What Should You Do To Prepare For EU (536/2014)?

By Ed Miseta, Chief Editor, Clinical Leader

In May 2022, Clinical Leader hosted a webinar on the EU (536/2014) regulation and the impact it could have on drug developers hoping to conduct trials in the EU. Our speakers included Sylvia Marecki, head of the operational design center at EMD Serono; Marieke Meulemans, founder and CEO of GCP Central; Adam Lambert, VP of product and process development for Pharmatech Associates; and Thomas Hagemeijer, healthcare lead for TLGG Consulting. This Q&A summarizes some of the questions addressed during the webinar.

Ed Miseta: What is the most important thing that our audience needs to know about EU (536/2014)?

Marieke Meulemans: What is important to know right now is that the clinical trial regulation (CTR) is here to stay. There will be no more delays in implementation. January 31, 2022 was the start of the transition period. What is also interesting and good to know is that this is not an iteration of the EU clinical trial directive (CTD). It is a brand-new regulation, and it will have a massive impact on your business processes, internal communication, and the way you work with CROs. It will change how people and companies prepare for clinical trials and will have a massive impact on IT systems and how they are used within organizations.

The regulation enables sponsors to apply for clinical trial applications (CTAs) for clinical trial authorization in 28 European countries and associated countries with one single online application. There will be no need to submit multiple applications. It also allows regulators to work together. The CTIS also enables transparency and access to information by the public, such as patients and physicians. That transparency is one of the main goals.

Miseta: Can you share some reasons why this new regulation was put in place?

Meulemans: For the drug development folks in Europe, the new regulation was needed. Since the implementation of the EU directives in 2001, which was 20 years ago, there has been a decrease in the number of clinical trials conducted in Europe. The EU directives tried to harmonize the way clinical trials are submitted the Europe, but it was not successful. The system of submitting and managing trials in the member states was too diversified and the administrative burden was increased rather than decreased. There had to be change in the way the EMA approached this regulation. A couple of years after the directive this new regulation was written which went live in 2014. To put it in numbers, there was a 25% reduction in the number of applications for clinical trials in the EU, which is massive and was quite devastating for Europe.

This CTR needs to change that. It raised the attractiveness for the EU for the conduct of clinical trials. With this regulation, we hope to come closer to the study startup times that are reached in the U.S. and other regions. We hope to have a faster application and assessment procedure than previously. Under the 2002 directive, it took a year to get the first patient into a trial, which is far too long. Those issues need to be solved and this CTR is going to help us with that.

Miseta: Adam, the intent behind the regulation is to ensure that rules for conducting clinical trials are identical throughout the European Union and the European Economic Area, and that those rules allow for coordinated assessment of clinical trial applications between member states. Will there still be country specific activities that require compliance?

Adam Lambert: The short answer to that is yes. When you look at the way the CTIS is put together, there are part one and part two documents. The part one documents are more of the centralized documents. But then there is still the member state specific documentation that needs to be put together. In addition, you have the country specific rules and laws that companies will need to comply with that might fall outside of the CTIS or the CTR. That could relate to radiological or biological sample handling. Companies conducting trials in the EU still must be aware of the legal requirements of specific member states to which they are applying. There is a place for a lot of that documentation in the CTIS but there are things that will fall outside the CTIS that sponsor companies will need to be aware of.

Miseta: Implementation of this regulation was dependent on the validation of the CTIS database, which took place in January of this year. What considerations do we need to stay on top of as full implementation begins early next year?

Lambert: The full implementation timeline has been published. Companies need to be aware of it and understand how they are going to transition to this new CTR. Companies should have transition plans in place for existing studies. If your study goes beyond the timeline, you are going to have to transition that clinical trial into the CTIS system. There are a lot of things that will come into play. Who is going to have access to the CTIS system? How are you going to control access? Who is going to add documentation? Who is going to have access to notifications?

Companies also need to understand how their CROs fit into their plans. For example, you may not want all CROs to have access to all data. User management and IT systems are going to be critical as well. Companies must also consider what trial sites are going to be used. After January 31^st of next year, new clinical trial sites will be added by the CTIS system, and those trials would have to be transferred into the CTIS system to do that.

There are other things to consider as you phase into the new CTIS system. Things like whether your clinical labeling is appropriate and if you will need to change that if you send product over to new trial sites. If you must manufacture new material, the labeling requirements are going to change. Therefore, you need to stay on top of the regulations and know if you are compliant with them. We are only five months into this, so the process is still new to a lot of people. The biggest piece of this is to be aware of what aspects of your clinical trials are going to be impacted by the regulation and making sure you have a transition plan in place.

Miseta: Pharma companies are thinking about things like study feasibility and operational planning because of this new regulation. What are some of the things that you believe companies are currently thinking about as we get closer to 2023?

Sylvia Marecki: There are a lot of moving parts here. From the study feasibility and operational and planning perspective, one area that is being discussed across the industry is this idea of strategy around dossier submissions. There are two parts. Part one is the health authority and ethics committee submission. Part two is the country specific submission. When we think about operational planning, particularly for multi-country and global studies, one area under discussion is regarding the optimal submission strategy. There are a few different options to do these submissions.

Submissions can be done in parallel. The nice thing about that is you can potentially accelerate your timelines, but there is a potential risk in that as you are front loading quite a bit of work. You are bringing a lot of resources together to get all the submissions done at once. The other option is to do sequential submissions. This involves submitting part one, getting your answer, and then moving on to part two. That can take more time but will mitigate some of the risk.

Still, imagine if you were able to open all your sites in all your countries in Europe at the same time. That could dramatically change the way your study enrolls versus the way that things are currently done, where countries open on a rolling basis. That can have an impact on enrollment.

Miseta: Thomas, what do you see as the critical considerations that need to be made by companies to their operations and strategy as they transition to this new regulation?

Thomas Hagemeijer: At an elevated level, this portal is a typical platform that reduces transaction costs. The key here is centralization. You might go to Eastern Europe because it is easier to run trials there. But we know in Europe there are a lot of differences between countries. I am based in Germany where we have stricter regulations. Many of those differences will be streamlined into this one portal. The decentralized model we have been dealing with will become more centralized.

One thing that we know about the centralized model is that it is never completely centralized as a touch point. There may be adjustments that need to be done outside the portal. A key point for companies to understand is what can be centralized and what can be decentralized. For example, should I take all my teams out of Europe and put in a European team to take care of the portal? Or should I keep some local teams to run the trials and submit the applications? I think this will remodel the whole clinical trial landscape in Europe.

When conducting clinical trials, you have the U.S., APAC, which has been growing, and Europe. Marieke noted that Europe has been losing 25% of trial applications and will need to catch up. The big question is whether it will work. I will say there is always a big gap in organization between the idea and the implementation.

Miseta: Marieke, when will full adherence to the regulation be required?  

Meulemans: The CTR went live on January 31, 2022. By January 31, 2023, all new trials should be submitted via CTIS. The CTD can still be executed and assessed. It is only after January 31, 2025, that the CTD will expire, and all ongoing research must meet requirements of the CTR. So, you need to be sure you have transitioned all ongoing trials by 2025.

This is for all trials that will not end before that date. That is something you really need to consider, because it requires some preparation and planning. Documentation needs to be put in line with the CTR requirements, which requires some analysis. That will take some time from a project team.

The first trial submitted by a pharma company was in mid-February. That shows pharma companies are still working towards their first submission. I believe it will take approximately 18 months to prepare for putting your first trial into the system.

For more insights into how EU (536/2014) might impact your trials in the EU, click here to view the entire webinar.