Best Practices For Setting TMF Expectations With Your CRO

By Brad Miller, Biosceptre

Developing a strong relationship and setting up-front expectations with your chosen CRO are critical keys to success in clinical studies. While the request for proposal (RFP) process will assist in framing the contractual relationship between sponsor and CRO, the traditional RFP approach is unlikely to outline the detailed operational expectations of the sponsor, leading to confusion and resentment as multiple change orders are presented or, in extreme cases, the inability of the CRO to satisfy your expectations.

In conjunction with the RFP process, sponsors should prepare a study expectation overview document for each functional area of responsibility delegated to the CRO, including, among others, medical writing, data management, clinical monitoring, project management, and the trial master file (TMF). These overviews should clearly and succinctly outline your expectations from the simple (i.e., a style guide for medical writing) to the complex (i.e., data residency and security of electronic information for each digital solution provider [i.e., EDC, CTMS, eTMF, etc.] used in the study). The project management overview should set expectations of good communication and appropriate escalation pathways (for both the CRO and sponsor organizations) to ensure that high-priority issues are assigned to the most appropriate resource to drive accountability in a timely manner.

A CRO that is unwilling or unable to reflect its understanding of your expectations in its study proposal and bid defense is unlikely to meet your expectations and its involvement as your partner in the study should likely be reconsidered.

Expectation Setting As A Tool To Meet Regulatory Requirements

ICH E6(R2)¹ requires (at 5.2.2) that the sponsor ensure oversight of any trial-related duties and functions carried out on its behalf, including trial-related duties and functions that are subcontracted to another party by the sponsor’s contracted CRO(s).

Everyone (hopefully) would agree that critically reviewing and querying interim monitoring reports with your CRO partner (and documenting that review and query process) would be one tool on your toolbelt to demonstrate adequate sponsor oversight activities. However, setting the expectation for how that information is distributed (i.e., format and timing of written reports, collation of site and project level non-compliance statistics, frequency of in-person presentations of the key findings, etc.), and the process to raise and resolve queries is critically important to the success of your study.

Setting Expectations Up Front

The TMF is an active study management tool that you should leverage throughout the study. The CRO’s performance in delivering the study should be judged, in part, on the completeness, timeliness, and quality of the TMF. Accordingly, some key up-front considerations that may assist you to frame your expectations regarding the TMF will likely include:

• Do you as the sponsor wish to own the eTMF instance and grant access to the relevant CRO personnel, or are you willing to use the CRO’s preferred solution, provided you have electronic access throughout the study? If so, what user permissions do you expect (i.e., read only, download and print permissions, ability to upload and file documents, etc.) and what training is the CRO expected to provide to enable you to effectively and efficiently use those permissions?
• Do you expect the CRO to use an out-of-the-box configuration of the DIA TMF Reference Model or do you expect the CRO to extensively modify a reference model in line with your proposed TMF design and standard operating procedures (SOPs)?
• How will inspection readiness be maintained at all times throughout the study? Would a quarterly bulk upload of documents by the CRO be acceptable and how would that affect your obligation to provide oversight of the CRO?
• If you expect the CRO to provide progress tracking metrics, what frequency and what metrics should be presented? Should this information be provided on a monthly basis by email or should the eTMF solution provide a dynamic dashboard to allow you to drill down and analyze the headline details without the intervention of the CRO?

Do you expect the ability to view any and all documents, reports, metrics, data, or information within the TMF or do you accept that some may be unavailable (i.e., the CRO doesn’t make available to you a specific performance metric report used as a project management tool)?

Sponsor Expectations Extend Across Functional Teams

While the TMF specialist may understand and accept the performance metrics used in the study, unless they are shared across functional boundaries, the reported performance metrics are likely to misrepresent actual performance. For instance, once data management has performed and completed user acceptance testing on the clinical database, a report should be completed and filed within the TMF. If data management completes yet doesn’t share that report with the TMF specialist in a timely manner, the completeness and timeliness metrics would be misrepresented. Accordingly, your expectations of various functional teams are not mutually exclusive, and your expectation of data management (timeliness of completing and distributing reports) is likely to have a direct impact on your expectations of the TMF (TMF completeness). The TMF specialist and all other functional leads need to be aware of the sponsor’s expectations and concurrently have the authority and support of senior management to enforce those requirements.

Measuring Actuals To Expectations

Once expectations have been adequately established, a sponsor must ensure that the CRO is held accountable to those expectations. You must have in place procedures to measure actual to expected performance and to escalate issues to ensure they are resolved prior to impacting the outcome of the study.

In judging the performance of the CRO on the completeness, timeliness, and quality of the TMF, you may wish to consider:

• Completeness metrics, including the percentage of documents completed vs. the percentage of documents expected for the stage of the study;
• Timeliness metrics, including the number of days between document creation and when the document is filed in the TMF and the time between the document being filed and when the document is quality controlled; and
• Quality metrics, including the number of documents accepted vs. rejected, the number of queries raised and the query aging (in days).

While you cannot expect a 100% compliance rate, a poor completeness metric may suggest an insufficient monitoring schedule to adequately capture the required documents, a poor timeliness measure may indicate that the CRO hasn’t assigned sufficient resources to the TMF function for this study, and a poor quality metric likely suggests that additional training (study specific or otherwise) is required. In any case, good communication and the CRO undertaking a root cause analysis are likely to resolve the issue prior to it becoming systemic.

Summary

Given the increasing complexity and intensity of clinical studies, sponsors are routinely stretched for resources. By spending time up front to define your expectations of your CRO partner prior to the RFP process, you are more likely to:

• Undertake a focused RFP that concentrates on how the CRO partner will provide value-add to your clinical program;
• Develop a long-term relationship built on trust and the knowledge that you are inherently working toward a common and well-defined goal; and
• Ultimately, identify a CRO partner that can exceed your expectations.

References

1. International Council for Harmonisation of Technical Requirements For Pharmaceuticals For Human Use (ICH), Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2).

About the Author:

Brad Miller is the clinical operations director at Biosceptre, a company developing antibody and CAR-T therapeutics against nfP2X₇. He can be found on LinkedIn.