Centralised submission

It is a commonly held belief that one can pass from one EU member state to another without noticing they’ve crossed a border. Nevertheless, a muchrepeated anecdote says that if you travel by bus from the Netherlands to Belgium, you can tell the very instant you cross the line between the two countries because the wheels are no longer rolling smoothly on pristine tarmac but are hitting potholes.

In many ways, this echoes the world of regulatory affairs, where supposedly harmonised rules are often implemented very differently across member states. This has become evident in 2023 with the introduction of the Clinical Trials Regulation (CTR) to replace the Clinical Trials Directive that had governed trial activity for more than a decade.

The EU made the bold decision to transition to CTR back in 2014, aiming to bring in a new regime to bolster the safety and ethical conduct of clinical trials in relation to investigational drugs. The new framework rests on the Clinical Trials Information System (CTIS) – a digital portal for application submission and oversight of clinical trials for all EU member states. The CTIS took eight years to develop. When the CTIS was finalised in 2022, the market was given a one-year grace period before all trials conducted in Europe had to abide by the new CTR rules. Almost a year later, there are some who feel that the reality of the new regime has not lived up to expectations.

Indeed, a joint statement released in August 2023 headed ‘Dysfunction of the Clinical Trials Information System harms Europe’ from The Association of Medical Ethics Committees (AKEK) – an association of public ethics committees that review biomedical research projects in Germany – pulls no punches.

The statement, signed by AKEK chair Dr Georg Schmidt, along with many others, points to the “massive functional deficiencies of the CTIS platform” and calls for an independent audit at EU level to “avert damage to patients and Europe as a research location”. These are strong views that are not universally shared, but they do highlight the need to rethink some aspects of the new regulatory landscape.

Expectation versus reality

A key goal for the change is to encourage more participation in clinical trials, as recruitment and retention of participants have been increasingly challenging, and trial enrolment has been in decline due to a lack of engagement and understanding of the clinical trial process. CTR requires a Plain Language Summary (PLS) for every trial conducted in Europe to explain the trial and its results without scientific jargon. Furthermore, under CTR it is mandatory for drug developers to anonymise or redact clinical trial documents in preparation for regulatory submission. Anonymisation involves the removal of variables that allow direct or indirect identification of a trial participant or staff member. There are two elements – Part I contains scientific and medicinal product documentation, while Part II contains the national and patient-level documentation.

So far, so good. There is little to no resistance to these changes in the market, and the motives behind the change are widely respected.

“The main benefit is that all EU member states are following the same regulation on clinical trials and a harmonised submission process through a single EU portal,” says Edyta Maciołek, Regulatory Affairs Manager at JJP Biologics and EU CTR (CTIS) Specialist at CTR Consulting. “I support the intentions behind the legislation. Clinical trials sponsors should prepare and transition ongoing projects, if needed, as soon as possible.”

The same perspective is held outside of commercial (bio)pharma companies too. Alexander Roussanov, life science and privacy partner at Arnold and Porter Kaye Scholer LLP was previously a senior legal adviser in the Legal Department of the European Medicines Agency – the regulatory body tasked with creating the CTIS database and transparency rules. “It could be a success and it is an improvement,” he says. ”It is a step in the right direction and companies will get used to it, but they need to adapt their processes and understand what new regulation means in terms of submissions and transparency.”

The CTIS could – and perhaps already has – revolutionised clinical trial initiation, amendment, and completion processes, which previously involved the submission of forms to several scientific and ethical review committees. The CTIS centralises and documents all submission milestones within its database. Furthermore, it facilitates the submission of annual safety reports, the addition of new member states to ongoing trials, the receipt of agency feedback and assessment information, direct responses to agency requests for information, and the uploading of redacted and anonymised trial details for public viewing. Though driven by the loftiest of motives, the implementation of CTR has nevertheless stumbled over practical problems with the CTIS, which was billed by regulators as being “at the cutting edge of the art and user-friendly so that there is no unnecessary work”, but that has not been borne out by responses from users, as the AKEK statement clearly shows.

AKEK members claim that the platform is unstructured, lacking in user-friendliness and prone to errors. As a result, the evaluation of study applications is “made more difficult with a considerable additional effort for unnecessary formalities”, as the organisation’s statement reads.

“Companies are now publishing less information but much faster, so my clients can’t kick the can down the road,” notes Roussanov. “They must provide information that is properly redacted, but they are nervous about the transparency issues. The need to provide heavily redacted documents that are reviewed by member states, though I’m not sure how carefully states check them.”

A lack of harmonisation

In comparing the new system with the Clinical Trials Directive, there are clear differences. Firstly, directives are not regulations, so rules were previously made on a state-by-state basis under the directive’s guidelines. Now, the rules are intended to apply consistently across all member states, but that is not happening.

“In my opinion, the regulation itself is clear and doesn’t cause any problems,” says Maciołek. The problems, she adds, start when it comes to the implementation of CTR at national level. “Unfortunately, we don’t see harmonisation here and local requirements for Part II dossiers vary from country to country. Large pharmaceutical companies and global CROs restructured their regulatory departments and now have one team, usually global, preparing Part I dossiers, but they have different teams, usually local, preparing country-specific Part II packages, and different teams of CTIS administrators to support technical aspects of the EU portal.”

Roussanov is also somewhat disappointed, because what was supposed to be one set of rules for the entire EU, has been complicated by some member states wanting their own specificities that require companies to complete Part I and Part II dossiers on a country-bycountry basis. Some of these differences arise from interpretations of the General Data Protection Regulation (GDPR). For instance, a hospital is usually the processor of personal data, and that is accepted by most states, but not Germany and the Netherlands, where hospitals are data controllers.

This is where the feel of the road under the wheels of the bus starts to change abruptly.

“The EU is marketed as a single market, but in practice, it is very different,” says Roussanov. “Countries have small quirks that are significant because they build up the complexity of running a trial in the EU. US companies wanted the new regime to be like the FDA, where you make one application and can then run trials across a whole jurisdiction, but in the EU, there are differences between countries.”

Now, some companies prioritise other jurisdictions over the EU, even though the aim of the CTR was to maintain or increase the number of studies being done in the EU. “So, it is not a clear win, though whether it is a failure is open to discussion,” he adds. “Maybe we expected more than we could achieve. Maybe we were delusional.”

Despite the teething problems with CTR, however, there is a sense that it would not take too much to iron out the rough edges and get the system and the rules around it working as intended. If innovative companies stop coming to Europe because it is not cost-effective to run trials in the bloc, then it would be a big blow for the industry, so there is good reason to get everyone working towards the same goal.

The magic ingredients are cooperation and collaboration, which are not always easy in a region as large as the EU or in an industry that is heavily regulated and demands the highest standards of risk management. In one sense, however, the journey towards CTR has proven that it is possible for disparate stakeholders to work together.

“One big positive is that this is one of few cases where industry, the EMA and all stakeholders are on the same page,” says Roussanov. “If that cooperation continues, it would be a very good sign.”

Good intentions are the bedrock of meaningful change. Now comes the hard work of making sure the tarmac is smooth and seamless between all member states.