From 31st January 2022, the European Union Clinical Trials Regulation Nº 536/2014 (commonly known as “EU CTR”) came into force and a new age to clinical trial applications for interventional trials in European Union (EU) and European Economic Area (EEA)1 began.
Since early 2022 ICON has gathered substantial exposure to the EU CTR process and interfacing with the Clinical Trial Information System (CTIS) portal. This experience has spanned initial submissions (including Part I and Part II), as well as substantial modifications, addition of Member States Concerned (MSC; new countries) and transitions from the Clinical Trial Directive to the EU CTR. Working with our sponsors we have gathered experience of EU CTR for a variety of indications, patient populations (including paediatrics) and investigational product types, including small-molecules, biologics, and advanced therapies.
Our experience so far has allowed us to work with 21 Member State countries under the EU CTR process. Including, 11 different Reference Member States (RMSs): Austria, Belgium, Denmark, Finland, France, Germany, Hungary, Italy, Netherlands, Spain, and Sweden. Having worked multiple times with Austria, Belgium, France, Germany, Italy, Netherlands, and Spain as RMS. In addition to those RMS countries, ICON have also worked with Bulgaria, Cyprus, Czechia, Greece, Ireland, Lithuania, Poland, Portugal, Romania, and Slovakia as MSCs.
What have we learned?
From our experiences to date we have been able to gather the lessons learned across a large spectrum of topics. Below are some of the key lessons we have learned.
Resources & communications
Like many other success stories, clear communications and clarity on roles and responsibilities, especially within CTIS, is important in EU CTR projects. Division of responsibilities across all parties involved need to be agreed and clearly documented from the beginning.
Close communication and collaboration between all stakeholders are imperative. This is especially critical at the time when the Requests for Information (RFIs) are issued, and the response timeline is a maximum of 12 calendar days.
Submission of high-quality documents for clinical trial authorisations are always critical, whether you are submitting via the EU CTR or to any other national regulatory agency or ethics committee. Taking the extra time to achieve this, prior to submission, and applying a “right first time” approach to submission documents is vital. Within the EU CTR process this need is further exacerbated due to the very short, up to 12 calendar days, RFI response timeframes. These responses may require updates to submitted documents, and any needed translations and redaction also must be submitted. If the response deadline is missed a re-submission is needed to re-start the submission process.
New transparency and deferral rules require any personal protected data (PPD) and commercial confidential information (CCI) to be redacted. The EU CTR redaction requirement is applied to initial submission and throughout the trial lifecycle. The Sponsor should limit CCI and redaction in the protocol, IB and IMPD safety and efficacy content. Having a clear definition of CCI early on, so submitted documents that will eventually be published can be written in a manner to reduce or remove the need for redaction is important. The extent of redaction will be assessed during the submission process and over-redaction will be commented on during the RFI phase. In contrast, the risk of over-publication is an important commercial consideration.
Based on ICON and our Sponsors experience of CTR, in practice, the overall timelines are generally longer than those stated in the regulation. This is because CTIS applies a set of rules stemming from the regulation, which defines legally defined delays. For example, Part II assessment projected timeline is based on each respective MSC calendar (including public holidays).
Due to the functionality of CTIS, close monitoring of the various tabs and notifications is fundamental to allow for planning of next steps.
EU CTR states that the RFI response timeline is up to 12 calendar days, however, due to multiple factors the RFI response window may in practice be shorter than those stipulated in the regulation. Thus, making it even more important to follow a right-first-time approach for documents submitted.
The CTIS portal was one of the most significant aspects of implementation of the EU CTR and has come with its own challenges. A CTR number is needed for various submitted documents, therefore, a study should be created in CTIS at the earliest opportunity to create this reference number so that it can be added to study documents.
As previously stated, clear division of responsibilities should be agreed between all stakeholders, and this is especially true for CTIS access. CTIS administrator roles and user permissions need to be clearly defined from beginning, which may include preparer and reviewer roles across multiple organisations.
CTIS pulls information from the Organization Management System (OMS) into the structured data (the application form). Therefore, it is important that all organisations that will be included in the submission are registered in OMS prior to submission. This may include the Sponsor, third party vendors, e.g., QP release site(s), and participating trial sites. The eXtended EudraVigilance Medicinal Product Dictionary (XEVMPD) system also provides information directly into CTIS. Ensuring all substances (investigational/developmental) are registered in XEVMPD prior to submission is essential, if they are not listed in XEVMPD they cannot be selected in CTIS.
Document management across CTIS is important and can cause issues if you don’t follow the rules correctly. If a document applies to multiple substances, e.g., an IMPD, this should be uploaded once, and a cross-reference document loaded to the other product sections. EMA file naming conventions should be strictly adhered to, which should also ensure the 100-character file name limit is met. There are certain mandatory documents required in CTIS. If any mandatory document is not provided, a document explaining the rationale for not including this must be submitted.
The EU CTR and CTIS portal has also proved challenging for regulatory agencies and ethics committees. Open communication lines with MSC national contact points are useful to flag study specific issues for resolution. Having an in-country network of ICON individuals responsible for reaching out to these national contacts has been invaluable.
Although there is no legal basis for national regulatory agencies and ethics committees to request additional documentation beyond what is defined in the regulation, ICON and our sponsor continue to see scope creep beyond what is defined.
Submission of initial clinical trial authorisations in the EU/EEA via CTIS is now mandatory, however, the system continues to suffer from technical issues and contains many unresolved problems. ICON, our sponsors, and other users, including regulatory agencies and ethics committees have highlighted a few functionality issues with CTIS. From ICON’s extensive experience of interfacing directly with CTIS we have faced the following challenges:
- RFIs not been received by the submitter within the due date, even though the assessors have pushed them from their side
- Inability to submit RFI responses due to CTIS performance problems
- Re-submission workflow functionality not enabled
- Documents duplicated after submission
The EMA have acknowledged many of the issues with CTIS and have a continuous improvement program in place; a CTIS upgrade is due in the coming weeks. Having a team of specifically trained and highly experienced CTIS Technicians working closely with all stakeholders to navigate the system and resolve the technical challenges, as and when they appear, has been invaluable for ICON and our Sponsors.
After the many years of anticipation waiting for the EU CTR to be implemented, we have found that, overall, our experiences have been mostly positive, and in line with what others have experienced. We continue to gain vital experience and apply the learnings across all the submissions ICON makes via EU CTR and within CTIS. The knowledge and capabilities gathered by our CTIS group and expert CTIS technicians has proven, again and again, to be invaluable.
Processes and workflows implemented have been refined based on the practical lessons learned and will continue to be monitored. Constant monitoring and detailed interrogation of all new EMA and national EU CTR-related instructions and guidance published has been a vital source of intelligence. The perpetual release of new information about the EU CTR has allowed ICON to stay on top of all plethora of change. Also, it is clear from the regular updates of the EMA Q&A guidance that there are still many aspects of the regulation, practical implementation at a national-level and CTIS that require further clarity.
To find out more information about the EU CTR please download our whitepaper EU Clinical Trial Regulation: Impact and strategic considerations for sponsors.