Clinical Trial Information System (CTIS) is a new platform for monitoring and assessing the process of clinical trials throughout the EU. CTIS contains a centralized EU portal and database for clinical trials. In addition to the European Databank on Medical Devices (Eudamed) and SPOR, CTIS is one of the large steps toward digitalization and harmonization for EMA and European Commission. CTIS will be available in January 2022, over 7 years after the functional specifications of the system were endorsed by EMA Management Board and almost 4 years later than originally scheduled.

Challenges aside, this will move the clinical trials towards simplification and digitalization in the EU. Below, we take a look at some key points about the new platform and legislation behind it.

Legislative updates

The Clinical Trials Regulation (Regulation (EU) No 536/2014) will become effective on 31 January 2022. The regulation will change how clinical trials are conducted in the EU [i]. The regulation aims to harmonize the assessment and supervision of processes for clinical trials across the EEA. And this should happen thanks to the new platform CTIS.

When the Regulation (EU) No 536/2014 becomes effective, it will repeal the existing EU Clinical Trials Directive (EC) No. 2001/20/EC and any national legislation that was put in place to implement the Directive [ii]. The new regulation will also apply to any trials authorized under the previous legislation if these are still ongoing three years after the Regulation will have come into operation.

The Member States will remain responsible for the authorization and oversight of clinical trials conducted in the country. EMA is responsible for the management of CTIS and for the supervision of the content publication on the public website. Sponsors will send their clinical trials applications through CTIS (and follow the Regulation’s other steps.)

Centralization and Harmonization

The basic ideas behind CTIS are familiar to anyone who has worked with any platform. Currently, sponsors must submit clinical trial applications (CTA) separately to national competent authorities (NCA) and ethics committees in each country to get regulatory approval to run a clinical trial (CT) [iii]. With CTIS, sponsors can apply for CTA (e-dossier) in all EEA countries with a single application. Thanks to CTIS, the sponsor and the authorities can collaborate on the maintenance of the application and trial information in one place.

The platform should also help with the different timelines applicable to different authorities. There is no need for a separate registration and submission of information to a public register of clinical trials (more on EudraCT below.)

The CTIS will also, together with other EMA IT tools (SPOR), support the coordinated assessment of safety reporting during clinical trials. This should build a better understanding of the benefits and the risks of medicinal products earlier and more comprehensively than with the current segregated systems.

Additional Transparency

The new clinical trial regulation makes all the information of CTIS database publicly accessible with a few exemptions [iv]. The public website for clinical trials should look similar to the adrreports.eu website for EudraVigilance (all the way down to the Oracle dashboard).

Sponsors have been obliged to publish the results of trials in EudraCT since 2014[v], but the sponsors have not been adding the results to EudraCT. In 2018, the launch of the EU Trials Tracker revealed large and widespread gaps in reporting. Currently, only 75.9 % of trial results that are due to be reported have been made available by the sponsors.

The usage of CTIS aims to enhance the compatibility and oversight in different stages of clinical trial research allowing to streamline the whole process from submission of application to authorisation.

According to Regulation (EU) No 536/2014, the summary of the results of the clinical trial for laypersons shall contain information on the following elements:

1. Clinical trial identification (including title of the trial, protocol number, EU trial number and other identifiers)
2. Name and contact details of the sponsor
3. General information about the clinical trial (including where and when the trial was conducted, the main objectives of the trial and an explanation of the reasons for conducting it)
4. Population of subjects (including information on the number of subjects included in the trial in the Member State concerned, in the Union and in third countries; age group breakdown and gender breakdown; inclusion and exclusion criteria)
5. Investigational medicinal products used
6. Description of adverse reactions and their frequency
7. Overall results of the clinical trial
8. Comments on the outcome of the clinical trial
9. Indication if follow up clinical trials are foreseen
10. Indication where additional information could be found

EudraCT vs CTIS

The current European trial registry EudraCT has been in operation since 2004. It has not been a complete success, to put it mildly. Despite significant efforts from individual authorities, around 5.900 clinical trials were missing results on EudraCT in mid-2020.

It has been suspected that, at least partially, the reason for the poor sponsor compliance has been the inadequate technical design of EudraCT[vi]. For example, in EudraCT, it is difficult to investigate the sponsor’s portfolio including sponsor’s institutional information because the organization name is a free text field. Also, the forms are missing data validation, so it is possible to, say, save the trial information with a completion date but leave the status as “ongoing”. EudraCT also lacked integrated automated reminder functions to submit clinical trial result in time.

In CTIS, the organization information is handled with Organisation Management Service (OMS). CTIS has clear and comprehensive trial status categories which can aid “Closing out” of necessary files, whereas sorting of different category file was impossible in EudraCT system. The system should in general make it easier to manage the workflows related to the trial.

Timeline for CTIS Implementation

CTIS will go live on 31st of January 2022 with a three-year transition period and it will be immediately available. The transition period is intended mainly for those applications and trials that are already ongoing.

The transition period has the following annual goals:

1st year (till 31st January 2023)

• Applicants can submit CTAs either through current system (EudraCT etc.) or CTIS.

2nd year (till 31st January 2024)

• Applicants submit their CTAs through CTIS only.

3rd year (till 31st January 2025)

• All new CTAs must be submitted via CTIS
• All ongoing clinical trial applications through the clinical trial directive system need to be transferred to the new regulation and to CTIS.

More Information about CTIS

EMA has made training resources and documentation available for the sponsors and the authorities [vii]. The agency is delivering an online modular training programme for self-study to help clinical trial sponsors, NCAs, ethics committees, European Commission and EMA staff prepare for using CTIS. Also, the same information is provided in CTIS sponsor handbook.

Conclusion

CTIS has been under development for a long time. There is a lot of material available. The testing and training have been ongoing throughout 2021 and soon we will see how the system works in practice. This will be followed by a lengthy implementation period during which it can be expected that number of updates will happen. Tepsivo will continue writing about this topic when we get to know it better and get our access to the training environment.