New European Clinical Trial Regulation from the 31th January 2022
In January 2022, the new Clinical Trials Regulation will be implemented. Under the Regulation, all clinical trial applications for trials with medicinal products in humans will have to be applied through a new Clinical Trial Information System (CTIS) along with amendments and other changes to ongoing clinical trials. This is done to harmonise and streamline the processes for application and supervision of clinical trials throughout the EU.
The Regulation will bring new requirements regarding application, deadlines, and communications with the competent authorities and ethics committees, and builds on the same central principles of good clinical practice as the current EU directive 2001/20/EF. The Clinical Trials Regulation can be found at the EU Commissions webpage along with their extensive Questions & Answers Document.
The new requirements regarding the application dossier are described in annex I of the Regulation. You can als
The European Medicines Agency (EMA) offers support and training in the new CTIS portal. The training and support materials are available at their webpage.
We will update this page with questions and answers regarding the Clininical Trials Regulation.
Questions and answers on the Clinical Trials Regulation
The Clinical Trials Regulation applies to clinical trials of medicinal products for human use
- Trials that will only take place in Denmark (Danish mono-national clinical trials, including trials from non-commercial sponsors), are they to be submitted through the EU portal?
All clinical trials of medicines must be submitted via the EU portal. However, please see the information on the transition period in the first year.
- Must all submissions take place via the portal, e.g. annual safety reports?
All submissions throughout the term of the clinical trial, including notifications, substantial amendments, annual safety reports, final report and results must take place through the portal. SUSARs are an exception and must be submitted directly to the EudraVigilance database (however, we do not know the final solution yet).
- When will the regulation enter into force/apply?
The regulation will not enter into force before the EU portal that is to support the communication between sponsor/applicant and the authorities has been fully developed. The EMA's Management Board has confirmed that portal will go live by 31 January 2022.
- How should I submit my application after the regulation has entered into force?
You are to submit your application for authorisation of a clinical trial to the EU portal. You will no longer be required to submit applications directly to the national authorities. This includes the application to the Danish Medicines Agency as well as the application to the ethics committee. However, please see the information on the transition period in the first year.
- How are ongoing national and VHP trials to be handled – is there a transitional arrangement?
A transitional arrangement will apply, which makes it possible to submit applications under the old legislation for up to one year after the entry into force of the regulation. If an ongoing clinical trial has not been completed within three years after the regulation entered into force, the regulatory framework of the clinical trial must switch to the regulation. The European Commission has published guidance on the transitional arrangements in section 11 of their Questions & Answers Document. This means that trials which are not concluded by 31 January 2025 have to be transferred to the regulation. If the trial is not transferred before this date, it will have to be stopped as it will be illegal to continue the trial.
- How should multinational clinical trials be transitioned from the EU Directive to the EU Regulation and what are the requirements?
Prior to transitioning a clinical trial to the EU Regulation and CTIS portal, the sponsor have to ensure that the documentation is harmonised across all member states concerned. The protocol have to be harmonised (identical procedures across member states) or consolidated (minor national differences highlighted in the same protocol). Other documentation such as Investigators Brochure and Investigational Medicinal Product Dossier have to be harmonised. Non-substantial changes to the protocol as a result of this harmonisation should not be submitted as substantial modifications prior to the transition. However, if the document version does not match that last approved version this should be highlighted in the Cover Letter. The EU member states have agreed on a expedited and harmonised transition procedure where the assessment phase is shortened to one week following the validation of the application. You can find more information on multinational transition trials and their requirements in the CTCG Best Practice Guide for sponsors of multinational clinical trials with different protocol versions approved in different Member States under the Directive 2001/20/EC that will transition to the Regulation (EU) No. 536/2014. For application of transition of multinational trials, please use the CTCG Best Practice Cover Letter Template.
- How can I see which documents to submit?
The regulation’s Annex 1 includes a list of the documents that must be submitted.
- What information shall be specified in the Cover Letter?
The Cover Letter shall, in accordance with annex I, section B of the regulation specify information regarding the EU trial number, protocol code/number, title and the sponsor of the trial. It shall specify to whom, the sponsor has delegated the task of GCP-monitoring of the trial and confirm that the monitor can understand Danish. Information regarding payment and billing can be mentioned in the Cover Letter or submitted as a separate document under Proof of payment. There has to be a list, including the regulatory status, of all investigational medicinal products (IMPs) and auxiliary medicinal products (AxMPs) involved in the trial. The location of reference safety information, in the application dossier, for all IMPs shall be specified. Furthermore, it shall be clearly stated if there are any special circumstances regarding the trial design, IMPs or population that the DKMA should be aware of, eg. first-in-human trials, decentralized trials, trials with children or other vulnerable populations. For a comprehensive list, please refer to annex I, section B of the regulation which specifies the requirements for the Cover Letter.
In case of a resubmission, it shall be clearly specified what changes are introduced to the documentation compared to the initial application.
- What protocol information is required in the EU regulation?
The EU regulation for clinical trials sets out a list of required information that have to be included in the trial protocol in annex I, section D. The Danish Medicines Agency have made a protocol template that is intended to help applicantsto comply with both the EU regulation requirements and the relevant ICH guidelines. This template is available through this link (in English as a Word-file).
- Will the Danish Medicines Agency keep us updated on the concrete changes in relation to applications for clinical trials of medicines?
Yes. Once we know more about how the EU portal will look, we will be holding information meetings and post information on our website. Should it become possible to practice using the EU portal, we will keep you updated about this.
- Which clinical trials are covered by the new legislation?
The new legislation applies to clinical trials of medicinal products for human use.
- Will I still have to submit my application to the Danish Medicines Agency and the Research Ethics Committee System after the regulation has entered into force?
Your application for authorisation of a clinical trial will be reviewed by us and the Research Ethics Committee System when it is submitted to the new EU portal. Applications should therefore not be submitted directly to the Danish Medicines Agency or the Research Ethics Committee System. However, this only applies to clinical trials of medicines.
- How should I report SUSARs?
When the regulation enters into force, SUSARs are to be reported directly to EudraVigilance and thus not simultaneously to the participating national member states. We do not know the final solution yet. However, it is now clear that SUSARs from trials approved under the current EU directive 2001/20/EU can be reported to Eudravigilance as well, once the regulation enters into force. Therefore, SUSAR reports to the Danish Medicines Agency (DKMAEUDRA) will no longer be a requirement from that point onwards.
- What are the requirements for reporting serious breaches?
Under the new Regulation, all serious breaches of both the protocol and the Regulation have to be reported. Please see our page regarding serious breaches for definitions. All serious breaches must be reported via the EU-portal, as described in Module 5 of Sponsor Workspace guidance in CTIS online training.
- Is it possible to submit a new substantial amendment, when the previous amendment is still under evaluation?
No, any application for new amendments (henceforth called substantial modifications) to trials that are approved under the Regulation, must await the conclusion of previous applications. The clinical trial has to be approved in all member states concerned and all additions of new member states to the trial must be concluded, prior to applying for any substantial modifications. There may be a larger degree of flexibility concerning modifications to Part II of the trial application, which only concerns the individual member state. You can find more details in the EU Commissions questions-and-answers, section 3.
- How to handle documents with a signature in the CTIS?
Please note that, in accordance with Regulation (EU) No 536/2014, all data and documents provided in the EU database are subject to publication rules , aiming amongst other things at protecting personal data and commercially confidential information. It is the responsibility of each user to ensure compliance with Regulation (EU) 2016/679 and Regulation (EU) 2018/1725 when uploading documents and processing personal data in CTIS.
In general inclusion of personal data should be minimized, and personal data in the document version ‘for publication’ must be anonymised, with exception of personal data of principal investigators at the clinical site, head of the facilities signing the state of compliance of the facility or contact details of a sponsor legal rep.
Should some documents (for example QP declaration) need to have a signature please use the functionality to upload a version of the document “not for publication” in addition to the “for publication” version, where personal information should be redacted.
- How can I see the timelines for the evaluation of applications in the CTIS?
In the CTIS, there is a 'Timetable' section for each application (both initial and substantial modifications). The timetable is generated automatically upon registration of the application and takes national holidays and weekends into account for all member states concerned. The timetable is also dynamic and some tasks are projected but can change depending on when other tasks are completed. You can read more about the timelines for applications in the EMA CTIS Evaluation Timelines publication.
Updated on 03 October 2023 - Added question regarding the content of trial protocols with a link to the Danish Medicines Agency's protocol template to ensure compliance with the EU regulation and applicable ICH guidelines.