When the inspectors come knocking, there is often a flurry of activity to prepare the trial master file (TMF). While regulatory authorities expect sponsors to maintain proper oversight of their TMF throughout its lifecycle, findings from the inspectors show insufficient oversight remains a problem[1].
To mitigate the risk of critical findings, sponsors can take some key steps to assess and improve the health of their TMF.
- Dig deep and uncover gaps. Tools such as heatmaps can help sponsors understand what condition their TMF is in. A heatmap with expert analysis can categorize the risk level of documents or artifacts based on document quality, poor indexing, or missing documents. The risk level – high, medium, or low – will help you to determine where to focus your efforts.
- Conduct regular review cycles. Quality reviews offer an assessment of your TMF’s completeness, timeliness, and accuracy. This allows you to assess key criteria such as: Are you uploading documents in a timely manner? Are you complying with your own processes? And is everything in the documents accurate? Be clear what the findings were and what the process was. For example, if it’s risk-based, how was the risk defined? Is it documented? And is there consistency in the approach taken?
- Check your TMF pulse. Just as a healthy lifestyle can help you to reduce the risk of chronic illness, by looking after your TMF from the outset you can stay inspection-ready. Check on your TMF health throughout its lifecycle to make sure you’re doing the right things so that when you face an inspection good practice is in place, the evidence is there, and all you’re doing is taking minor steps to make sure nothing has fallen through the cracks.
- Spread the investment. Putting time and effort into TMF health early on allows you to spread the cost across the life of the study rather than having dozens of people scrambling to clean up the TMF in a few weeks. Not looking after the TMF means that when you do have an inspection, it’s likely to be stressful and it’s likely that inspectors will flag issues. After all, it’s much harder to track down missing documents five years after the fact than it is if you stay focused on your TMF health.
- Demonstrate GCP compliance. In their guideline on managing the TMF, the European Medicines Agency (EMA) makes clear that the TMF must demonstrate the trial was conducted “in line with the applicable regulatory requirements and the principles and standards of GCP.[2]” To adhere to those requirements, sponsors should consider carrying out a risk-based quality review, with proper management of that review.
In our experience, there are two ways to manage the TMF. One is the last-minute panic to plug gaps in the TMF, which inevitably means throwing multiple resources at tidying it up and very likely facing critical findings. The other more enlightened way is to build TMF oversight into your processes from the outset. These sponsors manage their processes, commit time and effort to prepare for inspections, with heatmaps and quality reviews, and bring teams together to ensure everyone is engaged and inspection-ready. This approach is the best way to safeguard your TMF and ultimately your clinical studies.
About the author:
Martina Tanner is service line lead, TMF readiness, at PharmaLex. She leads the TMF inspection readiness group and helps customers to pinpoint the key issues within the TMF in order to be inspection-ready. Martina has been with PharmaLex for 19 years, gaining expertise in all aspects of the TMF.
[1] GCP Inspectorate, GCP Inspections Metrics Report, 29 March 2023, MHRA. https://assets.publishing.service.gov.uk/media/64357bfe89f19f00133cfb40/GCP_inspection_metrics_2019-2020.pdf
[2] Guideline on the content, management and archiving of the clinical trial master file (paper and/or electronic), EMA, Dec 2018. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-content-management-and-archiving-clinical-trial-master-file-paper-andor-electronic_en.pdf
