On the final day of the RQA 2025 International Conference titled Quality that Works: Pragmatism over Perfection, three regulatory agency staff members who helped draft ICH GCP E6 R3 spoke about the implications of the updated guideline for inspections by EMA and MHRA. Rebecca Stanbrook, a former Group Manager, Inspections at MHRA is pictured at left; Peter Twomey, Head of Inspections at EMA is at right; and Andy Fisher, Lead Senior GCP Inspector at MHRA joined remotely. Below are highlights from their talk:
Compliance with E6 R3. UK legislation has been revised to require compliance with the Declaration of Helsinki (also updated within the past year)and E6 R3. All speakers emphasized that compliance is expected. If any study processes were not conducted in accordance with R3, inspectors would expect to see the risks weighed in the risk assessment.
Critical-to-quality factors. Sponsors should anticipate a more in-depth focus on protocol development procedures, with inspectors looking for evidence of early identification of critical-to-quality factors, consideration of those factors during protocol design, and incorporation of patient perspectives. The MHRA speakers noted that their inspectors were trained to identify critical-to-quality factors based on the protocol and would be comparing their results with the factors identified by the sponsor. If the inspector identifies different factors than the sponsor, the inspector will initiate a discussion about the sponsor's rationale for selection. Sponsors who use a computerized system to generate this assessment may be asked to provide the inspector direct access to the system.
Continuous risk assessment. Inspectors will be looking for evidence of ongoing risk assessment and response. Speakers emphasized that risk assessment does not end after the initial identification of critical-to-quality factors and their associated data and processes.
Essential documents. Although sponsors are expected to determine for themselves which records are essential, any records deemed essential are expected to be retained. MHRA inspectors shared common inspection findings regarding the TMF, many of which were related to the common practice of maintaining records in different TMF repositories. First, they frequently find that sponsors don't have access to records in all repositories. Second, they can see in the audit trails that many sponsors are filing TMF records in authoritative repositories near the end of the study, which does not count as timely maintenance. Third, archiving processes frequently take into account records in the primary eTMF repository, but not the other repositories. (These are all issues we commonly note in TMF audits as well, along with a lack of index that identifies all relevant TMF repositories.)
Oversight of third parties. Speakers reviewed the difficulties in determining which of the two GCP responsible parties - sponsor or investigator - was responsible for third-party oversight. When a sponsor's vendor subcontracts with another vendor, it is clearly the sponsor's responsibility - although in response to an audience question of whether regulatory agencies expect sponsors to audit their vendor's subcontractors, they stated that sponsors are expected to "oversee" subcontractors, which could be accomplished in a variety of ways. For home health nurses performing study procedures, they emphasized that the investigator was responsible for oversight, even when nurses are contracted by the sponsor. When sponsors ship IMP directly to participants, however, the sponsor and investigator share oversight responsibility, with the sponsor responsible for shipment and the investigator responsible for training participants to handle and self-administer IMP.
Annex 2. Ms. Stanbrook requested that readers of Annex 2 use the terminology "decentralized elements of clinical trials" rather than "decentralized clinical trials," noting that most trials have decentralized elements. She noted that Annex 2 inspired quite a bit of public comment, so the working group is slightly behind schedule in finalizing the document. She did not anticipate a final version before the end of the year, but noted that anything is possible.
