Standing together: Supercharging the clinical trial in Europe

pharmafile | September 18, 2017 | Feature | Business Services, Manufacturing and Production, Medical Communications, Research and Development, Sales and Marketing |  EMA, biotech, clinical trials, drugs, pharma, pharmaceutical 

The European Medicines Agency is on the cusp of rolling out one of the most ground-breaking digital platforms for facilitating collaboration and efficiency in clinical trials. Matt Fellows talks with the agency on how it will work, how it will change the game, and why it is not fazed by the recently announced delay on its rollout

The clinical trial is the crucible through which all medical advancement is tested, but the traditional, established form has consistently proved to be unable to keep pace with the rapidly evolving, increasingly globalised world and the medical needs of its patients.

While the system has been honed and developed over time, glaring inefficiencies still persist, especially within an international context. Where the sharing of knowledge can mean a huge leap forward for researchers and patients in a particular disease area, it’s imperative that collaboration be facilitated. For instance, rare diseases pose a particular challenge in drug development due to the miniscule patient population in any given country; only when these populations are pooled can the disease be properly examined and the efficacy of treatments accurately assessed.

This is just one glaring weakness of the traditional clinical trial, which often proves to be insular and is conducted within the borders of a single particular country, adhering to one particular set of rules – rules which change from region to region. While the limitations of this approach become ever more apparent, clinicians are increasingly looking towards digital tools and systems to tackle these challenges. These e-clinical solutions, as they are known, seek to automate the clinical trial process, reducing inefficiencies and providing a more robust framework to support the application and execution of studies.

In the world of e-clinical innovation as it stands, there is arguably no bigger undertaking to push the boundaries of what clinical trials can achieve than the rollout of the European Medicines Agency (EMA)’s Regulation 536/2014: a project which includes the implementation of an EU-wide database and application portal, enabling a harmonised and streamlined approach to conducting clinical trials across all constituent member states.

To discover what this rollout means for the industry and the future of clinical trials, Pharmafocus contacted Fergus Sweeney, EMA’s Head of Inspections, Human Medicines Pharmacovigilance and Committees. He explained: “The portal and database is an IT tool which is required by the clinical trial Regulation 536/2014. That Regulation is to bring into place a new process for applications in the conduct of clinical trials, the management of authorisation of a clinical trial throughout its life cycle, and then to provide a platform for the submission of a summary of results.

“The whole point of the Regulation was that there were perceived inefficiencies and bureaucratic overlays and divergences between member states, and also the evolution of clinical trials was showing that they were moving to other parts of the world,” he continued. “The number of trials in Europe has been falling, so this was really to create a better basis for the conduct of clinical trials and enable researchers to apply for permission to conduct those trials more effectively, but also to better underpin an assessment of trials involving more than one member state across Europe in a harmonised way.”

All together now

This co-ordination is really at the heart of the Regulation. Currently, most trials rarely extend beyond the borders of a single nation, partly because the current system makes such ambitions very unintuitive. In order to get permission to conduct a clinical trial within the EU, the relevant sponsor must submit an Investigational Medicinal Product Dossier containing all of the necessary information, and this changes from region to region. Sweeney noted: “At the moment, people apply separately and possibly on different timelines with some variability in the content of the dossier, and they have to apply separately to the national competent authority and the ethics committee in each member state.”

Instead, Regulation 536/2014 aims to break down these restrictions by providing, “a single set of rules and a single dossier, in particular to enable multi-state trials – those which involve investigators in more than one member state,” as Sweeney explains. “If we look at historical data, trials – particularly those of academia but also those of commercial sponsors – tend to operate in one member state, or a relatively small number of member states. This Regulation was to facilitate expert investigators in different member states working together more directly, rather than working only within the silo of their own member state.

“In order to achieve that, the clinical trial and database will support one clinical trial application form and one dossier; it’s one application irrespective of the number of member states, so if you apply to one or 23, you still only submit one dossier, which addresses the needs of the national competent authority and the ethics committee in those member states.”

How it works

In practice, once a group has settled upon a design and goal for a clinical trial, they would then write up their protocol and other associated documents before compiling and submitting them via the online portal. Once submitted, the dossier is added to the database and will be accessible to all relevant parties across all member states. The portal also acts as a platform for correspondence between all groups; on receipt of the dossier, the appropriate authority will then assess the submission and send a consolidated set of validation questions via the portal. Once these are answered and everything is satisfactory, approval to commence the trial will be given within a fixed time period, which is set at sixty days in normal circumstances.

All users of the system will have a secure login, and from there can find out what’s happening with the clinical trials they have already commenced and find new applications for trials. They will be able to assign the team who are going to assess each trial, download and review the documents from the sponsor, build their assessment report and discuss it between member states, among other things. Should any urgent or unexpected safety issues arise throughout the trial, they can be reported through the portal by the sponsor. The same is true regarding issues of non-compliance or situations calling for supervisory action – these can be addressed via processes that run through the portal. “This will rationalise everything into one submission; one interaction with the authorities; one set of questions back from the member states and sponsors, and then one approval or disapproval,” Sweeney claimed.  

Building trust

Alongside facilitating greater harmonisation between trial conductors, the system also aims to provide much improved transparency to the public on the data generated from these studies – a key goal, argues Sweeney, as a strong rapport between the public and the scientific community proves instrumental to the success of clinical endeavours.

“It’s really important for building public trust in the clinical trial and regulatory process. If you’re transparent, people can see the information available and can start to establish trust,” he asserted. “It improves understanding of the way the clinical trial process works and how they operate, and through shared information it can propel research on how to develop new, more effective or safer medicines, as well as new applications of existing medicines. It helps patients to find trials that they may need to participate in if they have a particular unmet medical need.

“If you give people trust in the clinical trial, they will be more willing to take part in one, or to be an investigator and recommend a trial to their patient. It’s only through that altruistic willingness of patients, the public and volunteers to join clinical trials that the whole development of medicines and medical knowledge can be moved forward. Public participation based on public trust and assurance that each person’s results will be used well and properly is an important part of the whole clinical trial world.”

The system requires that both a structured summary and a layperson’s summary have to be loaded within 12 months of the end of each study, and the public will have open access to all published data on any trial conducted through the portal, irrespective of whether the study was done in Europe or in some other part of the world.

Sweeney was keen to stress that this new, increased level of transparency is to be achieved while assuring the same high standards of patient safety and scientific assessment. He argues that this openness with the public is not only beneficial, but a necessity: “Historically, publication rights for clinical trials have not been excellent across the board. It’s important that all trials on medicines are publicly registered, along with summaries of their results, which are also publicly available. This system provides the European part to that global enterprise; there shouldn’t be a clinical trial of medicines in human beings that is not publicly registered.”

A bump in the road

Regulation 536/2014 was adopted and entered into force in 2014 and its rollout was due to be completed by October 2018. However, in June of this year the EMA announced that it would be postponing the implementation until 2019. Speculations on the reasons for this delay were rife with a range of valid culprits, from the impact of Brexit negotiations to the relocation of the agency’s headquarters from its current base in Canary Wharf, London. On its website, the EMA stresses that, “the timing of [the Regulation’s] application depends on confirmation of full functionality of the EU portal and database through an independent audit. The Regulation becomes applicable six months after the European Commission publishes notice of this confirmation. EMA’s Management Board will discuss a new delivery time frame in October 2017 once the developer confirms progress.”

The statement echoes Sweeney’s assertions that the system hinges upon a fully functional and uncompromising delivery, and simply cannot be rolled out until it is up to the exacting standards required.  When queried on the reason behind the delay, Sweeney was candid: “This is a very large, complex system. It is designed to operate across 28 different member states, plus the European Economic Area, and brings together ethics committees and national competent authorities in the assessment of those trials. It also has to interact with the safety reporting and safety database systems with inspection processes. Something on this scale hasn’t been done before for medicines regulation; it needs to work very efficiently and to a high level of quality in terms of protecting patients and ensuring the proper information is provided to the public, but also that there’s an efficient system there for sponsors and member states to use in applying for and evaluating applications for clinical trials.

“Imagine the toll booth on a motorway,” he continued. “If all six booths are open that’s fine, but if three are closed, you get a queue. We don’t want a queue of research backing up because the portal is inefficient, so we have to make sure it’s of the proper level of quality. Because of this it’s not been easy to estimate the level of effort required across the board. It’s proved perhaps more challenging than was originally estimated.” 

Going further, Sweeney made clear that the delay was caused by unforeseen technical difficulties in its application and not a product of Brexit in any shape or form: “The issues that have arisen have nothing to do with Brexit or the developments that surround that. All of the planning and the rollout are independent of any considerations relating to Brexit. At the moment, the UK is a member state of the EU and they actively participate in our various expert groups around the design of this database system. They’re involved in the testing and the various discussions on the practical implementation of the Regulation.”

However, the far-reaching consequences of the UK’s exit from the EU are impossible to ignore, and in July the EMA released an official ‘business continuity plan’ outlining operational changes in preparation for this impact. Much of these changes included diverting resources from non-essential activities to free up staff, and instead commit them to a dedicated Brexit team. The implementation of Regulation 536/2014 is not above being affected, and Sweeney shared the agency’s stance to avoid any further delays.

“We have in place a taskforce which is preparing us for the effects of Brexit and what that may mean for the relocation of the agency, and one of the things we have to do is monitor whether any of the things arising during that process would have an impact on further development. This project has a high priority within the agency and our business continuity plans – it will be given very close attention. The actual developers are not located in the UK so they should not be affected, and because the functioning of the system itself is web-based, it doesn’t matter where the data centres are.

“So far as the UK’s interaction with the portal and database may or may not be, we don’t know what will be the final outcome of the Brexit negotiations.”

A collaborative future?

The task undertaken by the EMA is undoubtedly unprecedented and presents a wealth of obvious benefits for the future of efficiency, transparency and collaboration in medicine, despite the huge challenge to make it a reality, but is it indicative of a shift towards a more globalised era for the humble clinical trial? Could we be gazing into a future where the majority of trial operations are networked and synchronised, and international collaboration becomes the norm? It may be a long way off, but Regulation 536/2014 is certainly the first major step in the journey. It provides hope for those striving for more robust safety and efficacy assessments of medicines that are just not possible without co-ordinated, large-scale patient populations, particularly in the area of rare disease.

“Europe is a well-integrated, well-coordinated set of countries with structured decision-making processes and ways of agreeing on standards,” Sweeney weighed in. “The more countries you involve from around the world, the more challenging that may be so there’s a balance to achieve. However, I think it’s important that we continue to do so in order to facilitate international research, not just from the pharmaceutical industry but also in academia.”