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The FDA's Bioresearch Monitoring Compliance Program Manual provides sponsors with absolute transparency as to how the FDA will conduct sponsor GCP inspections. Still, there are a number of deceptively simple questions that sponsors find surprisingly difficult to answer.
Section E.2. What were the sponsor's criteria for selecting clinical investigators? Most sponsors and CROs lack a process step for documenting explicit selection criteria for study investigators. The criteria can sometimes be inferred from feasibility questionnaires or qualification visit checklists, and may be discussed at study start-up meetings. If your organization doesn't require a specific step for documenting criteria, consider modifying your SOP to require it, and look for informal documentation to support how you made site selection decisions.
Section F.1. What were the sponsor's criteria for selecting monitors, and did the monitors adhere to those criteria? Most sponsors also lack a process step for documenting explicit selection criteria for site monitors. If outsourced, the CRO contract or correspondence during study start-up may outline these criteria. If none were established, the inspector may ask to see the site monitors' job descriptions. The inspection team should review each site monitor's CV at the time of study start to determine whether general and study-specific requirements for education, training, and experience were met; this is the only way to be able to answer this question prior to the inspection.
Section F.2. How does the sponsor allocate responsibilities when more than one person is responsible for monitoring functions? This question is semantically confusing due to the term "monitoring functions," which is used in the broad sense of "anything done to evaluate data and compliance for the study." The inspector is simply looking for an explanation of how responsibilities are divided among site monitors, in-house or central monitors (if used), medical monitors, and any other personnel who evaluate data and compliance. Although the answer to this question may seem obvious, different sponsors organize functions in different ways.
Section G.3. Who can make corrections to CRF data? For studies using EDC, this question seems so simple that it must be a trick: Site personnel make corrections. For some studies, though, subsets of data are entered by central reviewers (adjudication data) or data management (normal laboratory values), so those data are corrected by those parties. In addition, some EDC systems permit "backend" changes executed by data management or by the EDC vendor. These include invalidating forms that were generated in error, or algorithms that make blanket changes to particular data fields to standardize data after a poorly-implemented change. In all these cases, the inspector wants to know two things: 1. How did you verify that ONLY the authorized changes were executed - for example, if data management personnel can enter and change lab values, how do you know they didn't enter and change anything else? 2. How did you confirm with the site that they authorized the change?
Section H.1. Which audits did you conduct for this program? Audit information needs to be reconciled across multiple sources: Sponsor QA's audit log; the CRO QA's audit log; the TMF sections containing audit certificates; and the NDA. Most sponsors don't clearly define in an SOP which audits will be reported in an NDA. Clinical site audits are obviously reportable, but what about site audits conducted by a CRO as part of its internal Quality Assurance program, but not contracted by the sponsor? Vendor qualification audits? In-process vendor audits? Internal sponsor audits that included study data from one of the studies in the NDA? Trial Master File audits? Similarly, there may not be a clear definition of which audit certificates are filed in the TMF.
With a little planning, you can come up with satisfying answers to these questions before the inspector calls.
Denise DeRenzo Lacey, RQAP-GCP, has over twenty years’ experience in clinical Quality Assurance and clinical development operations. Her practice focuses on application of quality risk management techniques for clinical studies, including risk-based approaches to auditing, data quality and integrity, and SOP development. She has provided consulting services to a wide range of pharmaceutical, medical device, biotech and CRO clients in the US and Europe and has held senior positions at Vertex Pharmaceuticals and Radius Health.