The CTCG is an HMA working group of experts in the classification, assessment and oversight of clinical trials from National Agencies.

The objective of CTCG is to contribute to increasing the attractiveness of the EU/EEA for clinical trials by harmonisation and optimisation of the regulatory environment while assuring the protection of rights, safety and wellbeing of the subjects and the generation of robust data.

Early clinical trials are the first contact of regulators with innovation. CTCG will monitor these trends and evolutions in clinical trials and will develop and publish guidance documents.

CTCG Mandate | pdf

• Representatives from the national competent authorities for the authorisation and surveillance of clinical trials on human subjects, the European Commission and the European Medicines Agency
• Representatives from other interested parties may be invited to attend the CTCG meetings on an ad hoc basis if deemed valuable and consensual and in agreement with the HMA rules on observers
• The chair and vice chair are elected amongst the members for a period of three years
• Currently chaired by two chairs: Marianne Lunzer, PhD (AGES MEA, Austria) and vice-chair: Monique Al, PhD (CCMO, Netherlands)
• The mentor of the group at the level of HMA is Björn Eriksson, MD, PhD (Läkemedelsverket, Sweden)

Contact Point

E-mail: ctcgnoSpam@noSpamhmanoSpam.eu

• CTCG Workplan | pdf
  July 2022

Two new advice pilots to improve clinical trials in Europe 

The Accelerating Clinical Trials in the EU (ACT EU) initiative is today launching two advice pilots aimed at improving the quality of applications for clinical trials, the foundation for the development of safe and effective medicines in Europe.

ACT EU is a collaboration between the European Medicines Agency (EMA), the Heads of Medicines Agencies (HMA) in the Member States and the European Commission (EC), which seeks to transform how clinical trials are initiated, designed, and run.

The first pilot offers developers of medicinal products scientific advice on clinical trials and on requirements for marketing authorisation applications (MAA). Assessors of clinical trials are not consistently involved in scientific advice procedures for MAAs, and vice versa. In this pilot programme, the Scientific Advice Working Party (SAWP), coordinated by EMA, and the Clinical Trials Coordination Group (CTCG), managed by HMA, will be the bodies assessing incoming requests of a scientific nature. The SAWP is responsible for advice on marketing authorisation applications and the Member States represented at CTCG oversee clinical trial applications (CTA). This pilot consolidates the views of these two groups to minimise avoidable divergences. It is the first time that both entities are providing joint scientific advice on clinical trials.

The second pilot is coordinated by the CTCG and provides technical and regulatory support on the dossier of a CTA prior to its submission through the Clinical Trials Information System. Before this pilot, applicants could only receive technical and regulatory support at national level from the Member State evaluating the application. The pre-CTA pilot will provide consolidated views of the Member States concerned on pre-submission topics. The scope of this pilot covers a number of areas such as advice on regulatory aspects of low interventional clinical trial status and submission of trials with decentralised elements or complex designs, to name a few.

Starting today, developers of medicinal products who wish to receive advice on the requirements for a MAA or a CTA may apply to these pilots. The duration of both pilots will be evaluated over time based on data and feedback collected from applicants. All this information will inform a possible change of scope and a final decision from the ACT EU steering group on how to optimise clinical trial support in the future.

By strengthening the coordination of the European medicines regulatory network, these advice pilots offer applicants additional support to enhance the quality of their applications for marketing and/or clinical trial authorisation.

Guidance for applicants: pre-CTA advice pilot

Guidance for applicants: SAWP CTCG pilot on scientific advice

Simultaneous National Scientific Advice (SNSA)

SNSA is intended to be used in situations where an applicant wishes to obtain national scientific advice from more than one NCA at the same time. The format is intended to enhance the quality and consistency of such advice. Following endorsement by the Heads of Medicine Agencies (HMA), phase 2 of the SNSA pilot will run for a two-year period until the end of 2024.

In conjunction with the ACT-EU initiative, this phase of the SNSA pilot will have a specific focus on scientific advice to facilitate clinical trials (CT) within Europe. It will facilitate sponsors / developers to obtain clinical trial-related national scientific advice from National Competent Authorities (NCA) in Member States (MS) where they intend to perform clinical trials. The experience gained during the SNSA pilot will be used to further develop the process and the provision of clinical trial-related advice as part of ACT EU Priority Action 7 (ACT EU PA7).

The following are examples of scenarios where developers may choose to seek SNSA:

• In preparation for clinical trials (CT) applications to be performed in more than one MS. Where during the SNSA the involved NCAs agree that the questions raised would benefit from discussions at the Clinical Trial Coordination Group (CTCG) level, it is also possible to obtain CTCG-coordinated clinical trial expert feedback as part of the SNSA procedure.
• Prior to applying for funding grants to support non-commercial clinical trials (academic researchers).
• To inform the early-stage development of innovative products for which clinical trials are planned, e.g. phase I/II clinical trials, especially where there is limited existing regulatory guidance. EMA scientific advice should continue to be used for scientific advice related to the suitability of the proposed clinical development to support a centralized marketing authorisation application.
• Prior to clinical trials intended to facilitate repurposing of authorised medicinal products e.g. to support new innovative therapeutic indications.

More detailed information on how to apply for SNSA and additional documents and information can be found at Heads of Medicines Agencies: EU-Innovation Network (EU-IN) (hma.eu) (search for SNSA).

In order to clarify the scope of scientific advice activities, ACT EU mapped information on voluntary procedures available within the European medicines regulatory network: Accelerating Clinical Trials in the EU (ACT EU) | European Medicines Agency (europa.eu) (look at PA 7).

Decentralised Clinical Trials (EU DCT)

Since March 2022, the Clinical Trials Coordination Group (CTCG) is responsible for the project management of the EU Decentralised Clinical Trials (EU DCT) project.
The EU DCT project is part of the priority actions conducted in the context of the Accelerating Clinical Trials in the EU (ACT EU), which started at the same time as the launch of the Clinical Trials Information System (CTIS) and the implementation of the Clinical Trials Regulation (EU) No 536/2014 (CTR).
The DCT project represents a broad collaboration across the European Medicines Regulatory Network with a cross-disciplinary project group including amongst others clinical trial authorisation experts, ethical experts and Good Clinical Practice (GCP) inspectors across Member States.
It aims to provide a harmonised and transparent approach for the use of DCT elements in clinical trials. To this end, a Recommendation paper on the use of DCT elements in clinical trials is planned to be published by the end of 2022.

The EU Decentralised Clinical Trials (EU DCT) project | pdf

TEMPLATE COVER LETTERS and RFI RESPONSE

Cover letters are essential documents providing relevant background information on the application, and a clear overview of what has been submitted in CTIS. A high-quality cover letter will facilitate validation and assessment. This also applies to the List of Changes to be submitted as a response to the RFI. Templates for transition trials can be found under section Guidance-Transitional trials.

CTCG provides the following templates, to be used in different situations:

• Initial application cover letter | docx  
  To be used for the initial application (or resubmission) of new clinical trials. 
  Version 1 July - 2024
• Substantial Modification (SM)
       - Cover letter | docx
         Provides background information on the SM application
         Version 2 July - 2024
       - Modification description | docx
         Provides an overview of all changes and submitted documents
         Version 2 July - 2024
• RFI Response List of Changes to the Application | docx  
  To be uploaded within each RFI – mandatory upload if Changes to the Application were made. 
  Version 1 July - 2024 

GUIDANCE

Transitional Trials

In the light of the huge number of Clinical trials to be transitioned to the CTR, the CTCG Best Practice Guide for sponsors of multinational clinical trials with different protocol versions approved in different Member States under the Directive 2001/20/EC that will transition to the Regulation (EU) No. 536/2014 will be adapted to newly arising problems as needed. Please check the guidance document regularly.
 

• CTCG Best Practice Guide for sponsors of multinational clinical trials with different Part I document versions approved in different Member States under the Directive 2001/20/EC that will transition to the Regulation (EU) No. 536/2014 | pdf
  Version 5 – June 2024
• Annex I - Cover letter template | docx
  Annex to the Best Practice Guide for sponsors of multinational clinical trials with different protocol versions approved in different Member States under the Directive 2001/20/EC that will transition to the Regulation (EU) No. 536/2014
  Version 5 – June 2024
• Annex II - Fees for transitional trials in MSs | pdf
  Version 1 – June 2024

First SM: document requirements after transition

The CTCG Best Practice Guide for sponsors – first substantial modification Part I after CTR transition, and its two annexes, provide guidance for sponsors on harmonised requirements agreed by CTCG members for updating Part I documents in line with the Clinical Trials Regulation at the time of the first SM Part I after a minimum trial dossier was transitioned from the Clinical Trials Directive to the Clinical Trials Regulation.
 

• CTCG Best Practice Guide to sponsors updating the application dossier Part I after CTR transition_vs 2.0 | pdf
• Annex I Cover letter template First SM after _vs 2.0 | docx
• Annex II Substantial modification template First SM after transition_vs 2.0 | docx
• Annex III First SM Part II after transition_vs._1.0 | pdf

CTIS Guidance

• Best practice guide naming of documents in CTIS | pdf
  CTCG has set up a best practice for the naming of documents in CTIS. The purpose of this naming convention is to provide a harmonised structured overview of the documents in the clinical trial application dossier, in alignment with the document types referred to in the sections of CTR annex I and II. This guide provides instructions on how to use the naming of documents in CTIS and on the use of the EU trial number within documents. CTCG accepts that the CT numbers within the documents uploaded into the system do not include the last 2 digits, so that they do not need to be changed for re-submission. Any feedback on this best practice guide for naming of documents can be sent here.

Complex Clinical Trials

• Complex clinical trials (CCTs) – Questions and answers
  The European Commission, EMA and CTCG have jointly issued new "Complex Clinical Trials - Questions and Answers" document for which “Recommendation Paper on the Initiation and Conduct of Complex Clinical Trials” issued in 2019 by the former CTFG has served as a basis. This document provides clarification or additional information and lays out certain considerations regarding scientific aspects, planning and set - up, submission for obtaining CT authorization (CTA), conduct, reporting and transparency, analysis and interpretation of Complex Clinical Trials (CCTs) under the EU Clinical Trials Regulation 536/2014 (CTR) and EU In Vitro Diagnostic Medical Devices Regulation 2017/746 (IVDR), as well as their use in submissions for marketing authorization.
  The document can be accessed here
• Submission of complex clinical trials (CCT) in the Clinical Trial Information System (CTIS)
  This Question and Answers document on CCT and CTIS  will give an answer on the most important factors to be considered.
• Recommendation Paper on the Initiation and Conduct of Complex Clinical Trials | pdf

Clinical Trial Safety

• QnA on Safety Addendum V1 clarifies topics in addition to section 7 of QnA in EudraLex Vol10, regarding Annual safety report, safety relevant notifications, reference safety information and request for information send within the ‘adhoc’ workflow which is used for supervison of CTs.
• CTCG’s developed a Simplified template of Annual Safety Report, April 2023.
  Non-commercial sponsors conducting a single clinical trial on IMPs with a MAH in any of the EU/EEA member states and where the SmPC is used as RSI submitting this simplified ASR based on the ICH-E2F may be appropriate. This template gives detailed instructions on what information is expected and what may be omitted in this setting. The simplified ASR should always be written in English.

Other Guidance and Q&A Documents

• CTCG jointly issues a new recommendation paper on principles of Good Laboratory Practices (GLP) for clinical trial applications under the EU Clinical Trials Regulation (Regulation (EU) No 536/2014), together with relevant EMA and EC working groups and parties. The aim is to provide transparency on the requirements and to clarify the expected level of information on the GLP status to include in the Clinical Trial Application in support of this.
     - Recommendation paper | pdf
     - Template table to provide the requested information | docx
• CTR/IVDR (In Vitro Diagnostic Medical) – Questions and answers
  Available here and here
• Recommendations related to contraception and pregnancy testing in clinical trials, version 1.2 | pdf
  Update to document has been adopted and implemented on 21/09/2020
  Summary of changes:
  • In the “Introduction and scope” section the references have been updated.
  • Section 1.2. Definition of end of relevant systemic exposure: with reference to the SWP/NcWP recommendations an example for “end of relevant systemic exposure” as five half-lives after end of dosing and for encapsulated compounds five half-lives of the free fraction after complete release or elimination from the encapsulating body has been added. In addition, for genotoxic compounds a reference to the practical approach how to deal with the five half-lives after end of treatment and in addition to the recommended time for contraception as given in the SWP/NcWP recommendations has been added
• Impact of the war in Ukraine on clinical trials
  CTCG recommendation to sponsors on managing the impact of the war in Ukraine on clinical trials | pdf
  Updated July 2022

Historical documents

National fees/information

• Overview of the fees charged by NCAs for submission of different types of clinical trial or amendments, January 2012| pdf
• Q and As - Frequently asked questions on CTs, updated January 2012| pdf

Clinical Trial Safety

• DSUR Q&A, 2012| pdf
• Covering Note - Q&A Reference Safety Information, March 2018 | pdf
• Q&A document – Reference Safety Information, November 2017| pdf
  DSUR Q&A and Reference Safety Information Q&A are incorporated into the COM Q&A. Please refer to Eudralex Volume 10, any updates will be done there.

Brexit
UK/EU transition period will end on December 31 2020.
Technical notice to sponsors regarding continuous compliance with the EU legislation for clinical trials following the withdrawal of the United Kingdom from the EU | pdf
 

CTFG Activity Report

• CTFG Activity Report 2008 - 2009 | pdf
• CTFG Activity Report 2010 - 2011 | pdf

Clinical Trials Authorisations (CTAs) - VHP Procedures

• Results of the Voluntary Harmonisation Procedure 2009 - 2021, February 2022 | pdf
• Conclusion of the Voluntary Harmonization Procedure project, July 2021 | pdf
• VHP - Brexit and Christmas Break, October 2020 | pdf
• Results of the Voluntary Harmonisation Procedure 2009 - 2020, February 2021 | pdf
• VHP procedures in preparation and in case of a no-deal Brexit | pdf
• European Union Member States national pilot projects in support of the transition to the new Clinical Trial Regulation EU 536/2014, October 2020 | pdf
• European Union Member States participation in VHP and VHP-related activities, October 2020 | pdf
• Guidance document for sponsors for a Voluntary Harmonised Procedure for the assessment of multinational Clinical Trial Applications, Version 5, October 2020 | pdf

COVID-19

• Guidance to sponsors on how to manage clinical trials during the COVID-19 pandemic | pdf
  Update of the guidance 28 April 2020 available here
• Link to National guidance on CT management during the COVID-19 pandemia | pdf
  Updated on 31 March 2020

Other Guidance and Q&A Documents

• Q and As on GLP, March 2017 | pdf
• Recommendations related to contraception and pregnancy testing in clinical trials, version 1.1 | pdf
  Update to document has been adopted and implemented on 21/09/2020
  The changes are as follows:
  • after the relevant systemic exposure to the medicinal product has ended for exposure to other types of genotoxicants than aneugenic compounds, the duration for applying highly effective contraception measures for women of childbearing potential, has been extended from 1 month to 6 months (one folliculogenesis cycle).
  • the need for informing participants to seek advice about donation and cryopreservation of germ cells in line with this guidance prior treatment if applicable, has been added to the section on the need for sexual counseling of study subjects, e.g. in adolescents, which should be reflected in the protocol.

Meeting schedule for 2025