UK MHRA summarizes clinical trial experience during the new crown epidemic

In its official blog, the Medicines and Healthcare Products Regulatory Agency (MHRA) reviews the lessons learned about clinical trials during the Covid-19 pandemic and how they can be used to build the UK clinical trial ecosystem and ultimately benefit patients

At the start of the pandemic, the MHRA assigned dedicated COVID-19 reviewers and developed a process for pre-assessing trial documentation so issues could be identified and resolved before protocols and supporting documentation were finalized and formally submitted for regulatory approval

MHRA has established a dedicated e-mail for Covid-related trial questions and submissions, which are easily identified, prioritized and resolved by a dedicated evaluation team

Early in the pandemic, the MHRA expressed its commitment to potential regulatory flexibilities and held regular meetings with industry to raise questions and discuss potential flexibilities

MHRA says it is one of the first regulators in the world to rapidly issue (and growing) guidance on trial applications (both Covid-19 and non-coronavirus) and manage trials during a pandemic

Remote monitoring

program deviation

Remote access to electronic health records (EHR) and instructions for pausing trials

Guidance on Minimizing Interference with the Conduct and Reliability of Drug Clinical Trials During COVID-19

challenges and lessons

MHRA's Clinical Trials Unit challenges Clinical Trials Unit (CTU) COVID-19 reviewers to develop new ways of working to evaluate and approve trials in less time, while maintaining a consistently high level of Scientific and regulatory reliability

triage work

Hold regular team meetings

Clear lines of communication (internal and external) and a pragmatic way of working

Responding to a pandemic is resource-intensive

CTU also interacts closely with the Expert Working Group of the Committee on Medicinal Products for Human Use to obtain advice from independent experts and to keep abreast of the latest scientific thinking on COVID-19

Some trials are suspended, some require procedural changes, and many require revisions, which are time-consuming for both sponsors and regulators

GCP Challenge

MHRA presents some very specific GCP challenges

Protocol-required visits can be made by phone or video call, so participants can be tracked, but there may be limitations if participants are required to attend in-person tests or blood draws

With patients unable to visit as planned, ongoing trials must use a different approach to delivering IMP to participants so they can continue treatment

Phase I trials in healthy volunteers also require review of potential risks

program deviation

As the pandemic unfolds, there will be significant implications for the data collected in ongoing trials

The MHRA anticipates an increase in the number of protocol deviations and recommends a risk-based approach to documenting protocol deviations

Therefore, the MHRA recommends that minor protocol deviations should be identified and that these deviations can be recorded at the trial level rather than the individual level

Following data quality issues with remote monitoring performed, MHRA recommends that sponsors re-monitor with a risk-based approach when it is safe to return to the site
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Therefore, sponsors may need to consider re-surveillance if there are concerns about the quality of the data, or if the data are critical to the reliability of the trial results, and the sponsor can only be confident in the data by performing on-site monitoring
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In most cases, however, the MHRA does not consider resurveillance to be performed
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risk adaptation approach

During the pandemic, sponsors have begun to use a more flexible and proportionate approach to conducting trials, largely out of necessity, but this flexibility is not new, and risk adaptation in clinical trials has become part of the MHRA regulatory environment
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In 2011, the MHRA developed guidance on approaches to risk adaptation in clinical trials, including a notification scheme for low-risk trials (such as those deemed risky no higher than the normal standard of care) and risk adaptation opportunities in certain areas of GCP-related trials
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Therefore, adaptations in safety reporting, drug administration, documentation, and monitoring could be considered for these low-risk trials, which allow researchers to use resources efficiently and adopt a commensurate approach to trial management
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In 2012, the GCP Inspector published GCP Guidelines that expanded on this topic, incorporating practicalities of how to adapt throughout the guidelines, and issuing additional guidelines to support the approach
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In 2013, the MHRA published risk assessment examples; these examples are real-world evaluations and adaptations reviewed by MHRA GCP inspectors and clinical trial division medical reviewers, providing examples of how these types of trials can be managed in a proportionate manner
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Further guidance and examples of remote monitoring were subsequently provided in 2014
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In 2020, this approach to risk adaptation also appeared in the MHRA's COVID-19 flexibility guidance
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Clinical trial sponsors have been reluctant to implement these flexibilities in the past, MHRA said
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These approaches are now more widely supported, including in the OECD Guidelines, EU Clinical Trials Regulations and ICH E6
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GCP check

Inspections have also been adjusted during the pandemic, the MHRA said
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Before the pandemic, the MHRA had started using office-based inspections as part of the inspection process, for example, the MHRA would often conduct remote inspections on the first day to ensure that needed systems were accessible
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In addition, the MHRA has conducted a pilot of a fully office-based centralized pharmacovigilance inspection
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MHRA has re-prioritized inspections based on Covid-19 vaccines and treatments, with the only on-site inspections being those deemed critical to public health and cannot be done remotely
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MHRA uses video conferencing, remote access systems and file sharing to request and review documents
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MHRA says these approaches have all proved successful
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The MHRA said, "Remote inspections require extensive document review with less human interaction and limited review of facilities as we cannot be physically present
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" The MHRA also noted, "One aspect of inspections that we all like is informality.
questions and chats, as well as providing general support and the opportunity to pass on best practices
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This is usually done during breaks or lunches, but there is no such opportunity with remote inspections
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MHRA has identified some significant deficiencies in remote inspections, which have proven to be very effective despite their limitations
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Remote inspections are suitable for focused inspections, such as issue-specific follow-up or corrective preventive action (CAPA) reviews, or those that are data-driven
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The MHRA noted that some technical difficulties were also encountered during the remote inspection, including poor network connectivity, stuttering video, and slow responses on some systems
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Additionally, the MHRA was challenged by the number of systems required for remote inspections, and for one research site, the MHRA had to access 7 different systems simultaneously
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Also, remote inspections take much longer and may not require time spent traveling, but accessing, requesting, reviewing and cross-checking documents, and asking questions takes much more time than expected
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