RFA-CA-18-030 Frequently Asked Questions

Cancer Prevention Clinical Trials Network (CP-CTNet): Data Management, Auditing, and Coordinating Center (DMACC) (U24)

Last updated: October 26, 2018

Note: Questions have been modified for clarity and thus the answers in this FAQ document should be considered final.

1. (Received by 10/1/2018) Does the DMACC have to be associated with one of the CP-CTNet clinical sites or can it be a stand-alone data coordination center?

Answer: No, they need to be separate.

2. (Received by 10/1/2018) Can you clarify if a center can apply for the DMACC grant if they have not previously been involved as a DMACC but have experience through NCTN and/or NCORP/DCP?

Answer: There is not a requirement to have served as a DMACC previously, but in the "Other Project Information," the applicants are asked to list their prior data management, auditing, and multi-site coordination projects. So, you will need to provide adequate information about your capabilities and track record (your experience through other programs, even if not exactly a DMACC).

3. (Received by 10/1/2018) Since the database chosen is Medidata Rave, does it mean that the DMACC must have a team working on Medidata Rave already? For the sites already have Medidata Rave running, not only that they have experience but also have site license.  For sites without Medidata Rave, it will be more expensive, too.

Answer: NCI will provide a site license. The team does not necessarily have to have had experience with Medidata Rave, but they do need to have had experience with data management.

4. (Received by 10/1/2018) For the clinical trials auditing, is it acceptable to contract out to a third-party company?

Answer: Yes, but we will want to know the group's track record and a very clear process and milestones for oversight of such a contractor.

5. (Received by 10/1/2018) What are the DMACC roles in study design, protocol development, data analyses and study finding interpretations?

Answer: The DMACC is intended to be very collaborative and advisory to the UG1s with respect to study design and protocol development. For collaborative studies that will be developed across the UG1 sites, it is expected that the DMACC will have a primary statistical role (for development and analysis and interpretation). The Steering Committee, which will include DMACC investigators, will have oversight of agent selection and developmental pathways. Finally, the DMACC will be asked to review all LOIs and will have an advisory role in protocol development. The UG1s may consult with the DMACC to ensure the select approach is appropriate for data capture and reporting even prior to LOI submission.

6. (Received by 10/1/2018) Could a joint statistical collaboration model be acceptable – wherein, the primary statistician could be outside the DMACC, but the DMACC statistician would then jointly be responsible for the statistical leadership for the trial?

Answer: The DMACC statisticians will be expected to have an advisory role in protocol development, working with the primary statisticians for each trial. This will be a collaborative effort. For cross-network trials, the DMACC statisticians will be expected to have a primary role in study development.  

7. (Received by 10/1/2018) If the individual sites are providing the scientific leadership in the development, conduct and data analysis, please clarify what it means for the DMACC to provide expertise in clinical trials methodology and biostatistics.

Answer: Please see the answers to Questions 5 and 6 above.

8. (Received by 10/1/2018) Based on our understanding, the CP-CTNet comprises five sites, which will be covered by the companion FOA, RFA-CA-18-029. To ensure that we are understanding this correctly, please confirm that there will be five consortia funded.

Answer: It is NCI's intent to fund five sites, but the ultimate funding plan will depend on the applications and scores received.

9. (Received by 10/1/2018) On average, how many trials do we expect the CP-CTNet sites to activate per year?

Answer: Each site is expected to activate one to three new trials per year (thus five to 15 new trials will be activated per year across the entire network).

10. (Received by 10/1/2018) Are applicants required to host an instance of Medidata Rave?If not, can Rave be hosted by Medidata or will NCI host it?

Answer: Rave will be hosted by Medidata.

11. (Received by 10/1/2018) Will NCI negotiate Rave license costs for this program with Medidata, or should applicants include the costs resulting from their own negotiations with Medidata?

Answer: NCI has negotiated Rave license costs, however, the DMACC will be responsible for negotiating professional services costs directly with Medidata. These services may include study build, training, reporting, patching local URL, etc. We encourage sites to have prior Rave experienced personnel to minimize professional services costs, but this is not a requirement.

12. (Received by 10/1/2018) Under Section IV.2, "Content and Form of Application Submission," subsection entitled "DMACC Functional Units," the RFA states "Costs for hosting, maintaining, and providing round-the-clock access for an instance of Medidata Rave as the Clinical Data Management System (CDMS) of record (The license and specifications for the CDMS will be provided by the NCI)." Please clarify, given that Medidata provides these services when Rave is hosted by them.

Answer: Medidata will provide hosting and maintenance of Rave. The DMACC will be responsible for professional services needed to operationalize the DMACC's Rave URL (i.e., study build, training, reporting, patching local URL, etc.). We encourage prior Rave experience to minimize costs, but this is not a requirement.

13. (Received by 10/1/2018) Will DCP issue a new set of DCP SOPs that will drive the operations for the CP-CTNet, as DCP did for the Consortia 2012 program?If yes, will DMACC be responsible for updating these new SOPs?If yes, who will host them and where, for public access?

Answer: No. The DMACC will be responsible for new/revised SOPs. The DMACC will work with NCI staff to make SOPs available for public access when applicable.

14. (Received by 10/1/2018) Under "Research Strategy" Subsection D, "Administrative and Coordinating Unit," 2nd bullet: "Development and maintenance of documents, such as the DMACC Manual of Operations, CP-CTNet standard operating procedures, website content for CP-CTNet, and other procedural documents and materials." Will the "website content for CP-CTNet" be hosted at DCP's current website (https://prevention.cancer.gov/clinical-trials), or will the applicant need to host it in another to-be-developed website?

Answer: DMACC's Manual of Operations, CP-CTNet standard operating procedures, website content for CP-CTNet, and other procedural documents and materials will be hosted/available via the current DCP website (https://prevention.cancer.gov).

15. (Received by 10/1/2018) Under "Resource Sharing Plan," the last bullet states, "The data sharing plan is also expected to address procedures ensuring that claims of agent efficacy are accurate and reliable (e.g., by establishing an independent response review panel)." Please clarify: Does this involve the replication of the statistical analysis conducted by the LAOs that generate the conclusions reflected in the manuscripts? Also, does the parentheses mean that the applicant needs to describe how we are going to set up adjudication committees? Finally, should this be articulated in the data sharing plan or in the research plan?

Answer: Replication of statistical analyses is not expected. The procedures for ensuring accuracy and reliability should be articulated in the Data Sharing Plan, as requested.

16. (Received by 10/1/2018) In multiple sections, there is reference to biostatistics; however, there is no specific requirement for statistical analysis. Please clarify.

Answer: Please see the answers to Questions 5 and 6.

17. (Received by 10/1/2018) The RFA mandates use of Medidata Rave for CDMS.However, over the 5-year grant cycle with five sites each running one to three small trials per year (accrual approximately 40 participants per year, etc.) the overall number of participants recruited will not be large. Why use such expensive technology?

Answer: While there are numerous CDMS products, NCI awarded Medidata a contract to provide CDMS services to NCI's Clinical Research Programs. Medidata was selected for several reasons but mainly for its economy of scale and ability to manage trials with large participation from multiples sites. In addition, NCI feels the use of a common CDMS is both efficient and cost effective. Efficient from the aspect of "one tool, one way" allowing for the development of best practices to be deployed across NCI funded clinical trials. Cost savings are obtained from developing system integrations one time with other NCI products and tools (no need to reinvent the wheel for each CDMS of choice).

18. (Received by 10/1/2018) Is there a specific software platform mandated for use with the virtual biospecimen repository also?

Answer: No.

19. (Received by 10/1/2018) The RFA states: "Costs for hosting, maintaining, and providing round-the-clock access for an instance of Medidata Rave as the Clinical Data Management System (CDMS) of record (The license and specifications for the CDMS will be provided by the NCI)." Please provide additional detail on what "the license and specifications for the CDMS will be provided by the NCI" means?

Answer: NCI has a hosting and maintenance contract with Medidata for the Rave application.  Medidata will provide a URL/instance of Rave for DMACC use. The DMACC will be responsible for professional services to operate Rave (i.e., study build, training, reporting, integration, patching local URL, etc.). We encourage sites to have prior Rave experience personnel to minimize professional services costs. 

20. (Received by 10/1/2018) Will the DMACC serve as the Central Data Repository for all CP-CTNet data including all analytic results data?

Answer: Yes and No. The DMACC will serve as the central data repository for all CP-CTNET data managed in Rave as the "database of record." However, the UG1 grantees are responsible for statistical analysis/analytic results. There is no requirement that such data must be housed at the DMACC.

21. (Received by 10/1/2018) Can you explain how ongoing data management and auditing will be handled, i.e., centrally at the coordinating center, or by the participating sites?

Answer: All auditing for CP-CTNet will be handled by the DMACC. The data management will be a shared effort, with the DMACC being responsible for the centralized database (including the build, maintenance, etc.) but with the Sites being responsible for data entry.

22. (Received 10/2/2018) I assume the data entry will be done by the clinical sites. Will DMACC be responsible to monitor the data quality including the timeliness, accuracy, missing and deficiency, etc.?

Answer: Yes. The DMACC is responsible for data quality.

23. (Received 10/2/2018) Can the auditing function be contracted to an outside commercial company? Since the cost is closely related with the frequency and volume, are their mechanisms for supplemental funding if the activities are much more than the budgeted?

Answer: Yes, auditing can be contracted to an outside company. The best estimate should be used to determine the budget based on the auditing plan in the RFA; however, DCP acknowledges that auditing will depend on the trials approved and the number of AOs involved. Remote auditing can be used to reduce costs when possible.

24. (Received 10/2/2018) Could you say more about the "virtual biospecimen inventory system"? Could you give an example?

Answer: The goal is to have an online system that tracks the number and types of samples available from the studies conducted. At the end of the study the system should be able to produce a list of samples collected and available for trial analyses. Once the study analysis is complete, the system should be able to produce a list of leftover samples that are linked to the clinical data from the trial and are available for future analyses. The goal is to allow the NCI, CP-CTNet investigators, and outside investigators to query the system for a specific type of sample (e.g., benign breast samples from postmenopausal women).

25. (Received 10/2/2018) Could you please elaborate on the role of DMACC in maintaining a virtual biospecimen inventory system? Where is this system located?

Answer: The DMACC will be expected to develop and manage a centralized electronic inventory that will permit real-time remote access to the status of biospecimens from CP-CTNet clinical trials. The virtual biospecimen inventory system will be located at the DMACC. See the answer to Question 24 above.

26. (Received 10/2/2018) Is the DMACC expected to develop a website (new), or just provide content as per the RFA?

Answer: Information that is available to the public will be housed on the NCI CP-CTNet website. If there is a need for information to be restricted to just the CP-CTNet investigators a website would need to be developed and maintained by the DMACC.

27. (Received 10/2/2018) Can you describe the Medidata Rave system a bit more? Is it a clinical trial management system, or data capture system, or both?

Answer: Medidata Rave is both. Rave is a clinical data management system used to electronically capture, manage, and report clinical research data.

28. (Received 10/2/2018) Will SIVs (Site Initiation Visits) be run by the DMACC?

Answer: SIVs are a trial specific function and will be under the scope of the CP-CTNet site.

29. (Received 10/2/2018) Will the DMACC be responsible for all data queries?

Answer: The DMACC and LAO will need to have a collaborative approach for data queries and resolution. This will be part of the SOP development process led by the DMACC after awards are made.

30. (Received 10/2/2018) Can NCI systems such as OPEN be used for CP-CTNet studies?

Answer: No, OPEN is not currently planned to be used for CP-CTNet studies. It is possible other NCI systems may be used for CP-CTNet in the future.

31. (Received 10/2/2018) Since sites have Laboratory Information Management Systems (LIMS), is the specimen tracking system required to provide label printing/scanning capabilities or not?

Answer: No, this is a virtual repository which tracks biospecimens housed at the participating sites.

32. (Received 10/2/2018) Who is responsible for SAEs? 

Answer: The enrolling site where the SAE occurred (LAO or AO) is responsible for reporting the SAE to DCP (and LAO, if the SAE occurred at an AO). Reporting to the FDA will be based on who serves as the IND Sponsor.

33. (Received 10/2/2018) What does QA/QC by the LAO entail?

Answer: The LAO will need to provide plans to assure quality of, and monitor adherence to, the trial protocol and data collection.

34. (Received 10/2/2018) Medidata Rave can also host imaging and omics data. Will the DMACC be responsible for capture and hosting of this type of generated data?

Answer: Like other biomarker costs in the study, the logistics for the capturing and/or hosting of imaging/omics data will be dependent upon the design and types of studies approved, as well as budgetary considerations (e.g., availability of supplemental/other funding, leveraging off other NCI/NIH platforms etc.).

35. (Received 10/2/2018) Will you still be working with CCSA?

Answer: DCP's regulatory support program contractor (currently CCSA, Inc.) will continue to facilitate IND submission, tracking of regulatory forms and other regulatory filings. Additional details on DCP's Regulatory Support Program are available at DCP Contract Resources.

36. (Received 10/2/2018) To avoid duplicate data entry, should we assume that the AOs will export data from their laboratory information management systems (LIMS) to the specimen tracking system, as opposed to typing the inventory in the tracking system?

Answer: The preferred method would be to use exported data when available to reduce duplicative data entry.

37. (Received 10/2/2018) You mentioned in the previous call that randomization is to be determined. Does this mean that Balance is not a required Medidata tool at this time?

Answer: Randomization is not to be determined. The LAO will perform study randomization. Balance is not required.

38. (Received October 5, 2018) Will CP-CTNet audits and audit reports be managed by CTMB AIS?

Answer: No, audits will be managed by the DMACC with oversight by DCP.

39. (Received October 12, 2018) Can you please confirm that Attachments 1, 2, and 3 for the NCI DMACC application are not restricted to the 30-page limit of the Research Strategy section?

Answer: This was addressed in question 5 of the UG1 webinar. The 30-page limit refers to the Research Strategy only. Attachments are separate.

40. (Received October 12, 2018) On pg. R93 of the SF424 (R&R) Application Packages Research Instructions for NIH and Other PHS Agencies under the requirements for human subject research, if the grant involves human subject research and is not exempt under exemption 4 then the applicant needs to provide the following:

• Section 2 – Study Population Characteristics
• Section 3 – Protection and Monitoring Plans
• Section 4 – Protocol Synopsis

The work for the NCI DMACC involves human subject research and is not exempt under exemption 4. Since the applicant's scope of work under this grant does not include Section 2, Section 3, or Section 4; then are Section2, Section 3, Section 4 not required to be completed for the NCI DMACC FOA?

Answer: The RFA specifically addresses this:

"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:

Do not complete study records.

Delayed Onset Study

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

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

Study Title — use: "Multiple Delayed Onset Studies"

Justification Attachment: Indicate that the clinical trials will be designed and conducted by the CP-CTNet Sites with NCI assistance during the Project Period. Each clinical trial protocol developed will be subject to approval through the standard NCI procedure that involves an initial concept submission and subsequent review. If the concept receives approval, the next stage will be development of the full clinical trial protocol, which will be subject to review and approval by NCI prior to activation through the CP-CTNet. The DMACC will participate as a CP-CTNet clinical trial infrastructure during the implementation of the approved clinical trials."

41. (Received October 12, 2018) The budget template includes an entry for "Fee" at Item J, so we presume that "for-profit organizations" are entitled to include a nominal (not to exceed 7%) fee in the application budget for this RFA. Please confirm.

Answer: Per the NIHGPS, 18.3.4, "Except for grants awarded under the SBIR/STTR programs, under an NIH grant, no profit or fee will be provided to a for-profit organization, whether as a recipient or as a consortium participant." The budget template is the same for all grant mechanisms, so just because the line item is there does not make it an allowable cost under an NIH grant.

42. (Received October 12, 2018) Please confirm if there is a NAICS code applicable to this RFA. (This will help determine whether a firm is considered a small business or not for this RFA.

Answer: No, there is no NAICS code applicable to this RFA. NIH uses the Small Business Administration's (SBA) definition for determining whether a business is considered small business. Since both Small Businesses and For-Profit Organizations are eligible to apply to this FOA, the distinction is not relevant in this context.

43. (Received October 14, 2018) Can an investigator who is named on the U24 leadership team also be named as a site PI on a UG1 application?

Answer: No. The RFA states, "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 FOA, RFA-CA-18-030." The intent of this statement is that any key personnel on a U24 cannot be key personnel on a UG1 and vice versa; this includes serving as an AO site PI.

44. When the UG1s have the primary statistical role, will the UG1s use their LAO's data safety and monitoring board (DSMB) and apply their LAO's standard operating procedures, for instance, in determining the frequency of reviews per calendar year and DSMB report requirements?  Or as the DMACC, will we use our institution's DSMB in this setting and apply our developed SOPs?

Answer: The convening of the DSMB is the responsibility of the PI of the UG1 Site.  Monitoring by the DSMB must occur at least annually per DCP policy. The DMACC will assist in providing documentation required for to assemble the DSMB report for each of the UG1 DSMBs.

45. Can the lead statistician within the DMACC (Co-PI of the DMACC in our case) also serve as the lead statistician (co-I) for a UG1?

Answer: (This has been answered and posted as Question No. 43 on the CP-CTNet webpage) No. The RFA states, "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 FOA, RFA-CA-18-030." The intent of this statement is that any key personnel on a U24 cannot be key personnel on a UG1 and vice versa; this includes serving as an AO site PI.

46. Please confirm that the Research Strategy section is limited to 30 pages and not 12 pages.

Answer: Yes

47. Does PIO use an electronic trial master file (eTMF) system for managing early phase cancer prevention trials?  If so, will the CP-CTNet DMACC be granted an access to the PIO's eTMF system.

Answer: DCP does not currently use an eTMF for early phase trials.  The potential of the eTMF to facilitate auditing could be discussed with DCP during the development of the SOPs if awarded.

48. RFA-CA-18-030 states that "The NCI will have access to all raw data (including imaging data) from clinical trial participants collected and/or generated under this Cooperative Agreement and may periodically review the data."  However, RFA-CA-18-029 states that "The NCI will have access to all data (including imaging data) collected and/or generated under this Cooperative Agreement and may periodically review the data." 

Please clarify the reason for the discrepancies and whether NCI will require access to the original participant records / source documents (e.g. redacted medical records, scanned images, lab reports, etc.).  Or is NCI's objective to obtain read-only access to the data entered into Rave?

Answer: NCI will collect a complete dataset including images at the end of the study for each trial from the DMACC.  NCI will also obtain additional datasets including analytic datasets from each UG1 Site and from the DMACC in the case of cross-network studies. NCI maintains the right to request read-only access to Medidata Rave as necessary to have adequate oversight of the raw clinical trials data.

49. Because we want to understand the roles and differences between clinical research auditing and monitoring, two distinctly different functions, please clarify what distinguishes the two functions within the context of both the RFA-CA-18-030 and the companion RFA-CA-18-029.

Answer: Monitoring will be the responsibility of the UG1 Site.  Monitoring is the act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, standard operating procedures (SOPs), GCP, and applicable regulatory requirements. It is a continuous process, can be conducted on-site or off-site, and involves oversight of all patients on a trial. Study monitoring includes:

• Precise tracking of patient accrual
• Ongoing assessment of patient eligibility and evaluability
• Adequate measures to ensure timely submission of study data
• Adequate measures to ensure timely medical review and assessment of individual patient data
• Timely reporting of adverse events and treatment-related morbidity information
• Periodic evaluation of outcome measures and patient safety information
• Auditing will be the responsibility of the DMACC.

Auditing is a systematic and independent examination of trial related activities and documents to determine whether the evaluated trial related activities were conducted, and the date recorded, analyzed, and accurately reported according to the protocol, sponsor's standard operating procedures, GCP, and the applicable regulatory requirements. It is a snapshot in time (as opposed to the continuous nature of monitoring), commonly an on-site process, and consists of reviewing a subset of patients on a trial.

The specific purposes of the auditing program are to document the accuracy of data submitted to Medidata Rave and NCI/DCP, to verify investigator compliance with protocol and regulatory requirements, adherence to the policies and procedures of the CP-CTNet and, if necessary provide site staff with resources for a more thorough understanding of the regulatory requirements, good clinical practices (GCP), data collection and data management practices.

The major objective of the audit program is to verify study data that could affect the interpretation of primary study endpoints. The three components of a study audit are:

• IRB/Informed consent content review
• Pharmacy and drug accountability; and
• Patient case review

50. Because the DMACC is expected to be responsible for overall, cross-network recruitment efforts, is it NCI's expectation that the DMACC will manage the AQuIP online accrual reporting system?

Answer: The DMACC is expected to provide data management support for tracking and improving participant accrual in CP-CTNet clinical trials by developing and managing tools and resources for the collection, review, analysis, reporting, and quality improvement and related information in partnership with CP-CTNet Sites and NCI staff.  As mentioned, these functions are currently managed by the Accrual Quality Improvement Program (AQuIP), a multi-component comprehensive accrual support program. The AQuIP Online Accrual Reporting System is one component of AQuIP, which is operated through a separate contract for the 2012 DCP Consortia studies. The DMACC will be responsible for all of the functions of AQuIP for the CP-CTNet.

51. Under the current contract, Brenda Maeske is curating Common Data Elements (CDEs) for the Cancer Prevention Network (CPN) and maintaining each CPN study's unique CDE spreadsheet.  Will Brenda Maeske or a qualified NCI colleague continue to take responsibility for curating under the new grant system?  Or will this be the responsibility of the DMACC?

Answer: CDEs will continue to be curated by NCI although the DMACC should ensure cross-study use of similar CDEs where possible.