Elements of the CTR

The EU Clinical Trials Regulation will repeal the existing EU Clinical Trials Directive (EC) No. 2001/20/EC and national legislation put in place to implement the Directive when it goes into effect on January 31, 2022. Trials already in progress on this date will also fall under this regulation if they are still ongoing three years after the moment of applicability.

The purpose of the new regulation includes:

Creating an environment that is favorable to the conduct of clinical trials in the EU
Harmonization of the approval process for clinical trials
Ensuring close coordination between Member States and supporting the conduct of multi-country trials
Ensuring the production of reliable and robust, high-level scientific data while ensuring patient safety
Increasing transparency of clinical trial data to patients and experts

The purpose of the new regulation includes:

Creating an environment that is favorable to the conduct of clinical trials in the EU
Harmonization of the approval process for clinical trials
Ensuring close coordination between Member States and supporting the conduct of multi-country trials
Ensuring the production of reliable and robust, high-level scientific data while ensuring patient safety
Increasing transparency of clinical trial data to patients and experts

Differences between the EU Clinical Trials Directive & EU Clinical Trials Regulation

Clinical Trials Directive 2001/20/EC	Clinical Trials Regulation (EU) No 536/2014
Transposed into national legislation	Binding in its entirety and directly applicable in all Member States
Supporting EC guidance on: Application dossier Safety reporting Labeling	Annexes to the Regulation: Application dossier Safety reporting Labeling
Interventional clinical trials	Interventional clinical trials Clarity of definitions, new terminology
No risk differentiation	Risk-based approach (Concept of low‐intervention clinical trial)
Multiple submissions (different dossiers, no IT collaboration tool, mainly paper)	Centralized single submission (Clinical Trials Information System)
National Competent Authority approval & Ethics Committee positive opinion	Member State authorization (including tacit approval)
Single sponsor only	Concept of co-sponsor
Limited transparency provisions	Increased transparency (trial progress, results)
No review clause (no change in 20 years)	Review clause – every five years

New & Updated Definitions

Auxiliary medicinal product (AMP):

A medicinal product used for the needs of a clinical trial as described in the protocol, but not an Investigational Medicinal Product; AMPs can be authorized (Authorized AMP) or unauthorized

Clinical study:

Any investigation in relation to humans with the objective of ascertaining the safety or efficacy of medicinal products

Clinical trial:

Any investigation where any of the following applies:

Assignment to the therapeutic strategy is decided in advance and not within normal clinical practice in Concerned Member State(s)
The decision to prescribe is simultaneous with the decision to include the subject in the trial
Diagnostic/monitoring procedures additional to normal clinical practice are applied

Start of the CT: The first act of recruitment of a potential subject for a specific CT, unless defined differently in the protocol

End of the CT: The last visit of the last subject or at a later point in time, as defined in the protocol

Co-sponsorship:

Where two or more parties (co-sponsors) share responsibility for the trial. Responsibilities can be divided via a written contract or (in case of no contract) lie jointly with all sponsors. Co-sponsors must establish:

A responsible party for compliance with the authorization procedures
A contact point for receiving and answering all questions from subjects, investigators, or Member States concerned
A responsible party for the implementation of corrective measures

Legal representative (EU):

A natural or legal person that is established in the European Union which acts as a legal representative for a sponsor not established in the EU

Ensures compliance with the sponsor's obligations, including responsibility for the initiation and management and for setting up the financing of a clinical trial (but not including civil or criminal liability)
Serves as the addressee for all communications with the sponsor
Member States may choose to accept only a contact person for clinical trials conducted solely on their territory
In case of multinational trials, all Member States must accept a contact person; if not, a legal representative needs to be established

Legally designated representative (LDR):

A natural or legal person, authority, or body which, according to the Concerned Member State law, is empowered to give informed consent on behalf of the subject who is incapacitated or minor

Low-intervention clinical trial (LICT):

Fulfills all of the following:

The IMPs are authorized (excluding placebo)
According to the protocol:
- The IMP is used in accordance with the MA, or
- The IMP use is evidence-based and supported by sufficient published scientific evidence
Trial procedures do not pose more than additional minimal risk or burden compared to normal clinical practice in the Member State(s)

Substantial modification:

A change to any aspect of the clinical trial which is made after notification of a decision as referred to Art. 8, 14, 19, 20, or 23 and is likely to have an impact on the safety or right of the subjects or the reliability and robustness of the data generated in the clinical trial