortium in conjunction with NIDDK to design and implement a uniform protocol. Information obtained from this study is expected to lead to improved approaches for screening for GDM, and inform the timing and approach for future clinical trials to decrease adverse perinatal outcomes and long-term sequelae of dysglycemia during pregnancy in both the mother and offspring.
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.
Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.
Applications that do not comply with these instructions may be delayed or not accepted for review.
There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.
This FOA invites applications for Clinical Centers to carefully characterize the course of glycemia over the entire duration of pregnancy. Centers selected to participate must agree to be part of a consortium that will collaboratively develop and implement a uniform protocol.
Observational studies have clearly demonstrated that varying degrees of dysglycemia during pregnancy, including pre-existing diabetes and gestational diabetes (GDM), are associated with adverse perinatal outcomes (e.g., macrosomia, large for gestational age [LGA], shoulder dystocia, congenital anomalies and fetal loss), as well as long-term sequelae for offspring, including the development of obesity and type 2 diabetes. Trials of GDM treatment have demonstrated improvement in some, but not all, perinatal outcomes and results have been inconsistent across trials; generally, trials have not been conducted to examine effects of GDM treatment on long-term sequelae.
Current clinical guidelines recommend screening for pre-existing diabetes at the first prenatal visit for high risk women, and screening for GDM at approximately 28 weeks of gestation. Given evidence that the intrauterine environment can have profound consequences for metabolic programming in the fetus, it is possible that beginning treatment of dysglycemia in the 3rd trimester may be too late to completely reverse "developmental origins of health and disease." However, the optimal time of screening and treatment for GDM is not known. Although there have been small, short-term physiologic studies of glucose metabolism in pregnant women, a comprehensive, longitudinal description of changes in glucose over the course of pregnancy and how glycemic levels earlier in pregnancy relate to traditional 3rd trimester GDM screening and perinatal outcomes is lacking.
This FOA will create a clinical consortium to characterize longitudinal changes in glycemia during pregnancy. The availability of non-burdensome, continuous glucose monitoring (CGM) technology provides new opportunities to accomplish this goal. For example, CGM could be used to obtain detailed glucose profiles during usual daily activities at multiple time points (e.g., 12, 20, and 28 weeks of gestation) and correlate glycemia earlier in pregnancy with traditional GDM screening as well as perinatal outcomes and, potentially, longer-term outcomes if the cohort is followed longitudinally. Samples could also be obtained that may be useful in identifying mechanisms underlying dysglycemia, as well as predictors of GDM. Such samples could potentially also be useful in advancing the mechanistic understanding of how dysglycemia, as well as other metabolic abnormalities (e.g., lipids, immune factors), contribute to metabolic programming, if longer term follow-up of offspring is conducted. Information obtained from this study is expected to lead to improved approaches for screening for GDM, and inform the timing and approach for future clinical trials to decrease adverse perinatal outcomes and long-term sequelae of dysglycemia during pregnancy in both mother and offspring.
This FOA invites applications from Clinical Centers to recruit and study pregnant women starting in the first trimester and continuing at least through delivery. A separate FOA (RFA-DK-18-019) will solicit applications for a Biostatistics Research Center (BRC) to provide additional scientific input as well as coordinate study design and protocol development, protocol implementation, and data analysis. Each Clinical Center applicant is expected to provide a detailed description of a proposed study that will accomplish the scientific aims described above, as well as detailed information about his/her own site's recruitment capacity. The proposed research study will enable reviewers to evaluate the applicant's ability to identify the critical issues to be addressed in the study and rigorously design such a study. Peer review will consider both the scientific merit of the application as well as the ability to recruit and conduct the study. The Awardees will then assemble to form a Steering Committee (see below), which will meet to develop a common protocol and manual(s) of procedures. The submitted applications will serve as a starting point for the Steering Committee's deliberations. It is expected that the Steering Committee will meet a minimum of three times at the NIH and have frequent contact by telephone during the planning phase, which is expected to take at least six months.
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 patients, subcontracts may be added to individual study sites or the BRC.
1. Clinical Centers
Clinical Centers (CC) will recruit pregnant women in their first trimester and retain them during the course of the study. It is anticipated that women with pre-existing diabetes will be excluded. The population recruited should have racial and ethnic diversity, and it is expected that the population recruited will be enriched for women at particularly high risk of developing GDM. Recruitment will take place over 2-3 years.
The PD/PI and key co-investigators at each CC will be expected to collaborate in designing and implementing the uniform study protocol. It is expected that each CC will include a scientific team that represents a collaboration between a diabetologist and an obstetrician or maternal-fetal medicine expert. Centers must not only have the requisite number of deliveries but also proven experience in recruiting and retaining pregnant women in research studies, including recruitment of women during the first trimester. Centers must also have expertise in utilizing CGM technology. The CC will collect data in accordance with established study procedures and submit all samples and data to the Biostatistics Research Center (BRC) and central laboratory and central reading centers, as appropriate and required by the protocol.
Investigators at the CC will conduct analyses in conjunction with the BRC. The study group will have exclusive access to data from the study population for a defined period, according to NIDDK and NIH data sharing policies. All study data analyzed for publication of the primary and secondary study outcome(s) are expected to be provided to the NIDDK Repository so that it can be shared as appropriate per NIDDK policy and consistent with achieving the goals of the program. The Steering Committee (see below) will establish policies under which ancillary studies may be conducted while the study is ongoing, consistent with applicable laws, regulations, and policies.
2. Biostatistics Research Center (BRC)
There will be a single BRC. The BRC biostatisticians will work with the Clinical Center investigators to develop the scientific design of the study. The BRC investigators will have primary responsibility for ensuring that the design of the study, including the primary outcome, is scientifically sound and is supported by appropriate power calculations. The BRC will also provide biostatistical and analytic expertise and conduct analysis and interpretation of the laboratory and clinical data in conjunction with investigators at the Clinical Centers. The BRC will be responsible for guiding development of the statistical analysis plan for the study as a whole and for each manuscript reporting pre-specified primary and secondary outcomes. The BRC will also be responsible for establishing all scientific collaborations for specialized outcomes.
In addition to these research functions, the BRC is responsible for the collection, management and analysis of all clinical and laboratory data, including establishment of any central laboratories or cores needed.. The BRC will be responsible for ensuring participant confidentiality and safety, and quality control. The BRC will conduct training and certification of study staff, and maintain and update the manual of operations. The BRC will oversee implementation of and adherence to the study protocol. The BRC will coordinate communication among and with the CC. The BRC will also be responsible for establishing and maintaining activities related to the single IRB. In addition, the BRC will develop procedures to require study investigators and other relevant personnel associated with the study to identify and manage financial and other conflicts of interest at least annually and share this information with NIDDK staff.
The BRC will coordinate the movement of biologic samples from the CC to the central laboratory and, subsequently, to the NIDDK repository, where samples will be stored for future analysis. The BRC will similarly coordinate with the CC to ensure the flow of CGM and other collected data to the appropriate central reading center. The BRC will also coordinate work with the NIDDK Data Repository to prepare all study data for eventual archiving and distribution.
The BRC will provide biostatistical, data management and analytic expertise. The BRC will prepare appropriately detailed reports to the Steering Committee and to the Observational Study Monitoring Board (OSMB), and to the NIDDK staff at regular intervals. The BRC will be responsible for the planning and logistics of meetings of the Steering Committee and its subcommittees, and will assist NIDDK with the logistics for OSMB meetings.
3. Steering Committee
The primary governing body of the study will be the Steering Committee, comprised of the PDs/PIs of the BRC and each CC, and the NIDDK Project Scientist.
The Steering Committee will develop policies and procedures for the study group, and ensure that these policies are properly implemented. These may include procedures for modification of study design, use of study samples and data, approval of ancillary studies, publication and presentation of study findings, monitoring study progress, determining completeness and quality of data collection, and other performance measures. NIDDK expects the investigators to develop robust ancillary study policies to provide opportunities for outside investigators to leverage collected data and biospecimens, as well as the recruited cohort, to expand the scientific output of the group.
4. Project Scientist
The NIDDK Project Scientist will assist the Steering Committee in designing and carrying out the study. The Project Scientist will provide scientific support to awardees' activities, including protocol development, quality control, interim data monitoring, final data analysis, preparation of publications, and overall performance monitoring.
The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
NIDDK intends to commit $3.5 million in FY 2019 to fund 5-7 awards. The number of awards is contingent upon availability of funds and the receipt of a sufficient number of meritorious applications.
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
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.
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.
The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:
Buttons to access the online ASSIST system or to download application forms 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.
For information on Application Submission and Receipt, visit Frequently Asked Questions – Application Guide, Electronic Submission of Grant Applications.
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:
John Connaughton, Ph.D.
Chief, Scientific Review Branch
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Clinical Protocol Synopsis : The file name "Clinical Protocol Synopsis.pdf" must be used.
Large multi-center clinical studies, even those that are not clinical trials, require a formal protocol to lay out a rigorous scientific design, and, to achieve standardization and fidelity of activities across all sites. The Clinical Protocol Synopsis must provide a narrative description of the protocol, briefly describing the objectives of the protocol and including:
Applications that lack the Clinical Protocol Synopsis are incomplete and will not be peer reviewed.
Statistical Analysis Plan: The filename "Statistical Analysis Plan.pdf" must be used.
The applicant must describe the statistical methods to be used, including the sample size and power calculations, plans for the primary and secondary analyses, and pre-specified interim analyses. This plan is critical to knowing whether applicants have selected the correct cohort size based on proper power calculations and/or are using the most appropriate methods to analyze the resulting data and make correct conclusions at the end of the study. The sample size and statistical power calculations should contain enough detail, including a discussion of assumptions made, so that a reviewer can readily duplicate the sample size projection. The power analysis should include a discussion of the anticipated rates of follow-up (i.e., drop out/lost to follow up) during key outcome collection contacts. A discussion of how missing data will be handled should be included. Any planned interim analyses should also be described.
Applications that lack the Statistical Analysis Plan are incomplete and will not be peer reviewed.
Milestone Plan: The filename "Milestone Plan.pdf" must be used.
Applicants are required to provide detailed interim performance measures and timelines for completing key objectives and administrative functions for the proposed clinical study, as applicable. The Milestone Plan is separate and distinct from the Study Timeline attachment. Milestones should be easily measurable and realistic. Milestones may include, as applicable, but are not limited to:
These milestones will be negotiated at the time of the award, as appropriate. Future year support is contingent on satisfactory achievement of performance milestones. If milestones are not achieved fully, NIDDK may request development of a remedial plan and more frequent monitoring of progress, or take other remedial actions.
Applications that lack the Milestone Plan are considered incomplete and will not be peer reviewed.
Consortium Assurance The filename "Consortium Assurance.pdf" must be used.
The PD/PI should provide a letter stating his/her willingness to participate in Consortium activities, including sharing the scientific portion of the application, participating in meetings at the NIH and regular conference calls and abiding by approved Consortium policies, and following the common protocol agreed to during the planning phase. In the letter, the PD/PI should also discuss past experiences participating in multi-center studies.
In addition, the PD/PI and an authorized Institutional Official must provide evidence that the Institution is willing to sign a standard reliance agreement and use the single IRB proposed by the BRC as part of its application, in accordance with NIH policy on the use of a single Institutional Review Board for multi-site research, https://grants.nih.gov/grants/guide/notice-files/NOT-OD-17-076.html.
All instructions in the SF424 (R&R) Application Guide must be followed.
The applicant should clearly articulate the significance of the proposed study, including why the study is needed and what evidence gap the study will address, including a discussion of how the results will be used to impact clinical or public health.
The application must include a detailed description and scientific rationale for the study design, addressing the population to be studied and the outcomes being assessed. The applicant should discuss the timing of CGM and OGTTs (and other proposed measures), and how tests performed earlier in the pregnancy will be correlated and compared with traditional GDM screening measures.
The application should include a discussion of potential biases or challenges in the protocol and how they will be addressed.
Preliminary data addressing the need for and supporting the feasibility of the study should be discussed. The discussion of supporting data that provide the basis for the study's design must address the adequacy and quality of previous studies.
Letters of Support:
Letters of support must be provided from all participating clinics and/or hospitals, well as collaborators at other sites.
The following modifications also apply:
The NIDDK has established Central Biosample, Genetic, and Data Repositories for the archiving and storage of data and biosamples collected in large, multi-site studies funded by NIDDK. The investigator(s) should be prepared to transfer all data and samples to the Repository at the conclusion of the study. The study group will have exclusive access to data for a defined period, according to NIDDK data sharing policies (https://www.niddk.nih.gov/research-funding/human-subjects-research/policies-clinical-researchers).
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 with the following additional instructions:
Section 2 -Study Population Characteristics
2.5 Recruitment and Retention Plan
The applicant must indicate how many participants he/she expects to be able to recruit. Please include a specific, detailed discussion of the availability of potential participants for the proposed study and anticipated yield from recruitment and screening efforts. The plan should address not only the total number of deliveries per year but the demographics of the population, including key characteristics relevant to various degrees of GDM risk (e.g., race/ethnicity, BMI, SES, etc.). The number of women evaluated per year in the 1st trimester of pregnancy and their characteristics (e.g., race/ethnicity, BMI, SES, etc.) should be included as well. Moreover, the number of pregnant women admitted or discharged with a diagnosis of GDM should be reported. Ideally, these estimates should be based on careful queries of the electronic medical record system. If there is more than one site, please discuss recruitment efforts at each site and overall. The plan must also include a detailed discussion of past experience in recruiting and retaining similar populations, expected challenges to recruitment and retention, and possible contingency plans. The plan must specifically address past experience and any special approaches/procedures necessary to recruit women in the 1st trimester and women at high risk of developing GDM.
Section 3 - Protection and Monitoring Plans
3.3 Data and Safety Monitoring Plan
Applicants to this RFA must include a Data and Safety Monitoring Plan. In addition to the description of safety monitoring, address plans to monitor trial performance, including plans to assure fidelity to the protocol and integrity of the data. Information about Data and Safety Monitoring Plans is available on the NIDDK website: https://www.niddk.nih.gov/research-funding/human-subjects-research/policies-clinical-researchers/data-safety-monitoring-plans.
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.
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 Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.
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 components of participating organizations , NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.
Use of Common Data Elements in NIH-funded Research
Many NIH ICs encourage the use of common data elements (CDEs) in basic, clinical, and applied research, patient registries, and other human subject research to facilitate broader and more effective use of data and advance research across studies. CDEs are data elements that have been identified and defined for use in multiple data sets across different studies. Use of CDEs can facilitate data sharing and standardization to improve data quality and enable data integration from multiple studies and sources, including electronic health records. NIH ICs have identified CDEs for many clinical domains (e.g., neurological disease), types of studies (e.g. genome-wide association studies (GWAS)), types of outcomes (e.g., patient-reported outcomes), and patient registries (e.g., the Global Rare Diseases Patient Registry and Data Repository). NIH has established a “Common Data Element (CDE) Resource Portal" (http://cde.nih.gov/) to assist investigators in identifying NIH-supported CDEs when developing protocols, case report forms, and other instruments for data collection. The Portal provides guidance about and access to NIH-supported CDE initiatives and other tools and resources for the appropriate use of CDEs and data standards in NIH-funded research. Investigators are encouraged to consult the Portal and describe in their applications any use they will make of NIH-supported CDEs in their projects.
Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.
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 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?
Specific to this FOA: Do the PD/PI(s) and key personnel have the expertise, experience, and ability to conduct research in pregnant women, and to organize, manage and implement the proposed multi-center clinical study? Is there a multi-disciplinary team including a diabetologist and obstetrician or maternal-fetal medicine expert?
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?
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?
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?
Specific to this FOA:
Does the application adequately address the following:
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? Is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Are the study populations (size, gender, age, demographic group) appropriate and well justified?
Is the process for obtaining informed consent 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?
Are the plans to standardize, assure quality of, and monitor adherence to the protocol and data collection or distribution guidelines appropriate?
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
Specific to this FOA: Does the application adequately address the capability and ability to conduct the clinical study at the proposed site(s) or centers? Is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?
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)?
Are the proposed milestones appropriate for the study? Will they allow meaningful tracking of study performance and are they feasible for the work proposed?
For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.
For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.
When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.
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.
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.
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).
Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).
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.
Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.
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.
Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.
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.
For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.
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:
1.Developing the research design and study protocol, including definition of objectives and approaches, sample size and power calculations, and establishing procedures for participant recruitment and follow-up, data collection, quality control, interim data and safety monitoring, final data analysis and interpretation, and publication of results.
2.Establishing a Steering Committee to implement, coordinate and manage the project(s). Awardee(s) will name investigators to serve as members on a Steering Committee and other subcommittees, as appropriate, meeting periodically. Awardees will be required to accept and implement the common protocol(s) and procedures approved by the Steering Committee.
3.Designating Protocol Chairs. The Program Directors/Principal Investigators (for studies involving multiple protocols) shall designate a single Protocol Chairperson (if the Program Director/Principal Investigator does not assume this role) for each protocol to be carried out by the study group. The Protocol Chairperson shall function as the scientific coordinator for the protocol and shall assume responsibility for obtaining approval to implement the protocol from the Steering Committee and for developing and monitoring the protocol. Significant modifications to approved protocols must be approved by the Steering Committee.
4.Implementing collection of data specified by the study protocol. For a multi-center study, each awardee/site is required to ensure that data will be submitted expeditiously to the Data Coordinating Center. Additionally, individual investigators/sites must demonstrate the ability to implement the strategy specifically designed for their individual study population.
5.Establishing procedures for data quality and completeness. Awardees are responsible for ensuring accurate and timely assessment of the progress of each study, including development of procedures to ensure that data collection and management are: (1) adequate for quality control and analysis; (2) for clinical trials, as simple as appropriate in order to facilitate cooperation/referral of study participants by physicians to avoid unnecessary expense; and (3) sufficiently staffed across the participating institutions. For research involving multiple sites, a plan for analysis of pooled data will be developed by the Steering Committee.
6.Submitting interim progress reports, when requested or agreed upon by both parties, to the NIDDK Program Official including at a minimum, summary data on protocol performance. For coordinated multiple awards or a multi-site single award, the NIDDK Program Official may require additional information from individual awardees/sites. Such reports are in addition to the required annual noncompeting continuation progress report.
7.Reporting of the study findings. Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies. The awardee must also be adherent to Study Publication and Presentation Policy. The NIDDK will have access to and may periodically review all data generated under an award. NIDDK staff may co-author publications of findings with awardees consistent with NIH and study policies.
8.Agree that any third-party (including both industry and academia) collaboration should be governed by a research collaboration agreement (e.g. Clinical Trial Agreement, Research Collaborative Agreement, Memorandum of Understanding, etc.) with terms that ensure the collaboration is conducted in accordance with the Cooperative Agreement, applicable NIH/NIDDK policies and procedures. The NIDDK Program Official may consult with others at NIH including the NIDDK Technology Advancement Office.
9. Any involvement of a third party (including both industry and academia) in the study, including access to any study data; study results; using the name of the study; or the name of the NIH or NIDDK, is permitted only after written concurrence by the NIDDK Program Official who may consult with others at NIH including the NIDDK Technology Advancement Office.
10.Study investigators are required to publish and to release publicly and disseminate results and other products of the study, in accordance with study protocols and steering committee policies on publications.
11.Maintaining confidentiality of information: The awardee(s) will maintain the confidentiality of the information developed by the investigators (i.e., protocols, data analysis, conclusions, etc.) as well as proprietary information of a company collaborating with the study.
12.The NIDDK has established Central Biosample, Genetic, and Data Repositories for the archiving and storage of data and biosamples collected in large, multi-site studies funded by NIDDK. Prior to enrolling participants, the PI or his/her designee will coordinate with the NIDDK Central Data Repository to develop a Data Sharing Plan and prepare the collected data for eventual archiving and distribution. In addition, if applicable, the PI or his/her designee will work with the NIDDK Biosample Repository to coordinate procedures for coding, shipping, processing, receipt, and storage of study samples that are to be maintained in the Repository. All samples and data transferred to the Repositories will be under the custodianship of the NIDDK, although the study's Steering Committee will have proprietary control of and exclusive access to the samples and data for an agreed-upon period of time. Subsequently samples and data will be available to the wider scientific community in accordance with the NIH policy on Data Sharing ( https://grants.nih.gov/policy/sharing.htm), as well as the NIDDK policy for data sharing in multi-center and large single-center clinical studies (https://www.niddk.nih.gov/research-funding/human-subjects-research/policies-clinical-researchers).
13. The Food and Drug Administration Amendments Act of 2007 (FDAAA or US Public Law 110-85) was passed on September 27, 2007. The law requires mandatory registration and results reporting for certain clinical trials of drugs, biologics, and devices. If trials conducted under this grant are applicable clinical trials subject to FDAAA, the sponsor or his/her designee will perform the mandatory study registration and reporting of study results to ClinicalTrials.gov. For more information about this law and requirements for sponsors and/or investigators, visit the PRS and U.S. Public Law 110-85 Information Page at http://prsinfo.clinicaltrials.gov/fdaaa.html. In addition, grantees should be aware that clinical trials not covered by FDAAA may still require registration in an approved registry in order to be published, according to the guidelines issued by the International Committee of Medical Journal Editors, http://icmje.org/recommendations/browse/publishing-and-editorial-issues/clinical-trial-registration.html.
NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:
An NIDDK Project Scientist with substantial involvement will:
1.Serve as the contact point for all facets of the scientific interaction with the awardee (s). As required for the coordination of activities and to expedite progress, NIDDK may designate additional NIDDK staff to provide advice to the awardee on specific scientific and/or analytic issues. Such staff may include another Project Scientist or Project Coordinator, who will provide direct technical assistance to the awardees to optimize the conduct and/or analysis of the study; or who may assist in the coordination of activities across multiple sites.
2.For multi-center studies, participate in the Steering Committee that oversees study conduct. The NIDDK Project Scientist or Project Coordinator will be a full participant and voting member of the Steering Committee and, if applicable, subcommittees.
3.Serve as a resource to study investigators with respect to other ongoing NIDDK activities that may be relevant to the study to facilitate compatibility with the NIDDK missions and avoid unnecessary duplication of effort.
4.Have substantial involvement assisting in the design and coordination of research activities for awardees as elaborated below:
a. Assisting by providing advice in the management and technical performance of the investigations, coordinating required regulatory clearances for investigational agents used in the study, which are held by NIDDK. The NIDDK may reserve the right to cross file
or independently file an Investigational New Drug Application or an Investigational Device Exemption form with the FDA.
b. The NIDDK Project Scientist or Project Coordinator may coordinate activities among awardees by assisting in the design, development, and coordination of a common research or clinical protocol and statistical evaluations of data; in the preparation of questionnaires and other data recording forms; and in the publication of results.
c. Reviewing procedures for assessing data quality and study performance monitoring.
d. The NIDDK Project Scientist or Project Coordinator may be co-authors on study publications. In general, to warrant co-authorship, NIDDK staff must have contributed to the following areas: (a) design of the concepts or experiments being tested; (b) performance of significant portions of the activity; (c) participation in analysis and interpretation of study results and (d) preparation and authorship of pertinent manuscripts.
The NIDDK Program Official identified in the Notice of Award will:
1.Interact with the Program Director(s)/Principal Investigator(s) on a regular basis to monitor study progress. Monitoring may include: regular communications with the Program Director/Principal Investigator and staff, periodic site visits, observation of field data collection and management techniques, quality control, fiscal review, and other relevant matters; as well as attendance at Steering Committee, data and safety monitoring board, and related meetings. The NIDDK retains, as an option, periodic review of progress by researchers not involved with the study.
2.Review and approve protocols prior to implementation to insure they are within the scope of peer review, for safety considerations, as required by Federal regulations.
3.The NIDDK Program Official will monitor protocol progress, and may request that a protocol study be closed to accrual for reasons including: (a) accrual rate insufficient to complete study in a timely fashion; (b) accrual goals met early; (c) poor protocol performance; (d) patient safety and regulatory concerns; (e) study results that are already conclusive; (f) low likelihood of showing a benefit of the intervention (futility); and (g) emergence of new information that diminishes the scientific importance of the study question. The NIDDK will not permit further expenditures of NIDDK funds for a study after requesting closure except as specifically approved by the NIDDK.
4.Make recommendations for continued funding based on: a) overall study progress, including sufficient patient and/or data accrual; b) cooperation in carrying out the research (e.g., attendance at Steering Committee meetings, implementation of group decisions, compliance with the terms of award and reporting requirements); and/or c) maintenance of a high quality of research, which will allow pooling of data and comparisons across multiple cooperative agreement awards for common data elements.
5. Appoint an independent Data and Safety Monitoring Board (DSMB) as appropriate for Phase III clinical trials or other high risk studies, or an Observational Study Monitoring Board (OSMB) for observational/epidemiologic studies; these Boards will review study progress, safety data, and interim results, as appropriate, and provide guidance to the NIDDK. The NIDDK Program Official or their Project Coordinator will serve as the Executive Secretary and/or NIDDK program representative on the DSMB/OSMB.
Areas of Joint Responsibility include:
In addition to the interactions defined above, NIDDK Project Scientist and Awardees shall share responsibility for the following activities:
A Steering Committee organized by the study investigator(s) will be the main governing body of the study.
The Steering Committee has primary responsibility to design research activities, establish priorities, develop common protocols and manuals, questionnaires and other data recording forms, establish and maintain quality control among awardees, review progress, monitor patient accrual, coordinate and standardize data management, and cooperate on the publication of results. Major scientific decisions regarding the core data will be determined by the Steering Committee. The Steering Committee will document progress in written reports to the NIDDK Program Official, and will provide periodic supplementary reports upon request.
The Steering Committee will be composed of all Program Director(s)/Principal Investigator(s), (including those of data coordinating /statistical centers, if any) and co-investigators as deemed necessary, and the NIDDK Project Scientist. The final structure of the Steering Committee and voting procedures will be established at the first meeting. The NIDDK Project Scientist will have voting membership on the Steering Committee, and as appropriate, its subcommittees. The frequency of Steering Committee meetings will be dictated by a vote of the members of the Steering Committee.
A Chairperson of the Steering Committee, other than the NIDDK Project Scientist, will be selected by the NIDDK, in consultation with the Steering Committee. The Chairperson provides leadership to the Committee by conducting the Steering Committee meetings, representing the study group to the External Oversight Committee established by the NIDDK and by interacting closely with the awardees during protocol development and implementation.
Any disagreement that may arise on scientific/programmatic matters (within the scope of the award), between award recipients and the NIDDK may be brought to dispute resolution. A dispute resolution panel will be composed of three members --one selected by the awardee (or the Steering Committee, with the NIDDK member not voting), a second member selected by NIDDK, and the third member elected by the two prior selected members. These special dispute resolution procedures in no way affect the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations at 42 CFR Part 50, Subpart D, and HHS regulations at 45 CR Part 16.
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.
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Barbara Linder, M.D., Ph.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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