Register clinical trials in CTIS

Introduction

According to the EU-regulation 536/2014, a clinical trial refers to an investigation in relation to humans intended to, for example, discover or verify the clinical, pharmacological or pharmacodynamic effects of a medicinal product as well as ascertaining its safety and efficacy.

From the 31 January 2023, all new clinical trials must be registered in the European web portal CTIS. CTIS is replacing the old web portal EudraCT. Compared to the previous procedure for clinical trials applications, everything regarding the clinical trial is now managed in one system. One single clinical trial application is submitted in CTIS, where Läkemedelsverket and Etikprövningsmyndigheten will have access to the application. These regulatory authorities will review the application and provide feedback and decisions to the applicant directly in the CTIS portal.

Karolinska Institutet (KI) uses an ”organization-centric approach” in CTIS, meaning that we at Compliance & Data Office (CDO) have an administrator account where we have an overview of all clinical trials registered through CTIS with KI as sponsor. We can also manage KI-users’ user roles in the system.

Create an account in CTIS

1. In order to log in to CTIS you first need to create an account with the European Medicines Agency (EMA). You can create an EMA account on their webpage.
2. After you create your EMA account, you can log in to CTIS.
3. Once in CTIS, you need to double-check that Karolinska Institutet is listed as your Employer. You do so by clicking on your name in the upper right corner and choose ”Personal profile”. Under ”My employer” it should say ”Karolinska Institute” and the address should be either ”Nobels vag 6, Solna” or ” Alfred Nobels Alle 8, Huddinge”.

Register a new clinical trial

To initiate a new clinical trial application, you need an EUCT-number (study number). Please contact compliance@ki.se in order to get the EUCT-number and in the email please provide us with:

• Name of Principal Investigator
• EMA username of Principal Investigator
• Email address to Principal Investigator (should be the same email that’s used for the EMA-account)
• Exact title of the clinical trial

Please also answer the questions below:

• Is the Head of Department/Head of administration informed?
• Are more countries than Sweden included in the trial?
• Which region(s) in Sweden are included in the trial?
• Will samples be taken within the trial? If yes, in which biobank will these be registered?

We at CDO will create a blank application for you and assign you the roles ”CT Admin for a specific trial” and ”ASR Submitter”. After this, you will get access to your application and the trial's EUCT-number, and you can then begin working on your application in the system.

If more than one person needs access to the same trial, the PI can provide access for the other researchers by assigning roles to the specific trial.

Application process

A clinical trial application in CTIS consists of two parts:

• Part I contains study specific information (the same for the entire EU in case the study is a multinational study), e.g. study protocol and information about the investigational medicinal product. Part I can be written in English or Swedish. However, the protocol and patient-related information should be in Swedish.
• Part II contains national information, e.g. trial site, recruitment arrangements, informed consent form and suitability of investigator. Part II should be written in Swedish.

More information on how to apply for a clinical trial in CTIS can be found on Läkemedelsverket’s webpage. There, you also find Swedish templates for Part II.

Once the application has been submitted, Läkemedelsverket and Etikprövningsmyndigheten will review the application in parallel. The decision will then be provided within the CTIS portal. During the review process, Läkemedelsverket and Etikprövningsmyndigheten can send so called RFI’s (Request For Information) to the PI if adjustments are needed for the application. Please note that no email notifications are sent out, so you as a PI need to log in to CTIS on a regular basis in order to take part of the decisions and notifications!

Timeline

The application review can take up to 60 days. However, including potential RFI’s the process might be extended to a total of 106 days. For each RFI, you as a submitter have up to 10–12 days to reply. If you don’t reply before the deadline, the application will lapse and you will then need to submit a new application. If you suspect that you won’t be able to meet the deadline of the RFI or the application requires substantial adjustments, it might be beneficial to withdraw your application and resubmitting at a later timepoint instead of risking the application to lapse or be rejected.

EMA has created a guide about timelines in CTIS where you will find more details around different deadlines.

Maintaining updates

Once the application is approved, it is important to regularly update the information about your trial in CTIS, e.g., report recruitment start date and study start. This should be reported within 15 days from the recruitment/study start has occurred. In CTIS, this is reported under the tab ”Notifications”.

In case any major changes are made to the protocol or any unexpected events occur during the course of the study, this should be reported as a ”substantial modification” or a ”non-substantial modification”. Modifications should be reported within 15 days in case of an unexpected event and 7 days for an urgent safety measure or a serious breach. See EudraLex Volume 10 chapter 5 (the Q&A document about the Regulation) for examples.

As long as the trial is ongoing, the PI must upload an Annual Safety Report (ASR) in CTIS. Unfortunately, the ASR function in CTIS doesn’t allow you to save and continue later, so please make sure to have all documentation ready at hand when submitting the ASR.  The ASR document should be in PDF format.

Reporting of results

According to the EU-regulation 536/2014 the sponsor should, regardless of the outcome of the trial (negative or positive results), report a summary of the trial results within 1 year after study completion (6 months if it is a pediatric trial). In Annex IV of the regulation you will find a description of what should be included in this summary. You should also include a layperson summary. The content of that summary is set out in Annex V of the EU-regulation.

Even if the results have already been published in a scientific journal, results must still be reported in CTIS.

If KI acts as a “participating research principal” (“medverkande forskningshuvudman”)

In ethical applications via Ethix, KI can be added as a “participating research principal” (medverkande forskningshuvudman). This term does not exist in CTIS, which means that there is no clear section to add KI as a participating research principal. However, for KI to be able to process personal data within the framework of research for a clinical trial, KI’s role in the trial needs to be clearly stated in the CTIS application. It is therefore required that KI is mentioned in the following sections in CTIS:

• Participant information sheet and informed consent form (i.e. information is added that data will be stored and analyzed at KI).
• Clinical trial protocol, for example in the sections "Handling, storage, and destruction of biological samples" (if biological samples are used) and in "Collection, handling, and archiving of data".

KI should only be added as "co-sponsor" in CTIS if KI actually has the role of a co-sponsor.

Clinical trials that include biobank samples

A clinical trial that includes biobank samples requires an approved biobank application. A biobank application is submitted separately to the Regional Biobank Centre (Regionalt biobankscentrum) on the same day as the CTIS application is submitted. The biobank application will be reviewed in parallel to the clinical trial application but cannot be approved until the clinical trial application has been approved. At Biobank Sverige’s webpage you will find more information on clinical trials with biobank samples. Biobank applications are sent to kliniskaprovningar@biobanksverige.se.

Register new investigational medicinal product in EudraVigilance/XEVMPD

Investigational medicinal products used in clinical trials must be registered in EudraVigilance/XEVMPD. Radiofarmaci at Karolinska University Hospital helps researchers at KI to register substances and products. If you need to get an investigational medicinal product registered for your KI trial, contact us at compliance@ki.se and we will help you further.

Transitional trials

PI:s with ongoing trials already registered in EudraCT and where the trial is expected to be completed after 31 January 2025 need to transfer these trials to CTIS. These trials must be submitted to CTIS by the 31 August 2024 the latest to ensure sufficient processing time, otherwise you risk having to register the trial as a completely new clinical trial application. Unfortunately, there is no simple function that auto-populates structured data from EudraCT into CTIS, this needs to be entered manually. However, EMA has agreed on an exception from some of the documents that are mandatory in the regulation but weren’t mandatory in the directive. If you have clinical trials that need to be transferred, please reach out to compliance@ki.se and we can help you get started.

The Medical Products Agency has decided to consider a transitional trial as a new application, which therefore requires a new application fee. If the application, however, is identical to a previously approved application (submitted via EudraCT), you could apply for a reduction of the fee.

For information on which documents in CTIS that are reviewed by Etikprövningsmyndigheten, please visit Etikprövningsmyndigheten's webpage on CTR.

Trials that have an ongoing application or amendment in EudraCT cannot be transferred to CTIS until the review of the application/amendment is completed.

Clinical trials funded by the Swedish Research Council (Vetenskapsrådet)

The Swedish Research Council (Vetenskapsrådet) has new guidelines from 2022 stating that all clinical studies/trials funded by the Swedish Research Council must be registered in a public clinical trial registry.

It is Karolinska Institutet’s responsibility to make sure that the PI of the study registers and continuously updates it. Relevant researchers will therefore be contacted by CDO with information and guidance.

Read more on the Swedish Research Council’s webpage.