An information resource for the EU Clinical Trials Regulation

This post is an attempt to provide an information resource for the Clinical Trials Regulation (EU) no 536/2014 (CTR). The information provided is by no means exhaustive.

Click on the ‘+’ sign next to each heading to access the information under each heading.

This post was last updated on 14 October 2021.

See history of updates at the end of the post.

The goal  is to create an environment that is favourable to conducting clinical trials in the EU, with the highest standards of safety for participants and increased transparency of trial information. The Regulation will require:

  • consistent rules for conducting clinical trials throughout the EU;
  • information on the authorisation, conduct and results of each clinical trial carried out in the EU to be publicly available.

It aims to foster innovation and research, while helping avoid unnecessary duplication of clinical trials or repetition of unsuccessful trials.

The main characteristics of the new CTR are:

  • A streamlined application procedure via a single entry point – an EU portal and database, for all clinical trials conducted in EEA. Registration via the portal will be a prerequisite for the assessment of any application.
  • A single set of documents to be prepared and submitted for the application defined in Annex I of the Regulation.
  • A single authorisation procedure for all clinical trials, allowing a faster and thorough assessment of an application by all Member States concerned and ensuring one single assessment outcome and authorisation per Member State.
  • A harmonised procedure for the assessment of applications for clinical trials, which is divided in two parts:
    • Part I is jointly assessed by all Member States concerned
    • Part II is assessed by each Member State concerned separately;
  • Strictly defined deadlines for the assessment of clinical trial application
  • The involvement of the ethics committees in the assessment procedure in accordance with the national law of the Member state concerned but within the overall timelines defined by the Regulation.
  • Simplified reporting procedures which will spare sponsors from submitting broadly identical information separately to various bodies and different Member States.
  • Clinical trials conducted outside the EU, but referred to in a clinical trial application within the EU, will have to comply with regulatory requirements that are at least equivalent to those applicable in the EU.
  • Strengthened transparency for clinical trials data.
  • A coordination and advisory committee that will serve as a forum for exchanging best practices between Member States.
  • Union controls in Member states and third countries to ensure that clinical trials rules are being properly supervised and enforced.

The expected key benefits of the Regulation include:

  • harmonised electronic submission and assessment process for clinical trials conducted in multiple Member States
  • improved collaboration, information-sharing and decision-making between and within Member States
  • increased transparency of information on clinical trials
  • highest standards of safety for all participants in EU clinical trials.

Although the Clinical Trials Regulation (EU) No 536/2014  entered into force on 16 June 2014, the timing of its application depends on confirmation of full functionality of the Clincial Trials Information System (CTIS) through an independent audit.

On 18 June 2021, EMA’s Management Board welcomed the progress in the development and preparations for ‘go-live’ of the Clinical Trial Information System (CTIS). Following the independent audit reported in April 2021 and the endorsement on full functionality of CTIS by the Board, the publication of the Commission decision is anticipated for 31 July 2021 in the Official Journal of the European Union(OJEU)  and go-live is currently on track for 31 January 2022. The CTR will will become applicable from this date.

As stated above, the commission decision was published in the OJEU on 31 July 2021. On 2 August 2021, the EMA has published further information on the implementation of CTIS.

CTIS will become the single entry point for clinical trial application submission, authorisation and supervision in the EU, and in the European Economic Area (EEA) countries Iceland, Liechtenstein and Norway.

Currently, sponsors must submit clinical trial applications separately to national competent authorities and ethics committees in each country to gain regulatory approval to run a clinical trial.

With CTIS, sponsors will be able to apply for clinical trial authorisation in up to 30 EEA countries with a single application. The Clinical Trials Information System will also, together with other EMA IT tools, support the coordinated assessment of safety reporting in the context of clinical trials and therefore contribute to the understanding of the benefits and the risks of medicinal products that are planned to enter or are already on the market of the Union.

When the Regulation becomes applicable, it will repeal the existing EU Clinical Trials Directive No 2001/20/EC and national legislation that was put in place to implement the Directive. It will also apply to trials authorised under the previous legislation if they are still ongoing three years after the Regulation has come into operation.

The Clinical Trials Regulation (CTR) harmonises the assessment and supervision processes for clinical trials throughout the EU, via a Clinical Trials Information System (CTIS). CTIS will contain the centralised EU portal and database for clinical trials foreseen by the Regulation. The European Medicines Agency (EMA) will set up and maintain CTIS, in collaboration with the Member States and the European Commission.

On 2 August 2021, the EMA confirmed that the go-live date for CTIS is 31 January 2022.

On 7 October 2021, the CTIS Go-live Planning document was published. This CTIS Go-Live Plan provides an overview of the final remaining activities with the aim to address several points including the following:

  • Address the functional and non-functional areas as set out in the CTIS Project Release Plan for golive, which includes working towards fixing the observations of the audit and of user-testing, and delivering priority areas as agreed by the EMA Management Board
  • Prioritise the development of the sponsor workspace, followed by the authorities workspace and the public portal.
CTIS training programme and other resources

The European Medicines Agency (EMA) continues to issue online training modules of the Clinical Trials Information System (CTIS) ahead of its planned launch.

Nineteen training modules are available as detailed in the table below. You can also access YouTube videos on the modules by visiting YouTube and searching for ‘EMA CTIS training modules’.

Introduction to CTIS
Module Title
1Introduction to the Clinical Trial Regulation 536/2014
2High level overview of CTIS workspaces and common system functionalities
Common functionalities for all registered users
ModuleTitle
3User access management
4Support with workload management
7Management of registered users and role matrix
12Data protection in CTIS
Authority workspace
ModuleTitle
6Evaluation of a Clinical Trial application: Selection of reporting member state (RMS) and validation of the clinical trial application
8Evaluation of a Clinical Trial application: assessment and decision making
14Supervise a Clinical Trial: Corrective measures
15Search, view and download a clinical trial and a clinical trial application
16Supervise a clinical trial: Inspection records
17Supervise a clinical trial: Inspection records
Sponsor workspace
Module Title
5Management of a Clinical trial through CTIS
9Search, view and download information on clinical trials and clinical trials applications
10Create, submit and withdraw a clinical trial
11Respond to requests for information received during the evaluation of a clinical trial application
13Clinical study reports submissions
18How to create and submit an annual safety report and respond to related requests for information
19CTIS for SMEs and academia
CTIS sponsor handbook

In July 2021, the EMA published Clinical Trial Information System (CTIS) – Sponsor
Handbook. This is a a compilation of key guidance, technical information, recommendations and references for getting ready for use of CTIS. You can view the handbook here.

The guidance has been developed by the European Medicines Agency (EMA) in collaboration with some representatives of industry stakeholders.

EMA will be updating this CTIS sponsor handbook with further priority topics as needed.

Further information

Here you can find more information on CTIS training and support available.

EMA CTIS webinar of July 2021

A CTIS webinar entitled ‘How sponsor organisations can prepare for CTIS’ was held in July 2021. You can find more information and presentations on this webinar here. The webinar can be viewed here.

Until the Clinical Trials Regulation (CTR) becomes applicable, all clinical trials performed in the European Union are required to be conducted in accordance with the Clinical Trials Directive (CTD). The Directive will be repealed on the day of entry into application of the CTR.

The table below details the relevant information on the applicability of the CTD and the CTR.

DateWhich is applicable, CTD or CTR?
Before 31 Jan 2022The CTD will apply to all Clinical Trials Applications (CTAs) submitted before the entry into application date of the CTR.
Any new CTA can only be submitted under the CTD.
31 Jan 2022This is the date on which the CTR will become applicable.

Once the CTR is applicable, for new CTAs submitted between 31 Jan 2022 and 31 Jan 2023, the sponsor can choose to submit either under the Legal Framework of the CTD or the CTR.
31 Jan 2023From this date, all new CTAs can only be submitted under the CTR.

CTAs approved under the CTD prior to this date can continue to be regulated under the Directive, unless the sponsor decides to transition these ongoing applications to the CTR.
31 Jan 2025On this date, the CTD will stop becoming applicable to all CTAs submitted before or after the entry into application of the CTR.

The three year transition period applies to CTAs regulated by the CTD regardless of whether they were submitted before or after the application of the CTR.  By 31 Jan 2025 all CTA must be regulated under CTR.

The European Commission has released a set of documents that will be applicable to clinical trials once the CTR is implemented.

Regulation, Directive, Guideline etc.What does it concern?Explanatory notes
Detailed commission guideline adopted on 8 December 2017.Good manufacturing practice for investigational medicinal products, pursuant as per Article 63(1) of the CTRIt is complementary to regulation EU 2017/1569 (see below) on the good manufacturing practice for investigational medicinal products, as per Article 63(1) of the CTR.
Commission Directive EU 2017/1572  of 15 September 2017 Good Manufacturing PracticeThe current GMP Directive 2003/94/EC will be repealed by this Directive on the date of entry into application of the CTR).
The Commission Delegated Regulation (EU) 2017/1569 of 23 May 2017Principles and guidelines for good manufacturing practice for investigational medicinal products for human use, and arrangements for inspections.This regulation supplementing the CTR will apply, as a matter of principle, to all clinical trials as of its entry into application.
During the transition period, EU countries may however continue to apply their national law, adopted in order to transpose Directive 2003/94/EC, to those clinical trials conducted under the CT Directive 2001/20/EC.
Implementing Regulation (EU) 2017/556 of 24 March 2017 Detailed arrangements for the good clinical practice inspection procedures pursuant to the CTR.
The Commission’s GCP Directive 2005/28/EC will apply to clinical trials submitted under the Clinical Trials Directive until the end of the transition period, except the provisions in chapters 5 and 6 related to inspectors and inspection procedures which will be covered by this Regulation (EU) 2017/556 and will apply to all GCP inspections (meaning inspections of CTs conducted under the CTR as well as the CT Directive).

Yes there is.

The document is entitled Clinical Trials Regulation (EU) No 536/2014 Draft Questions and Answers Version 4.1 September 2021.

The document is updated on an ad hoc basis.

In version 4.1 of the Q & A document, the changes are as follows:

  • Q 5.8 What should be included in the protocol synopsis described in Annex I, D.24 -(response revised (pgs 51-53))
  • Q 7.39 If the IBD is not available from these lists, it is possible to use a DIBD, which is the date of the 1st trial authorisation with this IMP by the sponsor. However, none of the ASR periods should be longer than 1 year. Question: How should the sponsor report the anticipated date of ASR submission? -New question and response (pg 83)
  • Q 8.4 What documentation is required in the application for the authorisation of a clinical trial relating to compliance with good manufacturing practice (GMP) for an investigational medicinal product. (response revised pg 90)
  • Annex II updated – (Pages 109 -111)


Some of the following acronyms will become familiar once you become familiar with the terminology of the CTR.

AcronymIn fullDefinitionCTR reference (if available)
AMSAdditional Member State concernedThis is when an additional member state is added to an already approved clinical trial application.
ARassessment reportFor each clinical trial, an assessment report will be generated. The report will be in two parts, Part I and Part II. Each part refers to the specific documents submitted in a clinical trial application dossier.
AxMPAuxiliary Medicinal Product(s)A medicinal product used for the needs of a clinical trial as described in the protocol, but not as an investigational medicinal product.Art. 2(8)
CTISClinical Trials Information SystemThe Clinical Trials Regulation (CTR) harmonises the assessment and supervision processes for clinical trials throughout the EU, via a Clinical Trials Information System (CTIS)
CTRClinical Trials Regulation No 536/2014Clinical Trials Regulation
MSCMember State concernedMeans the Member State where an application for authorisation of a clinical trial or of a substantial modification has been submitted under Chapters II or III of the CTR respectively.Art. 2(12)
NSMnon-substantial modificationAny change which is not substantial will be a non-substantial modification. A substantial modification is defined below.
RMSreporting member stateFor each clinical trial application,
the sponsor shall propose one of the Member States concerned as reporting Member State.
SMsubstantial modificationMeans any change to any aspect of the clinical trial which is made after notification of a decision referred to in Articles 8, 14, 19, 20 or 23 of the CTR and which is likely to have a substantial impact on the safety or rights of the subjects or on the reliability and robustness of the data generated in the clinical trial.
Art. 2(13)

The list of required documentation and information is set out in Annex I of the CTR.

Part I of the assessment report

The following documents (sections B to J and Q of Annex I) are required for Part I of the assessment report (AR):

  • B. Cover letter
  • C. EU application form
  • D. Protocol
  • E. Investigator’s brochure (IB)
  • F. Documentation relating to compliance with Good Manufacturing Practice (GMP) for the
  • G. Investigational Medicinal Product (IMP). Investigational Medicinal Product Dossier (IMPD)
  • H. Auxiliary Medicinal Product Dossier
  • I. Scientific advice in Paediatric Investigation Plan
  • J. Content of the labelling of the Investigational Medicinal Products
  • Q. Proof of payment of fee (information per member state concerned)
Part II of the assessment report

The following documents (all sections from K to R of Annex, except Q) are required for Part II of the assessment report (AR). This information is required per member state concerned.

  • K. Recruitment arrangements
  • L. Subject information, informed consent and informed consent procedure
  • M. Suitability of the investigator
  • N. suitability of the facilities
  • O. Proof of insurance cover or indemnification
  • P. Financial cover and other arrangements
  • R. Proof that data will be processed in compliance with the union law on data protection

The steps in the authorisation procedure for a clinical trial application are detailed below. They are as per Chapter II of the CTR. All of the steps are performed via the EU portal.

Step in trialLocation in CTRFurther information
Submission of an application dossier and validationArticle 5Validation will confirm the following:
– Whether the CT falls within the scope of the CTR
– Whether the application dossier is complete in line with Annex I of the CTR
Assessment of Parts I and II of the application (done in parallel upon validation of the application)Article 6 – Assessment report – Aspects covered by Part I

Article 7 – Aspects covered by Part II
For CTs with more than one MS, the assessment process shall include three phases:
(a) an initial assessment phase performed by the reporting Member State
(b) a coordinated review phase performed involving all Member States concerned
(c) a consolidation phase performed by the reporting Member State

Regarding the aspects addressed in Part I of the assessment report, the assessment report shall include one of the following:

The conduct of the clinical trial:
-is acceptable
– is acceptable subject to compliance with specific conditions
– is not acceptable
Decision on the clinical trialArticle 8 – Decision on the clinical trialEach MS shall confirm whether the clinical trial:
– is authorised
– is authorised subject to conditions
– is refused

Comprehensive guidance has been published on Good Lay Summary Practice (GLSP) for EU Clinical trials. The 85 page document was adopted in July 2021 and published on 4 October 2021.

What is the Lay Summary (LS) and is there a legal basis for it?

Article 37 of the Clinical Trials Regulation (EU) No. 536/2014 (CTR) requires trial sponsors to submit a summary (lay summary or LS) that is understandable to laypersons for
each clinical trial with pharmaceuticals into the EU Database, a core element of the
EU Clinical Trials Information System (CTIS).

As stated above, the CTR is the legal basis for the Lay Summary. It is a mandatory requirement and a transparency obligation to all trial participants and the interested public.

What is Good Lay Summary Practice (GLSP) guidance about?

The Good Lay Summary Practice (GLSP”) guidance provides key aspects and detailed recommendations on best practices for how to:

  • Plan
  • develop
  • translate and
  • disseminate (via CTIS) high quality lay language summaries of clinical trial results with medicinal products.
Who developed the GLSP guidance?

The guidance was developed in cooperation with the Roadmap Initiative to Good Lay
Summary Practice and adopted by the Clinical Trials Expert Group (CTEG), a working group of the European Commission representing Ethics Committees and National Competent Authorities (NCA)).

How is the GLSP guidance presented?

The GLSP guidance is presented in two parts:

  • Part 1, a GLSP Quick Guide (pages 6-15) – contains core extracts from the GLSP Handbook and may serve as an overview of the recommendations offered in the Handbook
  • Part 2, a GLSP Handbook.

The handbook is divided into seven sections, including those on on planning, development, translation and dissemination of a Lay Summary.

More about the GLSP guidance

The GLSP guidance :

  • provides recommendations on building Lay Summary (LS) processes with the aim to enable all sponsors to generate and disseminate objective and understandable information on clinical trial results.
  • contains recommendations on how to enable patient engagement all through the LS process although it is acknowledged that sponsors’ resource and infrastructure constraints can limit a routine involvement of patients in the different steps.
  • gives recommendations for LS dissemination aiming to inform trial participants and the general public to ensure fair access to information for all.
  • recognises and addresses the need for specific skills and strategies for LS on paediatric trials and highlights the limited experience available so far.
What are the timelines for the submission of a Lay Summary?

The Lay Summary (LS) must be submitted to the CTIS via the EU Portal no later than 12 months from the protocol-defined end of the clinical trial, 6 months for paediatric studies, and up to 30 months for nontherapeutic Phase 1 trials.

If the lay summary cannot be reported within these timelines for scientific reasons, it shall be submitted as soon as possible. In that case the protocol shall specify when the results are going to be submitted.

Deferral of the publication timelines can be requested for approval by the Member
States concerned either in the initial trial application or as a substantial modification.

Where can you find the details of the content required in the Lay Summary?

The content required in the lay summary is listed in Annex V of the EU CTR and will
accompany a ”Summary of Clinical Trial Results”, the content of which is laid out in
Annex IV.

Substantial modifications are covered by Chapter III of the CTR.

A substantial modification of a clinical trial can concern aspect(s) covered by one of the following:

  • Part I of the assessment report
  • Part II of the assessment report
  • Parts I and II of the assessment report

In all three cases, the steps for authorisation are:

  • Submission of an application
  • Validation of an application
  • Assessment of a substantial modification of an aspect(s) covered by the relevant part(s) of the assessment report
  • Decision on the substantial modification

In all three cases, each Member State concerned shall confirm whether the substantial modification:

  • is authorised
  • it is authorised subject to conditions
  • is refused.

Withdrawal and resubmission are covered under Chapter III of the CTR.

Withdrawal

In line with Article 12 of the CTR:

  • A sponsor may withdraw the application at any time until the reporting date.
  • In such a case, the application may only be withdrawn with respect to all Member States concerned (MSCs).
  • The reasons for the withdrawal shall be communicated through the EU portal.
Resubmission

In line with Article 13 of the CTR:

  • A sponsor may resubmit an application for authorisation to any intended Member State concerned following the refusal to grant an authorisation or the withdrawal of an application,
  • That application shall be deemed to be a new application for authorisation of another clinical trial.

In March 2021, the European Medicines Agency held an SME and academia 2 part training webinar. Here, you can view Day 1 and Day 2 of the webinar.


Presentations from the European Medicines Regulatory Network (EMRN) joint training sessions on the Clinical Trials Regulation (EU) 536/2014 are available.

To support the EU Member States with the implementation of the Clinical Trials Regulation (EU) 536/2014, the following three sections of the EMRN jointly organised training sessions on 9-10 March, 2021:

  • DG SANTE of the European Commission,
  • the European Medicines Agency and the
  • Clinical Trials Facilitation and Coordination Group of the Heads of Medicines Agencies

The aim of the training sessions was to provide an overview of key changes under the Clinical Trials Regulation. The agenda of the training sessions is available here.

There were approximately thirty different presentations during the two days. The presentations have now been made available on the Europa website and should be useful to anyone seeking to improve their knowledge of the key changes under the Clinical Trials Regulation.

Welcome to the Clinical Trials Regulation Quiz.

Please note the following before you start the quiz:

 

  • For questions where there is more than one correct answer, you only get a mark for the question if you are able to select all the correct answers.
  • To start the quiz, click on the 'Next' button.
  • You will be presented with a randomised set of 5 questions each time you attempt the quiz. Once you have answered all 5 questions, click on the 'Submit' button.
  • Once you click on the 'Submit' button, you will see a screen which will show 1) The questions and the answers.
  • A Green circle with tick (your chosen correct answer(s); A Green circle (correct answer); Red cross if you have chosen the wrong answer.

 

DateUpdate
14 October 2021Section entitled Is there a comprehensive Q & A document available on the CTR? updated to reflect the latest available version 4.1 dated September 2021.
7 October 2021Section entitled About the Clinical Trials Information System (CTIS) updated to include a link to and information on the the CTIS Go-live Planning document .
6 October 2021New section entitled Guidance on Good Lay Summary Practice for clinical trials added.
27 September 2021Section entitled About the Clinical Trials Information System (CTIS) updated, to add information on training module no 19.
26 August 2021Section entitled Is there a comprehensive Q & A document available on the CTR? updated as a new draft, version 4 of July 2021 of the Q&A document is now available. This update is substantial and the changes are as follows:
Chapter 3 (complete revision)
Q 11.6 (updated)
Q 11.7 (updated)
Q 11.14(NEW)
Q 11.15 (NEW)
ANNEX IV changes to the source country
(NEW)
12 August 2021Section entitled About the Clinical Trials Information System (CTIS) updated to include a link to the CTIS sponsor handbook released by the EMA in July 2021.
6 August 2021Section entited About the Clinical Trials Information System (CTIS) updated to add link to the Clinical Trials Information System (CTIS) webinar of 29 July 2021.
2 August 2021Table in section entitled Until when will the Clinical Trials Directive 2001/20/EC continue apply to clinical trials in the EU, after the CTR becomes applicable? updated to confirm that the CTR will become applicable from 31 January 2022.
2 August 2021Section entitled About the Clinical Trials Information System (CTIS) updated substantially with information on added on the CTIS training programme and other resources.
2 August 2021Section entitled When will the Clinical Trials Regulation (EU) No 536/2014 (CTR) become applicable? updated to include link to published commission decision of 31 July 2021 and also link to further information published by the EMA on 2 August 2021 concerning CTIS.
8 July 2021Heading of section Section entitled Until when will the Clinical Trials Directive 2001/20/EC continue apply to clinical trials in the EU updated to Until when will the Clinical Trials Directive 2001/20/EC continue apply to clinical trials in the EU, after the CTR becomes applicable?

The information table in the section has now been significantly updated/amended following clarification with the European Medicines Agency.
20 June 2021Section entitled Are there any training resources available to better understand the CTR? updated.
Links to EMA SME and academia 2 part training webinar added.
18 June 2021Section entitled When will the Clinical Trials Regulation (EU) No 536/2014 (CTR) become applicable? updated.
17 June 2021CTR quiz added
15 June 2021Section entitled What are the main characteristics of the new CTR? with accompanying information added.

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