Evidence from early adoption of digitisation central to the new European Union Clinical Trials Regulation suggests that the Regulation will revolutionise the region’s competitiveness. As of 31 January 2022, countries are finally applying Clinical Trial Regulation EU No 536/2014, six and a half years after it entered into force. But the delay has provided an opportunity to test whether its measures can deliver on the most important intended impact.
That key impact is reducing the time to approval of clinical trials, said José Antonio López-Guerrero, Head of the Molecular Biology Laboratory at Fundacion Instituto Valenciano de Oncologia, Valencia, Spain. He added that his country is already showing that this is possible. “In Spain, we have already adapted our regulation over the last two years,” López-Guerrero revealed. The country was one of the first to start training researchers in how to use the Clinical Trials Information System (CTIS), which is essential to the new regulation. Previously, by adopting similar digitisation, Spain had cut the time taken to sign contracts from 108 days in 2019 to 69 days in the first half of 2021.
The regulation’s key purpose is to make Europe competitive in research and counter a recent decline in the number of clinical trials conducted. It seeks to fix flaws with the preceding Directive 2001/20/EC, implemented in 2004, which imposes difficult regulatory requirements and high costs. One major problem was the need to make submissions and seek authorisations in each country, and even for each institution participating in a clinical trial.
How the regulation has streamlined clinical trial processes creates the biggest legal changes, said Chiara Perotti, an associate in the Life Sciences team Herbert Smith Freehills Studio Legale in Milan, Italy. The multiple national submissions conducted previously are being replaced, commented Perotti, who is a regulatory specialist and a patent litigator. Now trial sponsors can submit a single streamlined application and authorisation procedure for all clinical trials via the CTIS web portal, centrally managed by the European Medicines Agency (EMA).
Another major element in the new Clinical Trial Regulations is the emphasis on transparency, Perotti said. “The aim is to make access to clinical trial data easier, while preserving highest safety standards for patients, as well as preserving confidentiality in sensitive information,” she said.
Sponsors and their legal representatives will also have greater responsibilities under the new Regulation. “Some, such as liabilities in the case of co-sponsorship, have been defined and included within the legislation’s scope for the first time,” Perotti noted.
The key aspects of the new Regulation are interrelated via the CTIS, López-Guerrero explained. From a single application, clinical trial information will go to competent authorities and ethical committees from each participating nation for evaluation. Then, the CTIS serves as a portal to support the regulation's transparency goals, and a database for sharing information after it’s started. “All the information on all the ongoing clinical trials will be available for all the sponsors and participants,” López-Guerrero said.
Trial summaries, including a layperson summary, must be published via CTIS, explained Silvia García, Senior Manager, Regulatory, Drug Development and Manufacturing European Federation of Pharmaceutical Industries and Associations, headquartered in Brussels, Belgium. That “will enable patients and healthcare professionals to more quickly identify and understand clinical trials and evaluate the relevance of these to an individual patient’s condition”, she explained.
The Regulation divides the trial authorisation process into two parts, García said. The first part concerns technical-scientific aspects, she explained. These are assessed by a reporting or lead member state, in agreement with other member states, and will be valid throughout the EU.
The second part concerns ethical aspects, García said. This includes information given to patients, informed consent documentation, selection of subjects, recruitment, suitability of researchers and clinical trial sites, insurance, and damage compensation. Each country will assess use one or more ethics committees to assess these considerations. “Each member state has to decide how the competent authorities should cooperate with one or more ethics committee to reach a single national decision within the timelines of the Regulation,” said García.
The Clinical Trials Regulation entered into force on 16 June 2014, but its application was postponed until six months after the publication of the European Commission’s notice that the EU Portal and Database were fully functional. The complexity of the system the Regulation enacts meant that notice didn’t come until 2021, explained García.
“The delays were based on the need for full functionality of the EU Portal and the EU Database and the systems meeting the agreed functional specifications,” García said. “It required a multi-stakeholder discussion and alignment with multiple meeting discussions and several user-testing cycles to optimize the different functionalities of the system.”
Perotti expects to see some issues around matters that are subject to national law. “While this new system is in the form of a Regulation and, as such, is directly applicable, some issues it covers are strictly a matter for national laws and are left to the member states,” she said. “This includes, for example, civil and criminal liability of actors involved in the trials, and the design of template agreements between sponsors and trial sites. It is still early days, so we will have to wait and see how the new regulation takes shape and is adopted by the industry.”
The previous Clinical Trials Directive will still apply for three years to clinical trials applied for before 31 January 2022, or within one year from 31 January 2022 if applicants opt for the older system. As such, by 31 January 2025 all EU clinical trials should be conducted under the Regulation, said López.
However, the covid-19 pandemic has greatly emphasized how much the Regulation is needed, according to López. “In Spain, there are around 3,500 clinical trials ongoing, involving around 150,000 patients,” he stressed. “In the pandemic years there have been 1000 new clinical trials, which is a huge amount. We need to optimise all the processes and the new European Regulation has just this focus, to optimise the processes and facilitate swift approval”.
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