Brief Introduction to the CT Regulation

Several years after enactment, the Regulation EU/536/2014 (CT Regulation) governing clinical trials with medicinal products in the EU eventually became applicable on 31 January 2022. After a certain transition period, the CT Regulation will fully replace the former Clinical Trials Directive (2001/20/EC) (“CT Directive”) and the implementing laws of the EU member states. The CT Regulation aims to create a harmonized regulatory environment favourable for conducting clinical trials in the EU. To help achieve this goal, the CT Regulation clarifies the definition of “clinical trial”. Clinical trials conducted in the EU are now a type of “clinical studies” – a new concept introduced with the CT Regulation.

Clinical studies

A “clinical study” means any investigation in relation to humans intended (Article 2(2)(1) CT Regulation):

• to discover or verify the clinical, pharmacological or other pharmacodynamic effects of one or more medicinal products;

• to identify any adverse reactions to one or more medicinal products; or

• to study the absorption, distribution, metabolism and excretion of one or more medicinal products.

The objective of a clinical study is in any of these cases to ascertain the safety and/or efficacy of the medicinal products under investigation.

Clinical studies are now divided into:

• Clinical trials; and

• Non-interventional studies, which include all clinical studies that are not clinical trials (Article 2(2)(4) CT Regulation).

Non-interventional studies are considered to have the lowest risk among all clinical studies and, as already happened with the CT Directive, they are outside the scope of the CT Regulation and are therefore governed by the national laws of each EU Member State (Article 1 CT Regulation).

The dichotomy of interventional v. non-interventional studies that underlie the EU law on medicinal products is kept in the CT Regulation with this new distinction between clinical trials (also known as interventional studies) and non-interventional studies.

Clinical trials

A “clinical trial” is defined as a clinical study that fulfils any of the following conditions (Article 2(2)(2) CT Regulation):

• the assignment of the subject to a particular therapeutic strategy is decided in advance and does not fall within the normal clinical practice of the EU Member State concerned;

• the decision to prescribe the investigational medicinal products is taken together with the decision to include the subject in the clinical study; or

• diagnostic or monitoring procedures in addition to normal clinical practice are applied to the subjects.

Normal clinical practice is defined in the Clinical Trials Regulation as “the treatment regime typically followed to treat, prevent, or diagnose a disease or a disorder” (Article 2(2)(6) CT Regulation).

Therapeutic strategies that fall outside “normal clinical practice” include, for example, the administration of a medicinal product without a marketing authorisation in the EEA, the administration of a medicinal product in healthy volunteers or in patients without clinical indication or medical need, or the performance of additional diagnostic or monitoring procedures solely for the purposes of the clinical study (for other examples please refer to Question 1.9 on the Q&A Document - Regulation (EU) 536/2014, Version 6 of April 2022).

The off-label use of a medicinal product with a marketing authorisation in the EEA might be considered as “normal clinical practice” in case of established off-label use in a certain EU Member State, opening the possibility of sponsors investigating such off-label use in non-interventional studies. It is however up to each EU Member State to determine if the established off-label use can be considered within their normal clinical practice (cf. Question 1.9 on the same Q&A Document).

Low-intervention clinical trials

The new concept of “low-intervention clinical trial” is one of the most significant changes brought by the new CT Regulation. These are clinical trials that fulfil all of the following conditions (Article 2(2)(3) CT Regulation):

• the investigational medicinal products, excluding placebos, are authorised;

• according to the protocol of the clinical trial,

  • the investigational medicinal products are used in accordance with the terms of the marketing authorisation; or

  • their use is evidence-based and supported by published scientific evidence on the safety and efficacy of those investigational medicinal products in any of the EU Member States concerned; and

• the additional diagnostic or monitoring procedures do not pose more than minimal additional risk or burden to the safety of the subjects compared to normal clinical practice in any EU Member State concerned.

The “published scientific evidence” may include, for example, high-quality data published in scientific journal articles, national, regional or institutional treatment protocols and health technology assessment reports.

Low-intervention clinical trials are subject to the same application procedure as any other clinical trial. Sponsors shall include in the application dossier a detailed justification as to why the clinical trial is a low-intervention clinical trial (Article 25(1)(e) CT Regulation). There is no overall “simplified” or “accelerated” authorisation procedure provided for low-intervention clinical trials. However, they are subject to less stringent rules as regards:

• Monitoring (Article 48 CT Regulation): the extent and nature of the sponsor’s monitoring of the conduct of the clinical trial shall take into consideration, among others aspects, whether the clinical trial is a low-intervention clinical trial.

• Traceability (Article 51 CT Regulation): investigational medicinal products shall be stored, returned and/or destroyed as appropriate and proportionate, particularly taking into account whether they are authorised investigational medicinal products and whether the clinical trial is a low-intervention clinical trial.

• Master file (Article 57 CT Regulation): the content of the clinical trial master file shall take into account whether the clinical trial is a low-intervention clinical trial.

For cluster trials conducted exclusively in one EU Member State, qualified as low-intervention clinical trials (with the investigational medicinal product being used in accordance with the terms of the marketing authorisation) and fulfilling the requirements of Article 30, the subjects informed consent may be obtained by simplified means.

As regards damage compensation, if any possible damage that could be suffered by a subject resulting from the use of the investigational medicinal product in the context of a low-intervention clinical trial is covered by the applicable compensation system already in place, no additional compensation systems (e.g., insurance, guarantee) as provided under Article 76(1) of the CT Regulation will be required from the sponsor.

The Q&A Document - Regulation (EU) 536/2014, Version 6 of April 2022 includes in Annex I a decision tree to assist sponsors in determining whether a study is a “clinical trial” and a “low-intervention clinical trial”.

Please do not hesitate to contact our team should you have any questions concerning the new Clinical Trials Regulation.

Authored by Fabien Roy and Cláudia Mendes Pinto.