2. General Questions

2.1 Name of Regulatory Authority

European Medicines Agency (EMA)

2.2 Name of Ethics Committee

Multiple ethics committees exist in the 27 EU Member States, plus those of Norway, Iceland, and Liechtenstein (the European Economic Area - (EEA)-). Note that neither the UK nor Switzerland are part of the EU/EEA, therefore the content of this guidebook does not apply to these countries. 

A list of all ethics committees is not readily available. Links to useful national association websites can however be found via the European Network of Research Ethics Committees. Although the website does not allow deep linking, if you click on the button marked “Information for Researchers”, it brings you to a page that states “Ethics approvals are subject to national legislations. For questions regarding research proposals, please contact the respective EUREC member in the country concerned”. National associations of RECs can be reached via “RECs in Europe”.

2.3 Clinical Trial Application Language

A commonly understood language in the medical field, for example, English should generally be used, although it is for each Member State to determine the language of the application (see Recital 26 and Article 26 to the Clinical Trial Regulation (EU) 536/2014).

The relevant part of Recital 26 reads: “To ensure that the assessment of the application for authorization of a clinical trial functions smoothly, Member States should consider accepting a commonly understood language in the medical field as the language for the documentation not destined for the subject.”

The EMA's Questions & Answers re Clinical Trials Information Regulation, available under EudraLex Volume 10, provides clarification on language requirements for Part I and Part II of the dossier. Annex II included within the Q&A provides a description by each Member State of which documents from Part I (i.e. CTR annex I, sections to J) can be accepted in English, and what documents are (obligatory) to be submitted in other languages.

2.4 Is regulatory approval required from both regulatory authorities and/or EC?

Yes; regulatory approval is required by the EC and the relevant competent authority, as part of the assessment procedure under the CTR regulatory approval required from both health authorities and/or EC.

Art 4, Clinical Trial Regulation (EU) 536/2014: “A clinical trial shall be subject to scientific and ethical review and shall be authorized in accordance with this Regulation. The ethical review shall be performed by an ethics committee in accordance with the law of the Member State concerned. The review by the ethics committee may encompass aspects addressed in Part I of the assessment report for the authorization of a clinical trial as referred to in Article 6 and in Part II of that assessment report as referred to in Article 7 as appropriate for each Member State concerned.” 

Art 5(1), Clinical Trial Regulation (EU) 536/2014: “In order to obtain an authorization, the sponsor shall submit an application dossier to the intended Member States concerned through the portal referred to in Article 80 (the ‘EU portal’)…”).

Submission of the clinical trial application is performed electronically via the Clinical Trials Information System (CTIS). It is important to highlight that sponsors will also need to obtain a code for the investigational medicinal product from the Extended EudraVigilance Medicinal Product Dictionary (XEVMPD), also known as the Article 57 database.

While the type of information required for clinical trial applications remains the same, the submission process has been refined to coordinate and harmonize assessments of multinational applications. Instead of needing both Competent Authority (NCA) and Ethics Committees (EC) approvals, the EU-CTR enables a single CA and EC decision per participating Member State.

Below is a list of types of Clinical Trials Applications that can be submitted via the CTIS portal:

Initial Application: 

• An initial application provides comprehensive information about the trial to be conducted and the investigations of medicinal product(s) to be used, enabling the authorities of the Member State Concerned (MSC) to evaluate the acceptability of conducting the trial.
• Initial applications can involve one MSC (mononational) or more than one MSC (multinational trials).
• For more info on the application dossier for the initial application, see Annex I of the CT Regulation.

Substantial Modification:

• Application submitted after the notification of a decision on a CTA, related to any change of the CT likely to have a substantial impact on the safety or the rights of the subjects, or on the reliability and robustness of the data generated. 
• Examples include changes in the definition of the end of the trial, new insurance policy, amendment of the number of subjects included, etc.
• A substantial Amendment may affect Part I only, Part II only, or both depending on the scope of the modification.

Additional Member State:

• An Additional MSC Application (add MSC) refers to a request by the sponsor to extend an authorized CT to another MSC.
• For more info, see Art.14 of the CT Regulation.

 Non-Substantial Modification:

• A non-substantial modification (non-SM) is not a CTA. It refers to any change that the sponsor makes to keep the dossier of an ongoing CT up-to-date. These changes are not expected 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 CT. Hence, they are not subject to evaluation by the MSC.
• Examples include correction of typographical errors, update of contact details, etc.

2.5 Can regulatory authority and EC submission be done in parallel?

Yes, the evaluation process of an initial Clinical Trial Application (CTA) is divided into three main phases: Validation, Assessment, and Decision. The Assessment phase is divided into two parts (Part I and Part II),

Submission to Part I and Part II can be done at the same time, and the assessment for both parts will be assessed in parallel unless the application contains only Part I.

2.6 Requirement of any import permit/license before investigational product/study product is shipped from point of origin

It will depend on the type and marketing condition of the product, as well as the country where it comes from. Please refer to sections 5.12 and 5.13 for more information.

 Art 61, Clinical Trial Regulation (EU) 536/2014

“Authorization of manufacturing and import

1. The manufacturing and import of investigational medicinal products in the Union shall be subject to the holding of an authorization.

2. In order to obtain the authorization referred to in paragraph 1, the applicant shall meet the following requirements:

(a) it shall have at its disposal, for manufacture or import, suitable and sufficient premises, technical equipment and control facilities complying with the requirements set out in this Regulation;

(b) it shall have permanently and continuously at its disposal the services of at least one qualified person who fulfills the conditions of qualification set out in Article 49(2) and (3) of Directive 2001/83/EC (‘qualified person’)….”

2.7 Biological Specimen Export Requirements

This is a matter for the EU Member State concerned (i.e., a national matter); please see the relevant country guidebook.

The working assumption is ‘Yes’, that there are requirements in terms of imports/exports to/from outside of the EU, ‘’No’ to within it.

2.8 Are studies of GMOs permitted (e.g., GMOs used in vaccines/vaccine manufacture and other modified products)?

Yes; studies of GMOs are permitted subject to the applicable rules.

The inclusion of GMOs is contemplated by Clinical Trial Regulation (EU) 536/2014, which provides that the covering letter to the EMA, submitting an application to carry out a clinical study, must state whether the investigational medicinal product consists of or contains a GMO - see Annex I.B(f).

2.9 Is in-country sponsor presence/representation required?

Yes; if the sponsor is not established in the EU, the Sponsor needs to establish a legal representative within the EU.

Art 74, Clinical Trial Regulation (EU) 536/2014 states the following:

“1. Where the sponsor of a clinical trial is not established in the Union, that sponsor shall ensure that a natural or legal person is established in the Union as its legal representative. Such legal representative shall be responsible for ensuring compliance with the sponsor's obligations pursuant to this Regulation, and shall be the addressee for all communications with the sponsor provided for in this Regulation. Any communication to that legal representative shall be deemed to be a communication to the sponsor.

 2. Member States may choose not to apply paragraph 1 as regards clinical trials to be conducted solely on their territory, or on their territory and the territory of a third country, provided that they ensure that the sponsor establishes at least a contact person on their territory in respect of that clinical trial who shall be the addressee for all communications with the sponsor provided for in this Regulation.

 3. As regards clinical trials to be conducted in more than one Member State, all those Member States may choose not to apply paragraph 1 provided that they ensure that the sponsor establishes at least a contact person in the Union in respect of that clinical trial who shall be the addressee for all communications with the sponsor provided for in this Regulation.”

2.10 Is there any mandatory requirement to identify a local PI or can a PI be based in a foreign country?

Yes; a local investigator is required.

Art 49, Clinical Trial Regulation (EU) 536/2014 states the following:

“The investigator shall be a medical doctor as defined in national law, or a person following a profession which is recognized in the Member State concerned as qualifying for an investigator because of the necessary scientific knowledge and experience in patient care. Other individuals involved in conducting a clinical trial shall be suitably qualified by education, training, and experience to perform their tasks”.

2.11 Is there any mandatory requirement to identify a local chief or coordinating investigator?

No, there is no longer a requirement to appoint a Coordinating Investigator.

Art 2, Clinical Trial Regulation (EU) 536/2014 defines the principal investigator as “an investigator who is the responsible leader of a team of investigators who conduct a clinical trial at a clinical trial site” whilst an investigator is defined as “an individual responsible for the conduct of a clinical trial at a clinical trial site”.”. 

2.12 If the applicant is CRO or a third party, does regulatory authority need any authorization or transfer of obligations from the sponsor? Does the authorization letter need to be notarized and/or apostilled?

Yes, a written contract is required between the sponsor and the CRO, delegating authority. The contract does not need to be notarized and/or apostilled.

While it is required to have a written contract agreement, there is no requirement for any other authorization to be part of the submission package.

Sponsors who delegate submission responsibilities to a CRO will be required to grant permit to the CRO within the CTIS portal. EMA has published a Sponsor Handbook which provides detailed information on how to navigate the CTIS portal.

2.13 Is there a requirement to register clinical trials on a local registry or database?

From the 31^st Jan 2023, all initial clinical trial applications in the EU/EEA must be submitted through the Clinical Trials Information System (CTIS). The status and results of all trials submitted under the CTIS will be available to the public.

EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trials Regulations 536/2014 are publicly accessible through CTIS. 

2.14 What is the local requirement for clinical study documents archival; minimum of years for the archival, specific format followed (electronic/paper and/or both)?

The clinical trial master file (TMF) must be retained for at least 25 years after the end of a clinical trial, whilst retention of medical files of clinical trial subjects is as per national law (please refer to the individual country Guidebooks).

The format is unspecified and the requirements set are to be complete and legible – see Art 58, Clinical Trial Regulation (EU) 536/2014.  

“Archiving of the clinical trial master file”

“Unless other Union law requires archiving for a longer period, the sponsor and the investigator shall archive the content of the clinical trial master file for at least 25 years after the end of the clinical trial. However, the medical files of subjects shall be archived in accordance with national law.

The content of the clinical trial master file shall be archived in a way that ensures that it is readily available and accessible, upon request, to the competent authorities.

Any transfer of ownership of the content of the clinical trial master file shall be documented. The new owner shall assume the responsibilities set out in this Article.

The sponsor shall appoint individuals within its organization to be responsible for archives. Access to archives shall be restricted to those individuals.

The media used to archive the content of the clinical trial master file shall be such that the content remains complete and legible throughout the period referred to in the first paragraph.

Any alteration to the content of the clinical trial master file shall be traceable.”

2.15 Requirements around periodic safety reporting and timelines on SAEs/AEs/ADRs/SUSARs/DSURs.

Safety requirements for clinical trials conducted within the EU/EEA are identified in Art. 41 & 42 of the EU CTR Regulation 536/2014.

Art 41 CTR: 

“Reporting of adverse events and serious adverse events by the investigator to the sponsor

1. The investigator shall record and document adverse events or laboratory abnormalities identified in the protocol as critical to the safety evaluation and report them to the sponsor in accordance with the reporting requirements and within the periods specified in the protocol.
2. The investigator shall record and document all adverse events unless the protocol provides differently. The investigator shall report to the sponsor all serious adverse events occurring to subjects treated by him or her in the clinical trial, unless the protocol provides differently. 
   The investigator shall report serious adverse events to the sponsor without undue delay but not later than within 24 hours of obtaining knowledge of the events, unless, for certain serious adverse events, the protocol provides that no immediate reporting is required. Where relevant, the investigator shall send a follow-up report to the sponsor to allow the sponsor to assess whether the serious adverse event has an impact on the benefit-risk balance of the clinical trial….”

Art 42 CTR:

“Reporting of suspected unexpected serious adverse reactions by the sponsor to the Agency

1. The sponsor of a clinical trial performed in at least one Member State shall report electronically and without delay to the database referred to in Article 40(1) all relevant information about the following suspected unexpected serious adverse reactions:
   1. all suspected unexpected serious adverse reactions to investigational medicinal products occurring in that clinical trial, irrespective of whether the suspected unexpected serious adverse reaction has occurred at a clinical trial site in the Union or in a third country;
   2. all suspected unexpected serious adverse reactions related to the same active substance, regardless of pharmaceutical form and strength or indication investigated, in investigational medicinal products used in the clinical trial, occurring in a clinical trial performed exclusively in a third country, if that clinical trial is sponsored:
      1. by that sponsor, or
      2. by another sponsor who is either part of the same parent company as the sponsor of the clinical trial, or who develops a medicinal product jointly, on the basis of a formal agreement, with the sponsor of the clinical trial. For this purpose, provision of the investigational medicinal product or information to a future potential marketing authorization holder on safety matters shall not be considered a joint development; and
   3. all suspected unexpected serious adverse reactions to investigational medicinal products occurring in any of the subjects of the clinical trial, which are identified by or come to the attention of the sponsor after the end of the clinical trial.
2. The period for the reporting of suspected unexpected serious adverse reactions by the sponsor to the Agency shall take account of the seriousness of the reaction and shall be as follows:
   1. in the case of fatal or life-threatening suspected unexpected serious adverse reactions, as soon as possible and in any event not later than seven days after the sponsor became aware of the reaction;
   2. in the case of non-fatal or non-life-threatening suspected unexpected serious adverse reactions, not later than 15 days after the sponsor became aware of the reaction;
   3. in the case of a suspected unexpected serious adverse reaction which was initially considered to be non-fatal or non-life threatening but which turns out to be fatal or life-threatening, as soon as possible and in any event not later than seven days after the sponsor became aware of the reaction being fatal or life-threatening….”.

2.16 Requirement on any periodic clinical study update, specific template, and its frequency (e.g., interim or annual progress report and final report, etc.)? 

A safety report is required annually.

Requirements for annual reports are specified under Art 43, Clinical Trial Regulation (EU) 536/2014:  

“1. Regarding investigational medicinal products other than placebo, the sponsor shall submit annually through the database referred to in Article 40(1) to the Agency a report on the safety of each investigational medicinal product used in a clinical trial for which it is the sponsor.

2. In the case of a clinical trial involving the use of more than one investigational medicinal product, the sponsor may, if provided for in the protocol, submit a single safety report on all investigational medicinal products used in that clinical trial.

3. The annual report referred to in paragraph 1 shall only contain aggregate and anonymized data.

4. The obligation referred to in paragraph 1 starts with the first authorization of a clinical trial in accordance with this Regulation. It ends with the end of the last clinical trial conducted by the sponsor with the investigational medicinal product….”.

There are also other reporting/notification requirements, that will be required to be performed within the CTIS, those are:

2.17 Do the country regulations allow a Decentralized Clinical Trial (DCT) model (e.g., eICF, ePROs administration, remote investigator site, etc.)?

Yes; the EMA published in Dec 2022 a “Recommendation paper on the use of Decentralized elements in clinical trial”, this recommendation paper was created as part of the priority action 8 “Methodology guidance” of the ACT EU Initiative.

Within the recommendation paper, the EMA addresses the following topics:

• Roles and responsibilities of the sponsor and investigator
• Electronic Informed Consent form
• IMP delivery
• Trial-related procedures at home
• Data management
• Monitoring in a decentralized clinical trial setting

It also includes within the appendix an overview of the current national provisions applicable in each Member State (MS) in relation to the topics listed above.

It is at the discretion of the MS involved in the assessment of a clinical trial whether the use of certain decentralized elements is acceptable in a specific trial.

Sponsors are encouraged to seek scientific advice via the EMA Scientific Advice Working Party (SAWP), or via national competent authorities (national or simultaneous national scientific advice (SNSA) regarding the use of specific decentralized elements, especially on decentralized elements where experience and the evidence of their impact may be limited.

Sponsors can also request a consolidated opinion via the Clinical Trial Coordination Group (CTCG) for regulatory issues of general impact not related to a specific trial.

2.18 Has a fully virtual trial (DCT) been conducted in the country yet? If so, please provide an example including the registration number and any link to it, whether COVID/non-COVID trials.

Yes; one DCT trial has been approved and currently recruiting in Denmark, Germany, Italy, Spain, and Poland is the study ref number 2022-500449-26-00 organized by Trials@Home.

2.19 Are there any non-regulatory DCT initiatives in the country, such as where investigator sites and local CROs founded an alliance?

Within the EU, there are several DCT initiatives at the country level, such as in Denmark, France, etc. For more information, please refer to the Country-specific Guides.

2.20 Does the local regulation require notification of “serious breaches” of GCP or the trial protocol (that is a breach that is likely to affect to a significant degree either the safety or physical or mental integrity of the subjects of the trial; or the scientific value of the trial)?

Yes, notification is required within seven days of becoming aware of the breach (see details below).

Notification of a Serious Breach allows the sponsor to inform about a breach likely to affect to a significant degree the safety and rights of a subject or the reliability and robustness of the data generated in the clinical trial. These notifications must be made without undue delay but no later than 7 days from the date on which the sponsor became aware of the breach (article 52 of the CT Regulation). 

For more information, refer to the following: 

• Guideline for the notification of serious breaches of Regulation (EU) No 536/2014 or the clinical trial protocol 
• Appendix III b – Information to be submitted with a notification of a serious breach

2.21 Does RA/CA require insurance and indemnity to cover the sponsor and investigator’s potential liability?

Yes; on a member-state (national) basis, please refer to the country guidebook.  

Art 76, Clinical Trial Regulation (EU) 536/2014

“Damage compensation

1.   Member States shall ensure that systems for compensation for any damage suffered by a subject resulting from participation in a clinical trial conducted on their territory are in place in the form of insurance, a guarantee, or a similar arrangement that is equivalent as regards its purpose and which is appropriate to the nature and the extent of the risk.

2.   The sponsor and the investigator shall make use of the system referred to in paragraph 1 in the form appropriate for the Member State concerned where the clinical trial is conducted.”