Before the onset of COVID-19, 14,900 clinical trials were in progress globally (source: Informa), with each life sciences organisation planning to conduct 6.5 phase 1/2/3/4 studies in 2020. As social distancing measures and lockdowns have taken their toll, 41% of clinical trials in therapeutic areas other than COVID-19 have been delayed or put on hold indefinitely. Without early-phase data to support pivotal phase 3 trials, drug filings for new therapies are likely to be delayed, further prolonging the all-important drug-approval process.

In July 2020, in order to gain insight into the present and future of clinical trials, and into the management and archiving of trial data, Arkivum collaborated with Phlexglobal and the Ethical Medicines Industry Group (EMIG) to commission a survey of life sciences professionals: Arkivum ‘TMF Futures: Keeping Data Alive’.

Out of the 200+ people who responded to the survey, 70% said that COVID-19 has triggered a change in the way clinical trials will be conducted. Having experienced the disruption caused by the pandemic, 51% identified a need for more diversification of patient enrolment, for instance, by expanding the scope of trials beyond just one city, country or even continent, 37% said that more patients need to be enrolled to counteract possible future disruption and 56% cited the need for more virtual trials, making use of telemedicine, remote monitoring of patients, wearable technologies, and mobile apps and devices.

As the role of technology grows, sponsors, CROs and investigators handling clinical trials will be managing ever-greater volumes of patient-generated health data (PGHD) from multiple sources. To do so both efficiently and responsibly, they will need to be able to put their trust in reliable digital systems and the digital expertise of their teams. The same applies to the implementation of good practice in their stewardship of the trial master file (TMF), both during the trial and once the file is archived.

The TMF is central to drug development and key to any marketing authorisation application (MAA). As a structured and closely regulated repository for clinical trial data, it provides evidence of the good practice implemented by stakeholders in the trial. The integrity of clinical trial data in the TMF must be ensured during the live trial and, subsequently, the file must be kept in an archive for a minimum of 25 years and must always be available for any possible regulatory inspection.

In pharma, as in virtually every other major industry, digital transformation has been a hot topic for some time. Some experts would claim that pharma has not moved fast enough on digital innovation in recent years, but there has certainly been a transformation in the handling of the trial master file: it has largely shifted from paper to digital over the past decade or so.

‘Digital technology – from wearable technologies to applications for data management to bleeding-edge artificial intelligence – will be a key agent for change as medicines are developed and make their way through the product life cycle’

Our survey found that no fewer than 90% of sponsors and CROs have already adopted an eClinical application to improve study execution and data collection in live trials, while 36% of sponsors and 48% of CROs now use purpose-built digital applications to manage the TMF. It is becoming clear that the traditional paper TMF has been largely superseded by the electronic TMF (eTMF), a tool better suited to the demands of a digitised world and burgeoning volumes of data.

As the life sciences industry continues to embrace new technologies with enthusiasm, the survey findings suggest that data management can still prove to be problematic: 43% of all respondents and 50% of CRO respondents admitted to being unable to convert documents from multiple eClinical applications used in the course of a trial. Meanwhile, 65% of compliance, legal and regulatory professionals described their ability to access archived trial data as ‘extremely inadequate’ or ‘very inadequate’.

These apparent deficiencies give cause for concern. They could undermine progress made in restarting clinical trials in the wake of COVID-19 and compromise the benefits of technologies that have transformed the TMF into an eTMF. They could even have a negative impact on good clinical practice and engender regulatory risk during the trial, potentially causing delays to marketing authorisations. When it comes to the archive, patchy access to TMF data could hinder pharmacovigilance procedures and place obstacles in the path of scientific discovery and commercial growth.
Rightly, regulatory compliance is a top priority for the sponsors of a trial as they archive clinical data, but a well-curated digital archive could do more for them than maximising their chances of passing an inspection. Throughout the product life cycle, good practice in archiving can prove to be of value when dealing with pharmacovigilance, value-based pricing and reimbursement, as well as in the search for new indications and formulations. On the corporate side, it can come into play in licensing and partnership opportunities, in handling legal challenges and due diligence, and in mergers and acquisitions.

The TMF archive can also play an important role in the repurposing of drugs, a practice that is becoming more common, notably in the field of rare diseases, and prominently in 2020 in the bid to find treatments for COVID-19 in a radically compressed time frame.

In the past, repurposing has mostly been driven by academics looking for new possibilities in generics. Now, as part of life cycle management, pharmaceutical companies are looking more closely at drugs they have on their shelves. These might be licensed drugs that could hold potential for a patent extension, or drugs which failed efficacy trials for an intended indication.

In the quest to repurpose a drug, published scientific literature must certainly be revisited, but archived trial master files represent a much richer and more detailed source of data on a drug and its performance. Moreover, published literature tends to catalogue successful clinical trials, but data from an unsuccessful trial – provided its failure did not result from safety issues – can still help make the case for repurposing. For example, side effects in one population could constitute on-target effects in another.

All in all, the TMF is a body of data that is too valuable to simply be locked away in the archive until there is an audit, an inspection or a question about compliance.

Looking beyond regulatory requirements, a digital archive that is well-indexed, easy to search and interoperable can become a repository of knowledge for an entire organisation. It can create efficiencies, enhance collaboration and avoid duplication of previous effort when the search is underway for new applications and indications for an existing treatment. As we enter the age of artificial intelligence, data needs to be configured and stored with an eye to effective interrogation and analysis and to the development of new treatment hypotheses.
Many millions of pounds might well have been spent on acquiring the data that is held in a digital archive and its value deserves to be leveraged in a multitude of ways as pharma seeks to serve patients to best effect. Yet it seems that numerous archives of clinical trial data could be gathering layers of virtual dust.

From the results of our survey we can infer that only just under a third of life sciences organisations currently run a digital archive of sufficient sophistication to ensure that data is managed in full accordance with the FAIR data principles. These were established to further scientific study through keeping data Findable, Accessible, Interoperable and Re-usable – all key attributes when it comes to making the most of clinical trial data, both as a driver of scientific discovery and as a substantial company asset. Organisations across the board should recognise that the TMF archive is not something to be consigned to the past. On the contrary, it has an important part to play in pharma’s future.

The first Arkivum TMF Futures: Keeping Data Alive survey was conducted in July 2020 by Arkivum, Phlexglobal, the Ethical Medicines Industry Group (EMIG) and Survey Goo. The 206 senior representatives surveyed from global organisations have responsibility for/knowledge of clinical trials and hold senior and director-level positions in the following functions: general and senior management, regulatory, quality assurance, dlinical, operations. The full report can be found here: https://arkivum.com/ebooks/tmf-futures-keeping-data-alive/

Chris Sigley is CEO of digital archiving specialists Arkivum