### Funding Opportunity Announcements (FOAs) for the HIV/Cervical Cancer Prevention ‘CASCADE’ Clinical Trials Network RFA-CA-21-045: U24 Coordinating Center RFA-CA-21-046: UG1 Research Bases RFA-CA-21-047: UG1 Clinical Sites

#### Eligibility

Are foreign institutions eligible to apply for the UG1 Clinical Sites FOA? There seems to be an inconsistency between what’s outlined in the FOA language (about the focus/inclusion of clinical sites from low- and middle-income countries) and the eligibility criteria for the FOA.
A notice of clarification/change of eligibility for the UG1 Clinical Sites FOA (RFA-CA-21-047) has been published: Please see https://grants.nih.gov/grants/guide/notice-files/NOT-CA-22-009.html. The eligibility criteria have been revised to state that foreign institutions are eligible to apply directly—as well as be able to participate as foreign components of applications from domestic institutions.
Please clarify the statement in the RFA that PDs/PIs of applications submitted in response to this FOA must not be named as senior or key personnel or other significant contributors on any teams submitting applications to the competing FOAs.
NCI’s goal is to maximize participation of diverse institutions and permit applicants to tailor applications to their most suitable expertise/organizational elements. Although investigators cannot apply across FOAs, they can apply within a single FOA type for more than one application with This, of course, will need appropriate justifications regarding effort and scientific and budgetary overlap between the applications. (see slide 35 of the pre-application webinar (PDF, 2 MB))
Please explain how, for example, a PI listed on a UG1 research base application cannot be named as key personnel on a UG1 clinical site.
We hope to get maximal participation of diverse institutions and applicants who have tailored their most suitable expertise to the way that they are applying. We do not want a scientific conflict if a PI who is part of the research base, which proposes and oversees the science and provides statistical leadership, is also the PI implementing the protocol. That is why this initiative is deliberately designed to not allow cross-FOA participation. A particular PI can participate, for example, as part of two research bases or two clinical sites. This, of course, will need appropriate justifications regarding effort and scientific and budgetary overlap between the applications. (see slide 35 of the pre-application webinar (PDF, 2 MB)).
What will happen if all three RFA awards are not made simultaneously? For example, if an award is not made for the U24 Coordinating Center but awards are made for the research bases and clinical research sites. How will the NCI manage this?
These are three independent FOAs, but since this is a network, NCI intends to fund all three FOAs at the same time. As CASCADE is a brand-new network with no incumbents, we cannot predict which applicants will come in. It will depend on the interest from the community to submit applications and that they score high enough for funding. If a U24 Coordinating Center award is not possible to be made at the same time as the other awards, NCI has other programmatic approaches to fund the coordinating center activity. However, we do not anticipate this happening.
Can an application have two different recruitment sites in two different LMICs?
There is no restriction on having more than one LMIC as part of the application. Of course, it cuts down on your budget significantly if you split it across two different LMICs. If you choose this approach, it must be appropriately justified as part of your application.
Is it correct that a PI on one of the CASCADE programs (coordinating, research, clinical) cannot be a PI or serve as key personnel on separate program?
Correct—all three FOAs state as such (“The PDs/PIs of applications submitted in response to this FOA must not be named as Senior/Key Personnel or Other Significant Contributors on any teams submitting applications to the companion FOAs….”) For context, our goal is to maximize participation and permit applicants to tailor applications to their most suitable expertise/organizational elements.
Can a PI submit multiple applications under one FOA? For example, can he or she submit as PIs and/or key personnel for 2 different clinical sites?
Yes, there is no limitation in the FOAs regarding multiple applications within one FOA type. An investigator can be a PI and/or key personnel in two (or theoretically, even more than 2) UG1 Clinical Site applications. Of course, this will need appropriate justifications regarding effort and scientific and budgetary overlap between the applications.

### Network Activities

Will the UG1 Research Bases be responsible for communication with CTEP and CTEP submissions or will that be the role of the U24 Coordinating Center?
For clinical trial registrational elements, such as the NCI CTEP Registration and Credential Repository (RCR), the functions will be shared between the U24 Coordinating Center, which supports some of the coordination activities, and the UG1 Research Bases, which support regulatory and compliance activities.
Will trials in this network be submitted to the NCI Central Institutional Review Board (Central IRB)? Who will submit for IRB approval, UG1 Research Bases or UG1 Clinical Sites?
IRB submission is a function of the UG1 Research Bases. The NCI Central IRB’s mandate only extends to review and monitoring of biomedical research conducted at US-based, not foreign-based, sites. For CASCADE sites in foreign countries, we will need to rely on local (in-country) ethical review committees at the participating institutions to provide us with that assurance. If there are sites that are only focused within the US or protocols that are only focused in the US, there would be the potential for involvement of the Central IRB, or through other single IRB, as per current NIH Single IRB Policy.
Are there expectations for the number of participants to be enrolled in any one trial at a clinical site? For example, would a site be expected to enroll in a region of tens or hundreds or thousands of participants? This has implications on the clinical and scientific staff who would need to be supported.
This a challenge with developing a pragmatic network with a very wide range of trials that can be supported. What trials will be supported and whether those trials will be in the range of tens or hundreds or thousands is not something that we can predict at this point. There will be inherent flexibility and adaptability that will be part of the steering committee activities as things go forward.

In general, dependent on the type of design—the larger the trial, the lesser the granularity of data that would be expected to be collected. For example, a large community randomized trial will have data collection systems that may be very highly integrated with data collection already being done as part of a service delivery program. The intervention might be at a community level or at a cluster level and not at an individual level, so there will be less granularity of data collection for the study endpoints, even though the sample size is large. On the other hand, a smaller randomized trial might have individual-level granular data collection.
Are PEPFAR local partners implementing HIV cervical cancer programs eligible for UG1 clinical site applications?
Yes, PEPFAR ‘local partners’, assuming these are from foreign sites, are eligible to apply for UG1 clinical sites. There was a notice of clarification published on this. Please see: https://grants.nih.gov/grants/guide/notice-files/NOT-CA-22-009.html
Who will be in charge of the communications or regulatory work with the FDA or foreign counterparts for medication or device approval?
This network is different from other early phase networks that we have traditionally supported by the DCP and NCI. These trials will not be conducted for seeking FDA approval, nor will these be investigational new drug (IND) or investigational device exemption (IDE) studies. We are expecting ‘CASCADE’ studies to be effectiveness-focused evaluations of interventions that already have proven efficacy data and possibly even licensure data. For example, the thermal ablator is already approved by the FDA for clinical use but it's effectiveness in a setting of women with HIV has not been studied very well. We do not anticipate much or any interaction with the FDA as far as investigational devices. There may be some regulatory work involved for post marketing studies for example. Those efforts would be part of the compliance and regulatory functions for the UG1 research bases, and these applications would have to accommodate for that in their budgets or in their plans.
Will this network be using the NCI central license for Medidata rave as the collection system?
We have not specified a data collection or data management system. We hope to use a ‘fit-for-purpose’ data management system, and this will be proposed by the U24 Coordinating Center application as part of their data management unit functions and as part of their grant application budget. This system could range in terms of its utility. For example, for large scale studies there may be limited granular information on individuals collected because they are part of cluster randomized trials that happen at a community level, as opposed to some of the early phase trials, which have fewer participants but significant granularity of data that's collected on each individual.
I have a question related to clinical site infrastructure requirements for data collection and transmission building. Will the network likely use electronic data capture or online databases?
We do expect some form of electronic data capture, whether it’s online or offline, to be part of this network. We recognize that these are pragmatic trials and therefore some trials will be very tightly nested in routine clinical care settings and performed across sites with a range of resource constraints. They may not be very homogeneous, and certainly not to the same extent as one would expect in an early phase/intensive clinical trial with fewer participants. The infrastructural requirements for data collection are a function of what the coordinating center proposes as part of a centralized data management system. Then it will get evaluated, funded, and eventually incorporated as part of the network once the network is constituted.

### Budget

Please clarify the budget ceiling of direct costs of $200,000 or$400,000 for clinical research sites.
The UG1 research base applications have a budget ceiling of direct cost of $400,000 per year for up to 5 years. The budget ceiling for the UG1 clinical sites is$200,000 per year for up to 5 years. UG1 is a common code for the clinical sites and bases but they are different in their functions, budget caps, and application lengths.
Are indirect costs permitted?
Yes, they are permitted, but the specific indirect cost rate is not mentioned in the FOAs. This cost is negotiated individually between an institution and the Department of Health and Human Services (DHHS) directly and is published for every institution for various activity codes (off campus or on campus research, and international organizations, etc.). The NIH Office of Extramural Research (OER) offers answers to Frequently Asked Questions (FAQs) about NIH grants and funding, and extensive information on Foreign Grants.
Will there be additional protocol implementing funding?
At this point, there is no specific additional protocol implementation budget and we do not recommend any site to think about additional budget. We are limited in terms of what can be supported for each of these sites. We expect that the bulk of the service delivery costs will be accommodated as part of the ongoing program. We are expecting these to be pragmatic trials where the clinical sites already have ongoing programs which are delivering services. We are expecting the leveraging of ongoing service delivery programs as a form of a ‘cost sharing’ approach between what the grant supports and what the clinical site already has funding for various infrastructure service delivery elements. The grant is for the science, meaning the innovations that are expected to be evaluated in this network for their clinical effectiveness and implementation.
Can you clarify which costs of trials at the clinical sites will be covered by the UG1 Research Base versus the UG1 Clinical Sites themselves? For example: regulatory clinical trial coordinator staff, will these be covered by research bases or the clinical sites?
The FOAs describe these distinctions in greater detail. In short, we do expect the regulatory and compliance related costs to be within the domain of the UG1 Research Bases. The clinical site staff, the clinical site coordinators/research staff at the site will be within the purview of the UG1 Clinical Sites, and they will have functions that are largely clinical and operations management in nature.
In case of multi PD/PI applications, is the contact PI is still expected to have a minimum effort of 20%?
Yes, that is correct and is specified in the FOA.
Should UG1 Clinical Sites budget for in-country quality assurance and monitoring or will the UG1 Research Bases send external monitors for that?
There is an auditing function and there is a clinical day-to-day oversight and compliance with monitoring function. Monitoring for local clinical quality assurance and monitoring the day-to-day oversight aspects of the study will be responsibility of the UG1 Clinical Sites, although some efforts, dependent on specific protocols, will be shared by the UG1 Research Bases since the latter are responsible for compliance-related activities. Risk-appropriate clinical trial auditing (by external staff) is the role of the U24 Coordinating Center.

These FAQs will be updated periodically. Last updated: November 19, 2021.