Please see: NOT-CA-22-009—the eligibility criteria has been changed to state that for RFA-CA-21-047, “Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply, Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply, and Foreign components, as defined in the NIH Grants Policy Statement, are allowed”.
Women living with HIV (WLWH) have a higher risk for acquisition, persistence, and progression of cervical human papillomavirus (HPV) to precancerous lesions, which, in the absence of effective screening and treatment services, can progress to invasive cancer at five-to-six times higher rates than in women without HIV. The massive global mobilization of humanitarian resources spanning over the past couple of decades, through initiatives such as the US President’s Emergency Plan for AIDS Relief (PEPFAR), has resulted in millions of WLWH in low- and middle-income countries (LMICs) now accessing affordable antiretroviral therapy and consequently living longer lives. Yet, their risk for cervical cancer continues unabated since effective screening and precancer treatment services remain unavailable in most LMICs. The lack of such services has prompted efforts funded by PEPFAR and several public, private, and philanthropic-sector agencies to increase access to cervical cancer prevention services, especially within/linked to the clinics and facilities where WLWH routinely access HIV/AIDS care and treatment services. In addition, the World Health Organization (WHO), with endorsement of 194 countries including the United States, has launched a global initiative to accelerate progress towards the elimination of cervical cancer as a public health problem. Concurrently, there have been significant advances in key catalytic technologies (such as point-of-care visual and molecular screening approaches, and multiple portable ablative and excisional precancer treatment devices) and acceleration of regulatory pathways (such as imminent approvals for self-sampling for HPV-based primary screening) for key clinical interventions for cervical cancer screening and precancer treatment.
BSA PresentationPresentation to the NCI Board of Scientific Advisors (PDF, 942 KB)
By Vikrant Sahasrabuddhe, M.B.B.S., Dr.P.H.
Starting in Fiscal Year 2022, NCI will support a new initiative, the HIV/Cervical Cancer Prevention ‘CASCADE’ Clinical Trials Network that will seek to conduct pragmatic clinical trials evaluating the effectiveness of clinically proven interventions to optimize the cervical cancer screening, management, and precancer treatment cascade for WLWH. ‘CASCADE’ Network trials will be conducted in intended-use environments in resource-constrained settings in low and middle-income countries and in regions with health disparities in the United States, and will have four major scientific focus areas:
- increasing screening uptake,
- improving management of screen positives,
- facilitating precancer treatment access, and
- optimizing precancer treatment for cervical cancer prevention in WLWH.
The ‘CASCADE’ Network clinical trials will focus on the measurement of the clinical effectiveness of interventions in intended use settings while gathering crucial information informing the implementation and scale-up of such interventions across the cascade of screening and precancer treatment for WLWH. Such 'hybrid effectiveness-implementation' designs will primarily focus on clinical effectiveness endpoints such as HPV positivity rates and/or precancer detection/incidence/recurrence rates and will secondarily gather data on implementation-informing aspects such as costs, acceptability, and intervention fidelity while studying implementation strategy.
The ‘CASCADE’ Network will be structured around three types of organizational units (funded by individual Cooperative Agreement grants): a single U24-funded Coordinating Center, up to three UG1-funded Research Bases, and up to eight UG1-funded Clinical Sites, all working collaboratively and in partnership with the NCI. The ‘CASCADE’ network is expected to develop and conduct a total of six to eight multicenter clinical trials over a five-year project period.
Clinical trial concepts and protocols will be proposed and developed by UG1 Research Bases, and participant accrual will occur at multiple UG1 Clinical Sites, matching the scientific focus with the availability of infrastructure and access to appropriate study populations. The U24 Coordinating Center will facilitate network-wide coordination, scientific review, data management, and independent risk-appropriate auditing of network clinical trials.
A Network Steering Committee, with representation from principal investigators from the ‘CASCADE’ Network grantees and NCI staff will review and prioritize clinical trial concepts and selection of study implementation sites after balancing competing considerations around scientific focus, geographic distribution of studies across the network, trial accrual targets, protocol implementation complexity, and strategic partnership opportunities. Final approval for protocols will be provided via an NCI Oversight Committee.
‘CASCADE’ Network trials are expected to inform clinical practice guidelines and improve implementation of cervical cancer prevention and control programs globally.
Funding Opportunity Announcements for the ‘CASCADE’ Network
NCI has released three Funding Opportunity Announcements (FOAs) that invite applications for the three components of the ‘CASCADE’ Network.
RFA-CA-21-045: Coordinating Center for HIV/Cervical Cancer Prevention 'CASCADE' Clinical Trials Network (U24 Clinical Trial Required)
RFA-CA-21-046: Research Bases for HIV/Cervical Cancer Prevention 'CASCADE' Clinical Trials Network (UG1 Clinical Trial Required)
RFA-CA-21-047: Clinical Sites for HIV/Cervical Cancer Prevention 'CASCADE' Clinical Trials Network (UG1 Clinical Trial Required)
Key Information about the three components and the FOAs is as follows:
- The U24 Coordinating Center will (i) provide overall network coordination and facilitate scientific review of network clinical trial concepts and protocols, (ii) provide centralized support for data management for network clinical trials, and (iii) conduct independent risk-appropriate auditing of network clinical trials. The U24 Coordinating Center will serve as the organizational and coordination hub for the ‘CASCADE’ Network and is expected to provide multi-disciplinary expertise in program and operations management, clinical research informatics/information technology, and clinical trials auditing. The U24 applicants are expected to be a US PI(s)-led, self-organized, multi-disciplinary team of US- and/or LMIC-based domain-specific experts with substantial experience in leading each of the functional areas of the U24 Coordinating Center, i.e., network-wide coordination and facilitation of scientific review of clinical trial concepts and protocols, provision of centralized data management support for network clinical trials, and conduct of independent risk-appropriate auditing of network clinical trials.
- The UG1 Research Bases will (i) provide scientific and statistical leadership for developing network clinical trials concepts and protocols, overseeing their conduct, and analyzing and publishing their results, (ii) ensure compliance with human research participant protection and other regulatory and administrative reporting requirements, and (iii) work towards creating opportunities for training emerging investigators. The UG1 Research Bases will serve as the scientific hubs for the ‘CASCADE’ Network and are expected to provide scientific and statistical leadership for developing, implementing, and analyzing multi-institutional pragmatic clinical trial protocols via a self-organized, multi-disciplinary consortium of US-based and/or LMIC-based PIs with investigators with complementary expertise in areas such as clinical effectiveness research, HPV/cervical cancer prevention and control, HIV/AIDS care, and gynecology/women’s health/reproductive health issues.
- The UG1 Clinical Sites will (i) provide a pluripotent infrastructure for accruing participants to network clinical trials, (ii) provide insights and input on clinical significance and study feasibility during concept and protocol development, and (iii) provide on-site operational leadership for the successful conduct of network clinical trials. UG1 Clinical Sites will serve as the study implementation settings in the ‘CASCADE’ Network providing on-site operational leadership for the successful conduct of multi-institutional pragmatic clinical trial protocols. UG1 Clinical Sites can be located in LMICs, to be led either by LMIC PI(s) or co-led by LMIC and US-based PI(s), or can be located in regions of healthcare disparities in the US, to be led by US PI(s). UG1 Clinical Sites will have supportive infrastructure and experience in at least three of the four scientific focus areas of the ‘CASCADE’ Network, as well as experience in providing clinical care and cancer prevention services to patients and/or communities in underserved regions and in less organized or fragmented health care systems.
- (Optional) Letter of Intent Due Date: November 28, 2021
- Application Due Date: December 28, 2021
- Scientific Merit Review: March 2022
- Advisory Council Review: May 2022
- Earliest Start Date: July 2022