Remember back in 2014, when European Parliament published the new Clinical Trial Regulation No 536/2014 to establish uniform rules for conducting clinical trials throughout the European Union (EU)? 

Because of the time it would take to build and validate the portal and database – which are a key component of making the regulation work -- it wasn’t scheduled to come into effect for more than four years, giving biopharma companies plenty of time to adapt. But those four years will soon be over. The regulation is expected to come into effect no later than October 2018, and it is going to create significant changes in the way clinical trials are conducted across the region.

The new regulation lays out a formal structure for approving, conducting and reporting outcomes of trials conducted in any of the 28 EU member states. The new regulation establishes a streamlined clinical research application procedure that will be handled via the EU portal, which will be set up and maintained by the European Medicines Agency (EMA) in collaboration with the Member States and the European Commission; a single set of documents to be submitted for all clinical research applications; and a two-part procedure for assessing applications that includes a joint member state review and a review by each concerned member state.

The regulation is designed to simplify reporting procedures, which will spare sponsors from having to submit broadly identical information separately to various bodies and different member states, and to increase transparency around trials and their outcomes. In addition, clinical trials conducted outside the EU, but referred to in a clinical trial application within the EU, will have to comply with regulatory requirements that are at least equivalent to those applicable in the EU.

One submission, 28 states

This is all good news for Sponsors working on the EU, because it will streamline the trial process, making it easier and more efficient to plan and execute research. Prior to the rule, every one of the 28 EU member states had their own unique processes for submitting and assessing clinical trial data, forcing developers to juggle multiple documents, timelines, review steps, safety reporting requirements, and approval processes. The Clinical Trial Regulation eliminates these added steps to create a more consistent and harmonized research environment.

But it’s a dramatic change that requires Sponsors to educate themselves on how the new regulation will effect current and future projects, and to adapt accordingly.

The biggest difference will be seen in the new authorization process using a single submission in place of the separate Regulatory Authority and Ethics Committee submissions that are currently required in all EU countries. This has major implications for how studies will be submitted, assessed and approved, and leaves little room for error (due to the strict timelines for assessment dictated by the Regulation), or adaptation based on previous submission results. The two-part process will comprise of Part I, a coordinated assessment of key clinical trial documentation (e.g., Protocol, Investigators’ Brochure, Investigational Medicinal Product Dossier, Risk-Benefit Assessment) by all Member States, and Part II, which is a national assessment of country-specific information (e.g., Informed Consent, Compensation, Recruitment Arrangements, Suitability of Sites and Investigators) by each Member State.

The assessment of Part I and Part II will occur in parallel and strict timelines will dictate that this assessment will take between 60 – 106 days for all EU MS involved, depending on whether the Sponsor receives requests for information during the assessment. So while this new approach is likely to lengthen the time it takes to secure the first EU approval, it will shorten the time to final EU approval, whilst also introducing much greater predictability that is highly beneficial for researchers. However, it must also be appreciated that part of this speed comes from the requirement that sponsors respond to all questions within 12 calendar days during the assessment process, which means developers need to have all of their data in place when making submissions to be sure they can meet this strict deadline.

The new rule also requires developers to publish information on study status and outcomes publicly, so they will need processes to carefully assess what information they choose to include in their submission documents based on what is considered appropriate to release to the public. On the positive side, this transparency offers great benefits to patients, through permitting greater patient choice in relation to the nature of studies that may have been completed or be on-going. In addition, Investigators and Sponsors will have access to information on many more studies that are on-going or were previously conducted, to permit better planning of design and end-points for future studies, and to reduce redundancy and repetition of failed investigations.

Are you ready?

In preparation for this transition, Sponsors should familiarize themselves with the broad changes, as well as the intricacies of the rule, which could add value – or create risks – if their teams aren’t paying attention. From complying with notification requirements regarding study status, to understanding whether observational research is considered a “low interventional trial” and thus requires a separate submission and review, these seemingly small details could lead to non-compliance issues if a developer’s planning processes, systems and communication are not adequately prepared.

That includes understanding the transition process. Until the new regulation becomes applicable, all clinical trials will continued to be conducted in accordance with the Clinical Trials Directive, which will be repealed on the day of entry into application of the Clinical Trial Regulation. It will however still apply three years from that day for all clinical trial applications submitted before the entry into application, and all clinical trials applications submitted within one year after the entry into application if the sponsor opted for the old system (since Sponsors can choose whether to submit each study under the new EU CT Regulation or the ‘old’ EU CT Directive for the first 12 months after the EU CT Regulation becomes effective). This means that any studies submitted under the current EU CT Directive will be required to transition to the new EU CT Regulation requirements by no later than October 2021. So every Sponsor will need to keep up with the rate of change in the EU for quite a while, even after the EU CT Regulation becomes effective!

While there is still time to prepare, it is going by quickly. Once the new regulation is in place, Sponsors will need to ensure they understand the implications of the clinical trial application submission options available, appreciate that the opportunities for submitting notification of protocol amendments will be more restrictive, and that they will have to be ready to respond rapidly to questions within days of receiving them in order to comply.

Developers who begin preparing for this change now will be best positioned to address these challenges and to take full advantage of the new streamlined environment as soon as it comes online. 

The QuintilesIMS team is working with stakeholders from EMA and the member state authorities to fully understand the implications of the new regulations and its impact on our customers. We look forward to working with our partners and clients to ensure they are prepared for this coming transition.