Prevention of HPV-related Cancers in HIV-infected individuals: United States-Latin American-Caribbean Clinical Trials Network: Partnership Centers (U54 Clinical Trial Required)
Last Updated: November 13, 2018
1. The eligibility criteria states "Only one application per institution (normally identified by having a unique DUNS number or NIH IPF number) is allowed." Does this apply only to applicant institutions? Are partnering institutions in the US and LAC countries allowed to participate in more than one application?
Answer: The requirement of only one application per institution applies only to the US applicant institution. Partnering institutions from both the US as well as LAC countries are eligible to partner with more than the US applicant institution. It is expected that potential collaborators from US and LAC institutions will develop partnerships that have the best chance to collaboratively conduct and complete the most meritorious and appropriately designed prevention clinical trials within the project period.
2. Are subcontracts with other US institutions allowed? If there are multiple US PIs, should subcontracts be used to cover salary support for other PIs?
Answer: It is expected that subawards/subcontracts will be made by applicant institutions to cover support for specific programmatic activities (e.g., regulatory support), or for covering the salary support for multiple PIs and co-investigators located at other US and LAC institutions.
3. Is participation by (and subcontracts with) multiple institutions in LAC countries allowed? Is it recommended?
Answer: There is no specific recommendation or restriction in the FOA for partnering with institution(s) in either a single LAC country or multiple LAC countries, or more than one partner institution in a single LAC country. Each such partnership may require individual subawards/subcontracts. Applicants are expected to build on previous and newly available opportunities for partnering with experienced LAC country institution(s). Partnership decisions and plans should consider maximizing the team’s ability to have access to an adequately large population of HIV-infected participants for accrual to all three clinical trials that can be conducted and completed within the 5-year project period.
4. If the Administrative and Coordinating Core is in one institution can the other Cores be at other institutions?
Answer: The Administrative and Coordinating Core, which is required to be co-led by the US applicant institution Principal Investigator and the collaborating PI(s) at the LAC partnering institution(s), can be based at one institution (usually the applicant), while the Data Management and Statistical Core and the Central Laboratory Core may be based at other institutions, depending on the nature of the clinical trials being proposed and the overall composition of the Partnership Center.
5. What is the role of Puerto Rico in this FOA, considering it is a US territory located in the Caribbean?
Answer: For the purpose of this FOA, institutions in Puerto Rico can participate as LAC partnering institutions and serve as performance sites for the proposed clinical trials.
6. Are high-income countries in the LAC region allowed to partner in the application?
Answer: Countries classified as high-income countries by the World Bank Classification System at the time of application can serve as additional partners (e.g., hosting Partnership Center Support Cores, serving as Multiple PIs/Co-Investigators) as stated in Part 2, Section III of the FOA. However, performance sites for clinical trials will be limited to institutions in low- and middle-income countries in the LAC region.
7. Is there a co-PI role in this RFA? Can the US-based institution propose co-PIs (two PIs from the US-based institution) plus the PI from the LAC partner?
Answer: The role type, "co-PI" is not used by the NIH. This FOA requires the use of the multiple PI model and requires applicants to designate at least two PIs, one from the US applicant institution (serving as the contact PI) and one from the LAC partner institution, along with additional PIs from US and LAC partner institution(s) in a multiple PI format commensurate with their roles and responsibilities proposed in the Partnership Center application. (See Multiple Principal Investigators for more information.) Each such PI should be referred to as "Multiple PI" in the application rather than "Co-PI." As stated in the FOA, all individuals designated as PIs must have appropriate expertise in clinical trials related to either HIV/AIDS, oncology, infectious diseases, sexual and reproductive health, and/or gynecology/women's health.
8. Do each of the trial protocol co-PIs need to have previous clinical trial experience?
Answer: The proposed PIs for the partnership center are expected to have the expertise, experience, and ability to organize, manage and implement the proposed clinical trials program and meet milestones and timelines. U.S. and LAC Protocol Co-Chairperson(s) for individual clinical trial protocols may or may not be identified at the time of application and may be added/changed during the course of the project period, contingent on approval by the NCI. If these roles are proposed for junior investigators with no/limited trial leadership experience (but have other clinical and/or research experience and/or expertise), it is suggested that the team also be co-led by additional experienced Co-Chairperson(s) who can provide mentorship and advice while sharing research management responsibilities. In such cases, applicants are encouraged to discuss individual situations with the NCI Scientific/Research Contact for this FOA prior to submitting the application.
9. Is this FOA primarily focused on cervical cancer prevention? Is a focus on anal cancer screening permitted? Will oropharyngeal cancers be a focus that will be allowed?
Answer: Among the three central prevention science thematic focus areas for this FOA, Area 2 (screening and triage) is the only focus area where trials are specifically required to be focused on cervical cancer screening and triage in HIV-infected women. Area 1 (immunoprevention) and Area 3 (novel non-surgical precancer treatment approaches) are agnostic of both the target organ/site as well as sex/gender. Thus, when responding to Areas 1 and 3, clinical trials that focus on prevention of cervical cancer and/or prevention of anal, vulvar, vaginal, oropharyngeal cancers in HIV-infected females and/or males may be proposed, depending on the research question, study design, accrual feasibility, focus of the intervention. There are other NCI-funded programs (e.g., the AIDS Malignancy Consortium) that are currently conducting significant efforts via clinical trials to answer critical questions on anal cancer screening.
10. Is enrollment of HIV-uninfected individuals allowable for trials proposed in this FOA?
Answer: The FOA emphasizes the need for being responsive to high- and medium-priority HIV/AIDS research priority areas for the NIH (NOT-OD-15-137). As stated in NOT-OD-15-137, while "high priority" topics of research for support using AIDS-designated funds most certainly include focus on studies among HIV-infected individuals, "medium priority" topics encompass projects that demonstrate HIV/AIDS is a meaningful component of the project and/or knowledge about HIV will be enhanced by the project, as evidenced in the specific aims. Thus, such studies may include studies among persons who are living with HIV, are HIV exposed, and/or are at elevated risk for HIV infection as part of a broader sample or as a comparative cohort.
11. How important is innovation in this RFA? Would it be an acceptable degree of innovation to propose to evaluate the performance of "standard/accepted" interventions already recommended for HIV- individuals in a HIV+ population?
Answer: The Partnership Centers funded through this FOA are expected to enhance the evidence base for innovative clinical interventional approaches for preventing HPV-related cancers among HIV-infected individuals, gaining biologic insights into viral-host interactions and immunologic contributions to cancer development, and ultimately informing improvements in clinical care options for HIV-infected individuals globally. A proposed clinical trial application may include study design, methods, and interventions that are not by themselves innovative but may 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. Applicants are expected to describe how the results of the clinical trials that they propose may provide a novel or innovative approach that could have the potential to improve the preventive clinical care management of HPV-related cancers in the partnering LAC region country(-ies) and improve the health outcomes of patients with HIV.
12. Can one of the trials be a behavioral study, e.g., to increase treatment adherence?
Answer: The FOA does not specifically focus on evaluating behavioral interventions. Applicants are encouraged to discuss their proposed project aims with the NCI Scientific/Research Contact for this FOA prior to submitting the application.
13. Which component of the application should the budget for the Co-Investigators be presented?
Answer: Budgets for salary support of Co-Investigators can be presented in either the Administrative and Coordinating Core component, or in the Clinical Trials Program component, depending on their roles in the Partnership Center. Note that the FOA specifies that the Clinical Trial Protocol Team should be led by US and LAC Protocol Co-Chairperson(s). These Co-Chairperson(s) may or may not be identified at the time of application and may be added/changed during the course of the project period, contingent on approval by the NCI. Include research scientists and clinicians of appropriate profile from the applicant institution and collaborating institutions in the US and LAC region in each Protocol team.
14. If more than 1 LAC partner in grant, would each have 20% effort or split the 20% effort?
Answer: Each of the two Partnership Center PDs/PIs (from both the US and the LAC region) will be expected to have a significant effort commitment (at least 2.4 person-months required). However, in applications where more than one US and/or Latin American PIs are proposed (as part of a multiple PI leadership plan), the efforts should be commensurate with their proposed roles and responsibilities in the Partnership Center, and collectively should commit a minimum of 20% effort (at least 2.4 person-months) annually to the project on both the US and LAC sides.
In addition, a minimum level of effort of 1.2 person-months (10% effort) for each Protocol Co-Chairperson is recommended to be included in the Clinical Trials Program component of the application. However, in applications where more than one US and/or Latin American Co-Chairpersons are proposed, the efforts should be commensurate with their proposed roles and responsibilities in the conduct of the trial, and collectively should commit a minimum of 10% effort (at least 1.2 person-months) annually to the trial efforts on both the US and LAC sides.
15. Are there any recommendations for allocation of the Clinical Trials Program budget between individual trials?
Answer: There is no specific recommendation for budgetary allocation between the three trials proposed in the Clinical Trials Program component. It is expected that the budget for each clinical trial (total and annual) will be proportional to the expected activities during the appropriate phases (preparatory, launch, and conduct) of each trial. The budget request for the Clinical Trials Program (which should cover activities related to the development and conduct of three individual clinical trials) must be at least two-thirds of the total direct costs requested for the Partnership Center.
16. Do you have guidance about where to budget the costs for study assays? Can this be placed in the Clinical Trials Program or should it be placed in the Lab Core?
Answer: There is no restriction in the FOA on placing these costs in either the Clinical Trials Program budget or the Central Laboratory Core budget. This will be guided by when and where (US/LAC) the assays will be performed; how the role/functions of the Lab Core are highlighted in the application; and the budget of the Clinical Trials Program component, etc. A relevant budget restriction in the FOA is that the: "Budget request for Clinical Trials Program (which should cover activities related to the development and conduct of three individual clinical trials) must be at least two-thirds of the total direct costs requested for the Partnership Center."
17. Is there a requisite paradigm for reporting SAEs? Would we use the NCI Common Terminology Criteria for Adverse Events Reporting (CTCAE), or should the DAIDS reporting criteria be used since they have HIV specific toxicities?
Answer: NCI grantees are required to use the CTCAE criteria for SAE reporting purposes. These could be supplemented with specific NIAID-DAIDS adverse event reporting guidelines with HIV-specific information wherever needed for addressing HIV-specific toxicities. The safety reporting component will need to include reporting to the NIH/NCI as the sponsor, along with other regulatory, oversight, and administrative agencies (e.g., institutional review boards, US FDA, LAC-country regulatory bodies, other LAC governmental agencies, etc.) and other partners.
The final data safety and monitoring plan and the serious adverse event reporting plans will be finalized in consultation with the NCI in the post-award phase prior to initiation of the clinical trials. Please note that the Section VI. Section 1 (Award Notices) of the FOA specifies the following:
"Awardee-selected projects that involve clinical trials or studies involving greater than minimal risk to human subjects require prior approval by NIH prior to initiation. The awardee institution will provide NIH with written study protocols that address risks and protections for human subjects in accordance with NIH’s Instructions for Preparing the Human Subjects Section of the Research Plan. The awardee institution will provide NIH with specific plans for data and safety monitoring, and will notify the IRB and NIH of serious adverse events and unanticipated problems, consistent with NIH DSMP policies."
Applicants can refer to the following links for more information:
18. Who constitutes DSMB, if needed? Are there standards for protocol monitoring? Is this to be arranged and paid for by the grantee?
Answer: As described in Section VI. 2. Under "Cooperative Agreement Terms and Conditions of Award," the convening and liaison with data safety and monitoring boards, ensuring certification of all key personnel in training on the Protection of Human Subjects and Good Clinical Practices (GCP) will be the responsibilities of the applicants. Applicants are also responsible for, and are required to budget for the costs of, study monitoring and regulatory support. NCI staff will participate in overseeing clinical trials monitoring/auditing and quality assurance programs. The final data safety and monitoring plan will be finalized in consultation with the NCI in the post-award phase prior to initiation of the clinical trials.
19. How fleshed out does the AE reporting need to be?
Answer: At the time of application, applicants are expected to provide adequate details about their ability and plans for providing adequate adverse event monitoring and reporting for the trials proposed in the partnership center, keeping in mind that not all details of the protocol are expected to be described in the application. The partnership center application is expected to have a conceptual level emphasis on each of the proposed trials, and the protocol development and adverse event monitoring and safety reporting will be finalized in partnership with the NCI in the post-award period.
20. Which institution (NCI/applicant institution) will apply for and hold an IND for a proposed agent?
Answer: The grantee (or affiliate) institution, not NCI, will be required to apply for and hold an IND for any investigational agent proposed in the program.
21. The one clinical trial that is supposed to be fully ready to go; why is this delayed start?
Answer: The FOA expects that applicants will propose one clinical trial protocol concept that is fully developed but presented as a "delayed start" study in the PHS Human Subjects and Clinical Trials Information form, since the approval and date of launch will be dependent on its review by the NCI Clinical Trials Oversight Committee in the post-award phase. The NCI Clinical Trials Oversight Committee is expected to provide recommendations for coordination and harmonization with other relevant NCI-funded strategic initiatives. Similarly, two other trial concepts will be presented as "delayed onset" studies that will also undergo review and approval by the NCI Clinical Trials Oversight Committee before launch.
22. Can the specific requirements for the Facilities section be addressed in the overall or admin core document? or must they be addressed in all?
Answer: The "Facilities and Other Resources" section should be addressed for the entire application in the "Overall" component, following the specific instructions provided in the FOA for this section.
23. Can you explain "potential participants" document (Attachment 2)? Are resources for lab capabilities required in Attachment 2?
Answer: The "Other Attachment" section requires two attachments to be uploaded separately, each focused on a specific purpose. Attachment 1 (required filename "Previous Clinical Trials") requires a summary table of accrual experience in past clinical trials whereas Attachment 2 (required filename "Potential Participants") requires applicants to document their ability to recruit study participants for the proposed clinical trials. In particular, applicants are required to provide a summary of the potential facilities and resources (e.g., antiretroviral therapy clinics, HIV testing and counseling centers, other health care clinics/facilities) available in the implementation catchment area(s) to recruit potential participants for clinical trials proposed though this FOA. Resources for Laboratory Capacity are not requested in Attachment 2. These should be highlighted in the Facilities and Other Resources section in the "Overall" component.
24. Timeline for the delayed start trial will have to accommodate IRB in LAC, which is difficult to estimate. Any comments?
Answer: It is expected that applicants will refer to their experiences about IRB approval timelines for previous trials in these settings as they estimate the projections about timelines for their applications. Applicants are encouraged to discuss individual situations with the NCI Scientific/Research Contact for this FOA prior to submitting the application.
25. Can NCI program infrastructure (e.g., Medidata Rave) be available to be utilized for this program?
Answer: The NCI program infrastructure (such as Medidata Rave) is limited for use in specific NCI programs/initiatives (such as ETCTN, NCTN, among others). Due to the nature of this award mechanism (U54), this FOA expects applicants to propose the use of their institutional/other available physical/virtual database management systems/resources for the management and handling of the clinical trials data.
26. What are the data sharing expectations for this RFA? Will the data from this grant need to be submitted to a NCI data repository?
Answer: There is no FOA-specific recommendation on data/resource sharing plans and/or submission to a NCI data repository. Applicants are required to follow standing NIH policies to propose data/resource sharing plans in the context of the proposed clinical trials and overall implementation plans. NCI may request additional details prior to funding decisions, and/or in the post-award phase. Applicants can refer to the following links for more information:
27: How will experience of the Latin American Partner PIs in the conduct of large HIV trials be weighted versus their experience in taking care of patients with HPV versus leading HPV research projects? How important is prior HPV research experience in the LAC partner?
Answer: As specified in the application review criteria, the Partnership Center application will be reviewed in its entirety, rather than on any one such criteria in isolation. Among other aspects, the review will focus on whether the team of investigators have strengths in conducting collaborative, multi-institutional clinical research in HIV/AIDS, HPV, cancer, or other clinical areas related to this FOA (e.g., infectious diseases, reproductive health, gynecology, etc.), and whether past/ongoing collaborative partnerships resulted in substantially increased in-country clinical care delivery or clinical trials/clinical/public health research capabilities and benefited the LAC institution and LAC country (-ies)/LAC region. Applicants are encouraged to refer to the FOA-specific review criteria, in addition to the overall application review criteria, specified in Section V of the FOA.
28. Will each trial protocol concept be evaluated separately?
Answer: In this U54 partnership center FOA (unlike a R01), the proposed research studies (clinical trials) themselves do not receive a priority score during peer review. There is only one overall impact score for the entire partnership center application and individual "criterion scores" for the "Overall" component of the application, but not for the other components. All other components of the Center (i.e., Administrative and Coordinating Core, Clinical Trials Program, Data Management and Statistical Core, and Central Laboratory Core) will be evaluated, but each will receive only one overall adjectival (not numerical) rating. Applicants should note that the Research Strategy section in the Clinical Trials Program component is not restrictive in how to "split" the 12-page limit for describing the significance/innovation/approach for each of the three clinical trials, and applicants should use this page limit efficiently to provide adequate details of their concepts relative to the type of activities (i.e., stage of development/imminence of launch) that each protocol concept entails.
29. Is a specific career development plan for junior investigators required?
Answer: While a specific career development plan for junior investigators is not required in this FOA, it is expected that applicants will describe how their plans via the establishment of this Partnership Center will facilitate career enhancement activities and training for junior investigators, trainees and staff. Applicants should also describe any integration/coordination efforts with other NIH/non-NIH programs and initiatives for facilitating such training and capacity building efforts.
30. Do you expect that proposals will cover each of the three areas or will an application be equally competitive even when focusing on one topic area (for instance, three trials about screening)?
Answer: The FOA does not require applicants to propose trials in all three topic areas. The three trials could focus on each of the three areas, or focus on one or two areas. Applications are going to be reviewed as a whole, including the significance, investigators, innovation, approach and environment. Applicants are encouraged to refer to the FOA-specific review criteria, in addition to the overall application review criteria, specified in Section V of the FOA.
31. The trials planned will vary in terms of sample size and duration of follow-up. Is it important to complete three trials within 5 years or to initiate all three trials and possibly only complete one?
Answer: The FOA is very specific on the requirement for initiating as well as completing all three trials within the 5-year project period. Even though the trials will vary in their design and the duration of follow-up, it is expected that generally trials with longer follow-up will be initiated sooner in the project period compared to trials with a shorter follow-up.
32. Are full protocols permitted to be submitted as appendices in the application?
Answer: As per the revised NIH Appendix Policy, very limited items are allowed in the Appendices, and full clinical trial protocols are not allowed. This new policy coincides with the requirement for using the new PHS Human Subjects and Clinical Trials Information Form.
33. Will the trials at the two partnership centers be merged in any way post award?
Answer: It is not possible to envision any merger/harmonization of clinical protocols prior to receiving and funding the applications. However, the Partnership Center Coordinating Committee that will be convened in the post-award phase may propose coordinating and harmonizing scientific and regulatory activities between the funded Partnership Centers. The NCI Clinical Trials Oversight Committee may also provide recommendations for coordination and harmonization with other relevant NCI-funded strategic initiatives in the post-award phase.
34. What details are expected to be presented for the first trial (‘delayed start’ trial) and the second and third trials (‘delayed onset’ trials) in the new PHS Human Subjects and Clinical Trials Information Form (‘Forms E’)?
Answer: Please refer to the following instructions and information for the ‘PHS Human Subjects and Clinical Trials Information Form’:
- https://grants.nih.gov/grants/ElectronicReceipt/files/Annotated_Forms_General_FORMS-E.pdf (PDF, 2.8 MB) (annotated set of forms/instructions)
- https://grants.nih.gov/policy/clinical-trials/new-form/video/ (explanatory video)
For the ‘delayed start’ trial, the ‘Forms -E’ study record requires critical study design and human subjects-related information (e.g., title, focus, eligibility, age criteria, inclusion of women/minorities/children, recruitment and retention plan, timelines, protection and monitoring plans, data safety and monitoring plan etc.). As specified in the instructions, it is expected that the “Research Strategy attachment should be used to discuss the overall strategy, methodology, and analyses of the proposed research, but applicants should not duplicate information collected in the new PHS Human Subjects and Clinical Trials Information form”.
For the ‘delayed onset’ trials, please see more information at https://grants.nih.gov/grants/how-to-apply-application-guide/forms-e/general/g.500-phs-human-subjects-and-clinical-trials-information.htm#Delayed. For the required ‘Justification Attachment’, applicants may refer to the fact that the second and third trials are presented as ‘delayed onset’ studies as per requirements in the RFA-CA-18-018.