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How to manage transitional clinical trials to the new European online portal, CTIS

The European clinical trial regulation establishes a three-year transition period in order to adapt to the new clinical studies’ online portal. In this article you will learn how to manage the transitions of your studies. It is essential that the sponsors and the CROs actively collaborate with each other in the transition strategy regarding CTIS, according to the different phases over the next three years
By Lidya Domínguez
Clinical Research Director at Sermes CRO. Member of the CTIS work Group organized by EMA since 2017

CTIS go-live in January 2022 opens the three-year transition period. It is time enough to adapt to the new framework regarding the clinical trials documentation management in Europe, but there are several issues to be considered.

After the implementation of the platform, that shall take place on January 31^st, 2022, the only ones obligated to begin using CTIS starting from the very first minute shall be the Member States. It should be taken into consideration that it is up to each Member State involved to determine which agencies must participate in the assessment of the application to conduct a clinical trial. Member States must also articulate the participation of the ethics committees within the authorization deadlines of clinical studies as established in the Regulation. Meaning we could say that the Member State is the entity that shall issue the joint assessment/authorization of the Regulatory Agency and Ethics Committee.

Three-year transition period for the sponsors

Sponsors will have a transition period of 3 years. Thus, the CTIS can be implemented in our organizations gradually during this transition period, so that the impact on the operations of sponsors and CROs can be distributed throughout this time.

Logically, this means that during the transition period, CTIS and EudraCT shall run in parallel, both being valid options when it comes to managing documentation and the submission of clinical trials in countries of the European Union, but we should consider other aspects such as:

During the first year (starting 31/01/2022 until 31/01/2022), the request for new clinical trials can be made either through CTD as well as through CTR. The clinical trials that have been authorized under the CTD may continue under the CTD until the end of the 3-year transition period.
For the ongoing clinical trials, the request for the transition of CTD to CTR shall be submitted well in advance in order to carry out a complete assessment before the end of the transition period, considering that in order to carry out the transition we must consider the study’s completion in all of the Member States as the end date. Meaning that, considering that the end of the transition period is on January 31^st 2025, it is necessary to migrate the studies early enough in advance in order to carry out a complete assessment. Our recommendation is a minimum of 4-6 months, so that the Member States can issue clarifications (RFI).

Ultimately, if we have to submit a new study for it to be assessed, starting from 31/01/2022 and its end date in all Member States is after 31/01/2025, our recommendation is to submit it directly under the CTR, thus via CTIS. In this manner, we shall avoid following migrations and new assessments and workload. Furthermore, a migration strategy must be considered for all ongoing studies that conclude beyond the transition period in all Member States.

When does a clinical study change from CTD to CTR, meaning to CTIS?

But what conditions should there be in order to change the regulatory framework governing a clinical study? Meaning, when to change from CTD to CTR?

We must consider two premises:

Trials that currently aren’t subject to any ongoing assessment process under the Directive in none of the countries of the European Union.
Trials with a harmonized protocol in all the Member States.

In order not to suffer any unwanted delays, we must consider that, if premise number 2 is not met, a substantial amendment must be submitted to all Member States under the current directive (CTD), to harmonize the protocol and assure its compliance under the new Regulation (CTR). As always, the responsibility regarding the compliance under the CTIS, therefore, within the CTR parameters, falls upon the clinical study’s sponsor.

How should we make the clinical study migration request to CTIS?

We still need to wait for the announcement of the module by EMA regarding clinical studies transition. Meanwhile, we can state that regarding the application submissions for the Clinical Studies transition to CTIS, we must submit an initial application through the online portal, under Article 5 of the CTR. This application must be based on the last authorized version of the dossier under the CTD.

These are the documents that we shall need:

Part I documents:

Cover letter
The last version of the protocol, authorized by the Member State(s); this version must be harmonized in the case that it concerns several Member States.
Investigator’s Brochure.
IMPR (Investigational Medical Product Dossier), along with its GMPs, as well as the relevant documents concerning auxiliary medications, such as they have been submitted for assessment in the context of the initial application (if applicable).
Labelling

Part II documents:

Patient information sheet and informed consent.
Document regarding the procedures and recruitment material, facilities suitability, Principal Investigator’s suitability, meaning, all the documents listed in Annex I of the Regulation, as authorized in the context of the initial application under the current Management.

In the case that the sponsor cannot provide certain documents listed in Annex I of the Regulation, not required under the Management, the sponsor must upload a blank document to the CTIS.

Once we have completed the initial application, the migrated trial shall be evaluated by the Member States:

Selection of the Notifying Member State (Multi-phase Studies).
Validation of the clinical study Dossier.
Evaluation of Part I and Part II.

Once we have the study authorized in CTIS, the sponsor can include the start date of the recruitment of each Member State. When the recruitment start date is prior to the authorization of the study, it shall only be possible to include it as such in migrated studies. Thus, once the trial is authorized, the information shall be made public according to the transparency rules, unless the publishing rules have been deferred in CTIS. Henceforth, the rules to be followed in these trials shall be in full implementation to the regulation and the information/documentation must be updated onto the online portal according to this regulation.

Some advice to conduct Clinical Studies in Europe…

In view of the above, it is essential that sponsors and CROs actively collaborate with each other in the transition strategy regarding CTIS, considering the different phases over the next three transitional years that the regulation establishes in order to adapt to it.

Here are some examples:

If we have 200 ongoing clinical studies that are expected to continue beyond January 2025, we shall need to migrate all their documentation to CTIS, along with a new assessment of the record in all the Member States. It is important to consider that the study protocol must be harmonized in all the countries of the EU and if that is not so, it must be harmonized under the assessment of a substantial amendment in each Member State.
On the other hand, if we plan on submitting a new clinical trial in 2022, that is expected to continue beyond 2024, our recommendation is to submit it through CTIS from the very first moment. In this manner, we shall avoid following migrations, that could result in being complex and expensive.

We should consider that everything will be newly evaluated in CTIS, so that the deployment of resources and the structural impact that we could need in a large pharmaceutical company could be very large. How does this affect our SOPs? How does this affect our job descriptions? Which business model should we choose: centralized or decentralized? How can we manage the roles system? And the needed translations? How many resources do we need to address the change? Shall we outsource it to a CRO or shall we manage it at home? Many are the questions that we must make and the time to answer them is, without a doubt, now.