Trials and Tribulations: The impact of new clinical trial regulation in Europe
The clinical trial is the fulcrum on which drug development and treatment hinges. Even with the advent of new technologies and approaches which introduce more and more avenues for data collection and application, experts agree that the indispensable controlled clinical trial still has a key place at the centre of the life sciences R&D architecture.
The industry is moving further towards a more international and globalised approach to drug development and treatment, and this methodology brings with it a number of benefits for the clinical trial process and the data it generates. These include presenting wider, more diverse pools from which to draw participants, leading to larger, more representative trial groups and, in turn, enabling the development of medicines which are more likely to function safely and effectively in the real world. Trudie Lang and Sisira Siribaddana address the importance of this in their essay Clinical trials have gone global: Is this a good thing?
“Clinical trial data are often collected from varied populations to support a license application because geographically different trial sites are needed to ensure the product is safe and works in the same way in varying ethnic groups. This requirement is true whether it is a pharmaceutical company working on the next blockbuster drug or a non-for-profit partnership (which typically have a pharmaceutical partner involved in a non-for-profit capacity) developing a new drug or vaccine for a neglected disease,” they explain.
Another advantage presented is the reduction in cost – a concern that is becoming a growing obstacle for those conducting trials. The requisite drains on both a company’s time and money are on the rise, with complex regulatory conditions needing to be met to ensure that studies meet international standards. While this is of course essential to ensure the highest levels of quality and safety in any treatments which may result, an isolationist approach to the clinical trial process would do nothing to salve these issues.
Even beyond these advantages, a more collaborative and streamlined approach appears to be a no-brainer for many countries, and this is particularly true in the EU. Across the 28 constituent Member States, there is a wide range of varying application and reporting requirements, each needing a different approach. This makes for a laborious endeavour to meet each Member State’s conditions, but particularly impacts small and medium enterprises, presenting a sizeable obstacle for them to overcome in penetrating the region’s market with any new technologies.
Attempts have been made to tackle this issue before, with the introduction of Directive 2001/20/EC – also known as the ‘Clinical Trials Regulation’ – which was employed in 2001, according to the Official Journal of the European Union, to “simplify and harmonise the administrative provisions governing clinical trials in the Union”. However, upon review more than a decade later, it was deemed that the Directive had only managed to “partly achieve” these goals. The journal noted in particular the difficulty of conducting studies across EU Member States, due to the struggle inherent in attempting to adhere to a range of varying administrative requirements, again suggesting the necessity of a single, homogenised approach.
But problematic administrative procedures were not the only concern put forward by the journal in the case for legislative reform in the EU. Current scientific opinion also weighed heavily on the decision-making process, particularly the mounting discourse encouraging a more personalised approach to treatment with precision medicine. As noted in the journal, “Scientific development…suggests that future clinical trials will target more specific patient populations, such as subgroups identified through genomic information. In order to include a sufficient number of patients for such clinical trials it may be necessary to involve many, or all, Member States. The new procedures for the authorisation of clinical trials should stimulate the inclusion of as many Member States as possible.”
This acknowledgement and integration is significant as the potential benefits of any new regulation would not be limited to those involved on both sides of a clinical trial, but would further facilitate this effective methodology across the EU, as well as generate more compelling and comprehensive trial data to fuel future drug development.
A New Hope?
These observations formed the cornerstone on which a new clinical trial directive for the EU was created: Regulation 536/2014. Its core focus is “to simplify the procedures for the submission of an application dossier for the authorisation of a clinical trial”, homogenising applications across the EU with identical demands in the hope of creating an attractive and favourable environment for conducting studies.
Regulation 536/2014 is characterised principally by a single EU-wide application portal with a solitary set of necessary documents for all Member States. Established by the EMA, this portal not only acts as an entry point in the application process which enables authorisation by the trial’s sponsor, but also as a receptacle for all data generated throughout the study. This information will then be entered into a complementary EU-wide database, facilitating assessment by Member State authorities while also allowing access to the general public.
Public access to the database is legally necessitated, which is interesting as it encourages transparency on the part of sponsors, who must accept that any data generated throughout studies will be widely available. This will surely be welcomed by the industry, which has often been plagued by a reluctance to publish negative results.
The portal and database are the heart of the new regulation, accompanied by new, standardised procedures in the assessment of clinical trials, including a two-part process which firstly involves all concerned Member States coming to a joint assessment, followed by individual judgements in isolation. This system is of particular benefit to those who plan to conduct studies across multiple jurisdictions, requiring only a single application.
The new regulation is designed to repeal Directive 2001/20/EC and was adopted back in 2014. However, the rollout of the new rules, as well as the introduction of the EU portal and database, will not come into force until the prospective date of October 2018, while the system is subject to independent auditing. It is expected to be fully in place by October 2021, following a three-year transitionary period. During this time, sponsors and EU authorities will benefit from online training, with the new regulation requiring that all relevant users utilise the tools to an independently competent level.
Cutting the Red Tape
These changes promise big advantages across the 28 EU Member States, not least of which is the nullification of EU Clinical Trial Directive 2001/20/EC, which the European Commission attributed for a 90% increase in administrative red tape and launch time of trials; in turn, this starling surge led to a significant drop in the number of studies conducted in the region.
Simon Rule, Professor of Haematology, Clinical Trials and Health Research at Plymouth University, UK, spoke to Pharmafocus to discuss his experience conducting studies under the directive, focusing on the noticeable strain which had arisen since its adoption.
“The bureaucracy around clinical trials is not for the faint-hearted,” he explained. “That’s significantly got more and more onerous over the past ten to fifteen years. The regulators seem to have no common sense anymore, so things that happen tend to be just process rather than born out of any risk or safety issues.
“I’ve got a big team around me, so if I’m doing a study I have a lot of people who can do the paperwork. Now, I think it would be impossible to do it by yourself,” he continues. “The consequence of that is that small-time research just doesn’t happen anymore. The volume is less and it’s more and more led by pharma, just because of the nature of the cost and complexity – they can do it.
“I would let somebody show me that trials are safer today than they were ten years ago based on this mountain of paperwork. I would tell you it’s probably less safe now for patients, because you get deluged with so much stuff you just don’t read it anymore. Patients don’t read consent forms because they’re 30 pages long, so they don’t understand what they’re up for anymore.”
This damning indictment from Rule underlines the bureaucracy inherent in the previous system – an issue which is in sore need of correction and one that highlights the conscious step forward which 536/2014 is attempting to make.
Better Off Alone?
However, despite the advantages the new regulation promises, there is still one glaring obstacle looming on the horizon for one Member State: Brexit. With the UK entrenched in its slow divorce from the EU, what does this mean for the country with regards to adoption of the new system? While this is a complex area fraught with uncertainties, industry speculation has been rife. As a Member State, Britain is bound to comply with the new regulation until it finally exits the EU, which is currently expected to occur by 2018 at the earliest. Many have noted that the UK’s eventual efforts to establish its own application processes, distinct from those in Europe, could lead to severe complications, ultimately resulting in hundreds of thousands of British patients being denied access to potentially life-saving clinical trials.
Sally Shorthose and Toby Shears note in the essay Brexit: Life Sciences Implications “If the UK adopts significantly different national legislation to Regulation 536/2014, this is likely to make the clinical trials procedure increasingly complex with greater administrative burden and cost for companies wishing to conduct multi-centre clinical trials in the EU and the UK.
“In particular, UK companies will not have access to the single portal for applications for clinical trials, or if they do there may be a substantial fee, and separate centralised and national clinical trial authorisation procedures will need to be followed. Furthermore, companies will have to ensure that sponsors of a clinical trial have legal representation established in the EU.”
Beth Thompson, Senior Policy Advisor at the Wellcome Trust, echoed similar sentiments, highlighting that the new EU rules could lead to “a real risk that patients will miss out”.
She explained: “It’s going to become more complicated to run a trial here, with our population of around 60 million, than it is to go to the whole of the EU, which has a population of 500 million. There’s a risk that people might bypass the UK altogether and just go to Europe.”
MHRA heads, both present and past, have also voiced their concerns on the effect Brexit could wreak on the UK clinical study climate. Ex-MHRA Chair Sir Alasdair Breckenridge warned that foreign trial sponsors “may decide not to come to the United Kingdom”, because of the comparatively small size of the market compared to its larger, cohesive European counterpart. “There will be delay in getting new drugs,” he continued, “important new drugs – anti-cancer drugs, anti-infective drugs – for patients in the UK." Current chair Michael Rawlins also expressed concern by stating: “One of the biggest worries I have about Brexit and standing alone as a regulator is that we are only 3% of the world market for new drugs and if we are not careful we are going to be at the back of the queue.”
However, despite this chorus of apprehension, when Pharmafocus asked Jonathan Sheffield, Chief Executive Officer of the National Institute for Health Research, whether these claims are well-founded, he replied: “Absolutely not. 70% of the commercial research done in the UK is done by clinical research organisations [CROs] rather than individual pharma companies and those CROs are all global organisations operating trials across all markets; they will continue to operate in that way, they operate with individual countries all the time.”
Given the confidence in Sheffield’s riposte, could it be that the wave of criticism surrounding the UK life sciences industry’s departure is nothing more than doomsaying? Nonetheless, the potential risk faced by the UK, were it to become complacent in this key transitionary period, is very real. With so much at risk, it is only prudent to take precautions during this uncertain time. Pharmafocus contacted the Wellcome Trust’s Beth Thompson to discuss how these pre-emptive measures may be achieved in order to neutralise any damage which may be caused to the sector and, more importantly, patients.
“Harmonisation with the Clinical Trials Regulation (CTR) is important for the UK to maintain competitiveness, reduce business uncertainty and deliver benefits to patients for multi-national trials,” she explained. “Access to the new IT infrastructure, the EU portal and database must be prioritised as this is critical for participation in the streamlined processes of the CTR. An independent data protection regime in the UK may also impact our access to the EU portal for clinical trials.
“Beyond the near future and implementation of the CTR, it is mutually beneficial for both the UK and the EU to maintain close regulatory cooperation across Europe for clinical trials,” she continued. “Compatible frameworks that focus on equivalence of outcome can reduce the bureaucratic burden on research, making it easier to collaborate and share research across borders. This is vital to ensure UK patients, particularly those with rare diseases, maintain access to clinical trials and innovative medicines.”
The Bigger Picture
While it is clear that the unified clinical trial environment promised by Regulation 536/2014 could be of real benefit to sponsors and patients alike by accelerating and augmenting drug development, stripping away administrative red tape and encouraging greater transparency, the UK’s future in a few years’ time, like everything surrounding Brexit, remains contested and unclear.
Regardless, there is a lot to remain confident about. With Britain firmly established as a leader in the clinical trial space, 536/2014 could viably be seen, as is Sheffield’s view, as providing a platform to push comparatively underperforming European nations closer to the level at which the UK already operates. Regardless, with such focus on the regulation’s possible implications, it is all too easy to lose sight of the bigger picture in the coming years, as Sheffield notes:
“I do believe that we have to work in parallel with the EMA, but we also have to work in parallel with the FDA as well. We have to be very conscious of the fact that the drugs and products that we’re looking at are actually part of a global market and therefore we have to be competitive globally; just looking at Europe is not sufficient in the current environment, let alone when we actually exit the European Union.
“I believe that we’ve got the best infrastructure for health research in the world. The fact that we have the National Health Service and a single Patient Number means that our capacity and capability to find patients and deliver them into research on a large population scale is better than anywhere else in the world; that is what will stand us in good stead for the future.”