The merits of “regulation” is a hotly debated topic in both political and commercial settings. In preparing to write this blog, I was reminded of the scene in Monty Python’s ‘Life of Brian’ when the rebel leader asks, in a derisory tone:
“What have the Romans ever done for us?”
After a deluge of responses from his audience, he then restates the question:
“Alright, but apart from the sanitation, the medicine, education, wine, public order, irrigation, roads, a fresh water system, and public health, what have the Romans ever done for us?”
This light-heartedly highlights that appropriate regulation is a healthy thing and persuaded me to approach the subject matter of this blog with an optimistic mindset. So here goes!
The New EU Clinical Trials Regulation: When Is It Happening and How Will It Impact Clinical Research?
Highly anticipated, the new EU Clinical Trial Regulation No. 536/2014 was actually enacted back in 2014 – yet the industry still awaits its full implementation. What follows is a high-level look at the changes it will bring, when it’s likely to be actioned, and the impact it could have.
Why is EU Clinical Trial Regulation No. 536/2014 Being Introduced?
The new Clinical Trial Regulation replaces the previous 2001/20/EC Directive. The goal? To encourage more clinical study sponsors to conduct trials across EU member states. Fundamentally, the new legislation aims to do what the previous Directive failed to: to harmonize and simplify clinical trial regulation across the EU. The original 2001/20/EC Directive was an important step towards this, but as it was still subject to individual Member State interpretation, there were discrepancies in the laws between each country. This introduced requirements that resulted in higher costs for sponsors and meant that authorization of a clinical trial had to be obtained multiple times. Indeed, far from boosting the running of clinical trials in the EU, analysis of data from ClinicalTrials.gov suggests that the number of newly registered clinical trials per year in Europe is in decline, whereas the global trend is upwards. Recognizing the challenges that the previous Directive created for sponsors wanting to run a clinical trial across several EU member states, the new Regulation aims to create a uniform framework for clinical trial authorization and a single assessment of the results.
What Are the Key Changes in EU Clinical Trial Regulation No. 536/2014?
- Legislative power - The Regulation is a binding legislative act that applies to all EU Member States. This contrasts with the previous Directive, which set out a number of goals for Member States to achieve individually through changes in their own national legislation. The new Regulation will therefore remove the discrepancies that were previously a problem with the 2001/20/EC Directive.
- EU Clinical Trial Portal and Database - A key feature of the new Regulation is the creation of a single EU Clinical Trial Portal and Database, through which all clinical trial applications and related communication will be submitted electronically. The system will contain collaboration tools, as well as workflow and document management capabilities, which will be accessible via individual workspaces for sponsors, regulatory authorities, and the public. A significant change is that the authorization process will now be coordinated by one assigned “reporting Member State”, with input from the other “concerned Member States” (i.e. other EU countries in which the trial is proposed to be conducted). The regulation also provides defined timelines for the different stages of the authorization process.
- Transparency - Another major change is the level of transparency provided, since all of the information in the EU database will be publicly accessible (with the exception of personal information that could be used to identify participants or commercially sensitive information). The provision by the sponsor of a final summary report in layman’s language will be mandatory.
- Safety reporting - The new Regulation simplifies the rules on safety reporting for trials running in the EU. It allows the protocol to state that not all adverse events (AEs) and serious adverse events (SAEs) are recorded and reported, and for clinical trials involving more than one investigational medicinal product (IMP), a single safety report can be submitted in the EU Clinical Trial Portal and Database. Suspected unexpected serious adverse reactions (SUSARs) will also be reported centrally via the Database, rather than to each national authority.
- Commission legal obligations - Clinical trials are inspected for both the conduct of trials (Good Clinical Practice - GCP) and the manufacturing of IMPs (Good Manufacturing Practice - GMP). The Regulation includes legislation and guidance on both GCP and GMP, as well as arrangements for inspections. The supplementary Commission Delegated Regulation (EU) 2017/1569 and its associated Commission Guideline, specifying principles and guidelines for GMP and arrangements for inspections, will become applicable at the same time as the new Regulation.
- Clinical trials conducted outside the EU - If clinical trials are conducted outside the EU but submitted for marketing authorization in the EU, they have to follow similar principles to the provisions of the Clinical Trials Directive.
When Will the EU Clinical Trial Regulation No. 536/2014 Come Into Effect?
Although the Regulation actually entered into force on 16 June 2014, the timing of its application depends on the development of the EU Clinical Trials Portal and Database. The completion of a fully functional database will be confirmed by independent audit, and the Regulation will become applicable six months after notice of this confirmation. The significant technical complexities in perfecting the Portal and Database have so far deferred the enactment of the new Regulation. It is currently anticipated that the EU Clinical Trial Regulation will come into application during 2020.
Clinical trials that started before the new Regulation becomes effective can continue complying with the original Directive for three years from the Regulation’s effective date. Sponsors can also opt to use the previous system within one year of the Regulation’s effective date and operate under the Directive for a duration of a three-year transition period.
Impact of EU Clinical Trial Regulation (CTR) No. 536/2014 on Clinical Research
The new Regulation should bring benefits to sponsors and investigators running clinical trials in multiple EU countries because it means that they can rely directly on the single requirements of the new Regulation, as opposed to dealing with each EU Member State’s individual approach. They will have a harmonized electronic submission and assessment process for clinical trials, reducing duplication of effort and costs. It will also likely lead to improved collaboration, information-sharing, and decision-making between and within EU Member States.
However, the new Regulation may introduce subtle changes that could result in the need to evaluate and possibly adapt clinical supply chain operations. There is also the outstanding question of what will happen if and when the UK leaves the EU. The UK's Medicines and Healthcare products Regulatory Agency (MHRA) has pledged to align, where possible, but there is concern that two parts of the regulations – participation in the European Medicine Agency’s single-assessment model and shared use of a centralized IT portal for tracking trial progress – cannot be implemented outside of the EU bloc.
- The EU Clinical Trial Regulation is a legislative change that removes the individual EU Member State interpretations of the previous Directive, harmonizing clinical trial processes across the EU
- At its heart is a streamlined authorization process which includes a centralized Clinical Trials Portal and Database through which all clinical trial applications and communications will be submitted and updated
- The independent functional audit of this database needs to be completed before the Regulation ‘goes live’
- There are many benefits, but sponsors and investigators will need to evaluate some of the operational subtleties in the new Regulation