Matthew Lowrie, quality assurance manager, Almac Clinical Technologies explores how the evolving regulatory guidance around data integrity is impacting clinical trial applications and data.
Key insights:
- Tracing, storage, return, accountability and destruction arrangements must be in place and detailed in the clinical trial application.
- Annex VI also allows for the information on the label to be managed through alternative means, such as a central IXRS system, however some particulars cannot be omitted from labels - such as expiry date.
- IXRS also provides reporting and alert mechanisms to ensure the trial is on track, avoiding any end-of-study push to catch up on tasks and data reconciliation that should be done throughout.
EU Regulation 536/2014 came into effect for new trials in January 2023, impacting supply management practices for clinical trials conducted in the EU, replacing Directive 2001/20/EC. With an aim to simplify trials and enforce consistent rules throughout Europe, these changes have a definitive impact on clinical trial planning activities.
The regulation enhances patient protections and adds increased requirements for trial oversight and data integrity. Some examples are heightened GMP standards for investigational medicines, stricter oversight of auxiliary medicines, and consistent expectations for safety reporting.
There are significant changes that require attention and consideration in how you are using, and will use, established systems for supply chain management, which is the focus of this article.
A key change raising much concern is the restrictive labelling requirements inclusive of investigational and auxiliary medicinal products, laid out in Annex 6 of the regulation. One being the expectation that the expiry date must be printed on all primary and secondary container labels. The revision allows the expiry date to be omitted from the immediate container only when the immediate container will remain with the outer container or when the immediate container is small and has limited space for label text. In both cases, the immediate container must be provided with an outer container that has the expiry date printed on the label.
Annex VI also allows for the information on the label to be managed through alternative means, such as a central IXRS system, however some particulars cannot be omitted from labels. It never allows for the expiry date to be omitted from the outer container label. Allowances to exclude the expiry date from the immediate container label of IMP or Auxiliary MP are aligned with the specific circumstances detailed above.
This revision will make management of expiry updates significantly easier – whenever the immediate container is packaged and supplied with a labelled outer container, it will likely be possible for the sponsor to justify the omission of the expiry date from the immediate container. However, this has the potential to make expiry updates more complex because if there is outer packaging, it will need to be opened to expiry update the label on the immediate packaging.
Another requirement details that tracing, storage, return, accountability and destruction arrangements must be in place and detailed in the clinical trial application. Destructions and returns haven’t historically been an area of focus during the trial set-up phase but will now be required to be established and described upfront. What this means is you need a system or process that can address these arrangements while also maintaining the integrity and chain of custody. Your eClinical systems can be utilised to link and manage electronically these actions, often with greater accuracy and efficiency than performing the tasks manually on paper.
It is very common that IXRS includes features that facilitate and automate the accountability, reconciliation, returns and destruction processes. The benefit of including this functionality in the IRT is that the data already known about the medicinal products can be used to fuel these subsequent steps of the process. This streamlines the process, reducing data entry activities, helping to avoid mistakes, and reducing overall efforts. The technology also provides reporting and alert mechanisms to ensure the trial is on track, avoiding any end-of-study push to catch up on tasks and data reconciliation that should be done throughout.
Another important aspect, which should not be minimised, is the overall traceability of the supply. IXRS is commonly managing the trial supply activities electronically: drug release, supply transfers and shipments, patient assignments, accountability and returns/destruction, amongst others. Being able to track activities, but just as critical as the view of the data. Data must be presented in a way that allows easy review at both summary and detailed levels providing end-to-end traceability. This enables oversight of the data, providing assurances to the viewer that processes are occurring as expected. This is key to the prevention of large reconciliation efforts at the end of the trial and questions around why the data is being updated sometimes years after its initial entry. An electronic chain of custody solution that incorporates all IP events in a single system is the best way to comply thoroughly with GCPs and GMPs and to gain maximum efficiencies in the accountability process.
In line with these regulations, data integrity guidance from MHRA, FDA and EMA is evolving around sponsors' responsibilities with respect to trial data oversight. As stated in ICH E6(R2), inspectors expect to see documented evidence on how the sponsor performed oversight of the study data. We are seeing a rise in the number of findings where there was a lack of real-time data monitoring and/or data monitoring was not done in a contemporaneous manner to show continuous oversight of the trial. Inspectors are expecting to see established data monitoring processes. Planning the study’s approach to proactive data reviews and knowing what tools are available from your technology partners and how they will be used is key.
In summary, with EU Regulation 536/2014 now in force, modifications to practices around supply chain management are a necessity for clinical trials running in the EU. With upfront planning, leveraging eClinical solutions such as Almac’s IXRS, challenges can be overcome. A comprehensive end-to-end approach to clinical supply chain planning will ensure clinical trial integrity ensuring regulatory compliance.