Chris Sigley, CEO of Arkivum, says the transformation of clinical trials demands a transformed approach to trial data
The pandemic has created manifold challenges for clinical trials, but it has also proved a transformational force. The life sciences sector has succeeded in making a virtue of necessity as it has pivoted and embraced new digital technologies which hold enormous possibilities for the future.
In Autumn 2020 Arkivum published its inaugural TMF Futures report, based on a survey conducted during the first phase of the pandemic. At the time, 69% of survey respondents, all senior life sciences professionals, said that Covid-19 had compromised their ability to deliver on the objectives of their clinical trials. A second TMF Futures report followed in the summer of 2021. Based on a survey of 305 senior respondents in April this year, it found that the proportion had dropped from 69% to 56% and that 41% of clinical trials were back on track, with each organisation polled planning to conduct, on average, of 6.5 Phase I/II/III/IV studies in the course of the year. Notably, every major clinical trial sponsor was running at least one decentralised clinical trial.
“The pandemic has changed everything,” says Fran Ross, TMF Director at Advanced Clinical, a privately-held, single-owner global clinical research services organisation, providing full-service CRO, FSP and Strategic Resourcing solutions for biopharmaceutical and medical device organisations. “It has highlighted the need and opportunity to take a more holistic view on data sets and data records. We now have an awesome opportunity to treat the clinical-trial record set as an asset belonging to many. In each clinical trial, there is a whole set of stakeholders to consider and each will have a different perspective on what they need for ‘their’ records. Let’s now use technology to take care of everyone, including the health authority.”
As a structured repository for clinical trial data, the trial master file (TMF) provides evidence of the diverse forms of good practice followed by the various stakeholders in the trial. In managing the TMF, sponsors and CROs strive for constant readiness for regulatory inspection, while respecting evolving requirements for the safety, efficacy and reproducibility of trials. Inspectors from health authorities will wish to verify that i) the clinical trial has complied with regulatory requirements and the principle standards of Good Clinical Practice (GCP), and ii) that the clinical-trial data has been validated and stored correctly. If it has not, the TMF can fail the inspection, causing drug approval to be denied.
“In clinical trials, the dedicated and determined people across sponsors, sites and vendors take very good care of solving unexpected issues,” continues Ross. “The TMF issue is that the problem is not GCP-solved until the documentation is secured and filed.”
As they gather data, trial sponsors and CROs must follow trusted protocols and processes. It stands to reason that, both during and after the trial, the exchange and storage of that data should be conducted with similar rigour. The scientific, regulatory and commercial implications of clinical trial data are enormous, and it deserves to have a long and highly productive life. If stewarded in line with good practice – emphasising security, integrity, accessibility and usability – the data can continue to provide value for decades, or even indefinitely.
Over the past 10 years, the traditional paper TMF has been largely superseded by the electronic TMF or eTMF, which is better suited to the demands of a digitised world and ever-growing volumes of data – not least in such data-heavy areas as gene therapy, which are setting the pace for the future.
“We need to smooth the way for records to be appropriately available to any stakeholder who wants to review them, reverted should any owner require them, and protected as a valuable asset,” emphasises Ross. “What I would say to sponsors of clinical trials is this: you’re not paying for a trial, you’re not paying for the EDC [electronic data capture], nor a Clinical Study Report. At trial’s end, the only asset at hand is the entirety of the trial data and the related trial records, so take very good care of your trial master file and protect it forever.”
Arkivum’s particular interest is in the archiving of TMF data, which the EMA specifically requires to remain secure and inspection-ready for 25 years. The 2021 TMF Futures report, which places archived data in the context of digital transformation and broader corporate objectives, found that 90% of life sciences organisations currently face challenges in the conduct of clinical trials. Some 80% plan to reduce the cost and duration of trials – and to increase their chances of success – with the help of significant investment in technology, such as artificial intelligence, machine learning and cloud computing. This reflects a broader trend observed by the management consultancy McKinsey in October 2020: across industries, Covid-19 has accelerated the adoption of digital strategies by as much as seven years. In accelerating digital transformation, organisations in life sciences are seeking to increase efficiencies, enhance collaboration, and modernise and improve the entire clinical trial process. Their priorities are now to:
- improve the way the life sciences sector identifies and communicates with health care professionals and patient populations (50% of survey respondents cited this);
- improve archiving and integration of the eTMF and other data on a large scale (38%), and
- further the adoption of decentralised clinical trials (34%).
“Digitisation has increased the criticality of eTMF,” explains Ross. “The electronic audit trail makes any inconsistencies or anomalies more obvious, and the requirement for evidence of protocol action has become more explicit. Take for one example the implications for timeliness in record-keeping – the principle of contemporaneity in ALCOA+ [the set of principles for data management originally established by the FDA with the aim of ensuring data integrity in such areas as pharmaceutical research: Attributable, Legible, Contemporaneous, Original, Accurate + Complete, Consistent, Enduring and Available]. In the majority of eTMF systems, there’s a simple graphic representation showing whether or not the totality of your records have been managed in a timely fashion. If you can tell at a glance, so of course, can an inspector – as well as your manager, their management, your executives, and your quality auditor.
“At the same time the digitally enabled move to decentralisation is making the trial participants – the human heroes – the centre of the trial universe. This shift in focus is a game-changer. I believe we will need to re-engineer our record set to reflect this more mature and complex universe. The volumes of data – produced by wearable technologies, for instance – will proliferate and increase the pressure on management, analysis and archiving. The ideal clinical trial of the future will be geared to ensure that all its stakeholders, whether professionals or participants, benefit from appropriate access to the information that is relevant to their needs. The participants must feel confident of a complete understanding of the trial, of why they’re involved, and of risks and outcomes. Everyone will be united in serving the scientific mission and in keeping regulatory authorities up to speed – and this will all be done from our laptops.”
The life sciences industry indubitably recognises the crucial role that technology already plays – and will increasingly play – in clinical trials. Yet the 2021 TMF Futures report reaffirms a finding of the 2020 report that gives cause for concern: the fragility of certain critical systems in clinical trials, notably poor interoperability between eClinical systems. Over half of life sciences organisations confirm that sub-optimal processes for data transfer from site investigators to the CRO and sponsor, and for storage, are potentially compromising the integrity and inspection-readiness of the TMF. Clearly, this can result in breaches of regulatory compliance, undermining progress and causing delays to marketing authorisation applications (MAA). This comes at a time when the FDA plans to adopt electronic tools and is evaluating the pandemic’s impact on the integrity of clinical trials and the quality of clinical data.
Equally, the report reveals that many life sciences and biopharma companies struggle to protect, access and interrogate the data in their TMF archive. Just half (48%) of TMF Futures respondents said that, if they were inspected tomorrow by a regulator, they would be confident that their eTMF would pass an inspection. Indeed, 30% of all respondents and 80% of regulatory and compliance specialists went so far as to describe their TMF archive as very or extremely inadequate. Most confirmed that they are currently unable to use their archives to:
- keep their data secure, accessible, and inspection-ready for 25 years (59%);
- conduct searches in real time to locate files in seconds (66%);
- handle large volumes of data (75%);
- upload data from multiple sources (81%);
- provide a clear audit trail (83%).
These figures raise doubts as to whether current archiving practice across the sector consistently conforms with ALCOA+ principles, with the FDA’s guidance on enabling the “accurate and ready retrieval throughout the records retention period” (Part 11, Electronic records; electronic signatures – Scope and Application), and with any requirements for preserving the dynamic character of the audit trail. They certainly suggest that it is time for life sciences organisations to start prioritising preservation of valuable trial data in a secure, fit-for-purpose archive that can both ensure long-term inspection-readiness and enhance potential for extending the lifecycle of approved medicines. Beyond its regulatory role, TMF data can prove its value time and time again: in facilitating scientific discovery, pharmacovigilance, new formulations and marketing approvals, and in expediting corporate processes such as licensing, the establishment of partnerships, and due diligence for mergers and acquisitions.
In the context of digital transformation and technological acceleration, the eTMF’s strategic potential is becoming strikingly evident. TMF Futures 2021 reports that the vast majority (90%) of life sciences companies maintain a digital archive, and that living archive data is playing an increasingly important role in extending the applications of treatments. By definition, trial master files represent a much richer and more detailed source of data than published literature. Over the past year a total of four in ten life sciences organisations have accessed the TMF archive in order to locate data to support new submissions (34%), new indications (31%) and repurposing (7%). This compares to the 26% that accessed the archive in the context of a regulatory inspection. Long-term inspection-readiness is a key objective of TMF archiving. Traditionally, inspections have taken the form of a visit, but, remote inspections, made possible by digital technology, have gained ground during the pandemic.
“Of necessity, there has been a dramatic growth in remote inspections through the pandemic,” says Ross. “Inspections for GMP have continued in the flesh, but others have been carried out remotely. All round, huge efforts have been made to adapt in order to keep things moving while continuing to comply with the health authority laws. The particular procedures for remote inspection – for instance for provision of electronic files to the inspector, via FTP or other channels – have not been formally defined and may never become a formal requirement.
“I believe that inspections will always come down to this: doing what best meets the requests and expectations of the inspector, and what best serves the GxP situation. As ever, each inspection will have its individual dynamic, while always conforming to the applicable regulations. The eClinical expectations of regulatory inspectors are ever-changing. What I say to people with TMF responsibilities is ‘Plan for the worst and expect the best.’ I also say to them: ‘Treat the closed TMF as your jewel in the crown, and polish it at least once a year to ensure its value.’ How many today can easily read from a floppy disks? We still see them from time to time in the TMF archives. It is up to each sponsor to assess the risk inherent in their approach to archiving. They also need to bear in mind that each inspector will have their own experiences and preferences. An inspector who is a digital native may have different expectations to someone who prefers paper.”
In life sciences, the human factor is crucial, no matter how sophisticated technologies become. As decentralised trials are beginning to show, technology, and the data it produces, can empower the participating patients – ‘the human hero’” – as well as healthcare professionals, scientists and managers who are involved. In the quarter century that the world has been online, data has given consistent proof of its power to drive discovery and the economy, to shape our society and empower individuals. As digital transformation is achieved in life sciences, data will play a central and multi-faceted role in innovation, in streamlining the development of new therapies at lower cost, and – once marketing approval has been obtained for a drug – in maximising commercial and societal benefits. Legitimate multi-stakeholder access to data over the long term will be key to success at every stage of the product lifecycle.
Volume 22, Issue 4 – Fall 2021
About the author
Chris Sigley is CEO of Arkivum, a world leader in digital archiving and preservation.