Between 11 and 14 February 2020, the MHRA hosted a week-long series of events as part of the Good Practice Symposia Week. This included individual events from the GPvP, GCP and Laboratories Inspectorates where a host of regulators and delegates from across the globe came together.
The week concluded with the second joint MHRA GCP and US Food and Drug Administration (FDA) event following that hosted by the FDA in the USA in October 2018, and the first one hosted by the MHRA in the UK.
The first day of the event was attended by over 350 delegates in person and streamed to hundreds more from all over the globe. This was a new option, allowing regulators and stakeholders to join us virtually, watch presentations, participate in live polls and submit questions to speakers. We were joined by delegates from 29 countries as far afield as Australia, Canada, Brazil and Singapore.
The event focussed on the next steps in relation to data integrity for both GCP and bioequivalence (BE) inspections, providing both MHRA and FDA perspectives in all sessions. This included:
International Collaboration
Gail Francis, MHRA Expert Inspector, and Ni Khin, FDA Division Director, introduced how the FDA and MHRA work, highlighting both the similarities but also the differences. They outlined how the agencies are working together to share information relating to non-compliances, have observed each other’s inspections and are working towards a programme of collaborative and joint inspections. These regulatory updates were the main reason for attendees choosing to come to the symposium.
Sponsor Oversight: International Perspective
Stephen Vinter, MHRA Laboratories Operations Manager, kicked off the session by presenting the importance of sponsor oversight of clinical sites and laboratories, particularly increasing the awareness of areas of risk to clinical trial conduct. The presentation used examples from the inspections of bioequivalence clinical trials to highlight how risks exist in areas that may not always be obvious. Examples included how standardisation of tasks, if not properly managed, can lead to process failure and how technical knowledge can influence the conduct of a clinical trial.
Kassa Ayalew, FDA Branch Chief, presented the FDA’s perspective on sponsor oversight of international clinical trials. While acknowledging that this was a challenge, especially as sponsors will manage numerous, interrelated and interacting processes, Kassa described the elements of an effective quality system. This included focusing on what matters, developing a quality management plan, assessing performance, plus improved training and procedures.
eSource (including Electronic Health Records)
Andy Fisher, MHRA Lead Senior Inspector, introduced delegates to electronic source and the need to maintain the full patient journey. He also stressed the need for Investigators to be in control of and have all their source data and metadata. Andy’s closing message also raised a smile, that eSystems should be implemented to facilitate not frustrate!
Phillip Kronstein, FDA Lead Medical Officer’s presentation included case studies from recent inspections and feedback on how to improve compliance including the need for timely entry of eSource data to ensure reliability and ensuring clarity of protocol requirements to ensure consistency.
Protocol Deviations: Identification, Impact, and Reporting
Jean Mulinde, FDA Senior Advisor, posed the question ‘Violations and Deviations: Is Anyone Really Happy with Current Handling?’ She took the opportunity to discuss we are making advances in the ways we identify deviations in trial conduct. However, our ability to leverage this data to more efficiently and effectively protect the safety, rights and welfare of participants, as well as to ensure the data from clinical trials is of sufficient quality for stakeholders to make treatment, development and regulatory decisions is still lagging.
Jennifer Martin, MHRA Lead Senior Inspector and Operations Manager, took on the mantle to remind delegates of the need to have good processes for identifying non-compliances from all the sources where deviations can occur, a robust procedure for recording these then reviewing and assessing them, both during the trial for identification of any issues that need corrective and preventive actions and/or regulatory reporting (e.g. serious breaches in the UK) and at the end of the trial for inclusion in the clinical study report. Consideration is also needed about how the non-compliances will be used in the analysis including a robust and consistent decision on inclusion or exclusion of subjects in the statistical analysis and listing all important deviations in the clinical study report (CSR).
Julia Cho, FDA Division Director, returned to BE inspections and the impact of protocol deviations on bioanalytical data. Julia gave examples of findings due to analyte stability (due to the use of a -20°C freezer instead of -70°C), sample processing (where a lack of documentation meant it was not possible to verify proper sample handling and processing), PK sample collection (unacceptable samples were analysed and data included in the analysis) and reserve samples (samples of investigational medicinal product were not properly retained).
Challenges in Ensuring Data Quality in Novel Clinical Trial Design
Cheryl Grandinetti, FDA Pharmacologist and Mandy Budwal-Jagait, MHRA Senior Inspector, reviewed the challenges in ensuring data quality in novel clinical trial designs, particularly for de-centralised/virtual or hub and spoke trials. These integrate the use of telemedicine, digital health technology tools and other electronic systems to perform some or all trial-related procedures at locations remote from the trial site and may use the participant’s existing healthcare ecosystem or mobile trial personnel to make it more convenient for participants to participate in the trial). They also covered adaptive trials (allowing for prospectively planned modifications to one or more aspects of the design based on accumulating data from participants). While the use of novel clinical trial designs are encouraged, including basket, platform or umbrella, inspectors have seen some issues with sponsor oversight while on inspection; there needs to be a robust, considered and documented risk assessment at the start of the trial in order to factor in changes throughout and ensure decisions and changes are clearly documented contemporaneously.
Michael McGuinness, MHRA Inspector, concluded the day with a case study about the importance of data quality requirements for use in dose escalation decisions in a Phase 1 trial. On inspection of a laboratory, it was discovered that during analysis a number of analytical runs had failed. However, as there wasn’t enough time to repeat the analysis, the laboratory made the decision to release the data from theses runs for the scheduled dose escalation meetings, where PIs were unaware they were making decisions with invalid data. It goes without saying that safety should never been compromised in favour of timelines! However, this was not just a single case and has been identified at several inspections.
Delegates also had the opportunity to discuss queries with the inspectors during the inspector’s surgeries, as well as ask questions to the panel. Whilst we try to answer as many questions as we can, it is not possible to answer all those submitted. If your query was not answered on the day and you would like a response, please send it to the Clinical Trial Helpline (clintrialhelpline@mhra.gov.uk).
Day 2 of the event saw parallel, practical workshops allowing delegates the opportunity to work on relevant case studies and expand on their learning from the previous day. These covered electronic patient reported outcomes and bioanalytical approaches for BE clinical site inspections then protocol deviations and laboratory audit trails. Great feedback was received, including one participant who described the workshop as ‘simply AWESOME’.
You can follow the take home messages and highlights of the event using #MHRAGCP20.
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