The European Commission has announced that the Clinical Trials Regulation (EU) No 536/2014 (Regulation) will take effect from 31 January 2022.
The Regulation repeals the existing regime under the Clinical Trials Directive 2001/20/EC (Directive) and, as a Regulation, will be directly applicable across the EU. It aims to streamline and harmonise rules for the assessment and conduct of clinical trials across the Union.
Below, we look at key aspects of the Regulation.
CTIS - Streamlining the Clinical Trial Process
Although enacted more than seven years ago, the application of the Regulation is dependent on the new Clinical Trials Information System (CTIS), a single clinical trial portal and database, being fully functional. One of the key innovations of the Regulation, its operation has been stymied by technical difficulties. It has proven to be the missing piece of the regulatory puzzle that has delayed the Regulation's application for several years.
However, on 31 July, a Decision of the Commission confirmed the system's functionality. As necessitated by Article 82(3) of the Regulation, this Decision sets a go-live date for the Regulation of 31 January next year.
Functionally, the CTIS will operate as a central portal for EU clinical trials, which will harmonise the submission, assessment, and supervision processes for trials across the Union. This harmonisation will be principally achieved through a single application and authorisation procedure, discussed in further detail below.
The streamlining and digitisation of the clinical trial process has received strong industry support. Indeed, the CTIS effectively pursues the overarching aim of making the EU a more attractive location to conduct clinical trials. Challenges, however, are likely to arise as stakeholders get to grips with the new system. To aid this transition and to prepare stakeholders, the EMA has established a dedicated CTIS training page providing helpful technical guidance on the operation of the system.
What Else is New?
Once implemented, the Regulation will bring about significant changes to how clinical trials are applied for, authorised and ultimately, conducted. These include the following:
- Clinical Trial Definition - The Regulation
clarifies the concept of a clinical trial under EU law by creating
the broader concept of a "clinical study" of which a
"clinical trial" is a sub-category. As a result, the
Regulation does not apply to a "non-interventional"
study, defined as "a clinical study other than a clinical
Further, the Regulation introduces the concept of a "low intervention clinical trial". This is a trial that uses medicinal products that are already the subject of a marketing authorisation (MA) and that are being used in accordance with the MA or in accordance with published scientific evidence on safety and efficacy in any of the member states concerned, and where 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. Such trials are subject to a lighter regulatory regime, particularly concerning safety reporting, traceability, requirements for the contents of the master file, monitoring and insurance requirements.
- Streamlined Application and Authorisation
Procedure - Under Article 5, to apply for authorisation
for a clinical trial, a clinical trial sponsor must submit through
the CTIS portal a single set of application documents to the
competent authority of the member state(s) where it intends to
conduct the trial. Where the application concerns a
multi-jurisdictional trial, the sponsor must propose a single
reporting member state (RMS), whose role is to assess and validate
the single application. This harmonised system is in contrast to
the Directive, which required that a clinical trial application be
submitted separately to each member state .
Similarly, the Regulation also introduces a more streamlined, partially harmonised assessment procedure for a clinical trial, divided into two parts:
- Part I - Involves a scientific assessment of
the core clinical trial documentation (described in detail in
Article 6 of the Regulation). In a multi-jurisdictional
application, this assessment involves three phases and the drawing
up of an assessment report. The RMS carries out the initial review,
followed by a coordinated review by all Member States concerned and
finally the consolidated phase is carried out by the RMS. All of
the review phases must be carried out within specified timelines.
According to Article 8(2), where the conclusion of the RMS as
regards Part I is that the conduct of the clinical trial is
acceptable or acceptable under conditions, that conclusion shall be
considered as the conclusion of all member states concerned subject
to minimal exceptions.
- Part II - Involves an ethical assessment of the country-specific and site-specific documents and is assessed by each member state individually for its territory.
- Part I - Involves a scientific assessment of the core clinical trial documentation (described in detail in Article 6 of the Regulation). In a multi-jurisdictional application, this assessment involves three phases and the drawing up of an assessment report. The RMS carries out the initial review, followed by a coordinated review by all Member States concerned and finally the consolidated phase is carried out by the RMS. All of the review phases must be carried out within specified timelines. According to Article 8(2), where the conclusion of the RMS as regards Part I is that the conduct of the clinical trial is acceptable or acceptable under conditions, that conclusion shall be considered as the conclusion of all member states concerned subject to minimal exceptions.
Following this two-part assessment, each member state concerned will reach a single assessment outcome and notify the sponsor of its decision through the CTIS.
- Transparency Requirements - Under the
Directive regime, limited information on clinical trials was made
publicly available. One of the key aims of the Regulation is to
increase transparency in this area. As such, Article 81(4) of the
Regulation requires all information stored in the CTIS database to
be publicly available unless exempted under the Regulation.
Specifically, this will exclude personal data, commercially
confidential data, confidential communications between member
states and information about clinical trial applications that have
not yet been approved.
The result of these increased transparency obligations in practice, means that any interested party can access the vast majority of data uploaded to the CTIS. This includes, for example:
- a summary of the results of the clinical trial (including a summary for laypersons), submitted within one year of the end of the trial, irrespective of the outcome of the trial;
- conclusions on the assessment of the clinical trial application and decision on the clinical trial (including reasons for refusal);
- where a clinical trial was intended to be used for obtaining an MA, the clinical study report (which should be provided within 30 days after the day the MA was granted, the procedure for granting the MA was completed or the application for the MA was withdrawn); and
- information relating to the clinical trial protocol.
A transition period will follow next year's go-live date. While the use of the CTIS will be mandatory for new clinical trial applications, applicants may still choose whether to submit their application to start a clinical trial under the old system of the Directive or according to the Regulation until 31 January 2023. From this date, submission under the Regulation will be mandatory. Further, by 31 January 2025, all ongoing trials approved under the Directive must transition to the Regulation.
While some comfort may be drawn from this relatively long lead-in period, stakeholders are advised to familiarise themselves with the content of the Regulation and, in particular, the operation of the CTIS in advance of the go-live date.
The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.