It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

The purpose of this Funding Opportunity Announcement (FOA) is to solicit applications for Statistical and Data Management Centers (SDMCs) for the HIV/AIDS Clinical Trials Networks. The SDMCs will be responsible for the statistical and data management leadership and coordination critical to the NIAID HIV/AIDS Clinical Trials Networks.

The National Institute of Allergy and Infectious Diseases (NIAID) and its IC partners currently support five HIV/AIDS clinical trials networks: the AIDS Clinical Trials Group (ACTG), the HIV Prevention Trials Network (HPTN), the HIV Vaccine Trials Network (HVTN), the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT), and the Microbicide Trials Network (MTN). NIAID is soliciting applications for FY21 award consideration for the following four HIV/AIDS Clinical Trials Networks: HIV Prevention Clinical Trials Network, HIV Vaccines Clinical Trials Network, HIV/AIDS Adult Therapeutics Clinical Trials Network, HIV/AIDS Maternal, Adolescent and Pediatric Therapeutics Clinical Trials Network.

Since the beginning of the HIV/AIDS pandemic, the National Institutes of Health (NIH) has advanced understanding of disease mechanisms and used basic science to create opportunities for the discovery, development, and clinical evaluation of novel prevention and treatment strategies. With this approach, the scientific community has created an array of effective tools to treat and prevent HIV infection. Over the last 35 years, these interventions have been made safer and more effective. However, according to the latest Joint United Nations Programme on HIV/AIDS (UNAIDS) Global summary of the AIDS epidemic, there are approximately 36.9 million people living with HIV, 25.7 million of whom are living in sub-Saharan Africa, with 1.8 million new infections per year across the world. Significant challenges remain in delivering treatments and methods of prevention to the people who need them most. Although rates of death due to HIV/AIDS and rates of new HIV infections are declining in many areas of the world, these declines vary by region and in many places are slower than anticipated in reaching 2020 goals. In many parts of the world with generalized HIV/AIDS epidemics, new HIV infections far outpace access to effective antiretroviral treatment (ART). Even in the U.S. and other industrialized nations, where the HIV epidemic continues unabated particularly in most at-risk populations, a large portion of individuals who meet treatment guidelines do not have access to ART.

The success of the NIAID HIV/AIDS Clinical Trials Networks rests on the foundation provided by the SDMCs; strong data management and statistical leadership and expertise, and robust, flexible data management systems that support a large number of clinical and laboratory studies undertaken in both resource-rich and resource-limited settings.

As a result of rapidly evolving information technology and regulatory requirements, clinical data management systems and regulatory agencies increasingly require electronic submissions of standardized data compliant with regulatory standards (e.g., 21 CFR Part 11) and international guidelines (e.g., ICH E6(R2)). The need for cost-effective clinical data management has driven the need for electronic data capture (EDC) and remote data capture (RDC) to facilitate high-quality data, ability to support remote monitoring, and to use electronic communication tools to query and resolve data issues. Finally, the ability to exchange and analyze multiple large complex data sets holds promise for learning more from existing and future clinical trials. In this context, the SDMCs adopted an industry-leading electronic clinical data management system using EDC that supports flexible data models for downstream reporting and manipulation of clinical trials data. The SDMCs develop and deploy global electronic case report form (eCRF) libraries to support Clinical Data Interchange Standards Consortium (CDISC) standards using EDC. This is a multipronged effort with specific focus on producing CDISC-compatible data sets from existing noncompatible databases. To support efficiency, the SDMCs and the clinical trials networks adopted beginning-to-end CDISC compatibility for new studies implemented in the clinical data management system. The SDMCs continue to participate in development of CDISC Standards for HIV providing subject matter expertise for specific data and analytic components.

The SDMCs have provided laboratory data management support for i) the network Laboratory Centers (LC) operations to accommodate millions of records consisting of assay results on primary and secondary protocol objectives, ii) a validated specimen management system, and iii) the development of pipelines for transfer of LC data from new assays for storage, analysis and reporting.

The SDMCs continue to play a central role in harmonizing statistical and data management activities across studies and clinical trials networks, both to allow cross-study data analyses and to maximize the efficiency with which studies can be developed and implemented.

The SDMCs have developed and refined practices and procedures to share data with other network awards, other NIAID HIV Clinical Research networks, and researchers outside the network structure.

The SDMCs provide the networks in-depth understanding of statistical and epidemiological theory, broad practical experience in the design and analysis of clinical trials, observational studies, and assay validation, standardization, and optimization. The SDMCs have also provided expertise for studies that contribute to knowledge of pathogenesis and of mechanisms of drug action, studies evaluating new diagnostic methods, as well as interventions for prevention or treatment, which may include studies in every phase of product development. Examples include refinement of i) study endpoints (for measuring safety, infection, viremia and disease progression), ii) clinical trial adaptive design sequential monitoring procedures, which optimize ethics, scientific integrity, resources and adaptivity, iii) statistical methods to assess durability of vaccine efficacy, iv) methods to compare vaccine efficacy and durability among different vaccine arms within a trial compared to one placebo group, post-infection vaccine effects, host genetics and risk behavior and adherence. The SDMCs have also played a pivotal role in the development and refinement of novel quantitative methods (such as integrating biostatistics, bioinformatics, and computational immunology) for assessing and developing immune correlates of protection against HIV-1 infection and post-infection endpoints for regimens showing efficacy, including immune response biomarker optimization, assessment of correlates of risk (CoRs) and correlates of protection (CoPs) and sieve analysis.

Finally, the SDMCs collaborate to address issues that span multiple networks, such as those related to Medical Dictionary for Regulatory Activities (MedDRA) coding in network studies; the FDA Electronic Data Capture guidance; and cross-network laboratory data activities and standardization. They have contributed to the trial issues related to adherence to treatments; and standardization of ascertainment of gender/transgender across networks.

NIAID is soliciting applications for FY21 award consideration for the following HIV/AIDS Clinical Trials Networks:

• HIV Prevention Clinical Trials Network
• HIV Vaccines Clinical Trials Network
• HIV/AIDS Adult Therapeutics Clinical Trials Network
• HIV/AIDS Maternal, Adolescent and Pediatric Therapeutics Clinical Trials Network

Research Priority Areas for each of the HIV/AIDS Clinical Trials Networks can be found on the NIAID website here.

NIAID plans to fund one SDMC award for each network. Each application in response to this FOA must address only the research priority areas of ONE HIV/AIDS Clinical Trials Network. Applications addressing the research priorities areas of more than one HIV/AIDS Clinical Trials Network will be considered non-responsive and will not be reviewed.

Each HIV/AIDS Clinical Trials Network is composed collectively of a Leadership and Operations Center (LOC), a Laboratory Center (LC), a Statistical and Data Management Center (SDMC) and affiliated Clinical Trials Units (CTUs) and Clinical Research Sites (CRSs). Each will be funded via an independently-solicited FOA and each will contribute specific essential functions necessary to support a large-scale, complex clinical research program. While the emphasis of each network is on clinical trials, clinical research studies that aren't NIH-defined clinical trials are also in scope when undertaken to support the program. For the purpose of this FOA, the term "clinical study" refers to both clinical trials and clinical research studies, and "clinical trial" is used to refer to clinical trials only.

The LOC will manage the network’s scientific priorities and the corresponding alignment of clinical studies with those priorities. The LOC has primary responsibility for the prioritization, selection and development of clinical protocols and project management of the full spectrum of activities needed to plan and conduct clinical trials including the coordination of efforts by the LC and SDMC, and clinical sites. The LOC has responsibility to assure that the research is conducted according to principles of Good Clinical Practice (GCP).

The LC will lead the development, implementation and evaluation of the laboratory activities that are required to carry out the network research agenda. The LC will ensure that there are relevant state-of-the-art expertise and technologies to provide clinically useful study data and enable sound product development decisions. The LC will oversee laboratory operations that allow for consistent and reproducible laboratory results that can support study reconstruction.

The SDMC will provide comprehensive data management and data analyses for network clinical studies in compliance with regulatory standards. The SDMC will provide leadership and services for biostatistics, study design, analysis, interpretation and publication of results, including innovative statistical methods, along with state-of-the-art clinical trial management systems and laboratory information management systems to ensure complete, high-quality data.

The CTUs will provide scientific and administrative expertise as well as the infrastructure to conduct clinical studies within the network. A CTU is composed of at least one, but no more than eight, Clinical Research Site(s) (CRSs) that can contribute to at least two HIV/AIDS Clinical Trials Networks.

Each Clinical Trials Network will have an Executive Management Committee (EMC) to coordinate the activities of the Network's LOC, LC and SDMC. The EMC will include the PDs/PIs from the LOC, LC and SDMC and will be chaired by the PDs/PIs from the LOC.

Additional Resources provided by NIAID:

• Safety Oversight Committees: NIAID oversees the safety of all participants in clinical trials funded by NIAID. Generally, NIAID DAIDS will provide NIAID-convened Data and Safety Monitoring Boards (DSMBs) to monitor Phase II, Phase III and Phase IV multicenter, randomized clinical trials.
• Other Support Services: NIAID will provide additional support services for network trials that must be conducted under an Investigational New Drug (IND) or Investigational Device Exemption (IDE). These services may include domestic and international regulatory sponsorship, management of clinical study products, and clinical site monitoring. In addition, there are resources for clinical laboratory quality assurance and proficiency testing. A detailed description of these NIAID contract resources can be found at this website.

The SDMC provides a framework for statistical and data management leadership, services, and systems that contribute to the development and implementation of its network's research agenda. A research agenda is a broad strategic plan to address the stated research priority areas of the network. The LOC, in collaboration with the LC and SDMC, articulates the network's scientific agenda, establishes a framework for the initial studies, and plans for future studies. The SDMC collaborates and coordinates with the LOC, LC and CTU/CRS to support the research priority areas of the network (as described in the companion FOAs) through development, implementation, and sharing the results of clinical studies. The SDMC provides leadership, services and systems for clinical and laboratory data collection and management required for complete, high-quality data, and leadership and services for biostatistical analysis, study design, analysis, interpretation and publication of results, including innovative statistical methods.

The SDMC is responsible for the integrity of study design and statistical analysis for all clinical studies. The SDMC is responsible for compliance with all applicable federal regulatory standards and international guidelines that apply to studies conducted under an Investigational New Drug or Device Exemption (IND/IDE). The SDMC has a central role in standardizing and harmonizing data management and statistical activities within the network and coordinating with other NIH-sponsored programs. Other SDMC responsibilities for governance include:

• Supporting the overall management, integration and coordination of all SDMC activities with the LOC, LC and CTU/CRS.
• Aligning SDMC priorities with the network research agenda as coordinated by the LOC.
• Tracking and reporting protocol status data to the LOC, LC, CTU/CRS and NIAID using project management software to allow transparent network and NIAID resource planning and real-time communication and adjustment.
• Promoting mentorship and involvement of early-stage investigators, under-represented minorities, and investigators from resource-limited settings in SDMC activities.

Data Collection and Management

The SDMC provides, maintains, supports and updates commercial off-the-shelf (COTS) clinical trial management systems that include electronic data capture (EDC) and are interoperable with the laboratory information management systems (LIMS). These systems provide data collection, exchange, storage, tracking and retrieval of clinical and laboratory data for the network including CTUs/CRSs and Protocol-Specific sites.

Both clinical trial management systems and laboratory information management systems must be 21CFR part 11 and ICH E6 compliant. DAIDS reserves the right to audit the vendors and their sub-contractors.

As needed, the SDMC interfaces, integrates or adapts its information system(s) to be interoperable with NIAID systems.

The SDMC supports collecting, storing and providing data in accordance with regulatory requirements as defined by FDA and ICH and collaborating with other DAIDS-affiliated SDMCs in the development of data elements that do not currently exist within CDISC.

The SDMC provides specific capabilities including:

• an Interactive Response Technology (IRT) System for subject registration and randomization
• a laboratory information management system that integrates with IRT to manage study specimens in real time, for use by the SDMC, study sites, laboratories and others.
• an electronic data capture clinical data (EDC) system(s) and associated electronic case report forms (ECRFs) that are compliant with 21 Code of Federal Regulations (CFR) Part 11 and Health Insurance Portability and Accountability Act (HIPAA) for remote/direct data entry and transmission of subject data from study sites and laboratories to the central data management location. The EDC system must be interoperable or fully integrated so that data from various sources can be merged to yield generalizable results. The system provides for targeted source data verification.

The SDMC may establish procedures for alternative data capture (e.g., a system for off-line data entry when internet connection is not available) as described in NIAID DAIDS policies.

When Electronic Health Record (EHR) Systems are used the SDMC will ensure the interoperability of the EHR data and the EDC system and maintain a record of EHR systems used by each clinical research site and status of data sharing agreements.

The SDMC provides timely data access, statistical analysis and reports for:

• Safety Oversight, and the Safety Oversight committees.
• Clinical research site and protocol-specific reports: Provide reports such as accrual, demographics, protocol deviations, data queries, timeliness of data submission, and response to queries for quality assurance purposes and for protocol project management.
• Clinical research source data collected in studies sponsored/funded by NIAID/DAIDS and its IC partners for purposes of clinical monitoring.

Regulatory Compliance/Adherence to Regulations and Standards

Under the coordination of the LOC, the SDMC has primary responsibility for compliance with 21 CFR and ICH guidelines as they relate to clinical trial data management at the SDMC, LC and CTU/CRS and statistical aspects of study design.

The SDMC provides the necessary SOPs, personnel, data management, statistical, and communications expertise and systems, and follows U.S. regulations, Good Documentation Practice, Good Clinical Data Management Practices, and relevant international guidelines (ICHE6R2) to support network operations and meet NIAID requirements, to include:

• Ensuring timeliness, accuracy, confidentiality and integrity of data transferred within the network (i.e., laboratories, CRSs, SDMC)
• Ensuring timeliness, accuracy, confidentiality and integrity of data transferred between the network and NIAID systems, NIH systems, and other federally required IT systems.
• For timely submission of data as required by the Food and Drug Administration (FDA) and other regulatory agencies.

The SDMC operates in compliance with:

• current applicable US regulatory authority and/or public laws regulations located at Code of Federal Regulations Title 21 and 45 CFR 46 (e.g., 21 CFR 11, 21 CFR 50, 56, 312, 612 and 812 as applicable, 45 CFR 46 and/or similar statutes), including U.S. Public Law 110-85 or the Food and Drug Administration Amendments Act of 2007, as well as local regulations as applicable.
• current globally-accepted standards, including the following:
• International Conference on Harmonization (ICH) E2, Clinical Safety Data Management, ICH E3 Clinical Study Reports, ICH E6 Good Clinical Practice, located at ICH Guidance Documents.
• M1 MedDRA Terminology and ICH M5, Data Elements and Standards for Drug Dictionaries, located at: http://www.ich.org/products/guidelines.html.
• the World Health Organization Drug Dictionary, located at https://www.who-umc.org/whodrug/whodrug-portfolio/whodrug-global/
• current industry standards for clinical data management, current example Clinical Data Interchange Standards Consortium (C-DISC) located at: http://www.cdisc.org. Provisions to maintain compliance with changing industry standards must be in place.

Data Quality Management, Assurance, and Control

The purpose of Quality Management is to ensure protocol regulatory compliance, ensure human subjects protection and data integrity, and compliance with all applicable regulatory requirements. The SDMC will maintain a Quality Management Plan (QMP) including Quality Assurance and Quality Control processes and procedures for monitoring the accuracy, completeness and timeliness of the data entered into the SDMC clinical data system by CTU/CRS and PSS sites from study initiation/subject enrollment to database lock. The system needs to allow verification of study data and the following capabilities:

• Electronic validation and error-checking (e.g., range checks, user logics) to evaluate and improve the accuracy, timeliness and completeness of data submitted by the clinical sites.
• Strategies to assure uniform standardized data collection and implementation of multi-center studies across participating clinical sites.
• A data query system to notify and request resolution from clinical and laboratory sites.
• Periodic (at least annually) review and revision of manuals and procedures documenting data collection, editing and validation procedures and standards.
• Evaluation of the quality of data including data quality improvement plans, when necessary.
• Ongoing risk management assessments of the overall SDMC enterprise and trial-specific activities.

The SDMC will participate in independent quality audits initiated by NIAID DAIDS.

Data Access and Storage

The SDMC works cooperatively with counterparts from other NIH-supported clinical trials networks to conduct collaborative research projects and provide capability for cross-protocol and cross-network data analysis through:

• Establishment of standard data interfaces and common data elements, protocol status definitions, endpoint verification, formats for data collection, and site identification systems;
• Preparation and sharing of datasets for meta and epidemiologic analysis
• Adaptation of current data systems and structures to accommodate multi-network collaboration and data exchange

The SDMC provides validated data storage for studies conducted through the network and other datasets upon request by NIAID.

Data sharing is expected to increase the value of the significant public investment in the HIV/AIDS Clinical Trials Networks. NIH expects that datasets will be shared with the scientific community for research, while carefully observing standards of patient privacy, confidentiality, and management of health information. Information such as study protocols, descriptions, and publications are expected to be made available through open access public web sites, and publication in the scientific literature.

SDMCs are expected to prepare and transfer data to NIAID-approved controlled-access repositories when requested, as appropriate and consistent with achieving the goals of the program.

Clinical Site and Laboratory Training, Assessment and Technical Assistance

The SDMC serves as a network resource for CTU/CRS and protocol-specific sites for assessment, training and evaluation with respect to data collection and management. The SDMC:

• prepares materials for the implementation of clinical studies including electronic Case Report Form (eCRFs), protocol-specific and site-specific randomization and data entry screens, and other study-related materials as needed.
• develops instructional materials and conducts training as needed for data-related study implementation.
• provides data on site performance to evaluate site performance.
• provides assessment of site and laboratory capabilities for:
• technical expertise
• data entry and data management systems used to collect, manage, secure, validate, and analyze data.
• verifies site and laboratory data management readiness prior to protocol implementation (opening to enrollment) including review of training documentation for information systems.
• trains clinical research site and protocol-specific site and laboratory staff on data management and laboratory information management systems to track specimens.

Study Design, Data Analysis, Data Reporting

The SDMC provides leadership and expertise for protocol selection and development, informing experimental study designs, and providing statistical advice concerning issues such as approach, power, sample size, and impact of interim analyses. The biostatisticians support early-phase and late-phase, multi-institutional clinical trials including integral and integrated biomarker/correlative science studies. When needed, the SDMC develops new applications of statistical or information science theory.

• For each protocol the SDMC has the primary role in the performance of analyses including interim analyses, analysis in support of Safety Monitoring Committees (SMCs), Data Safety Monitoring Boards (DSMBs), final statistical analyses, and preparing information for ClinicalTrials.gov results reporting requirements. (Submission of the information to ClinicalTrials.gov will depend on the entity that is the responsible party.)
• The SDMC has a central role in data analysis for preparation of abstracts, journal articles, scientific presentations, Clinical Study Reports, and Annual Reports.
• The SDMC provides capacity to conduct ad hoc analyses, including analyses on datasets not generated by the network when requested by NIAID DAIDS.

Network Meetings. Each network will hold at least one annual meeting to share recent findings and facilitate collaborations. All key personnel and NIAID program staff are expected to attend and participate. External Advisors may also attend the program update portion of the meeting.

External Interactions and Opportunities. The SDMC will be strongly encouraged to coordinate with other HIV/AIDS Clinical Trials Networks, their respective SDMCs and other NIH-supported networks and other Federal and private sector clinical research programs, and to interact with government, non-government and community organizations (including the private and non-profit sector), to maximize the impact of research efforts and effective use of resources. Opportunities for such synergy include development of clinical infrastructure in resource-limited settings and harmonization of common data elements and data entry interfaces.

The SDMC will need to coordinate with NIAID groups including but not limited to: the NIAID Strategic Working Group (SWG), DAIDS Office of Clinical Site Oversight (OCSO), the DAIDS Clinical Laboratory Oversight Team (DCLOT) and the Office of HIV/AIDS Network Coordination (HANC).

Funding to carry out the network's research agenda falls into two categories:

Core Funds. NIAID will provide core funds directly to the LOC, LC, SDMC and network-affiliated CTUs on an annual basis. Core funding is the initial fixed-base funding and provides infrastructure and salary support that is not protocol-specific. Examples include, but are not limited to:

• Administrative and management support
• Community education and engagement structures and activities
• Clinical quality management activities
• Maintenance and replacement of equipment
• Travel to attend clinical trials network meetings
• Mentoring and training of staff
• Record retention to meet regulatory requirements

Protocol Funds (PF). NIAID will provide PF to the LOC, LC and SDMC on an annual basis. In addition, NIAID anticipates providing PF directly to network-affiliated CTUs on an annual basis. PF provides support to conduct protocols, including protocol-specific infrastructure or other requirements needed to conduct protocols at a site. PF varies annually, depending on costs of ongoing protocols and will be awarded to cover expenses attributable to protocol development, implementation or close-out of a clinical trial. Protocol funds include, but are not limited to, the following protocol-specific expenses:

• Personnel salary (protocol-specific)
• Good and Services Tax (GST) where required
• Protocol-specific data management
• Protocol specific data analysis
• Travel for protocol-specific personnel, as required by network, to attend clinical trials network meetings
• Travel to attend or conduct protocol-specific trainings or to evaluate site data management readiness for individual protocols
• Equipment and supplies

NIAID expects that equipment and services funded via Core or PF will be made available, as appropriate, for other NIAID-funded network activities regardless of how funds were initially provided to purchase those items.

Based on communications with the LC, SDMC and CTUs/CRSs, the LOC will estimate protocol funding needs for the network (salary and non-salary PF) annually and submit a budget request to NIAID. NIAID will then determine the amount of PF to be provided in the coming grant year. Adjustments in PF allocation will be made at regular intervals during each budget period, based on both performance and availability of funds.

Distribution of Protocol Funds to Network-Affiliated SDMCs

PF will be distributed to SDMCs directly from NIAID prior to enrollment of study participants following the process described above.

PF may also be provided to the LOC for its use and distribution to the SDMC to provide additional support for protocol-related expenses for activities that are not directly related to participant accrual.

Note: For further information please visit the following website for general information and questions and answers.

See Section VIII. Other Information for award authorities and regulations.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this FOA.

Higher Education Institutions

• 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:

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o 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

Other

• 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 not 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.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

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

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

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

• 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).

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.

It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

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:

Kumud K. Singh, Ph.D.
Telephone: 301-761-7830
Email: [email protected]

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed, with the following additional instructions.

The Research Strategy must consist of the following sub-sections with the indicated page limits:

Sub-section A. SDMC Overview, Structure and Governance - one required - 30 pages

Sub-section B. Data Collection and Management- one required - 12 pages

Sub-section C. Regulatory Compliance/Adherence to Regulations and Standards - one required - 12 pages

Sub-section D. Data Quality Management, Assurance and Control- one required - 12 pages

Sub-section E. Data Access and Storage- one required - 12 pages

Sub-section F. Clinical Site and Laboratory Training, Assessment and Technical Assistance - one required - 12 pages

Sub-section G. Study Design, Data Analysis, Data Reporting one required - 12 pages

Sub-section H. External Interactions and Opportunities - one required - 6 pages

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

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

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

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions.

Facilities & Other Resources: In addition to standard documentation for this attachment, applicants must identify the COTS clinical trial management system in place.

Other Attachments: Applicants must provide the following additional material specified below. The attachment should be uploaded as a separate PDF using the indicated filename (which will serve as an application bookmark).

Attachment 1. Quality Management Plan

Provide a full SDMC Quality Management Plan including quality control, quality assurance and quality improvement. If appropriate, provide an example protocol-specific Quality Plan for a protocol opened for enrollment since March 2018. (use filename: Quality Management Plan)

All instructions in the SF424 (R&R) Application Guide must be followed , with the following additional instructions.

In the biosketch, describe the relevant experience of the PD/PIs in leading and managing a Statistical and Data Management Center for multi-center clinical trials in a complex structure, including the roles and responsibilities served. Describe the experience of the PD/PIs and other key personnel in implementing and using a COTS clinical trial management system that includes an electronic data capture (EDC) system and development of electronic case report forms.

All instructions in the SF424 (R&R) Application Guide must be followed , with the following additional instructions.

The applicant should only request Core funding. Core funding is the initial fixed-base funding and provides infrastructure and salary support that is not protocol-specific. Examples include, but are not limited to:

• Administrative and management support
• Community education and engagement structures and activities
• Clinical quality management activities
• Maintenance and replacement of equipment
• Travel to attend clinical trials network meetings
• Mentoring and training of staff
• Record retention to meet regulatory requirements
• Information technology systems and equipment, including subcontracts
• Hardware and software maintenance, including lifecycle replacement and security updates
• Maintenance of up-to-date versions of current software licenses
• Technical support (indicate types, e.g., software as a service, vs. site licenses, cloud costs, hardware)

Protocol Funds (PF) should not be requested; PF will be determined and provided as protocols are initiated through a collaborative process between the NIAID and awardees as previously described.

If a single PD/PI is proposed, the PD/PI will be required to devote at least 6 person-months effort to the project. If two or more PD(s)/PI(s) are named, each PD/PI must devote at least 3.6 person- months effort to the project.

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

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

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Specific Aims: Describe the scientific aims of the Statistical and Data Management Center. The applicant must state which one of the four HIV/AIDS Clinical Trials Networks the SDMC proposes to support. (Research priority areas for the networks, including the cross-collaborative areas, are listed on this website.)

Research Strategy: The Research Strategy section must consist of subsections A-H as designated below.

Sub-section A. SDMC Overview, Structure and Governance

• Provide a general overview of the SDMC and describe the general features and operations of the SDMC. Based upon the two primary functions of the SDMC, (1) data collection, quality and integrity, and (2) biostatistical leadership: provide a diagram illustrating the organizational structure of the SDMC. The diagram should include the relationship between the Data Management and Statistical Analysis activities and illustrate how the SDMC would interact with the other key functions of the network in the LOC, LC and CTU/CRS. Discuss how the structure promotes effective leadership of data management and statistical functions and integration with clinical sites. Tables, diagrams, flow charts and organizational charts are strongly recommended.
• Discuss how the proposed structure and the individual strengths of the key personnel will facilitate designing and implementing statistical analyses and the development, validation and utilization of data systems designed to support research.
• Describe the overall strategy, methodology, and analyses to be used to accomplish the specific aims of the SDMC.
• Broadly describe data management, information technology (IT) and statistical analysis systems.
• Broadly describe the IT support for central storage, security, analysis and retrieval of clinical data.
• Describe the approach to project management needed to plan, balance, track, manage and report protocol activities in a timely manner.
• Provide plans for statistical and data management mentoring opportunities and involvement of early-stage investigators, under-represented minorities, and investigators from resource-limited settings.

For renewal applications: Progress Report should be included in sub-section A.

Sub-section B. Data Collection and Management

• Describe your clinical trial management systems and how they will provide data collection, exchange, storage, tracking and retrieval of clinical and laboratory data for the network research agenda being supported including CTUs/CRSs and Protocol-Specific sites. Describe the nature and type of data to be collected, and how these data taken together will address the overall goals and objectives for network clinical studies for the network that will be supported.
• Describe your policies and procedures for interfacing, integrating and or adapting information system(s) to interact with clinical research management systems such as NIAID N-CRMS or other information systems or components specified by NIAID.
• Describe your capabilities for:
• an Interactive Response Technology (IRT) System for subject registration and randomization
• a laboratory information management system that integrates with IRT to manage study specimens in real time, for use by the SDMC, study sites, laboratories and others.
• an interoperable or fully integrated electronic data capture clinical data (EDC) system(s) and associated electronic case report forms (ECRFs) that are compliant with Title 21 Code of Federal Regulations (CFR) Part 11 and Health Insurance Portability and Accountability Act (HIPAA) for remote/direct data entry and transmission of subject data from study sites and laboratories to the central data management location.
• targeted source data verification.
• Describe procedures for alternative data capture (e.g., a system for off-line data entry when internet connection is not available) as described in NIAID DAIDS policies
• Describe the process and timelines for reports, data access and statistical analysis for
• Safety Oversight, and the Safety Oversight committees.
• Clinical research site and protocol -specific reports such as accrual, demographics, protocol deviations, data queries, timeliness of data submission, and response to queries for quality assurance purposes and for protocol project management.
• Clinical research source data collected in studies sponsored/funded by NIAID/DAIDS for purposes of clinical monitoring.
• Determining co-enrollment for protocol status reports.
• Describe your procedures for interoperability of the EHR data and the EDC system when Electronic Health Record (EHR) Systems are used. Describe the documentation you maintain for a record of EHR systems used by each clinical research site.
• Describe procedures for compliance with NIAID DAIDS policies, regulations and procedures. Describe procedures used to guide software development including project planning, requirements definition, system design, implementation, integration and testing, deployment, maintenance, and system retirement. Describe validation processes.
• Describe efforts to establish processes and methods for common IT architecture in the clinical research community including defining technical standards, identifying security requirements, and identifying and integrating existing resources, promoting the use of clinical and research data that are machine readable and that adhere to the FAIR (findable, accessible, interoperable, and re-useable) principles.
• Describe the implementation and use of validated data collection systems, forms and formats, and identify any innovations in adapting database systems and structures to accommodate various clinical site, laboratory and collaborator needs.
• Address compliance with 21 CFR 11, HIPAA, and ability to support data interchange standards. Describe alignment with workflow systems.
• Describe the system for subject randomization and procedures for strict maintenance of blinding throughout studies. Describe procedures used for study randomization, randomization systems supported (web-based allocation, touch tone allocation, permuted block allocation, etc.), and procedures for verification and validation of eligibility prior to randomization. Describe the integration of your randomization system with the workflow and ability to generate protocol status reports.
• Describe the system and capabilities of the validated laboratory information management system to track specimens.
• Describe how the SDMC will support Good Data Practices. Describe efforts to develop and implement standard uniform protocols for data collection (e.g., Common Data Elements [CDE]).
• Outline the process and timeline for the SDMC to prepare for the implementation of an individual study including electronic Case Report Form (eCRFs), protocol-specific and site-specific randomization and data entry screens, and other study-related materials as needed.
• Describe plans to shift current data collection and management practices to address changes in regulatory requirements or opportunities provided by information technology advances and any advantage they may have over existing methodologies.
• Describe your project management system for forecasting the timelines for protocols and the need to provide data management, collection, and retrieval of data. Include the process for ongoing tracking of planned versus actual milestones. Describe the plans for communications to and from the LOC and means for adjusting resources as needed to meet agreed upon protocol schedules.

Sub-section C. Regulatory Compliance/Adherence to Regulations and Standards

• Describe measures used to ensure compliance with US regulatory authority and/or public laws and international standards (e.g., Title 21 CFR Part 11, ICH, CDISC) and Good Documentation Practices.
• Describe plans to prepare for and support external audits for regulatory compliance required by NIAID or regulatory agencies.

Sub-section D. Data Quality Management, Assurance and Control

• Describe challenges and approaches to manage
• timeliness, accuracy, confidentiality and integrity of data transfer within the network (i.e., laboratories, CRSs, SDMC)
• timeliness, accuracy, confidentiality and integrity of data transferred between the network and NIAID systems, NIH systems, and other federally required IT systems.
• timely submission of data as required by the FDA and other regulatory agencies.
• Describe your procedures for verification of study data and the following capabilities:
• Electronic validation and error-checking (e.g., range checks, user logics) to evaluate and improve the accuracy, timeliness and completeness of data submitted by the clinical sites.
• Strategies to assure uniform standardized data collection and implementation of multi-center studies across participating clinical sites.
• A data query system to notify and request resolution from clinical and laboratory sites.
• Periodic (at least annually) review and revision of manuals and procedures documenting data collection, editing and validation procedures and standards.
• Evaluation of the quality of data including data quality improvement plans, when necessary.
• Describe procedures tracking study progress as well for data quality control and accuracy verification, including how the data management staff works with the statistics staff on central monitoring and auditing activities. Describe procedures for active trial tracking, including procedures for accrual and biospecimen collection tracking, assessing case eligibility and evaluability, ensuring timely assessment of subject data, and monitoring of data timeliness.
• Explain SDMC guidelines for institutions/sites for data timelines, including a summary of data quality and timeliness as an indication of its potential to provide timely, high-quality data on clinical studies in an efficient manner.
• Describe proposed processes for the resolution of performance problems for the SDMC, sites or laboratories and processes for the development of remediation/improvement plans to avoid future problems.
• Describe procedures to prepare for and participate in independent quality audits initiated by NIAID DAIDS for review of processes, procedures and operations to document regulatory compliance and participate in sponsor/client audits and inspection by regulatory authorities.

Sub-section E. Data Access and Storage

• Describe efforts to establish standard data interfaces and common data elements, protocol status definitions, endpoint verification, formats for data collection, and site identification systems.
• Describe the process and timeline for preparation and storage and sharing of protocols and datasets for meta and epidemiologic analysis.
• Describe plans for adaptation of current data systems and structures to accommodate data exchange and multi-network collaboration.
• Describe the plans for data storage for network studies and for the long-term storage of complete data sets and associated metadata following publication of results.
• Identify any data sets that you have made available through deposition in data repositories and your plans for this in the future.

Sub-section F. Clinical Site and Laboratory Training, Assessment and Technical Assistance

• Describe the process for establishing and verifying data management standards required for clinical sites and laboratories. Describe the process to verify that clinical data is provided according to protocol and SDMC standards and procedures, addressing clinical monitoring results and resolving deficiencies. Describe the processes for resolving monitoring findings at clinical sites that impact data management.
• Describe plans for providing training for CTUs/CRSs investigators and staff and laboratory staff on the clinical trial management system and laboratory information management system for tracking specimens. Discuss how the SDMC will coordinate across network components to ensure appropriate training needs are met.

Sub-section G. Study Design, Data Analysis, Data Reporting

• Describe the information technology (IT) support for central storage, security, analysis and retrieval of clinical data for analysis.
• Discuss innovations in statistical methodologies, e.g., study design, control/comparison groups, sample size/power estimates, endpoints, stratification/blocking methods, that may broadly impact the field of HIV clinical research and improve the ability to understand HIV.
• Describe approaches to the experimental and/or refinements in trial design and monitoring and collection methods being proposed and potential problems.
• Explain how relevant biological variables (e.g., sex, race, ethnicity, biomarkers) are factored into research designs and analyses for clinical studies.
• Describe the procedures for study data and safety monitoring from the perspective of the SDMC and interactions with DSMBs, Safety Monitoring Committees, and NIAID/DAIDS data and safety monitoring, as well as sponsor audits and inspections by regulatory agencies. Provide SDMC policies and procedures for the timely provision of confidential closed and/or open data sets and presentation of data to the DSMB or Safety Monitoring Committee.
• Explain the processes for planning and conducting interim and final analyses (including safety analyses) of clinical studies, including the development of Statistical Analysis Plans. Discuss your procedures for preparing information for ClinicalTrials.gov results reporting requirements so that timelines for reporting are met. Describe the process for coordination with data management staff for data retrieval and statistical support for timely reports, presentations, and publications.

Sub-section H. External Interactions and Opportunities

• Describe ongoing collaborations related to data harmonization, data collection, data management, study design and analysis, and innovations in information systems to allow greater use of clinical studies data.
• Describe opportunities for such synergy including development of clinical infrastructure in resource-limited settings and harmonization of common data elements and data entry interfaces.

Letters of Support:

Provide appropriate letters of support, including any letters necessary to demonstrate the support of collaborators. Note that letters establishing intra-network and cross-network collaborations are not necessary.

Include a letter from the applicant organization(s) describing the role of institutional support of the following:

• negotiation and execution of subcontracts, and other legal agreements including but not limited to software licenses, cloud data services, hardware, direct electronic data capture process, specimen tracking, negotiation of data use agreements, and system validation processes.

Progress Report Publication List:

Provide the requested information in the application instructions with the most recent publications and patents first.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Appendix:

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When involving NIH-defined human subjects research, clinical research, and/or clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

Other Requested Information

For Renewal applications with ongoing clinical studies, applicants must include a list of all ongoing clinical studies and/or the unique ClinicalTrials.gov identifiers. All information must be combined in one single attachment using the filename "Ongoing Clinical Studies". If appropriate, please indicate for each study the NIAID Division of AIDS (DAIDS)-defined study status (https://rsc.niaid.nih.gov/networks-protocol-teams/developing-protocols).

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:

Although applicants must be prepared for clinical trials, definite plans for such involvement will not be possible at time of application. A Study Record MUST not be completed.

Delayed Onset Study

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, with the following additional instructions:

Both Renewal and New Applications must add and complete the Delayed Onset Study record and must check box "Anticipated Clinical Trial?".

Study Title-- use: "Multiple Delayed-Onset Studies"

Justification Attachment: Indicate each clinical study protocol developed during the project period will be subject to approval through a procedure that involves an initial concept submission and subsequent review by the HIV/AIDS Clinical Trials Network. If the concept receives approval, the next stage will be development of the protocol, which also must undergo review and approval prior to implementation through the HIV/AIDS Clinical Trials Network.

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

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

This initiative is not subject to intergovernmental review.

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

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

• Awards issued under this FOA will be incrementally funded awards for project periods of up to 7 years. Multi-year funded grants will not be awarded.
• Grants awarded under this FOA will be excluded from automatic carryover all carryover requests must be approved.
• Grants awarded under this FOA will not be provided the authority to automatically extend the final budget period one time for up to 12 months beyond the original expiration date shown in the Notice of Award all extensions, including the first extension, will require approval.
• Progress and financial reporting will be required and reviewed annually.
• All funds must be expended within the approved project period.

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.

Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

Only the review criteria described below will be considered in the review process.

Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

Specific to this FOA:

How well does the application balance needs for data management and statistical support? How well does the application demonstrate evidence of data management systems compliance with the necessary regulations and are the systems interoperable across all the duties and responsibilities of the SDMC and the network? Is the biostatistical research agenda novel, feasible and sufficiently flexible to address the clinical studies for the network it will support? Does the SDMC application depict an ability to adjust to future regulatory and other requirements, scientific opportunities, and activities?

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?

With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

Specific to this FOA:

How well does the data management team address the evolving regulated environment within which the SDMC must operate? Is the expertise of the data management staff appropriate for the types and phases of trials in the network research agenda it will support? Does the data management team demonstrate current knowledge of regulatory standards and guidelines?

Are the biostatisticians appropriate for the types and phases of trials being designed and conducted? Is documentation provided to support that investigators work as a cohesive research team to efficiently develop the statistical analysis plans for clinical trials as well as analyze results from completed trials? Does/Do the PD(s)/PI(s) plan to devote sufficient effort to perform his/her role within the SDMC?

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?

Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

Specific to this FOA:

Does the applicant propose any innovations in adapting information systems and structures to accommodate network or collaborator needs? Are innovations proposed in statistical methodologies, e.g., study design, control/comparison groups, sample size/power estimates, endpoints, stratification/blocking methods, that may broadly impact the field of HIV clinical research and improve the ability to understand HIV?

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?

Does the application adequately address the following, if applicable?

Study Design

Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?

Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

Data Management and Statistical Analysis

Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

Specific to this FOA:

• Is there an appropriate and clear organizational structure for the SDMC?
• Are there adequate lines of authority and strong, feasible governance plans for the SDMC?
• Are there feasible contingency plans and ability to re-direct efforts in response to direction from the Executive Management Committee?
• Do the SDMC Quality Management Plan and approaches described support regulatory compliance of clinical trials?
• Are there appropriate and feasible procedures to measure and assess the productivity and quality of the statistical support and data management and to adjust, as needed?
• Are there strong and feasible plans and procedures for providing data management services required by the network, including database design, security, confidentiality and administration, participant randomization/registration, data collection, quality control, data retrieval, report generation, and site training?
• Are there appropriate plans for continuous refinement of the data management infrastructure and approaches?
• Is there adequate consideration of validation and alternatives that allow interoperative systems?
• Are training and mentoring plans appropriate? How appropriate are training plans related to data management for clinical research site and laboratory staff?
• Are there strong and feasible plans and procedures for planning and conducting interim and final analyses of clinical studies and for strict maintenance of blinding throughout the study?
• Are the SDMC Quality Management Plan and supporting approaches sufficient to ensure data quality and integrity and ensure compliance with US regulatory authority/public laws?
• Does the SDMC describe policies and procedures for the timely provision of confidential closed and/or open data sets and presentation of data to the DSMB or Safety Monitoring Committee?
• Does the application demonstrate evidence of collaboration and experience in harmonizing processes to allow data analyses and approaches beyond individual trials?

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

If multi-sites/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?

Specific to this FOA:

Do the Information Systems described support the scale and scope of the data management and data analysis required for the network research agenda? Are information security and integrity well addressed? Are the software and hardware maintenance plans well aligned with the scope and scale of the network?

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Study Timeline

Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?

Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

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.

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.

Not Applicable

For Renewals, the committee will consider the progress made in the last funding period.

Not Applicable

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Not Applicable

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.

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the National Institute of Allergy and Infectious Diseases, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

• Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Allergy and Infectious Diseases Council. The following will be considered in making funding decisions:

• 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.

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

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

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.

ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain applicable clinical trials on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration of all trials whether required under the law or not. For more information, see http://grants.nih.gov/ClinicalTrials_fdaaa/.

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that the application as well as all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights 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.

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.html; and https://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.

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.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 75, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

PD(s)/PI(s) of the LOC, LC, and SDMC will have primary responsibility for the overall performance of the network, including, but not limited to the following within their individual awards:

• Identifying and implementing a clinical research agenda that addresses the NIAID scientific priorities and adapting the agenda over the period of the award.
• Establishing policies and procedures for collaboration with network elements and decision-making within the LOC to adapt to evolving research priorities over time.
• Maintaining close communication and coordination among the LOC, LC, SDMC, and affiliated CTU/CRS(s).
• Ensuring that the Quality Management Plans are implemented
• Convening or participating in meetings and teleconferences to facilitate collaboration and communication, to accomplish the objectives of the network.
• Overseeing all aspects of studies supported through the individual award, including study design, design modifications, conduct of the study, quality control and assurance, data analysis and interpretation, preparation of publications, dissemination of data, tools, and technologies, and collaboration with other investigators. PD(s)/PI(s) agrees to accept close coordination, cooperation, and participation of NIAID staff in those aspects of scientific and technical management of studies supported by this award as stated in these terms and conditions.
• Verifying that studies are conducted in compliance with 21 CFR Part 11 and ICHE6R2 guidelines.
• Adhering to NIAID DAIDS policy for the conduct of clinical trials.
• Managing involvement of industry or any other third party in studies supported by this award.
• Informing NIAID in the event that network grantee institutions enter into agreements that provide essential support (financial or in kind) to NIAID-sponsored clinical studies but are not actions as part of the network awards. The network grantee will inform NIAID of the terms of the agreement within 30 days of execution and provide updates in annual progress reports.
• Providing by-laws, policies and standard operating procedures to NIAID Program Staff within 90 days of issuance of an award, to include, at a minimum, the following:
• A Conflict of Interest (COI) Policy consistent with FDA regulations for Financial Disclosure by Clinical Investigators (21CFR54) in addition to requirements in the NIH Grants Policy Statement.
• Procedures to assure compliance with Division of AIDS Clinical Research Policies and Standard Procedures Documents and to ensure adequate protection of the rights and safety of subjects involved in the research.
• Detailed lines of authority and communication within the network and with NIAID program staff.
• Procedures to identify, qualify, and approve specific sites to address specific clinical research needs. In cases when clinical site capacity cannot be addressed within the existing CTU/CRS portfolio the LOC may identify, qualify, and approve protocol-specific sites as part of the LOC or associated with a CTU.
• Clinical Quality Management Plan, developed in accordance with DAIDS Requirements for Clinical Quality Management located within https://www.niaid.nih.gov/research/daids-clinical-site-implementation-operations and to be approved by DAIDS.
• Procedures for providing input to project protocol budgets and resource requirements, and tracking progress on protocols relative to award responsibilities, and communications to network and NIAID program staff to allow adjustment of the flow of resources to enable timely spending of funds and resources provided from outside the network awards.
• Determine the distribution of protocol funds, monitor expenditures relative to award responsibilities.
• Coordinate with NIAID and NIAID clinical research support programs to facilitate collection of site essential regulatory documents, activation of study sites, clinical site monitoring and quality assurance services, pharmacovigilance (SAE reporting) and safety oversight, in adherence with NIAID standards and processes.
• Coordinate with NIAID DAIDS Clinical Research Products Management Center (CRPMC) contractor to facilitate availability and distribution of study products.
• Ensuring the following are provided to NIAID Program Staff for each clinical trial:
• Project Management and communication plans
• Timelines and budgets
• Recruitment and Retention plan
• Clinical data management plan, including a process for sharing data with DAIDS and safety oversight group

Grantees are required to work closely with Clinical Monitors or Regulatory Auditors to ensure proper completion of all actions and steps associated with on-site monitoring or auditing, including review of corrective and preventative action plans when problems are detected.

If NIAID determines that a grantee fails to comply adequately with NIAID guidelines for the conduct of clinical trials, PD(s)/PI(s) will assure that the accrual of new patients to network protocols is immediately suspended and that the suspension remains in effect until notified that NIAID has conducted any required audit and the audit report or remedial action is accepted by NIAID. The PD(s)/PI(s) will assure that during the suspension period, no funds from this award are allowed for new accruals.

PD(s)/PI(s) of the Leadership and Operations Center (LOC) will have primary responsibility for the scientific leadership, administration and coordination of all network activities and the LOC, including, but not limited to:

• Convening and chairing the network's Executive Management Committee (EMC) to coordinate activities across the LOC, SDMC and LC and to coordinate activities with affiliated CTU/CRSs. The EMC is chaired by the LOC and includes the PDs/PIs of the LC and SDMC.
• Developing and implementing procedures for selecting and prioritizing research concepts
• Ensuring that protocol development is initiated only when:
• there is sufficient preclinical safety and supportive scientific data for the proposed study
• there is a commitment to supply sufficient study product, and financial resources are assured via an established system
• there is sufficient commitment and capacity within the network and CTU/CRSs to expeditiously complete protocol development, site approvals, accrual, conduct the study, analyze study data, and publish the research results
• there are transparent procedures in place for selecting members of a protocol team and selecting network-affiliated appropriate CTUs/CRSs
• there is a plan for assessing capacity of CRSs prior to site selection
• the protocol team is constituted with all the necessary expertise, including representation from the network Community Advisory Board and DAIDS
• the protocol chair has and commits adequate time throughout all phases of the protocol
• there are processes to ensure study reports are completed in a timely manner
• Ensuring that protocol implementation and oversight adhere to the following:
• established criteria for determining operational futility and when primary endpoints will not be reached within a pre-defined time boundary, prior to protocol initiation
• protocol approval by NIAID prior to protocol implementation
• resources to support the protocol such as study product, clinical site approvals for laboratories and pharmacies, and data management plans are in place
• mechanisms for monitoring study progress and participant safety, and provision of status reports to NIAID on an agreed upon schedule are in place
• previously outlined feasible follow-up plans, contingent upon study results, are in place
• results provided to study participants upon study un-blinding and to the community as soon as can be accomplished
• Ensuring that clinical trials are conducted in compliance with 21CFR Part 11 and ICHE6R2 guidelines
• Developing, training, and supporting network community advisory boards
• Implementing procedures for regular transparent assessment of CTU/CRS performance, which must include processes for the addition, reduction, expansion or elimination of network-affiliated CTUs/CRSs
• Determining, recommending and requesting protocol funds for the LOC, LC, SDMC and network-affiliated CTUs/CRSs and adjusting requested funds with protocol progress
• Meet administrative, oversight, and regulatory requirements by prompt submission of required information to NIAID including but are not limited to:
• Reports required by the IND sponsor, to fulfill regulatory requirements, compliant with federal regulations and NIAID procedures for clinical trials.
• Protocol documents; patient accrual and demographics; information concerning network-affiliated CTUs/CRSs; names, contact and additional information requested of all senior/key personnel; and training records
• PF reports as requested by NIAID
• As part of the annual non-competing RPPR, summarize all research accomplishments and provide detailed metrics on network performance and for the LOC, LC, SDMC and network-affiliated CTUs/CRSs. This annual report will also discuss activities, difficulties, corrective actions, and future directions with complete budget justifications.

PD(s)/PI(s) of the Laboratory Center (LC) will have the primary responsibility for the overall planning, execution and review of all laboratory center activities including, but not limited to:

• Aligning LC priorities with network research priorities as coordinated by the LOC
• Delegating responsibilities to lead investigators of the individual laboratories comprising the LC
• Ensuring that laboratories supported by the LC:
• Utilize necessary SOPs, permits, personnel, data management system and other resources to perform and report the results of laboratory assays to support network operations in timely manner to the required standards
• Domestic laboratories that perform any tests, including Clinical Laboratory Improvement Amendments (CLIA)-waived tests, on materials derived from the human body for providing information for the diagnosis, prevention or treatment of any disease or impairment, or the assessment of the health of human beings must be CLIA-accredited/College of American Pathologists (CAP) certified or equivalent.
• International laboratories performing endpoint testing to determine product efficacy that do not fall under CLIA must conduct operations under Good Clinical Laboratory Practice (GCLP) conditions, are subject to GCLP audits, and must receive a satisfactory evaluation when an audit is performed.
• Provide scientific expertise to the design and execution of clinical protocols, including evaluation of laboratory data
• Participate in network Quality Assurance/Quality Control (QA/QC) programs and NIAID External Quality Assurance (EQA) programs, proficiency testing and/or confirmatory retesting of samples when necessary to ensure the quality of performed tests.
• For clinical laboratories: Conduct tests for protocols being carried out under an Investigational New Drug Application (IND), New Drug Application (NDA) or Biological License Application (BLA) using FDA-approved tests and reagents. When not feasible, appropriate validation processes should be used with approval from the DAIDS Program Officer.
• Ensuring, wherever appropriate, that new assays are qualified or validated following current FDA guidelines on Biomedical Assay Validation and GCLP guidance.
• Engaging, where appropriate, non-network expert investigators and laboratories and other NIH-supported resources when identifying, evaluating and implementing new tests, reagents and instruments for clinical studies
• Transferring technology and sharing scientific information between LC specialty laboratories and CTU/CRS-affiliated laboratories
• Ensure security of any personally identifiable information associated with test specimens.
• Make specimens available for cross-trial and cross-network evaluation when required.
• Provide specimen access to non-network investigators when appropriate.

PD(s)/PI(s) of the Statistical and Data Management Center (SDMC) will have primary responsibility for the biostatistical and data management activities, including, but are not limited to:

• Under the coordination of the LOC, the SDMC has primary responsibility for compliance with 21 CFR and ICH guidelines as they relate to clinical trial data management at the SDMC, LC and CTU/CRS and statistical aspects of study design.
• Aligning SDMC priorities with network research priorities as coordinated by the LOC
• Ensuring that the SDMC has all the necessary SOPs, personnel, data management, statistical, and communications expertise and systems, and follows U.S. regulations, Good Documentation Practice, and relevant international guidelines to support network operations and meet NIAID requirements, to include:
• Ensuring timeliness, accuracy, confidentiality and integrity of data transferred within the network (i.e., laboratories, network-affiliated CRSs, SDMC).
• Ensuring timeliness, accuracy, confidentiality and integrity of data transferred between the Network and NIAID systems, NIH systems, and other federally required IT systems.
• Providing data to NIAID or a NIAID contractor upon request by NIAID to permit review of data as recorded on the case report forms (CRFs), electronic CRFs, or in the SDMC clinical trial management system.
• Providing closed and open reports required by data and safety monitoring committees; ensuring confidentiality of reports.
• Ensuring timely submission of data as required by the Food and Drug Administration (FDA) and other regulatory agencies.
• Interfacing, integrating or adapting the network’s information system(s) to be interoperable with NIAID systems.
• Adopting information systems or components specified by NIAID
• Collecting, storing and providing all data in accordance with Clinical Data Interchange Standards Consortium (C-DISC) requirements
• Collaborating with other DAIDS-affiliated SDMCs in the development of data elements that do not currently exist within C-DISC
• Serving as primary reporter for electronic reporting and updates about network studies to NIH in the eRA Humans Subjects System (HSS)
• Working cooperatively with counterparts from other NIH-supported clinical trials networks to conduct collaborative research projects and ensure capability for cross-protocol and cross-network data analysis. This may include:
• Establishment of standard data interfaces and common data elements, protocol status definitions, endpoint verification, formats for data collection, and site identification systems;
• Creation and exportation of datasets for meta and epidemiologic analysis
• Adaptation of current database systems and structures to accommodate multi-network collaboration and data exchange
• Sharing data publicly through NIAID-specified portals (e.g., ImmPort, ImmuneSpace), as appropriate and consistent with achieving the goals of the program. The PD/PI will establish procedures within the network to ensure that all members of that network conform to the data sharing and other resource-sharing plans.

Each network will have the responsibility to collaborate and promote inter-network interactions, including but not limited to:

Coordinating with other NIAID- and NIH-supported clinical trials networks to:

• Support observance of and compliance with federal regulations and international standards for clinical studies
• Avoid redundancy and ensure harmonization
• Establish performance measures for evaluating the efficiency and effectiveness of the LOC, LC, SDMC, and network-affiliated CTUs/CRSs
• Standardize and share training for common needs
• Develop cross-network communication strategies, including community participation

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

• NIAID Program Staff. NIAID staff assistance will be provided by an NIAID Program Officer along with other NIH staff. These staff will be identified at the time of award and their roles and responsibilities will be addressed in the Notice of Award. These NIAID staff members will have substantial scientific/programmatic involvement during the conduct of this activity through provision of technical assistance, advice and coordination above and beyond the normal program stewardship role for grants:
• Provide specific guidance on expectations for clinical studies and clinical trials.
• Ensure that network research efforts are consistent with NIAID priorities for HIV clinical research and complement other NIH and NIAID programs;
• Facilitate coordination among the NIAID- and other NIH-supported clinical trials networks and research groups, clinical research support programs, and other U.S. Government agencies, promoting collaborations and facilitating information exchange;
• Review and accept processes for identifying, qualifying, and approving protocol-specific sites to address specific network needs after award;
• Serve as members of protocol teams;
• Monitoring progress of grant awards with regard to protocol development, implementation, and study conduct, and making adjustments as necessary;
• Participate in meetings, training activities, and conference calls;
• Serve as resources for scientific and policy information;
• Provide information regarding promising new agents, strategies, and developments when appropriate;
• Identify scientific gaps and organize meetings to facilitate exchange of scientific and regulatory information, including during network meetings;
• Periodically conduct an independent review of the constituent parts of the network for reliability and compliance with clinical and regulatory requirements including third party audits;
• Coordinate contract resources that facilitate the provision of support services for clinical trials;
• Participate on scientific committees as a voting member;
• Participate in the presentation of research results, including publications;
• Retain the option to recommend reduction of support from any cooperative agreement that substantially fails to achieve its goals or fails to comply with the Terms and Conditions of the award.
• Under urgent public health situations, the NIAID may re-direct funds or provide additional funds to individual awards to support research of direct relevance to the emergency.
• Clinical Trials Agreements. NIAID will lead the negotiation of Clinical Trials Agreements (CTAs) and serve as the liaison with pharmaceutical companies (or other providers of investigational agents).
• Trial Sponsorship. NIAID will have the option to independently file an IND on investigational agents or an IDE on investigational devices evaluated in NIAID-supported clinical studies. NIAID will advise the investigators on the specific regulatory requirements for IND/IDE sponsorship. In situations where NIAID is the IND sponsor, NIAID through its contractors will also assemble, review, and submit the required regulatory documents to the FDA. When holding an IND or IDE, NIAID has responsibility for the data management and reporting of safety information in accordance with FDA requirements and preferences. In order to provide for consistent reporting of serious adverse experiences across the NIAID-supported clinical trial networks, NIAID will provide current policies and procedures that govern the reporting of adverse events in NIAID-supported trials.
• Pharmaceutical Support. For studies in which NIAID is the IND or IDE sponsor, IC staff and/or contractors will provide consultation on study treatment-related issues, including manufacturing, preparation, administration and availability of active dosage forms and placebo. NIAID staff and/or contractors may also interact with pharmaceutical company collaborators to facilitate adequate and timely supply of study product; and oversee the distribution of study product to the clinical research sites. When NIAID is not the regulatory sponsor, pharmaceutical support is provided based on a case-by-case determination.
• Trial Monitoring. NIAID will oversee an external clinical site monitoring contract that evaluates GCP, regulatory compliance, protocol implementation, internal quality assurance, and test article accountability at the clinical research sites for clinical trials conducted under IND/IDE. The monitoring contractor, with or without accompanying NIAID staff, will visit the clinical research sites periodically to review selected protocols, provide training on general protocol conduct, review internal QA/QC plans, and audit pharmacies. When NIAID is not the regulatory sponsor, clinical monitoring support is provided based on a case-by-case determination.
• Training. NIAID staff will provide a variety of training activities to appropriate network personnel to help the network ensure that consistent standards for protection of human subjects and clinical trial conduct and documentation are achieved across the NIAID-supported clinical trials networks. Training areas include, but are not limited to, regulatory requirements, GCP, adverse event reporting, human subject protections, informed consent, and NIAID and NIH policies and procedures.
• Protocol approval. NIAID will review and provide approval for all protocols. NIAID or designee will return comments and recommendations to the network after review. The network must address in writing all safety, regulatory, ethical, and conflict of interest concerns raised by NIAID to the satisfaction of NIAID before participant enrollment can begin. If a protocol is disapproved, NIAID will not provide investigational products or permit expenditure of NIH funds for the proposed investigation. When a protocol is not initiated within twelve months of NIAID approval, re-review and approval by NIAID will be required.
• Safety Monitoring. NIAID participates in development of appropriate safety monitoring plans for all planned clinical trials, and must approve the plan for all trials involving investigational drugs, devices, biologics and other clinical research perceived to involve more than a minimal risk. The frequency and intensity of safety monitoring will be based on individual study characteristics and experience with study products and may require review by an Independent Safety Monitor, Safety Monitoring Committee (SMC) or Data and Safety Monitoring Board (DSMB). NIAID Medical Officers will be part of network-organized protocol safety review teams to monitor the safety and efficacy of the intervention(s) for ongoing studies and will be provided with appropriate reports. Medical Officers will be responsible for the disposition of Serious Adverse Events. Approval of the final monitoring plan, including the composition of the review committee, by NIAID is required prior to study initiation. NIAID independently supports Data and Safety Monitoring Boards (DSMBs) that oversee Phase IIb/III and other select clinical trials at the discretion of NIAID.
• Protocol Termination. NIAID reserves the right to terminate or curtail a clinical study for any of the following reasons:
• risk to subject safety
• the scientific question is no longer relevant, or the objectives will not be met (i.e., slow accrual)
• failure to comply with GCP, U.S. Federal regulations, or Terms and Conditions of Award
• occurrence of unforeseen drug safety issues or data from preclinical studies indicate a presence of unanticipated toxicity
• risks that cannot be adequately quantified
• ethical concerns raised by the community or medical care/health care authorities
• failure to remedy deficiencies identified through site monitoring
• substandard data
• reaching a major study endpoint substantially before schedule with persuasive statistical significance

Data Access. The awardees retain the rights to the data, consistent with current DHHS, PHS, NIH and NIAID policies; however, NIH will have access to all data generated (raw and analyzed) and may periodically review it. This includes a review of data as recorded on the case report forms or in the central database, and external checking against the original source documentation as required by federal regulation and NIAID as the IND/IDE sponsor. NIAID may request from the network specific data analysis needed for programmatic activities or for issues related to NIAID plans with other partners. The NIH may provide public access to selected data sets generated with the use of public funds within a reasonable time after primary analysis and publication. 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.

Areas of Joint Responsibility include:

• Research Plans. Implementing, monitoring, and updating the clinical research priorities for the network to ensure consistency and relevance
• Research Activities. Reviewing the network's research activities and goals on an agreed upon schedule (but no less than once every year).
• Protocol Development. The LOC will assemble and manage protocol teams, but NIAID staff and support contractors, as required, will participate in these teams.
• Oversight of Clinical Trials. On an ongoing basis, the LOC, LC, and NIAID staff will jointly evaluate the progress of clinical trials, including enrollment milestones, site and laboratory quality, and data quality. NIAID and NIAID contractors may audit sites, SDMC, and laboratories to assess GCP and data quality and integrity.
• Performance Assessment. NIAID, in conjunction with the EMC will assess the performance of the LOC, SDMC, and LC and CTUs/CRSs in an ongoing manner. The EMC will develop an evaluation plan with defined goals and measurable objectives linked to specific performance metrics and include remedial actions for sites failing to meet acceptable standards. Clinical research sites that fail to meet performance standards may be subject to withdrawal of funding.
• Community Partners. Representatives of network Community Advisory Boards (CABs) will participate with NIAID staff and network representatives to:
• Review and assess the community engagement program and activities, to include identifying strengths and weaknesses and recommending improvements
• Enhance intra- and inter-network community communications and input
• Identify needs for training and support of local and network community advisory boards
• External Advisors. NIAID may seek evaluation, advice and recommendation concerning ongoing and planned research activities of the network from external advisors. Advisors will not include key personnel or collaborators of the key personnel of any of the awardees. Network investigators will participate in these evaluations with attendance supported through the LOC budget and will provide written materials and oral presentations regarding the status of ongoing research activities, future (including proposed new research activities/investigators), and plans to curtail, discontinue and/or modify current research activities.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

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Contact Center Telephone: 800-518-4726
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Phillip Renzullo, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-627-3041
Email: [email protected]

Eric Lorenzo, Ph.D.
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-443-4993
Email: [email protected]

Raul N. Mandler, Ph.D.
National Institute on Drug Abuse (NIDA)
Telephone: 301-480-2541
Email: [email protected]

Gallya Gannot, DMD, Ph.D.
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-451-5096
Email: [email protected]

Pim Brouwers, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 240-627-3863
Email: [email protected]

May Wong, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1431
Email: [email protected]

Kumud K. Singh, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-761-7830
Email: [email protected]

Jenny Greer

National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-669-2949
Email: [email protected]

Bryan Clark, MBA
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6975
Email: [email protected]

Pam Fleming
National Institute on Drug Abuse (NIDA)
Telephone: 301-480-1159
Email: [email protected]

Diana Rutberg, M.B.A.
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-4798
Email: [email protected]

Rita Sisco
National Institute of Mental Health (NIMH)
Telephone: 301-443-2805
Email: [email protected]

Tijuanna DeCoster, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9531
Email: [email protected]

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