Part 1. Overview Information

Key Dates

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.

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Purpose

This funding opportunity aims to stimulate multi-disciplinary collaboration and secondary analyses of existing clinical research datasets, from two or more multi-site clinical research studies, for addressing scientific and / or clinically relevant hypotheses that have the potential to address knowledge gaps to inform future clinical trials and/or improve clinical care in research areas within the NINDS mission. For purposes of this RFA, existing clinical research datasets refers to datasets from clinical trials, natural history studies, and / or comparative effectiveness research studies but excludes mechanistic clinical studies and basic experimental studies of humans (for definitions see https://grants.nih.gov/grants/guide/notice-files/NOT-NS-18-011.html and https://grants.nih.gov/grants/glossary.htm#BasicExperimentalStudieswithHumans, respectively). This RFA will support the curation and analyses of datasets from two or more multi-site clinical research studies to conduct additional secondary analyses; it will not support the collection of new data.

Background:

The substantial investments in clinical research from research participants, investigators, clinical staff, and funding agencies led the National Academy’s Institute of Medicine to recommend that clinical data be shared globally ( Sharing Clinical Trial Data: Maximizing Benefits, Minimizing Risk Institute of Medicine (U.S.), Eds., 2015), and the International Committee of Medical Journal Editors concluded that it is an ethical obligation to share clinical trial data, provided it is done responsibly (Taichman et al., 2016; https://doi.org/10.1371/journal.pmed.1001950). NIH encourages data sharing wherever possible, and has made significant investments in developing tools and resources to conduct large scale data science through initiatives such as the Big Data to Knowledge (BD2K) Centers, which provides tools spanning the data landscape, including metadata development, harmonization, processing, and analyses.

The NINDS directly supports activities to improve data aggregation and secondary analyses through the development and use of common data elements (CDEs) to improve data harmonization (https://www.commondataelements.ninds.nih.gov/#page=Default), and by making Phase 3 clinical datasets available through the NINDS archived clinical datasets (https://www.ninds.nih.gov/Current-Research/Research-Funded-NINDS/Clinical-Research/Archived-Clinical-Research-Datasets). Additionally, many datasets and samples from NINDS funded clinical studies are available through data management requirements in Traumatic Brain Injury (Federal Interagency TBI Research (FITBIR): https://fitbir.nih.gov/, NOT-NS-17-029 as well in Parkinson’s Disease, Lewy Body Dementia and Parkinsonisms (Parkinson’s Disease Biomarkers Program Data Management Resource (PDBP DMR)): https://pdbp.ninds.nih.gov/researcher, NOT-NS-11-020). NINDS funded datasets are also available through the Rare Diseases Clinical Research Network (https://www.rarediseasesnetwork.org/about).

This RFA is designed to support the curation and analysis of combined existing clinical research datasets. Secondary analysis of existing clinical research datasets from more than one study is infrequent in neurological disorders and conditions due to the challenges of cross-project harmonization and curation. Combining data from two or more separate studies requires significant effort, expertise, and assessment in order to determine if datasets are compatible for additional analyses. For example, two studies may use the same data dictionaries, and therefore be harmonized; yet, in-depth review of study protocols and data collection practices may reveal differences that alter or confound interpretation. Data curation improves overall data quality through careful review of processes and procedures related to data collection, documentation, and interim analyses that can identify potential differences in administration, collection, procedural differences, scoring / measurement, and / or missing data. NINDS acknowledges that for pooled analyses to be possible, studies must be able to do the critical, yet time and labor-intensive effort of curating data across studies to determine where there is sufficient compatibility for aggregated analyses. As a consequence, this initiative provides funding for multidisciplinary teams that include extensive clinical, statistical and data informatics expertise to do secondary analyses of existing clinical research datasets from multiple multi-site projects. Applicants are encouraged to apply with applications that seek to address broad issues of heterogeneity related to demographics (age, race, ethnicity, gender, socio-economic status, and cultural diversity), disease state, point of care, and/or clinical protocols (e.g. treatment, primary outcome, and differences in care conditions, etc.). Although valuable in their own right, re-analysis of individual datasets is not appropriate for this opportunity.

Specific Research Objectives:

Applications to this RFA are expected to harmonize, curate and analyse data from two or more multi-site existing clinical research to promote discovery and / or validation of scientific or clinically-relevant hypotheses that 1) were beyond the scopes of the original studies, 2) would not be possible using a single-site or single multi-site dataset , 3) validate or expand clinically significant findings, and / or 4) utilize new or advanced methods of analysis that allow exploration of important disease-related scientific or clinical questions. It is expected that the data used will primarily consist of individual participant level data (i.e. primary data). This RFA will not support the collection of new data.

The investigative team must include clinical subject matter expertise as well as statisticians and bioinformaticians/data scientists. Teams should include investigators involved in the original data acquisition either as part of the investigative team or as consultants. Inclusion of trainees and young investigators on the investigative team is also highly encouraged. This multi-disciplinary team-science strategy should encourage cross-fertilization of knowledge and utilize appropriate subject matter expertise for interrogating data. To ensure maximal value of the project, applicants to this FOA are expected to include open-source cataloging of the processes and tools used for harmonization, curation, and analysis, as well as provide a sustainable plan for controlled-access to the curated datasets.

Examples of potential research topics include, but are not limited to:

• Validation of diagnostic and/or prognostic models of outcome
• Comparative effectiveness hypotheses
• Mediation analyses of biological, cultural and environmental factors that affect treatment response or course of disease
• Evaluation of biomarker validity (including clinical outcome assessments (COAs)), in new populations and/or new context of use
• Discovery or validation of multi-domain clinical and/or biological measures for diagnosis, prognosis and/or treatment response using existing genetic and biological samples along with clinical and physiological assessments
• Extended characterization or validation of natural history disease course
• Novel methods for improving patient stratification

Examples of research that this RFA will not support include:

• Studies using non-human animal models
• Studies using data from a single clinical research study
• Multiple single-site clinical research studies
• Studies of harmonization, curation, and analysis where the primary data source is Electronic Health Record (EHR) data
• Studies of harmonization, curation, and analysis where the primary data source is metadata

Data Management Resources

In lieu of preliminary data, applications should provide sufficient information demonstrating that the datasets proposed to be combined are, or can be, sufficiently harmonized to proceed with curation and analyses. Investigators are encouraged to make use of existing resources, tools and training from the NIH’s BD2K Centers (https://commonfund.nih.gov/bd2k/centers), such as:

• The Center for Expanded Data Annotation and Retrieval (CEDAR) provides a computational ecosystem for development, evaluation, use, and refinement of biomedical metadata; https://more.metadatacenter.org/tools-training
• Center for Causal Discovery (CCD) develops computational methods known as causal discovery algorithms that can be used to discover causal relationships from a combination of observational data, experimental data, and prior knowledge; https://www.ccd.pitt.edu/tools/
• Big Data for Discovery Science (BDDS) provides software tools and data resources developed for the management, manipulation, and mining of large-scale biomedical data along with education and training resources; https://bd2k.ini.usc.edu/tools/.
• armonization to Existing Standards: Applications are expected to include plans to harmonize data, wherever appropriate, to the NINDS Common Data Elements (CDEs; https://www.commondataelements.ninds.nih.gov/#page=Default) for both outcome and non-outcome variables. CDISC standards (https://www.cdisc.org/) should also be incorporated where applicable. Investigators are also encouraged to review and incorporate other relevant validated consensus standards to improve overall harmonization with other sources. Standards should be cited, and the selection should be justified.

Reproducibility and Data Sharing: To advance the goal of FAIR data and enhance reproducibility, investigators will be expected to share code/scripts, analytic tools/statistical models, protocols/processes and metadata -- used or developed for harmonization, curation, and analysis -- through open-access repositories. Therefore, investigators are strongly encouraged to use open-source software, analytic tools, and programming languages to promote interoperability as well as reproducibility. In this way, the FAIR principles for data sharing and the rigor and reproducibility of research will be enhanced. Applications should also describe where the original controlled datasets exist and how obtaining access to them may be requested.

Rigor: The research strategy should clearly describe how the application will utilize a rigorous design, execution, and interpretation of the proposed studies. NINDS encourages investigators, whenever possible, to address these elements directly in their applications. Investigators are urged to discuss these issues with Scientific/Research staff prior to submission of applications (see: NOT-OD-16-011 and NOT-OD-18-228).

Go/No-Go Criteria: Applicants should demonstrate feasibility of the planned analyses and hypotheses testing based on data harmonization and curation, as well as quantitative curation standards that establish the Go/No-Go Criteria needed to move from the R61 phase to the R33 analysis phase.

Section II. Award Information

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.

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

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

Applicant organizations

Applicant organizations must complete and maintain the following registrations as described in the 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.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration , but all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

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

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

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.

2. Cost Sharing

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

3. Additional Information on Eligibility

Number of Applications

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101)

Section IV. Application and Submission Information

1. Requesting an Application Package

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

2. Content and Form of Application Submission

Letter of Intent

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Patrick Frost Bellgowan, PhD
Telephone: 301-496-1447
Fax: 301-480-1080
Email: [email protected]

All instructions in the SF424 (R&R) Application Guide must be followed.

Specific Aims: Provide the overall goals or hypothesis of the entire project and list separate Specific Aims to be accomplished: briefly outline the methods proposed and summarize the expected outcome. Briefly describe how the hypotheses being tested are unique from, are a significant advancement of original studies hypotheses, or provide a unique opportunity to validate or expand the knowledge gained in the original studies. Within the Specific Aims section, include headers titled R61 Phase Specific Aims and R33 Phase Specific Aims. Under each header, state the specific objectives and goals of that phase, technical challenges to be addressed and/or scientific or clinical hypotheses to be tested. Since the goal of the R61 phase of this FOA is data harmonization and curation, hypothesis testing, per se, may not be applicable in the R61 phase.

Premise: Describe the overall scientific or clinical need and significance of the research question and how it may impact future clinical trials or clinical care. Applicants must propose to harmonize, curate and analyze data from two or more multi-site existing clinical research datasets and justify the need for the combined cohort, including relevance and necessity of any non-U.S. study populations. Provide feasibility evidence that the multi-site existing clinical research datasets to be combined have been, or can be, harmonized. Include evidence that the datasets to be combined were collected in a rigorous and unbiased way with sufficient quality assurances to assure value, (e.g. blinding, randomization, documentation of data collection practices, quality checks and version control).

Collaboration: Applicants must form multidisciplinary teams that consist of the relevant expertise to accomplish the goals outlined in the research plan. Teams should include, at minimum, a mix of clinical, statistical and informatics and/or computational experts. Additionally, applications should include plans for incorporating trainees and/or young investigators into the research team to facilitate cross-fertilization of data-science and scientific/clinical research expertise in the next generation of researchers.

The R61 Research Plan should describe the goals, processes, and deliverables of data harmonization and curation, and operational definitions of "harmonization" and "curation" must be provided. Descriptions of the data types, provenance, and accessibility must be provided for each of the multi-site existing clinical research datasets including verification that the data to be harmonized, curated, and analyzed consist primarily of individual participant level data.

The data harmonization component should demonstrate the feasibility of the project; for example, by providing evidence that the projects data dictionaries (nomenclature) are aligned to validated consensus standards including use of all applicable NINDS CDEs and CDISC standards and that relevant outcome assessments or diagnostics protocols have sufficient similarity to be harmonized. A plan for obtaining or retrieving the relevant datasets should also be addressed with letters of support provided where necessary, including evidence that the datasets were collected with the appropriate consent forms to allow for the proposed studies. The data curation component should provide detailed descriptions of how the datasets will be interrogated for quality assurance and reviewed for reliability, including, but not limited to security, user access documentation, data entry quality assurance checks, audit trails, and data version control. Clear data quality criteria must be included that provide justification for inclusion, imputation, and exclusion of relevant data points and data elements. Successful applications will include in-depth reviews of study protocols and data collection practices to identify where differences may alter or confound interpretation, along with plans to address such issues. Applicants should include a description of the intended curation pipeline, ensuring it is documented, reproducible and uses approaches/code/software designed for interoperability. Software, code/scripts, tools, and metadata standards developed for harmonization and curations should be shared (e.g., using open-source software code repository) and should consider interoperability with other sources. Metadata created during the harmonization and curation process must also be shared. Applicants should request appropriate staff and computational time to allow for unforeseen challenges that may arise.

The R33 (phase 2) Research Plan should describe the analysis/es plan, and directly address the risk for spurious findings from aggregated datasets. Applicants should include sufficient background to demonstrate how the scientific or clinically relevant hypotheses are unique from, or will sufficiently expand upon, the studies where the data originated, as well as how the combined cohort provides a unique opportunity to test the research question(s). Additionally, applications should discuss and report effect size (e.g., percentage of variance explained) relative to the expected variance due to differences in data collection practices. A description of the approaches for dealing with missing data, and data outliers should also be included. Applicants are strongly encouraged to pre-register hypotheses, aim(s), design(s), and plans for statistical analyses to journals for peer review prior to beginning their project. All applicants are strongly encouraged to make use of the tools and resources available through the BD2K Centers wherever possible (https://commonfund.nih.gov/bd2k/centers). Resource sharing plans should include plans to publish the analyzed dataset with a data object identifier (DOI), include information on where and how to request controlled-access datasets and/or indicate what repository(ies) the data will be deposited. Additionally, the resource sharing plan should specify if a data sharing agreement will be required and the timeline (within one year after the end of the project end date). The resource sharing plan should also describe how or where any harmonization, curation and analytical protocols, scripts, and tools are/will be available.

Go/No-Go Criteria:

Transition from the R61 to the R33 phase is contingent upon the successful completion of the Go/No-Go criteria that demonstrate the feasibility of proceeding to the R33 analysis phase. The Go/No-Go criteria are to be included as the last element of the Research Strategy section of the application and will be evaluated as part of the scientific and technical merit of the R61/R33 application. The Go/No-Go criteria proposed in the application should be well-described, quantifiable, and provide scientifically justified decision-making goals for program staff to assess progress and successful completion of the R61 phase. A discussion of the curation goals relative to the progress of the R61 phase and the implications of successful transition to the R33 phase should be included. The clarity and completeness of the R61/R33 application with regard to specific goals and feasibility Go/No-Go criteria are critical. The Go/No-Go criteria should provide clear indicators of a project's continued success or emergent difficulties and will be used to evaluate the application as part of the consideration of the awarded project for funding the R33 phase by the Program Director(s)/Principal Investigator(s), and Program Official and Project Scientist . The final Go/No-Go criteria will be included in the Notice of Award and progress towards their achievement will be required in the annual progress reports.

The following modifications also apply:

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan. The Data Sharing plan should include information on:

• How and when the protocols, related tools, metadata, software and/or code used for harmonization, curation and analyses will be made available (open access is expected).
• How and where the final curated datasets will be located. If the data are privately held, information regarding the location, duration and process for requesting access to the data must be described. In such cases, a letter of support from the manager of the data archive should be included in the application indicating that the archive will accept the data set.

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.

The application include sufficient information to assure that the data to be used are in accordance with the patient informed consent forms, as well as any local, national or regional laws and policies.

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.

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

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

4. Submission Dates and Times

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.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement .

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

7. Other Submission Requirements and Information

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 components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Section V. Application Review Information

1. Criteria

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

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?

Further criteria specific to this opportunity:

Reviewers should specifically address and consider if the application is significant in one or more of the following criteria:

• Will the successful completion of the aims have the potential to inform future clinical trials and / or clinical care?
• Does the proposed analysis of the combined datasets extend the scope of the original studies to address a question or problem that would not be possible using a single-site or single multi-site dataset?
• Is the application utilizing the combined datasets to validate or reproduce clinically significant findings, and / or use new or advanced methods of analysis that allow exploration of important disease-related scientific or clinical questions?
• Does the application have the potential to address clinically important knowledge gaps or technological/methodological approach gaps that would not be possible or feasible in a single standalone study?
• Is the hypothesis unique from what could be tested in a standalone study?

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?

Further criteria specific to this opportunity:

• Does the investigative team include sufficient clinical, statistical and informatics expertise to achieve all aspects of the project?
• Does the investigative team include researchers from the studies involved in collection of the original datasets and/or have letters of support confirming members of the original studies will act as consultants on the research project?
• Is there evidence that the investigators will work as multi-disciplinary collaborative teams?
• Are there plans to incorporate trainees and early stage investigators into the research team? If not, is there a justification for their absence?

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?

Further criteria specific to this opportunity:

Reviewers should specifically address and consider if the applicatioin is innovative in its plan to use the combination of datasets (obtained from two or more multi-site clinical studies). Reviewers should consider if the application is innovative in at least one of the following aspects:

• Is the hypothesis to be tested unique from, or a significant advancement of, the research questions tested in the multi-site clinical studies where the data were collected? Alternatively, does the proposed analysis provide a unique opportunity to validate or expand on the knowledge gained in the original studies?
• Does the combined cohort provide a unique opportunity to understand a scientifically or clinically important question in a way that could not be achieved from analysis of each of the multi-site existing clinical research datasets separately?
• Are innovative and reproducible harmonization or curation strategies proposed and/or are unique tools or statistical approaches being developed?

Approach

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?

Further criteria specific to this opportunity:

• Does the application provide clear and justified operational definitions for data harmonization and curation ?
• Does the project propose to curate and analyze datasets from two or more existing multi-site clinical research studies ( existing clinical research studies includes clinical trial data, natural history studies, and / or comparative effectiveness research studies; for the purposes of this FOA it does not include mechanistic studies or basic experimental studies of humans : see https://grants.nih.gov/grants/guide/notice-files/NOT-NS-18-011.html and https://grants.nih.gov/grants/glossary.htm#BasicExperimentalStudieswithHumans).
• Will the proposed scientific or clinically relevant hypotheses address significant knowledge gaps that inform future clinical trials or clinical research and / or impact clinical care?
• Do the investigators provide sufficient evidence that the datasets can be successfully harmonized and curated to answer the research objectives?
• Do the data from the combined studies consist, primarily, of individual participant level data?
• Will the datasets be harmonized to NINDS CDEs and CDISC standards where appropriate?
• Do the investigators include plans to standardize the datasets to other appropriate validated consensus standards?
• Are clear data quality inclusion and exclusion criteria provided and justified?
• Is there a clear plan for assessing data quality?
• Is there evidence that the original datasets were collected in a rigorous and unbiased way, including, but not limited to: blinding, randomization, and documentation of data collection practices, quality checks and version control?
• Were the datasets collected with the appropriate study participant consent forms necessary to allow for the new application? If not, is there an appropriate and feasible plan for re-consenting participants where needed?
• Have the investigators presented a clear statistical plan to address relevant variables, including missing data and outliers?
• Is the statistical or informatics approach appropriate to address the proposed hypotheses?
• Does the applicantion propose a plan for sharing curation and analytic tools, code/scripts, protocols and / or processes and metadata, as well as computational and statistical models through a sustainable open-access repository?

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?

Does the application include sufficient information to assure that the data to be used are in accordance with the patient informed consent forms, as well as any local, national or regional laws and policies? If not, is there an acceptable plan to re-consent or obtain the necessary approvals?

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?

Go/No-Go criteria and timelines:

• Are the go/no-go criteria robust and associated with clear, quantitative milestones for success that allow go/no-go decisions at the R61/R33 transition point? If a milestone is not to be used for go/no-go decisions, is it justifiable?
• Do the go/no-go criteria provide confidence that the investigator will be able to successfully achieve the R33 phase?
• Are the timelines proposed for achieving the goals set in the R61 phase realistic and inclusive?

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

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

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).

Reviewers should include specific comments on whether the Resource and Data Sharing plan includes adequate information on the following questions:

• How and when will the metadata, protocols, related tools, software and/or code used for harmonization, curation and analyses be made available?
• How and where will the final curated datasets be made available? Is the archive/repository or central database specified and appropriate?
• Is there a plan for documenting any transformations to prepare the data for preservation and sharing?
• What metadata documentation will be submitted with the data?
• Will a data sharing agreement be required and, if so, what will the agreement include?
• Will data be provided directly to the researchers, or will access be provided to a restricted online database or at a CDC-controlled site (e.g., the National Center for Health Statistic’s Research Data Center)?
• What is the expected timeline from data analysis to release or anticipated date of release (note that release should be within one year from the project end date)?

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.

2. Review and Selection Process

• 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.
• Will receive a written critique.

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

3. Anticipated Announcement and Award Dates

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

Section VI. Award Administration Information

1. Award Notices

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.

2. Administrative and National Policy Requirements

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 https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-individuals/section-1557/index.htmlhttps://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html. 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. 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.

3. Reporting

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.

Section VII. Agency Contacts

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: [email protected] (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: [email protected]

Patrick Frost Bellgowan, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: ?(301) 496-1447
Email: [email protected]

Ernest Lyons, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-4056
E-mail: [email protected]ov

Tijuanna Decoster, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9231
E-mail: [email protected]

Section VIII. Other Information