Reflections from the ICR GCP & Ethics Forum April 2024

It has taken me a while to digest all the information from the incredible speakers at the ICR GCP & Ethics Forum last week - it was jammed pack with information on changes coming up in clinical research and if you get the opportunity to attend in the future, I would recommend it!

I thought it would be useful to provide my key takeaways from the sessions to share with the community and what better place than LinkedIn to share my musings.

First up in the day was Lord James O’Shaughnessy reflecting on progress made in the year following his independent review of commercial clinical trials in the UK. I found this session to be balanced, with evidence of changes that have been happening as a result of the review but recognition that there is still a way to go and Lord O'Shaughnessy was keen to hear from community members about the challenges and issues that they are still facing. He engaged thoroughly and with delicacy on attendees thoughts.? ?

Summary

Lord O'Shaughnessy highlighted 8 of the urgent challenges from the report noting that a year ago the UK was second slowest countries in the world to carry out Clinical Trials (CT) and how there had been a collapse in commercial CT by 50% meaning there was a 60% decrease in recruitment.

It was interesting to learn how other countries had approached solving issues relating to CT set up such as Spain who had a Royal Decree to speed up approval and set up times and Australia who have introduced R&D tax credits for SMEs. It provided clarity on why the UK would not be as attractive for the global market due to CT set up times when countries, such as Poland, can recruitment 3 times faster.

Essentially, as research professionals we want to provide better care for our patients. It was noted that if we maintained the numbers being recruited in 17/18, 125,000 patients would have had access to new drugs. Not only that there would have been an additional ￡570m income into the economy resulting in ￡360m savings! As stated by the NIHR, research is really for the health and the wealth of the nation.

Lord O'Shaughnessy noted that whilst COVID-19 was catastrophic, it demonstrated what we can do. He noted how Primary Care is negligible in CT activity and the UK is unique in the NHS setting to be able to provide opportunities for the population at scale but we need to help the public engage differently (participant demand rather than the other way around) to quadruple commercial CTs by 2027.

Changes since the report

Whilst it was noted that recruitment for commercial studies from a baseline of 3,200 had increased by March 24 to 10,974, there was a long way to go. Reassurance was provided that if government changes, there is support to continue with plans proposed in the review.

In addition to that regulatory assessments by the MHRA are being turned around within required timelines.

What is next?

It was noted that protected time was not covered in the report due to NHS pressures but Lord O'Shaughnessy stated that this would be something that would help increase research delivery.

Focus on Primary Care to work on decentralised CTs to take advantage of their key role in NHS care.

Attention is needed on later phase studies as the low price of drugs in the UK has an effect on the market and there is a wealth of data within the NHS infrastructure which will allow growth in this area.

Next was an update from Andy Fisher, from the MHRA. His presentation began with providing an update on the amount of studies which have taken place since the Medicines for Human Use Regulations (2004) were introduced - 1,700 inspections!

It was noted that there has been a change in the way inspections take place as a result of COVID with a third of inspections now either remote or taking a hybrid approach as a result of a smaller inspection team and an increase in the complexity of studies.

Trends in recent MHRA inspections

1. Reference Safety Information (RSI) - Specific inspections relating to RSI have had to take place as there have been cases where the RSI being used for safety reporting (PV) is not the same as the submitted approved RSI. My advice - If RSI is updated, this must be submitted and approved prior to use and ensure this is documented appropriately when disseminated to participating sites.
2. Change control unclear - Evidence has been lacking in when protocols are updated and when the change is implemented within sites including lack of PI approval. My advice - If a protocol amendment is approved, ensure that there is appropriate documentation noting when this was implemented within the TMF/ISF.
3. Informed consent - Due to changes in delivery of studies during the pandemic, there were a number of cases where patients were not appropriately consented. My advice - If remote or online consent is used, consider how this can be documented appropriately - check out the NIHR Learn eLearning on Remote Consent for more guidance Course: Remote Consent | NIHR Learn.
4. Patient confidentiality - Again, as a result of changes in delivery, there has been a case on a decentralised trial of a CRO collecting Patient Identifiable Data (PID). My advice - Consider completing a Data Protection Impact Assessment (DPIA) prior to your study opening, to consider what and when data is collected to ensure only those who are authorised to have access to PID are documented and clearly stated.
5. Lack of PI Oversight - No documentation to demonstrate a clear oversight of eligibility and decision making. The cases highlighted related to where labs are required but have not been reviewed prior to eligibility sign off and in the case of portables collecting safety notifications not having been looked at (evident from audit trail). My advice - Map out the patient pathway and eligibility requirements prior to study start up to identify and plan best time for PI eligibility review. For studies using devices for safety monitoring, plan appropriate timepoints (based on participant risk) prior to the study and diarise to ensure regular oversight.
6. Inadequate Risk Assessment - Failure to demonstrate clear risk assessment but primarily the review of risk assessments following changes to the study (i.e. point of amendment, study extension etc.) My advice - A risk assessment is not a one-off review at the beginning of the study and should be revisited every time there are changes in the study delivery - build these reviews into your C&C checks to ensure risk is appropriately managed.

Summary on the upcoming Medicines for Human Use Regulations update Emphasis was given on a proportionate approach and changes such as aggregated pharmacovigilance (PV) reporting rather than individual to RECs and regulatory bodies. In addition, considering risk assessments specific to each individual study based on study endpoints not overall standard risks. It was noted that GCP would be the reference rather than EU directive and we are likely to see a relaxed view on who can be a Principal Investigator, if it is proportionate to risk. The new statutory instrument is due to be presented to parliament in the next couple of months.

Summary on ICH E6 Revision 3 progress

Work is happening at pace with 2 meetings per week with an aim to complete guidance in Autumn 2024 ready for adoption (12 months after to implement).

Check out this useful blog from Andy Fisher on the upcoming changes ICH E6 (R3) Good Clinical Practice – MHRA Inspectorate (blog.gov.uk)

General guidance

Andy Fisher provided some examples of considerations which need to be given more care and attention as we move to fully computerised approaches. Some key ones are as follows:

• Ensuring you remove access for leavers from all systems when their employment contract ends.
• Checking activation of unblinding process - if a PI has not 'activated' an account then if this is needed, unblinding cannot take place.
• Adding in checks on doses per protocol into User Acceptance Testing (UAT) and validation on eCRFs - not just functionality of the system.
• Ensuring appropriate access available for Electronic Health Records (EHR) with read only access and availability for tailored training for monitors/inspectors based on access needs.
• Consider naming conventions including dates for eTMFs and if both an ISF and TMF is needed if a single site study.
• Ensuring audit trails are GCP compliment i.e. providing a clear reason for change within the records.

I was brave and asked a question in this session. I regularly use the MHRA Grey Guide and asked if there were plans to produce a new one when ICH E6 Revision 3 is released but was advised there is no immediate plan to do so, which seems a real shame.

Jen Harrison from the HRA was next up, providing an update on the upcoming contractual agreements both for non-commercial and commercial studies.

Summary of contracts

Non-commercial

• New non-commercial Hub and Spoke Agreement to sit alongside the non-commercial CT Agreement.
• Update to non-commercial Organisation Information Documents
• Call for comment (until June 2024) for new non-commercial Model Investigator Initiated Study Agreement

Commercial

• New commercial finance appendix
• New commercial Master Confidentiality Disclosure Agreement ( instead of individual study CDAs)
• Updated model CDA

Up and coming contracts

• Commercial CI agreement
• Commercial ATIMP model CTA
• Commercial and non-commercial Data Access Agreements for Secure Data Environments (SDEs)

Other updates

Highlights were made to the various newsletters issued from the HRA to keep you in the know and you can find these HRA Latest - Health Research Authority.

Whilst it is not a legal requirement, the HRA are encouraging that all new research study applications include an Inclusion & Diversity Plan in applications as part of their work with the MHRA to ensure people underserved by research are not overlooked. This will be a key element for RECs to use in their review of new studies.

Confidentiality Advisory Groups (CAGs) are now all held on Zoom similar to standard REC meetings and researchers are encouraged to attend when their studies are being reviewed.

At this point, we were given a break to digest all this information and grab some lunch!

The brilliant Carolyn Maloney was next to engage us in the post-lunch session on behalf of the R&D Forum. I was surprised to hear this was the first time the Forum had provided an update at this meeting and as the event was attended by a wide range of research professionals, it was fantastic to see Carolyn provide insight to those in industry about the reality and challenges of working in research within the NHS.

Summary

An overview of the various working groups, hosted by R&D Forum but with membership from national experts working in R&D, was provided. It was great to see new groups which have been recently formed such as a sustainability working group created on the back of R&D community request. More information on the working groups can be found here Groups & Current Work - NHS R&D Forum (rdforum.nhs.uk).

In addition to this, Carolyn detailed some of the challenges to NHS research and provided recommendations of how this could be improved - she definitely knew her audience and was approached by several industry staff at the end of thank her for these insights. Recommendations included:

• A clear communication plan - During Site Initiation Visits (SIVs), plan who the contacts are to ensure a streamlined approach.
• FAQs on websites - If queries can't be answered from a protocol, consider creating a FAQ document or adding to a website as this will help speed up the feasibility process.
• Consider the process - Investigate local processes before carrying out feasibility to reduce delays.

Next we had the pleasure of listening to Heidi Chandler and Steve Burmester who are both Research Ethics Committee (RECs) to gain an insight of their top tips.

Summary

We were reminded that REC boards now all take place online and that RECs all over the country have different specialities.

It was great to hear about the specific areas of focus they thought about when considering applications and provides an insight of how to make your application for REC approval successful!

Key areas to note are:

Scientific validity

Is the research question important and necessary?

What level of Patient and Public Involvement (PPI) has taken place in the study design?

How will the statistical analysis ensure the research question can be answered?

Is there equipoise?

Recruitment

What is the inclusion and exclusion criteria and is it ethical?

Have PPI been involved in the recruitment approach?

How is diversity considered?

What is plans for ongoing care post study?

How will payments be made and is this fair?

Risk vs Benefit

What is the risk to individuals and impact to society?

Is this proportionate to the individuals involved?

Safeguarding for individuals involved - is anything included?

A key point was that information should not be buried in Patient Information Sheets (PIS). Anecdotally, Heidi and Steve discussed how they had received PIS which were 28 pages long and that as a community, we should be creative in how information is provided for studies with other methods such as video, audio and diagrams.

Valid Informed Consent

Heidi and Steve discussed how an integral part of the Informed Consent review is that they consider the use of language and ensuring this not coercive in any way i.e. not adding 'you have been chosen' instead of 'you are being asked' as it is a choice for the participant.

Great attention is given to the consideration of who approaches a participant for the first time and when this happens as well as the time given to consider.

Applications must state clearly the study procedures and the burden to the participant to allow the REC review to consider if it is ethical.

If you would like to find out more about how RECs review applications, why not apply to observe a meeting to find out a bit more about the process Observing a Research Ethics Committee meeting - Health Research Authority (hra.nhs.uk).

Final talk of the day, and by no means least, was Jo Burmester with a summary of changes in GCP-related regulations. Jo's talk complemented what had been discussed earlier in the day by Andy Fisher, from the MHRA, and provided additional clarity on the upcoming changes.

Summary

It was really useful to hear about Jo's insights on linking ICH E8 R1 (E8-R1_Guideline_Step4_2021_1006.pdf (ich.org)) Quality by Design to compliment the upcoming structural changes to ICH E6 in revision 3 and how we should be considering the quality management for individual trials rather than a cover-all approach, echoing Andy Fisher's discussion earlier to consider the critical parts of that particular study based on study endpoints.

Jo navigated us through the changes to the following:

• A new structure with a change to responsibilities of RECs and PI/Sponsor
• The introduction of data governance responsibilities for PI/Sponsor
• Change for a flexible approach based on adapting to risk and individuality of studies
• Applying risk-based quality management (RBQM) and Quality by Design (QbD) throughout the research study lifecycle.
• Ensuring all stakeholders (participants, vendors, sponsors, research sites) included throughout to allow for decentralised clinical trials approach.

However the subject that I found particularly interesting was the move from Essential Documents to Essential Records and how this will now expand to include the TMF, EDC and eConsent. This change will allow for a pragmatic approach with 'essential records' being specified by study rather than a standardised approach for all.

All in all, it was a fantastic and informative event where I was able to connect with old colleagues (including bumping into them on the street after not seeing them for over 10 years!) and lots of food for thought for the next changes we will see in the coming months. I look forward to the next Virtual meeting in the Autumn, thank you ICR!