Are you an innovator with a product undergoing clinical trial? This article covers all you need to know about the CTR transition of clinical trials. The long-awaited Clinical Trials Regulation (CTR) EU No 536/2014 entered into force when the CTIS (Clinical Trial Information System) went live on the 31st of January 2022.
As a reminder, a three-year staggered transition period for implementation is currently running.
By 31 January 2025, all trials will be governed by the new CTR. This includes ongoing trials approved under the current CTD.
Since the opening of the CTIS ten months ago, sponsors are becoming acquainted with this new system and way of submitting clinical trial applications. In our recent experience with new trials, bugs and unforeseen technical issues have occurred during the use of the system. However, the CTIS still appropriately supports the flow of information between various entities. These include clinical trial sponsors, European Union (EU) Member States, European Economic Area (EEA) countries and the European Commission.
The main goal of the CTIS 2022 delivery plan is to ensure the stability of CTIS, according to information provided by the European Medicines Agency (EMA). Additionally, it is to focus on fixing both the accumulated issues reported by end users and the bugs already recorded (backlog).
Even though the volume of reported bugs seems to discourage sponsors to transition their trials, it is still a necessary step in some cases.
Which Ongoing Clinical Trials are Impacted?
There is a common misconception that the CTR transition of clinical trials can be performed only from 31st January 2023. However, it is already possible, since the CTR launch.
If you expect at least one of your clinical trial sites to be active in the EU after 31st of January 2025, then transitioning to the CTR now may be required. See the different contexts below for more clarification:
- If your clinical trial has an end date planned after 31 January 2025, a transition will be required.
Our recommendation is to not wait, but instead to plan ahead to ensure a successful transition to the CTR, particularly for large clinical trials. This has the added benefit of earlier access to the advantages of the CTR for amendments (coordinated assessment, single submission portal…)
- If your clinical trial has an end date planned long before 31 January 2025 and there is NO risk of delays.
A transition should not be required, unless additional EU/EEA countries are going to be added after 31 January 2023. If so, the entire trial would need to be transitioned before the addition of a new EU/EEA participating country.
- If your clinical trial has an end date currently anticipated prior to 31 January 2025 and there is a risk of delays.
In this instance, there remains an element of uncertainty, and close monitoring of the timelines is recommended. This is to ensure that, if a transition is required, it can be performed before the deadline.
Note: If your clinical trial is not affected by any of these obligations, it may still be beneficial to transition to the CTR.
How Does the CTR Transition Work?
One must submit a transition application in the CTIS to change the regulatory framework of a clinical trial. This transition application submission is only required in the Member States involved in the clinical trial. It also relies on the existing dossier having already been assessed and authorized by the Member States in question. The process will require a new cover letter and all clinical trial application data (Part I and II) to be completed in CTIS.
It is the sponsor’s responsibility to assess compliance of the ongoing Clinical Trial with the CTR. They must also declare in the transition cover letter that the clinical trial is in line with the requirements for transitioning.
If a clinical trial does not fully comply with the CTR, the sponsor must request a substantial amendment under the CTD, before switching. Here, they must specify the intention to align the trial with the CTR. Only after the substantial amendment is accepted, a sponsor can follow the procedures to transition the clinical trial to the CTR.
The transition of multinational clinical trial is more complex than mono national trials. It requires having all common documents for Part I of clinical trial application harmonized. This includes the Study Protocol, Investigator’s Brochure and Investigational Medicinal Product Dossier. Depending on the number of member states involved in a clinical trial and the presence of local versions of documents, pre-submission of amendments for harmonization of the core documentation is required.
In addition, for Part II of the application, each Member State may have its own requirements. Thus, sponsors should also remain informed about the publication of country-specific guidelines. In case of any country-specific questions, we recommend contacting the corresponding national contact point.
Importantly, redacted versions of the documents may be expected, in compliance with transparency requirements. Experience shows that planning ahead is critical for a successful transition. In particular, there should be no ongoing assessment of any substantial amendment in any of the EU/EEA countries involved in the clinical trial.
What Are the Consequences of the CTR Transition?
The sponsor must declare that the clinical trial is in line with the requirements of the transitioning application. But the clinical trial should still be in line with the authorization given under the CTD.
Moving forward, the transitioned clinical trial will be governed by the CTR from the moment of (implied) authorization. All requirements of the regulation will then apply. For example, there are obligations of notification via CTIS, safety reporting rules, archiving requirements, and transparency requirements (including deferrals). There are also procedural rules of the Regulation for requesting substantial modification and addition of a Member State.
How to Tackle the CTR Transition?
Sponsors should consider the best moment to transition based on ongoing/planned assessment for their trials. In addition to timing, a crucial aspect of the transition is to assess in advance the impact on your study/conduct and study documentation. This strategy should be tailored to sponsor’s trial and specific needs. The transition period can be a real challenge, for both sponsors and regulatory agencies. As such, being supported by experienced professionals would be highly valuable for your transition.
We encourage you to carefully review the available following official resources to facilitate the transition:
- CTFG Best Practice Guide for sponsors of multinational clinical trials with different protocol versions approved in different Member States. This is under Directive 2001/20/EC that will transition to Regulation (EU) No 536/2014.
- EMA Regulation (EU) No 536/2014 Questions & Answers.
Both documents are critical source of information concerning general aspects of the transition.
As of 30 September 2022, 343 clinical trial applications have been submitted in CTIS since the launch of the system on 31 January 2022. Among these, 313 are initial clinical trial applications, 26 are substantial modification applications, and 4 are applications for the addition of a new Member State Concerned.
In these 313 initial clinical trials, only 6 involved a CTA transition without deferral. However, this number is an underestimate. Clinical trials with deferrals, and with a decision issued after mid-August 2022, are not yet published.
Based on our experience, CTR transition of clinical trials is still limited. Moreover, many sponsors admit they are waiting for the bugs in the system to be solved before initiating a transition.
How Can VCLS Help You?
VCLS is an innovative partner in the conduct of your clinical trials, and we can support you on any aspects related to the CTR transition. We have recently shared our insights, suggestions and experience on the following questions. See “Ask the Experts” session – EU CTR/CTIS Early Adoption and Experience.
- When should you transition your ongoing trial to the EU CTR?
- Can you switch from the trial-centric approach to the organization-centric approach?
- How and to whom to submit your safety reports under the EU CTR?
You can also review our tailor-made solutions for a seamless EU-CTR implementation here.
We advise sponsors to develop a transition strategy that suits their specific needs and fits within the transition period.
Posted on Nov 17th 2022