Introduction
What are the main changes under the CTR?
What are the benefits of the CTIS?
To which clinical trials will the CTR apply?
What about ongoing clinical trials?
Does the CTIS pose risks in regard to data protection?
What is the interplay between the CTR and the GDPR?
What is the situation regarding informed consent in cluster trials under the CTR?
What is the new registration process for multinational trials?
What are the new safety reporting obligations?
What do sponsors need to do?
The EU Clinical Trials Regulation (CTR)(1) entered into force in 2014. Once it becomes applicable, it will repeal the existing EU Clinical Trials Directive(2) and replace the system of nationally diverging rules for the assessment and conduct of clinical trials on medicinal products for human use with a regime that is largely harmonised across the European Union.
However, the CTR will become applicable only six months after the European Medicines Agency (EMA) has confirmed that the EU clinical trial portal and database – one of the main deliverables of the CTR and the key component of the clinical trial information system (CTIS) – is fully functional.
The live date of the CTIS has been postponed several times between 2015 and 2020 due to technical issues. Finally, earlier in 2021, the EMA published a statement which said that its management board was able to confirm that the CTIS met the agreed requirements. Subsequently, on 31 July 2021, the European Commission published a notice in the Official Journal of the European Union confirming that all of the requirements set out in the CTR were met by the current system.
Therefore, the CTIS is finally going to be accessible to all users on 31 January 2022, resulting in the applicability of the CTR starting that day. With the CTIS finally going live and the CTR becoming applicable, this article looks at the key changes and main questions in terms of the CTR to keep in mind.
What are the main changes under the CTR?
The CTR is designed to increase efficiency in the registration, conduct and supervision of clinical trials in the European Union and especially to facilitate the processes relating to cross-border trials. The CTR shall strengthen the international competitiveness of the European Union as the CTIS will be the single EU entry point for clinical trial applications – applications for each EU member state participating in a trial are no longer necessary. It further helps EU member states to cooperate more easily and avoid duplication of trials, and grants greater transparency in respect to the trials and their results by making information publicly available.
The above objectives are mainly implemented through the following changes:
- transparency by publication of clinical trial results and related information;
- establishment of EU portal and database;
- new registration processes regarding multi-jurisdictional trials;
- informed consent in cluster trials; and
- detailed safety reporting obligations.
What are the benefits of the CTIS?
The CTIS will function as a single entry point – that is, there will be only one EU portal responsible for clinical trial applications in the European Union. Trial sponsors are therefore required to submit only one application for each trial, instead of an application for each involved EU member state as was the case previously. It is expected to lead to a significant administrative relief.
The CTIS will also function as a database in which all EU trial sponsors will enter their study details.
This centralisation offers better opportunities for trial sponsors and other stakeholders from different EU member states to collaborate and share their outcomes. The system itself will provide for different tools to facilitate the supervision and monitoring of trials. Another aspect is the assumed facilitation of reaching out to potential trial participants by easily connecting to other EU member states' pools.
To which clinical trials will the CTR apply?
The CTR will apply to all clinical trials that are conducted within the European Union. Article 2 of the CTR provides for a new, more detailed definition of a "clinical trial". The European Commission's recently published Q&A document provides a decision tree, which will help sponsors to assess whether a trial intended to be conducted constitutes a "clinical trial" in the meaning of the CTR.
What about ongoing clinical trials?
Within three years of the CTR's application date, all ongoing trials must be converted to comply with the CTR. This means that sponsors of ongoing trials must switch the underlying framework of their trials from the EU Clinical Trials Directive to the CTR within three years of 31 January 2022.
Sponsors have the option to commence a trial under the old system (ie, following the provisions of the EU Clinical Trials Directive) during the first year of the CTR's application (ie, until 31 January 2023).
The above transitional provisions do not apply to interventional trials that commenced before the application of the EU Clinical Trials Directive – those will have to obtain a CTR authorisation as soon as the CTR applies.
Does the CTIS pose risks in regard to data protection?
Although one of the main objectives of the CTR is to provide transparency concerning clinical trial data, information published within the CTIS does not include data under privacy protection – specifically, personal data. The CTR also allows the exclusion of commercially confidential data and communications or unapproved data, which is why the CTIS is considered unproblematic in this regard.
What is the interplay between the CTR and the GDPR?
As the execution of clinical trials naturally involves large amounts of sensitive personal data, it is important to ensure compliance with all relevant provisions. As references in both frameworks show, the regulations apply simultaneously, which is why sponsors must be aware of critical data protection requirements, such as the obligations of the sponsor being a data controller under article 24 of the EU General Data Protection Regulation (GDPR) or handling data in order for it to be processed while preserving its confidentiality and protection (eg, in article 56 of the CTR).
Research activities carried out within clinical trials may also constitute public interest or legitimate interest under the terms of article 6 of the GDPR under certain circumstances.
It is especially important to note that consent under the CTR is not to be confused with consent concerning the processing of personal data under the GDPR. The same applies to consent withdrawal.
What is the situation regarding informed consent in cluster trials under the CTR?
Regarding "cluster trials" (ie, trials in which patient groups instead of individual patients are randomised), the CTR has simplified the means for obtaining a patient's informed consent. This simplification, as per article 30 of the CTR, applies provided the special requirements set out in the same article are met. Under strict prerequisites, informed consent to cluster trials can even be deemed to have been obtained.
What is the new registration process for multinational trials?
Under the CTR, trial sponsors can submit a combined application for all concretely involved EU member states. The application itself will be divided into two parts, with the first part being assessed jointly by all involved EU member states and reported by one of them – the selected reporting EU member state. The second part will be assessed individually by each involved EU member state. It is hoped that this new system will save time and resources EU-wide.
What are the new safety reporting obligations?
The CTR has streamlined safety reporting. It differentiates between and defines:
- adverse events;
- serious adverse events;
- adverse reactions;
- serious adverse reactions; and
- unexpected serious adverse reactions.
Suspected serious adverse reactions shall be assessed using the so-called "reference safety information", which must present the nature and frequency of the suspected reaction in a table format. This shall facilitate the handling of information and EU-wide cooperation.
Sponsors planning to commence a clinical trial after 31 January 2022 must consider whether they will submit their application under the old framework or the new one. Decisive aspects may be the obligation to publish data within the CTR's CTIS (ie, assessing potential commercially confidential data) or their preparedness to comply with the new safety reporting obligations.
Sponsors of ongoing trials must prepare for switching legal frameworks – specifically, by ensuring timely implementation of the CTR's requirements and identifying and providing data to be inserted in the CTIS. Also, it should be noted that the CTR authorisation process may take up to 60 days and must be completed by the end of the transition period (three years from the CTR's application date).
For further information on this topic please contact Magdalena Kotyrba-Hagenmaier or Tobias Maier at Eversheds Sutherland LLP by telephone (+49 89 54565 0) or email ([email protected] or [email protected]). The Eversheds Sutherland LLP website can be accessed at www.eversheds-sutherland.com.
Endnotes
(1) Regulation on clinical trials on medicinal products for human use (536/2014/EU).
(2) Directive on the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use (2001/20/EC).