Clinical Trials Regulation (EU) No 536/2014 in practice
1
Important notice: The objective of this document is to provide sponsors and investigators a
quick guide on the rules and procedures of the Clinical Trials Regulation (EU) No 536/2014 with
a view to facilitating its implementation. This document should be read in combination with the
legislative text. Ultimately, only the European Court of Justice can give an authoritative
interpretation of Community law.
More specific documents published on Eudralex 10: https://health.ec.europa.eu/medicinal-
products/eudralex/eudralex-volume-10_en
March 2024, version 05
The rules governing medicinal products in the European Union
VOLUME 10 - Guidance documents applying to clinical trials
Clinical Trials Regulation (EU) No 536/2014 in practice
Quick guide on the rules and procedures of the EU Clinical Trials Regulation drawn up by the
Clinical Trials Coordination and Advisory Group (CTAG) as its members are the National
Contact Points defined in the abovementioned Regulation.
Document history:
Date of discussion of draft by CTAG
Version 05 is adopted by written procedure by
CTAG.
Date of publication:
01 March 2024
Supersedes:
04
Changes compared to superseded version:
Annex I:
- Update in line with latest version on CTCG
Best practice on naming of documents.
Clinical Trials Regulation (EU) No 536/2014 in practice
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TABLE OF CONTENT
ABBREVATION LIST............................................................................................................................................................. 3
1. Introduction .................................................................................................................................................................. 4
1.1 Some key principles of the CTR ....................................................................................................................... 4
1.2 Transition period of the Clinical Trials Regulation ........................................................................................... 5
2. Steps before the start of the clinical trial .................................................................................................................... 5
2.1 User, product and organisation registration ....................................................................................................... 6
2.2 Clinical trial application content and submission via CTIS............................................................................... 7
2.2.1 Submission of IMPD-Q in CTIS if sponsor is not allowed access to IMPD-Q ................................................. 8
2.2.2 Complex clinical trials and submission in CTIS ............................................................................................... 8
2.3 Validation, assessment and decision by Member States Concerned.................................................................. 9
3. Steps while the clinical trial is being conducted ...................................................................................................... 10
3.1 Applications for substantial modifications, non-substantial modifications per article 81.9 and other non-
substantial modifications on the authorised clinical trial ............................................................................................ 10
3.2 Addition of MSC ........................................................................................................................................... 11
3.2.1 Addition of MSC and IMPD-Q for decentral point of care ............................................................................ 11
3.3 Safety surveillance ......................................................................................................................................... 12
3.4 Other necessary notifications for the sponsor ................................................................................................ 14
4. Steps once the CT has ended .................................................................................................................................... 15
4.1 Notifications by the sponsor via CTIS ........................................................................................................... 15
4.2 Archiving ....................................................................................................................................................... 16
5. Transparency ............................................................................................................................................................. 16
5.1 Protection of commercially confidential information ..................................................................................... 16
5.2 Protection of personal data ............................................................................................................................. 17
6. CT specific information ............................................................................................................................................ 18
6.1 Clinical Trials on Advanced Therapy IMP .................................................................................................... 18
6.2 Specific requirements for CT on IMP being a GMO ..................................................................................... 19
6.3 Other relevant guidances for CT .................................................................................................................... 19
REFERENCES ...................................................................................................................................................................... 21
Annex 1. Composition of the clinical trial application in CTIS .......................................................................................... 26
Annex 2. Calendar for the initial authorisation of a CT ..................................................................................................... 28
Annex 3. Overview notifications CTR ................................................................................................................................... 29
Clinical Trials Regulation (EU) No 536/2014 in practice
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ABBREVATION LIST
Adverse Event
Accelerating Clinical Trials in the EU
Annual Safety Report
Advanced Therapy Investigational Medicinal Product. An ATMP is defined
as either a gene therapy ‘medicinal product’ (GTMP), a somatic cell therapy
‘medicinal product’ (sCTMP) or a tissue-engineered product (TEP)
Auxiliary Medicinal Product
Commercial Confidential Information
Clinical Trial
Clinical Trial Application
Clinical Trials Coordination and Advisory Group
Clinical Trials Coordination Group
Clinical Trials Directive
Clinical Trials Expert Group
Clinical Trials Information System
Clinical Trials Regulation
European Commission
European Economic Area
European Medicines Agency
European Union
Good Clinical Practice
Good Distribution Practice
General Data Protection Regulation
Genetically Modified Organism
Good Manufacturing Practice
Identity and Access Management system
Investigator’s Brochure
International Council for Harmonisation of Technical Requirements for
Pharmaceuticals for Human Use
Investigational Medicinal Product
Investigational Medicinal Product Dossier on Quality data
Investigational Medicinal Product Dossier on Safety and Efficacy data
In Vitro Diagnostic Medical Devices Regulation
Multi-Factor Authentication
Member State
Member State Concerned
Out of Specification
Question and Answer document on CTR, see reference 3
Request for Information
Reporting Member State
Serious Adverse Event
Suspected Unexpected Serious Adverse Reaction
eXtended EudraVigilance Medicinal Product Dictionary
Clinical Trials Regulation (EU) No 536/2014 in practice
4
Clinical Trials Regulation (EU) No 536/2014 in practice
1. Introduction
This is a quick guide on the main rules and procedures of the Clinical Trials Regulation (EU)
No 536/2014 (CTR) [1] for sponsors who wish to conduct clinical trials (national and
multinational) in the European Union (EU) / European Economic Area (EEA) or have ongoing
clinical trials in this region. The list of documents applicable to clinical trials authorised under
Regulation (EU) No 536/2014, are published at the Eudralex Volume 10 website [2]. The first
document recommended for reading is the Questions and answers document – Regulation
536/2014 (Q&A –CTR) [3] in chapter V. Additional documents (guidelines, guidances,
recommendation papers, Q&As) to be considered are given in chapter 6.
To find out if a particular clinical study is a clinical trial on a medicinal product or not, see
decision tree in Annex I of the Q&A – CTR [3].
A clinical trial
1
may be conducted only if:
a. the rights, safety, dignity and well-being of participants are protected and prevail over all
other interests; and
b. it is designed to generate reliable and robust data.
The design and conduct of the clinical trial should comply with the CTR and General Data
Protection Regulation (EU) No 2016/679 (GDPR) [4] together with the complementary national
legislation
2
. The following guidelines are also applicable:
- Investigational Medicinal Product (IMP) manufacture and distribution should comply
with Good Manufacturing Practice (GMP) [5] and Good Distribution Practice (GDP)
principles [6].
- The clinical trial should be conducted under the principles of good clinical practice
(GCP) [7].
In case the provisions of CTR and International Council for Harmonisation of Technical
Requirements for Pharmaceuticals for Human Use (ICH) GCP guidelines differ, rules defined
in the CTR prevail.
1.1 Some key principles of the CTR
The main principles of the CTR are as follows:
- A single EU application with a single Clinical Trial (CT) dossier (including a part I common
for all Member States concerned (MSC) and a part II specific per MSC) is required.
- A prior national authorisation of the CT applications in a MSC is necessary before starting
the clinical trial in that MSC.
- An EU coordinated assessment applies for the part I is led by one of the MSCs, named
Reporting Member State (RMS). The CT dossier part I conclusion together with national
aspects in part II is the basis for a single decision on each application by every MSC,
irrespective of the number of bodies/institutions involved in the assessment. Common EU
principles for the CT assessment are performed in most MSs by the national competent
authority and by one MSC Ethic Committee.
1
See definitions of ‘clinical study’, ‘clinical trial’ and ‘low intervention clinical trial’ in article 2 (1) to (3) of the CTR
2
National legislations may be found in MS websites as mentioned in Annex III of the Q&A –CTR
Clinical Trials Regulation (EU) No 536/2014 in practice
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- Increased transparency requirements with respect to the CT data and documents that should
be made publicly available.
- A Clinical Trial Information System (CTIS)
3
facilitating the procedures to fulfil the
requirements of the CTR
- Clear maximum timelines set in calendar days resulting in tacit decision (article 8.6, CTR)
or application lapse if not adhered to.
- Relevant notifications to CTIS to document the status of the CT conduct and the safety
surveillance activity by sponsor.
- Clinical trials with vulnerable subjects should comply with specific requirements
4
.
- A damage compensation mechanism according to national legislations is necessary.
- Simplification is foreseen for a CT on authorised IMPs involving minimal additional risk
and burden compared to normal clinical practice (low intervention CT)
1
[8].
1.2 Transition period of the Clinical Trials Regulation
The CTR is applicable in the EU/EEA since 31 January 2022 and has a three-year transition
period.
This transition period is as follows:
• Until 30
th
January 2023 sponsors have the chance to submit new initial clinical trial
applications (CTAs) under the CTR via CTIS or under national laws implementing the
CT Directive 2001/20/EC (CTD) documented in EudraCT;
• From 31
st
January 2023 all new initial CTAs should be submitted under the CTR;
• As of 31
st
January 2025 all ongoing clinical trials with an active site in the EU/EEA
should be conducted under the CTR.
For CTs authorised under the CTD and not transitioned to CTR, substantial amendments and
other reporting obligations should take place according to CTD procedures until the end of the
three-year transition period (i.e. 31 January 2025).
CTD trials can be transitioned to CTR during the transition period where the CTD decision will
be respected. The procedure for transition is described in Guidance for the transition of clinical
trials from the Clinical Trials Directive to the Clinical Trials Regulation [49]. The CTCG best
practice for sponsor for the transition of multinational clinical trials [50] and template cover
letter [50] is published at the CTCG website
5
at key document list.
2. Steps before the start of the clinical trial
Sponsors should carefully assess the pertinence and feasibility of the planned CT. The protocol
and the rest of the CT dossier should be prepared, an insurance/compensation should be in place
and the safety surveillance and capability for Suspected Unexpected Serious Adverse Reactions
(SUSAR) reporting to EudraVigilance should be organised.
In order to be prepared for submitting applications and notifications via CTIS, sponsors are
advised to check the training modules for CTIS [9], the CTIS sponsor handbook [10] with
details on how to use CTIS and the overview of structured data to be completed in CTIS [11].
3
https://euclinicaltrials.eu/
4
The CTR has specific rules for clinical trials with incapacitated subjects (CTR, article 31), minors (CTR, article 32), pregnant and
breastfeeding women (CTR, article 33), additional national measures (CTR, article 34) and clinical trials involving participants in emergency
situations (CTR, article 35).
5
https://www.hma.eu/about-hma/working-groups/clinical-trials-coordination-group.html
Clinical Trials Regulation (EU) No 536/2014 in practice
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A quick guide for getting started with CTIS is also available [12]. In the following chapters the
main steps are described.
2.1 User, product and organisation registration
User registration
To access the CTIS sponsor workspace [13], a user will need to have a European Medicines
Agency (EMA) account (i.e. username and password). Users already using other EMA
applications (i.e. Eudralink, SPOR, IRIS, EudraVigilance, OMS) can use the same EMA
account to access the CTIS sponsor workspace.
For individuals without an EMA account, it is necessary to create one by self-registration at the
EMA account management page, i.e. Identity and Access Management site (IAM) [14]. The
self-registration process is described in module 03 of the CTIS training material catalogue [9].
A multi-factor authentication (MFA) for CTIS users will be rolled out in 2023 (date to be
decided). In preparation for the introduction of an MFA, it is recommended that each user is
equipped with a mobile phone, or an office phone that can be used for second factor
authentication.
Organisation-centric vs CT-centric approach
If one works for a sponsor that has a sponsor administrator user appointed in IAM (in CTIS
called organisation-centric approach), roles with permissions must be given by the
administrator(s) of this organisation before starting to work in CTIS.
For organisations that have no administrator users appointed in IAM (in CTIS called ‘CT-
centric approach’), no roles to sponsor users need to be assigned and the user can create a new
CTA in CTIS directly. In that situation, this user will automatically receive a CT administrator
role for the clinical trial(s). Access will be restricted to the trials created by the user, regardless
of other CTAs created by another user from the same organisation. More information on user
registration and management can be found in chapter 2 and 3 of the CTIS sponsor handbook
[10].
Medicinal product registration
Before completing the clinical trial application in CTIS, sponsors of clinical trials should ensure
that the details of the medicinal products used in the clinical trial are already registered in the
eXtended EudraVigilance Medicinal Product Dictionary (XEVMPD). The dictionary includes
all medicinal products that are authorised in the EU/EEA as well as products under
development. More information on registration of investigational and auxiliary medicinal
products (IMPs and AxMPs respectively)
6
can be found in chapter 6 of the CTIS sponsor
handbook [10] and module 10 of the CTIS training material catalogue [9].
A placebo can be added manually without pre-registration in XEVMPD.
6
Auxiliary medicinal product’ means a medicinal product used for the needs of a clinical trial as described in the protocol, but not as an
investigational medicinal product (CTR definition, article 2.2.8). For more information, see the recommendation paper on auxiliary
medicinal products [17]
Clinical Trials Regulation (EU) No 536/2014 in practice
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Organisation registration
CTIS retrieves organisational data (i.e sponsor, CT sites) from the Organisation Management
Service (OMS) [15]. If the organisations to be recorded in CTIS are not registered in OMS yet
(sponsor should check this first), it is necessary to register them via a change request in OMS.
The registration process for a new organisation in OMS takes from five to ten working days.
More information about how to check if an organisation is already registered and how to register
an organisation can be found in chapter 2 of the CTIS sponsor handbook [10] and module 3 of
the CTIS training material catalogue [9].
If registration in OMS is not feasible, an alternative is to record the organisation directly in
CTIS, without the need to first register them in OMS. This is possible for a third party
organisation (part I application dossier - sponsor section), trial sites (part II application dossier),
site where a serious breach has occurred, inspection site (third country as well as EU/EEA
Member States) [16].
For data quality and consistency reasons, prior registration in OMS is preferred. In case of any
issues, contact the EMA service desk [18].
2.2 Clinical trial application content and submission via CTIS
Documents required will vary depending on the type of application or notification submitted.
As an example, the content of the application for the initial authorisation of the clinical trial is
outlined below.
CTIS has three sections which must be completed
7
before submitting an initial clinical trial
application:
1. Forms and MSC
− Forms, including placeholder for cover letter, proof of payment of fee, statement on
compliance with GDPR and deferral setting, including justification for trial category
(defining the transparency rules)
− Overview of the MSCs including the proposed RMS by the sponsor
2. Part I consisting of trial details (including placeholders for upload of protocol and protocol-
related documents and, if applicable, summary of scientific advice(s) and paediatric
investigational plan), sponsor and product information (including placeholders for upload
of the Investigator’s Brochure (IB), Investigational Medicinal Product Dossier on Quality
data (IMPD-Quality) and Investigational Medicinal Product Dossier on Safety and Efficacy
data (IMPD-Safety and Efficacy), GMP documents and labels).
3. Part II consisting of clinical trial site details and placeholders for documents part II
(recruitment arrangement, informed consent form, CV for principal investigator etc.).
In Annex 1 to this quick guide, the composition of the full clinical trial application is given
including the name to be referenced in CTIS to easily identify the document according to the
Clinical Trials Coordination Group (CTCG) naming convention [19]. Although part I is the
same for all MSCs, there can be specific language requirements per MS. These language
requirements are given in Annex II of the Q&A – CTR [3]. On Eudralex volume 10 [2] under
7
Partial submission (only part I, without part II) is possible (see CTR, article 11). In that case, part II in CTIS can be submitted after
conclusion on part I. It is important to know that a CT cannot be authorised until the conclusions of the assessments on both part I and part
II are favorable to authorize the CT.
Clinical Trials Regulation (EU) No 536/2014 in practice
8
chapter I ‘Application and application documents’, some templates for part II documents are
published, but it is up to each MS to decide on the use of these templates for their national
documents. Annex III of the Q&A-CTR provides the link to the respective MS websites, where
the requirements for part II documentation is provided. Therefore, it is advised to consult the
respective MS website for the requirements on the use of templates and acceptable languages.
A list of contact points for queries on part I and/or part II applications and the relevant website
with information on MS specific requirements, can be found Annex III of the Q&A – CTR [3].
In addition, a list of national contacts points, one per MS represented in the Clinical Trials
Coordination and Advisory Group (CTAG), is available under chapter V of the Eudralex
volume 10 [2].
The sponsor is allowed to submit a full initial application (part I and part II at the same time to
all MSCs) or a partial initial application (part I to all MSC and part II to none or some MSC).
For more information, see also section 2 of Q&A CTR [3].
For a partial initial application (only part I) the following rules apply:
− A part II application cannot precede a part I application.
− A part II application can be submitted after the assessment part I has been concluded.
− A part II application must be submitted within two years after the part I conclusion. If this
is not done, the application part I will lapse.
− The part II application shall be accompanied by a statement from the sponsor in which it is
declared that the sponsor is not aware of any new substantial scientific information that
would change the validity of any item submitted in the application on the aspects covered
by Part I of the assessment report, in which the MSC participated.
Important for partial initial applications in a multinational clinical trial:
The sponsor can only submit a substantial modification or an additional MSC if all MSCs have
issued a decision on the clinical trial, after having received both part I and part II. See also
question 2.3 (additional MS) and 3.6 (substantial modification) of the Q&A – CTR [3].
2.2.1 Submission of IMPD-Q in CTIS if sponsor is not allowed access to IMPD-Q
In case the sponsor of a clinical trial is not the product owner (PO) of the IMP and should not
have access to the IMPD-Q or associated considerations/RFI in order to protect commercially
confidential information, there are several options for the sponsor and PO in CTIS as described
in question 2.15 of the Q&A – CTR [3]. One of the options is the submission of the ‘IMPD-Q
only application’ by the PO at the same time as the submission of the initial application of the
clinical trial for which the IMP is intended by the sponsor. The conditions and procedure for
this ‘IMPD-Q only application’ are also described in question 2.15 of the Q&A – CTR [3].
2.2.2 Complex clinical trials and submission in CTIS
In case of a complex clinical trial, a sponsor can submit the clinical trial as one single trial
(master protocol plus all subprotocols under one EU CT number) or as separate clinical trials
(master protocol with at least one IMP specific subprotocol with a specific EU CT number and
several other subprotocols each with its own EU CT number with a cross reference to the EU
CT numbers of the other subprotocol(s) and master protocol) in CTIS. CTCG has published a
Q&A on the submission of complex clinical trials in CTIS (new or transition complex clinical
Clinical Trials Regulation (EU) No 536/2014 in practice
9
trials) which addresses the most important factors to be considered for a complex clinical trial
application in CTIS [20].
2.3 Validation, assessment and decision by Member States Concerned
The sponsor proposes an MSC to be RMS for a multinational clinical trial. During the validation
phase, the RMS will be selected by all MSCs on the basis of fair workshare and mutual
agreement. For mononational clinical trials, the MSC who receives the clinical trial application
is RMS by default. The RMS, in conjunction with MSCs, will validate if the clinical trial
application is complete and within scope of the CTR. If the clinical trial application is valid,
the assessment phase starts. The part I assessment is coordinated involving all MSCs and led
by the RMS who prepares a draft assessment report, sends the request for information (RFI)
with considerations, when applicable, (including also those from other MSCs, if applicable) to
the sponsor and issues a conclusion for the part I assessment after reviewing the answers to the
RFI.
The part II assessment is done by each MSC separately. Each MSC prepares an assessment
report part II, sends an RFI with considerations, if necessary, to the sponsor and issues a
conclusion of the part II assessment.
Within 5 days after part I and part II conclusions have been notified to the sponsor, each MSC
notifies the sponsor whether the clinical trial application is authorised, authorised subject to
conditions, or not authorised. The maximum timelines for each of these phases are provided in
Annex 2 of this quick guide.
The Part I conclusion of the RMS is also valid for the MSC, unless that MSC disagrees with
the conclusion of the RMS on the following grounds:
a. when it considers that participation in the clinical trial would lead to a subject receiving an
inferior treatment than in normal clinical practice in the MSC;
b. infringement of its national law
8
;
c. considerations regarding subject safety and data reliability and robustness were raised by
an MSC during the assessment coordinated review phase.
A sponsor can appeal in each Member State to a refusal on these grounds. Another ground to
appeal to a refusal is if the conclusion on part II is not acceptable. There could also be national
legislation applicable with respect to an appeal, e.g. allowing appeal also on an authorisation
with conditions.
Along the authorisation procedure, tacit approval or lapsed application principles apply:
− During the validation phase: a) if the RMS has not notified the sponsor within the applicable
timelines, the application will be considered complete and valid and b) when the sponsor
has not answered a request for information within the applicable timelines the application
shall be deemed to have lapsed in all MSCs.
− During the assessment phase: in case the sponsor does not answer a request for information
with respect to part I within the applicable timeline, the application shall be deemed to have
lapsed in all MSCs. In case the sponsor does not answer a request for information with
8
See CTR article 90, prohibiting or restricting the use of any specific type of human or animal cells, or the sale, supply or use of medicinal
products containing, consisting of or derived from those cells, or of medicinal products used as abortifacients or of medicinal products
containing narcotic substances within the meaning of the relevant international conventions in force such as the Single Convention on
Narcotic Drugs of 1961 of the United Nations.
Clinical Trials Regulation (EU) No 536/2014 in practice
10
respect to part II within the applicable timeline, the application shall be deemed to have
lapsed in that MSC.
− During the decision phase: Where the MSC has not notified the sponsor of its decision
within the applicable timeline, the conclusion on Part I of the assessment report shall be
deemed to be the decision of that MSC on the clinical trial application (tacit decision).
The sponsor has the option to withdraw an application for a clinical trial until the decision is
made.
In cases of withdrawal of an application before the part I conclusion is notified to the sponsor
(reporting date), the withdrawal will apply to the entire application in all MSCs. After the
reporting date, but before the decision is taken by a particular MSC, the sponsor has the option
to withdraw the application in that MSC. Once the decision regarding an application is taken in
a MSC, a sponsor no longer has the possibility to withdraw the application in that MSC. After
a withdrawal has taken place, resubmission of the application is possible.
If no subject has been included in the clinical trial in an MSC within two years from the
notification date of the authorisation, the authorisation shall expire in that MSC unless an
extension, on request of the sponsor by submission of a substantial modification application,
has been authorised.
3. Steps while the clinical trial is being conducted
After a clinical trial has been authorised, the sponsor is required to monitor the CT conduct in
order to ensure adherence to the protocol and submit applications for authorisation of a
substantial modification or an additional MSC as well as fulfilling certain non-substantial
modification notifications should they occur. There are also several mandatory notifications
and obligations for the sponsor with respect to safety surveillance and the status of the clinical
trial. The process for their submission via CTIS is shown in the sponsor’s handbook [10].
3.1 Applications for substantial modifications, non-substantial modifications per article 81.9
and other non-substantial modifications on the authorised clinical trial
In annex IV of the Q&A – CTR [3] an overview is given of the different types of CT
modifications requiring either authorisation or notification. See also section 3 of the Q&A –
CTR [3]. At the time of their submission, there should be no other application in the MSC under
assessment.
The article 81.9 changes to a clinical trial are those which are not substantial modifications
(SMs) but are, nevertheless, relevant for the supervision of the clinical trials by the MSCs.
Before an SM can be applied, the SM application
9
needs to be assessed and authorised by the
MSC, comparable to the procedure required for the initial application and according to the
maximum timelines for an SM assessment
10
.
9
See substantial modification definition in article 2 (13) of the EU Regulation 536/2014. It also includes addition of a clinical trial site or the
change of a principal investigator at a clinical trial site.
10
See chapter 3 (articles 18-24) of the CTR for the applicable legal maximum timelines.
Clinical Trials Regulation (EU) No 536/2014 in practice
11
The sponsor or the investigator may take urgent safety measures without awaiting prior
authorisation. If such measures constitute a temporary halt of the clinical trial due to safety
reasons, the sponsor should submit an SM application before restarting the clinical trial. An
application for the authorisation of a SM on part I is submitted to all MSCs, while an application
for the authorisation on part II should be submitted to each MSC individually in CTIS. There
is also the possibility to submit a combined SM part I/part II application.
Currently, substantial modifications on part I can only go to MSs that have authorised the CT.
This requires that the sponsor submits part II in those MSC that only received a partial initial
application (part I only), in order to be able to submit an SM involving part I.
The sponsor can also only submit an SM application if there is not an ongoing assessment of
any other substantial modification (either part I only, part I and II or part II only). There is one
exception: an SM part II can be submitted to an MSC with no other ongoing assessments while
in another MSC has a part II assessment is ongoing. The procedure for substantial
modifications in partial initial applications will be modified in the future, see also section 3.6
of the Q&A – CTR [3].
3.2 Addition of MSC
A procedure to add another MSC to an authorised clinical trial (article 14 CTR) can be applied
for:
− after the clinical trials is authorised in all MSCs receiving a full (part I and Part II) initial
application; and
− if there is no ongoing assessment of an SM part I or part I/II in any of the MSC.
Submission of an application for the extension of a clinical trial to another MSC is possible if
there is an ongoing assessment of i) a substantial modification application part II only in any of
the other MSCs or ii) another additional MSC. See also section 2 of the Q&A-CTR [3].
3.2.1 Addition of MSC and IMPD-Q for decentral point of care
In case the manufacturing of the IMP is done at a decentral point of care (PoC), e.g. at one of
the clinical trial sites in the additional MS (eg. CAR-T cells production), there is no placeholder
in CTIS to submit the IMPD-Q for this decentral PoC. This is due the fact that all slots part I to
upload documents in CTIS, except the translation slots, are blocked in an additional MS
procedure. To solve this issue, a work around is set up and included in the list of know issues
and proposed workarounds [51]. The sponsor should indicate the cover letter for the additional
MS application that the IMPD-Q of the decentral PoC is not part of the application because part
I is blocked and will be uploaded after receiving a RFI from the RMS to upload the IMPD-Q.
This will trigger the RMS to send an early RFI to the sponsor, during the validation step in
CTIS, requesting to upload the IMPD-Q. The sponsor can upload the IMPD-Q in the slot
“uploading a document linked to this consideration”. This slot has the label quality in order to
prevent public disclosure of the IMPD-Q. At the next SM part I, the sponsor should complete
the Part I application dossier in the part I – IMPD-Q section.
Clinical Trials Regulation (EU) No 536/2014 in practice
12
3.3 Safety surveillance
11
The sponsor together with the investigators is responsible for the safety surveillance and
minimisation of risks for the trial participants along the clinical trial duration, taking, if
necessary, appropriate urgent safety measures to protect the subjects. The MSC will monitor
the risks of investigational medicinal products (IMPs) considering the available information
according to the procedures laid down in the implementing Regulation on rules and procedures
for the cooperation of the Member States in safety assessment of clinical trials [21].
Safety reporting with regard to authorised AxMPs shall be made in accordance with the normal
safety reporting requirements for authorised medicinal products
12
.
For non-authorised AxMPs, the same requirements as those provided for the IMP in the CTR
should be applied with regard to the obligations of the investigators and the sponsors for the
collection, recording, management and reporting of adverse events. See also section 7 of the
Q&A – CTR [3] and the overview of notifications given in this chapter.
Notifications required from sponsor or investigator in relation to safety of the CT
subjects:
1. Reporting of adverse events and serious adverse events
The investigator shall record and document adverse events (AE) 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.
Any exception to the need to record and document all AEs should be included and justified in
the protocol.
The investigator shall report a serious AE (SAE) to the sponsor not later than within 24 hours
of obtaining knowledge of the events, except for the SAE for which the protocol indicates that
no immediate reporting is required.
2. Reporting of suspected unexpected serious adverse reactions (SUSARs)
The sponsor of a CT shall report electronically to the EudraVigilance
13
database all relevant
information about the following suspected unexpected serious adverse reactions (SUSARs):
- All SUSARs related to an IMP that occurred in any of the countries participating in the
CT, even if the sponsor is aware of it only after the end of the CT.
- All SUSARs related to the same active substance that occurred in a CT conducted in
third countries by the same sponsor or by another sponsor within the same parent
company or who develops the medicinal product jointly.
The reporting period starts from the day the sponsor became aware of the reaction:
- in the case of fatal or life-threatening suspected unexpected serious adverse reactions,
as soon as possible and not later than seven days.
- in the case of non-fatal or non-life-threatening suspected unexpected serious adverse
reactions, not later than fifteen days.
11
More information may be found at chapter VII and annex III of the CTR and section 7 of Q&A – CTR [3]
12
Title IX of Directive 2001/83/EC.
13
See https://www.ema.europa.eu/en/human-regulatory/research-development/pharmacovigilance/eudravigilance
Clinical Trials Regulation (EU) No 536/2014 in practice
13
To be able to report SUSARs in EudraVigilance, one must have an account. The
EudraVigilance registration documents [22] describes in detail what is needed for registration
with EudraVigilance, including the links to the different EMA systems. With an EMA account
(see chapter 2.1 on user registration) a request for the role ‘EV CS/NCS’ can be submitted via
the EMA Account Management Page [14]. Thereafter a ticket should be created for the EMA
Service Desk [18] in which the requested documents should be attached. An overview of the
documents that are needed, can be found on page 2 of the EudraVigilance registration
documents [22]. One of the documents that should be attached to the ticket is a copy of the
‘notification of successful completion of the EudraVigilance ICSR and XEVMPD knowledge
evaluation’ for the EudraVigilance user.
Non-commercial sponsors can complete an online training:
https://www.ema.europa.eu/en/human-regulatory/research-
development/pharmacovigilance/eudravigilance/eudravigilance-training-
support#eudravigilance-online-training-and-competency-assessment-for-non-commercial-
sponsors-section
A more extensive (online) training (subject to fee) is being delivered by DIA. Information can
be found at: https://www.ema.europa.eu/en/human-regulatory/research-
development/pharmacovigilance/eudravigilance/eudravigilance-training-support#virtual-live-
hands-on-training-course-for-clinical-trial-sponsors-section
In case a sponsor, due to a lack of resources, does not have the possibility to report to
EudraVigilance and the sponsor has the agreement of the MSC, it may instead report the
SUSAR to the MSC. This MSC shall then report the SUSAR to EudraVigilance. This
procedure is not feasible in all MSCs and should be verified first by contacting the MSC [23].
3. Other unexpected events relevant for the CT subject’s safety
The sponsor shall notify the MSC through CTIS of all unexpected events that affect the benefit-
risk balance of the CT that are not SUSARs. Reporting should be as soon as possible and no
later than 15 days from the date the sponsor became aware of this event (e.g. the early end of
another clinical trial with the same IMP due to safety reasons or results of a study showing
genotoxicity for the IMP).
4. Annual safety report
The sponsor shall submit annually via CTIS a report on the safety of the investigational
medicinal product used in a CT for which it is the sponsor. The format for an annual safety
report (ASR) is according to the ICH guideline E2F on development safety update report [24].
This obligation starts with the authorisation of the first CT under CTR and ends with the end of
the last CT conducted by the sponsor with this investigational medicinal product in any MS of
the EU/EEA.
In case of a CT 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 CT. A simplified report is acceptable for low intervention CTs
and CTs with authorised IMPs.
Clinical Trials Regulation (EU) No 536/2014 in practice
14
5. Reporting of serious breaches
The sponsor shall notify the MSCs about serious breaches
14
of the CTR or of the version of the
protocol applicable at the time of the breach through CTIS as soon as possible and not later than
seven days after becoming aware of that breach. Notification should take specific guidance [25]
into account.
6. Urgent safety measures
The sponsor shall notify the MSC, through CTIS, of an event likely to seriously affect the
benefit-risk balance for the CT subjects and the measures taken. That notification shall be made
without undue delay but no later than seven days from the date the measures have been taken.
This is irrespective of the substantial modifications that could be necessary to update the CT
dossier in relation to revert the potential risk.
7. Temporary halt of the CT
15
due to safety reasons
The sponsor shall notify the MSC of a temporary halt of a CT for reasons affecting the benefit-
risk balance through CTIS. That notification shall be made without undue delay but not later
than in 15 days of the date of the temporary halt. It shall include the reasons for such action and
specify follow-up measures. The restart of the CT following a temporary halt will require an
authorised SM application.
3.4 Other necessary notifications for the sponsor
- Intermediate analysis of results
Where the clinical trial protocol provides for an intermediate data analysis date prior to the
end of the clinical trial, and the respective results of the clinical trial are available, a
summary of those results shall be submitted to CTIS within one year of the intermediate
data analysis date
16
.
- A temporary halt of the CT not for safety reasons
The sponsor shall notify each MSC of a temporary halt of a CT for reasons not affecting
the benefit-risk balance through CTIS. This notification should be performed within 15 days
from the date of such temporary halt and shall include the reasons for such action. In this
case, when the CT is resumed, the sponsor shall notify each MSC within 15 days through
the CTIS. If the CT is not resumed within two years, the expiry date of this period or the
date of the decision of the sponsor not to resume the CT, whichever is earlier, will be the
date of the end of the CT.
- The start of the CT, first visit of the first patient and end of recruitment dates in every MSC,
in all cases within the 15 subsequent days to such date through CTIS.
A full list of all notifications is given in Annex 3 of this quick guide.
14
‘Serious breach’ means 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.
15
‘Temporary halt of a clinical trial’ means an interruption not provided in the protocol of the conduct of a clinical trial by the sponsor with
the intention of the sponsor to resume it. Depending on the reasons, it may affect all or part of the CT activities and may be implemented
in all or in only certain CT sites.
16
Article 37.8 CTR
Clinical Trials Regulation (EU) No 536/2014 in practice
15
4. Steps once the CT has ended
4.1 Notifications by the sponsor via CTIS
- The end or early termination of the CT in every MSC in EU/EEA as well as globally in case
third countries participate. The date of the early termination of the CT is the same as the
end of the CT. The end of trial or early end of trial in all cases must be notified within the
15 subsequent days to such date, providing also in the case of an early termination the
reasons for the end of the CT and consequences for the CT subjects.
In case of a complex CT with a master protocol and several sub-protocols, every sub-
protocol should have an end of sub-protocol date, which is the date of the last visit for the
last participant in the sub-protocol or, if justified, as defined otherwise in the sub-protocol.
In addition, the CTR definition of early termination
17
of a clinical trial applies to any sub-
protocol.
- Summary of the CT results
Irrespective of the outcome of a clinical trial, and also in the case of an early termination of
a CT (except when no subjects were recruited), within one year from the end of the clinical
trial in all MSCs or within six months for clinical trials in paediatric populations, the sponsor
shall submit to CTIS a summary of the results.
Such summary should include the information set in Annex IV of the CTR. A summary
understandable to laypersons according to Annex V of the CTR is also required.
Where, for scientific reasons detailed in the protocol, it is not possible to submit a summary
of the results within one year, for example when the clinical trial is still ongoing in third
countries and data from that part of the trial are not available, i.e. the statistical analysis
would be irrelevant, the summary of results shall be submitted as soon as it is available. In
this case, the protocol shall specify when the results are going to be submitted, together
with a justification.
- Clinical study report
In cases where the clinical trial was intended to be used for obtaining a marketing
authorisation for the investigational medicinal product, a clinical study report should be
submitted to CTIS by the applicant for marketing authorisation within 30 days after the day
the marketing authorisation has been granted, the procedure for granting the marketing
authorisation has been completed, or the applicant for marketing authorisation has
withdrawn the application.
17
Early termination of a clinical trial’ means the premature end of a clinical trial due to any reason before the conditions specified in the
protocol are complied with. If the protocol mentions circumstances for early termination, and these circumstances are fulfilled, the
notification on early termination should still be performed (See Section 10 of the Q&A-CTR [3])
Clinical Trials Regulation (EU) No 536/2014 in practice
16
4.2 Archiving
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. The medical files of the subjects shall be archived
in accordance with national law.
5. Transparency
The CTR brings unprecedented standards for transparency and publication of clinical trials data
in the European Union
18
that are detailed in more specific guidance [26]. Access to clinical
trials data supports clinical research as well as provides valuable information for researchers,
health care professionals, patients and general public.
In order to promote trust in the society in relation to CTs and to support innovative and
meaningful trials in European Union, while at the same time recognising the legitimate
economic interests of sponsors, information on authorised and refused CTs has to be published
in the CTIS public domain according to article 81.4 of the CTR [27].
The CTR also recognises that personal data, commercially confidential information (CCI),
preparation of draft assessment reports and supervision measures from the Member States
should be exempted from publication rules. To enable protection of personal data and/or CCI
CTIS offers the users the possibility to upload redacted document versions ‘for publication’ and
unredacted document versions ‘not for publication’.
5.1 Protection of commercially confidential information
At the time of submission of an initial clinical trial application the sponsor has the option to
define the deferral settings in accordance to the current transparency rules [26] to delay the
publication of clinical trials data and documents. The deferral settings enable sponsors to protect
commercially confidential information (CCI) without redaction in their documents. However,
following the publication of the CTIS revised transparency rules [28] and until their
implementation in the system, for initial clinical trials applications sponsors may already follow
the principles of the revised rules, as described in section 4 of the ACT EU Q&A on the
protection of Commercially Confidential Information and Personal Data while using CTIS [29].
A sponsor may therefore refrain from defining deferral settings and provide a version ‘for
publication’ and ‘not for publication’ only for those documents in scope of the revised rules
and detailed in Annex I of the revised CTIS transparency rules [28]. In the slot ‘for publication’
of those document types that will no longer be subject to publication, the sponsor can upload a
page with the wording suggested in Annex I of the mentioned ACT EU Q&A [29]. Regarding
the other applications that are not initial applications, but that are submitted on trials that are
already present in CTIS, such as substantial modifications and the addition of a new MSC,
sponsors should consider the preferred approach on protection of personal data and CCI, with
the aim to decrease burden depending on the status of the trial, i.e. for example whether deferrals
are already in place (see ACT EU Q&A[29]).
When submitting an initial clinical trial application, the sponsor will be able to choose whether
the clinical trial falls into category 1, 2 or 3
19
, in particular by taking into account the marketing
authorisation status of the IMP. The category chosen allows to define the type of deferral that
18
Article 81(4) of CTR on clinical trial database being public
19
Category 1 CT includes: phase 0 and phase I CT, bioequivalence and bioavailability CT and similarity trials for biosimilar products or
equivalence trials for combination or topical products where pharmacokinetic and or pharmacodynamics studies are not possible. Category
2 CT include phase II and phase III CT and Category 3 CT includes phase IV and low intervention CT [24].
Clinical Trials Regulation (EU) No 536/2014 in practice
17
can be requested under the current transparency rules [26], or the timing of publication of data
and documents under the revised rules [28] (this is going to be appliable once the revised rules
are implemented).The MSC will evaluate appropriateness of the category proposed by the
sponsor.
Where a clinical trial protocol sets out a multiphase or adaptive study design that falls in both
category 1 and 2, the trial will be treated in line with category 2.
Emergency situation CTs
20
, where the informed consent is sought after the first trial-specific
intervention, are always Category 2 or 3. CT protocols in situations of a declared public health
emergency of international concern cannot be deferred, i.e. publication occurs at the time of
decision on the CT application. It should be noted that for clinical trials, category 1, in
paediatric populations and/or part of a paediatric investigational plan, it will not be possible to
defer publication of main characteristics, notifications, summary of results and intermediate
data analyses.
Under the current transparency rules [26], Member States Concerned are able to delay the
publication of their documents (i.e. Assessment reports part I and part II) and requests for
information part I and part II, in line with the sponsor's timelines for deferrals. However, until
the technical implementation of the revised transparency rules [28] in CTIS, also the Member
States may already follow the principles, as described before, and upload a page with the
wording suggested in Annex I of the relevant ACT EU Q&A [29] in the slot ‘for publication’
of all documents that are no longer subject to publication in line with the revised rules, such as
final assessment reports or decision letters.
Under the current transparency rules [26], once that the trial with a deferral has been authorised,
the applicable data/documents subject to deferrals will not be published at the time of the
decision. In case the CT with a deferral is rejected by all MSCs receiving the application, the
clinical trial information will be published in CTIS public domain according to the same
deferral rules as for authorised clinical trials and the date of decision of the last MSC receiving
a full Part I and Part II application is taken as the date of the end of the clinical trial [26]. Under
the revised transparency rules [28] the structured data fields for all trials’ categories of trials
submitted before implementation of the rules will be published in line with the timelines and
principles of the said rules; however, all documents contained in applications submitted to CTIS
before the implementation of the technical changes will not be published. This is defined in the
mentioned ACT EU Q&A [29] and it applies to all the so called ‘historical trials’ in the system,
and regardless of the previous use of deferrals or publication status. Documents in scope of
publication as per revised rules [28], that will be provided in applications, or submitted as
results after the implementation of the technical changes, will be published in line with the
timelines and principles of the revised rules.
5.2 Protection of personal data
Personal data included in documents uploaded in CTIS should be kept to the minimum and be
provided when necessary to support the exchange of information between the parties
21
. If any
personal data is needed, e.g. on pseudonymised subjects, this should be included in the
document version ‘not for publication’ and anonymised in the document version ‘for
publication’.
20
Article 35 CTR
21
Article 81(6) of CTR referring to 81(2) of CTR
Clinical Trials Regulation (EU) No 536/2014 in practice
18
More information on protection of personal data can be found in module 12 of the CTIS training
material catalogue [8]. More detailed information on how to protect personal data and CCI
when using CTIS can be found in the Guidance on publication of commercially confidential
information and personal data and the associated ACT EU_Q&A on protection of commercially
confidential information and personal data while using CTIS which includes recommendations
from the members states and product owners on frequently asked questions [30, 29].
6. CT specific information
This chapter highlights specific legislation for CT on Advanced Therapy Medicinal Products
and important guidance and recommendations to take into account for the clinical trials.
6.1 Clinical Trials on Advanced Therapy IMP
Advanced Therapy investigational Medicinal Products (ATiMP) have to comply not only with
the general legislations for clinical trials [1] and ATiMP [31] but also with legislation from
different frameworks, such as Directive 2004/23/EC [32] for the donation, procurement and
testing of the starting materials to be converted into cell-based medicinal products or that for
genetically modified organisms (GMO) Ref (Directives 2001/18/EC [33] and/or 2009/41/EC
[34] when the product belongs to this category.
Due to the particularities of this IMP, clinical trials with ATiMPs have to comply with specific
good clinical practice [34] and good manufacturing practice [36] rules that cover among other
things the need for paying special attention to the selection criteria and to potential safety
problems, even during long term follow up periods.
The use of each ATiMP has to be traceable and the sponsor is responsible of organising this.
The individual product should be traceable from delivery to the clinical trial site up to the
administration to the clinical trial subject and vice versa.
In addition, when the IMP is an ATiMP that contains cells or tissues of human origin, the
traceability from the recipient of the product to the donor of the cells or tissues should be
ensured. The traceability system should be bidirectional (from donor to subject and from subject
to donor) and data should be kept for 30 years after the expiry date of the product, unless a
longer time period is required in the clinical trial authorisation [35].
The guideline on Good Manufacturing Practice specific to Advanced Therapy Medicinal
Products [36] described that for some ATMP, in exceptional situations, the administration of
out of specification (OOS) product may be necessary for the patient to avoid an immediate
significant hazard to the patient. The treating physician should justify the administration of the
OOS product taking into account the availability of alternative options for the patient and the
benefit/risk for the patient of not receiving the cells/tissues contained in the product,
The protocol should describe the procedure for an OOS administration within a clinical trial.
Also, the investigator needs to inform the trial participant about the possibility and chance on
receiving an OOS product. This should also be described in the trial participant information
letter.
Clinical Trials Regulation (EU) No 536/2014 in practice
19
The procedure on the use and notifications of OOS batches of authorised ATMPs is described
in the questions and answers document from the EMA committee for Advanced Therapies
(CAT) [36].
An OOS administration of a not authorised ATMPs is considered an unexpected event (CTR,
article 53) as it may affect the benefit/risk balance of the clinical trial. The sponsor has to notify
the Member States concerned via CTIS within maximum 15 days after the administration of an
OOS product. For authorized products periodic reporting in CTIS is acceptable. The description
of the event should start with: Out of Specification administration. In case reporting via CTIS
may lead to unblinding of the trial, these notifications need to be done outside of CTIS via mail
to all national contact points of the Member States concerned [23].
6.2 Specific requirements for CT on IMP being a GMO
The CTR does not specifically address environmental aspects. However, clinical trials with
medicinal products that contain or consist of GMOs must comply with applicable requirements
under the GMO framework and may require specific national authorisations related to this
legislation [38]. In some MSs the applications for a CT and GMO can be submitted in parallel,
for others the GMOs need to be approved prior to the CT.
In order, to facilitate the development of CT with medicinal products consisting or containing
GMO, lack of harmonization between different GMO authorities across the EU has prompted
the development of common voluntary procedures for some categories of products [39].
In spite of these requirements, in order to facilitate the development of new treatments for
COVID-19, Regulation 2020/1043 [40] considers acceptable that all operations related to the
conduct of clinical trials, including packaging and labelling, storage, transport, destruction,
disposal, distribution, supply, administration or use of investigational medicinal products for
human use containing or consisting of GMOs intended to treat or prevent COVID-19, with the
exception of the manufacturing of the investigational medicinal products, shall not require a
prior environmental risk assessment or consent in accordance with Directive 2001/18/EC [31]
or Directive 2009/41/EC [34]. In these cases, sponsors shall implement measures to minimise
foreseeable negative environmental impacts resulting from the intended or unintended release
of the investigational medicinal product into the environment.
6.3 Other relevant guidances for CT
There are many other guidance documents, recommendation papers and Q&A for specific
clinical trials. In addition to those in Eudralex –volume 10 [2], some relevant ones are
highlighted with reference to useful web page:
- World Medical Association. Declaration of Helsinki [41]
- ICH E8 (R1) on general considerations for clinical studies [42]
- Recommendations and Questions and Answers related to CTs with complex design (e.g.
umbrella, basket or platform trials) [43, 44]
- Recommendation paper on decentralised elements in clinical trials [45]
Clinical Trials Regulation (EU) No 536/2014 in practice
20
- Questions and Answers on the interface between CTR and Regulation (EU) 2017/746 on in
vitro diagnostic medical devices (IVDR) [46]
- Human regulatory – EMA scientific guidances to different aspects of the development of a
medicinal product (i.e multidisciplinary, about quality aspects of the IMP, about non-
clinical studies or early phase clinical trials) [47]
- ICH guidelines [48]
Clinical Trials Regulation (EU) No 536/2014 in practice
21
REFERENCES
1. Regulation (EU) No 536/2014 of the European parliament and of the council of 16 April
2014 on clinical trials on medicinal products for human use, and repealing Directive
2001/20/EC. OJ L 158, 27.5.2014, p. 1–76
https://eur-
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European Union, Volume 10: Question and Answers document – Regulation EU
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https://www.ema.europa.eu/en/documents/scientific-guideline/ich-guideline-good-
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8. Risk proportionate approaches in clinical trials:
https://health.ec.europa.eu/document/download/be80ee91-f7b8-4100-be72-
42efd8362d71_en?filename=2017_04_25_risk_proportionate_approaches_in_ct.pdf
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form/clinical-trial-information-system-ctis-structured-data-form-initial-application-
additional-member_en.xlsx
Clinical Trials Regulation (EU) No 536/2014 in practice
22
12. Quick guide getting started with CTIS :
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guide_en.pdf
13. Clinical trials in the European Union (CTIS): https://euclinicaltrials.eu/
14. EMA account management page (IAM):
https://register.ema.europa.eu/identityiq/home.html
15. EMA SPOR management services
https://spor.ema.europa.eu/sporwi/
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2023_en.pdf
17. Recommendation paper on auxiliary medicinal products:
https://health.ec.europa.eu/document/download/47ad006a-6ad4-488d-bb51-
ab91d11e2871_en?filename=2017_06_28_recommendation_on_axmps.pdf
18. EMA service desk: https://euclinicaltrials.eu/support-info/#support-user-support
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https://www.hma.eu/fileadmin/dateien/HMA_joint/00-_About_HMA/03-
Working_Groups/CTCG/2023_04_CTCG_Best_practice_guide_naming_of_documents
version_2.0.pdf
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for the application of Regulation (EU) No 536/2014 of the European Parliament and of the
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https://eur-lex.europa.eu/legal-
content/EN/TXT/?uri=uriserv:OJ.L_.2022.005.01.0014.01.ENG
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https://www.ema.europa.eu/en/documents/regulatory-procedural-
guideline/eudravigilance-registration-documents_en.pdf
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points_clinical-trials_reg-536-2014.pdf
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EMA/CHMP/ICH/309348/2008
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development-safety-update-report-step-5_en.pdf
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No 536/2014 or the clinical trial protocol
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26. EMA Appendix, on disclosure rules, to the “Functional specifications for the EU portal
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Clinical Trials Regulation (EU) No 536/2014 in practice
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27. CTIS public domain : https://euclinicaltrials.eu/search-for-clinical-trials/?lang=en
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11/ACT%20EU_Q%26A%20on%20protection%20of%20Commercially%20Confidential
%20Information%20and%20Personal%20Data%20while%20using%20CTIS_v1.3.pdf
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https://accelerating-clinical-trials.europa.eu/system/files/2023-07/guidance-document-
how-approach-protection-personal-data-commercially-confidential-information-
while_.pdf
31. Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13
November 2007 on advanced therapy medicinal products and amending Directive
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on setting standards of quality and safety for the donation, procurement, testing,
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lex.europa.eu/search.html?scope=EURLEX&text=%22Directive+2004%2F23%2FEC%2
2&lang=en&type=quick&qid=1673646297464
33. Directive 2001/18/EC of the European Parliament and of the Council of 12 March 2001
on the deliberate release into the environment of genetically modified organisms and
repealing Council Directive 90/220/EEC - Commission Declaration OJ L 106, 17.4.2001,
p. 1–39
https://eur-lex.europa.eu/legal-
content/EN/TXT/?uri=CELEX%3A32001L0018&qid=1673646763121
34. Directive 2009/41/EC of the European Parliament and of the Council of 6 May 2009 on
the contained use of genetically modified micro-organisms OJ L 125, 21.5.2009, p. 75–97
https://eur-lex.europa.eu/legal-
content/EN/TXT/?uri=CELEX%3A32009L0041&qid=1673647289198
35. European Commission. Guidelines on Good Clinical Practice specific to Advanced
Therapy Medicinal Products. C(2019) 7140 final.
https://health.ec.europa.eu/document/download/2d8842cb-e785-488f-bfd0-
bf8f2dab1efe_en?filename=atmp_guidelines_en.pdf
36. European Commission. EudraLex, The Rules Governing Medicinal Products in the
European Union, Volume 4: Guidelines on Good Manufacturing Practice specific to
Advanced Therapy Medicinal Products, 2017.
https://ec.europa.eu/health/documents/eudralex/vol-4_en
Clinical Trials Regulation (EU) No 536/2014 in practice
24
37. EMA/CAT/224381/2019 Questions and answers on the use of out-of-specification batches
of authorised cell/tissue-based advanced therapy medicinal products:
https://www.ema.europa.eu/en/documents/other/questions-answers-use-out-specification-
batches-authorised-cell-tissue-based-advanced-therapy_en.pdf
38. European Commission. Genetically Modified Organism (GMO) aspects for
investigational medicinal products.
https://health.ec.europa.eu/medicinal-products/advanced-therapies/genetically-modified-
organism-gmo-aspects-investigational-medicinal-products_en
39. European Commission. Advanced Therapies.
https://health.ec.europa.eu/medicinal-products/advanced-therapies_en
40. Regulation (EU) 2020/1043 of the European Parliament and of the Council of 15 July
2020 on the conduct of clinical trials with and supply of medicinal products for human use
containing or consisting of genetically modified organisms intended to treat or prevent
coronavirus disease (COVID-19) OJ L 231, 17.7.2020, p. 12–16
https://eur-lex.europa.eu/legal-
content/EN/TXT/?uri=CELEX%3A32020R1043&qid=1673646503901
41. World Medical Association (WMA). Declaration of HELSINKI – ethical principles for
medical research involving human subjects
https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-
medical-research-involving-human-subjects/
42. E8 (R1) on general considerations for clinical studies adopted by the CHMP as
EMA/CHMP/ICH/544570/1998 Corr*ICH guideline
https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e-8-general-
considerations-clinical-trials-step-5_en.pdf
43. Q&A on complex clinical trials
https://health.ec.europa.eu/system/files/2022-06/medicinal_qa_complex_clinical-
trials_en.pdf
44. CTFG - Recommendation paper on the initiation and conduct of complex clinical trials:
https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2019_02_CTFG_Recommendation_paper_on_Co
mplex_Clinical_Trials.pdf
45. Recommendation paper on decentralised elements in clinical trials
https://health.ec.europa.eu/document/download/2ccc46bf-2739-4b9a-ab6b-
6f425db78c61_en?filename=mp_decentralised-elements_clinical-trials_rec_en.pdf
46. Q&A on the interface between CTR and Regulation (EU) 2017/746 on in vitro diagnostic
medical devices (IVDR)
https://ec.europa.eu/health/document/download/59abcc81-fd32-4546-a340-
24c8fad4e2ac_en?filename=mdcg_2022-10_en.pdf
47. EMA Human regulatory - scientific guidances
https://www.ema.europa.eu/en/human-regulatory/research-development/scientific-
guidelines
48. ICH. Harmonization for better health. ICH guidelines
https://www.ich.org/page/search-index-ich-guidelines
49. Guidance for the transition of clinical trials from the Clinical Trials Directive to the
Clinical Trials Regulation
https://health.ec.europa.eu/document/download/10c83e6b-2587-420d-9204-
d49c2f75f476_en?filename=transition_ct_dir-reg_guidance_en.pdf
Clinical Trials Regulation (EU) No 536/2014 in practice
25
50. The CTCG best practice for sponsor for the transition of multinational clinical trials and
template cover letter
https://www.hma.eu/fileadmin/dateien/HMA_joint/00-_About_HMA/03-
Working_Groups/CTCG/2023_07_CTCG_Best_Practice_Guide_for_sponsors.pdf
https://www.hma.eu/fileadmin/dateien/HMA_joint/00-_About_HMA/03-
Working_Groups/CTCG/2023_07_CTCG_Cover_letter_template_Best_Practice_Guide_f
or_sponsors.pdf
51. List of known issues and proposed work arounds in CTIS
https://euclinicaltrials.eu/website-outages-and-system-releases/
Clinical Trials Regulation (EU) No 536/2014 in practice
26
Annex 1. Composition of the clinical trial application in CTIS
Documents are shown following the order in Annex 1 CTR including naming convention [19]
with clear self-explaining names for documents (including relevant identification) to be
indicated in the CTIS field at the time a document is uploaded in order to ensure documents
are easily found in the system.
Section Forms and MSC (placeholders in CTIS)
B1_Cover letter EU CT number
Proof of payment of fee
22
Statement of compliance with Regulation (EU) 2016/679 (GDPR)
23
Section Part I
D. Protocol (placeholder protocol information in CTIS)
D1_ Protocol EU CT number
D1_ Protocol synopsis
24
_ EU CT number (include MS language code in title)
D1_ Master protocol EU CT number and name and sub-protocol name and specific
number/ID (applicable for CCT)
D2_ Protocol modification nr number EU CT number (in case of SM as separate doc.)
D3_ DSMB Charter EU CT number
D4_ Patient facing documents e.g. questionnaire or diary (if applicable)
E. Investigator’s Brochure (placeholder product information in CTIS)
E1_ IB product name
E2_SmPC product name
F. Documents GMP compliance (if applicable) (placeholder product information in CTIS)
F1_ Marketing/importing authorisation MIA product name and abbreviated name
manufacturer/importer
F2_ QP GMP declaration product name and abbreviated name manufacturer/importer
F3_ Other statements/licences (e.g. import license) product name and abbreviated name
manufacturer/importer
G. Investigational Medicinal Product Dossier (placeholder product information in CTIS)
G1_ IMPD_Q product name
G1_ IMPD_E-S product name
G1_ Simplified IMPD_Q product name
G1_Simplified IMPD E-S product name
H. Auxiliary Medicinal Product Dossier (placeholder product information in CTIS)
H1_ AxMPD- product name
I. Scientific advice and pediatric investigational plan (PIP) (same placeholder in CTIS)
I1_ Scientific advice summary name organisation
22
This could be proof of payment of fee or invoice details. See information from each MS in Annex III of Q&A - CTR
23
Template for this statement is published on chapter I of Eudralex volume 10: https://health.ec.europa.eu/medicinal-
products/eudralex/eudralex-volume-10_en
24
See information on language requirements from each MS in Annex II of Q&A - CTR
Clinical Trials Regulation (EU) No 536/2014 in practice
27
I1_Scientific advice Quality name oganisation
I2_ PedCo opinion
I3_ EMA PIP decision name agency
J. Labelling (placeholder product information in CTIS)
J1_ Label IMP_MS product name (include MS language code in title)
20
J2_ Label AxMP_MS product name (include MS language code in title)
20
Section Part II – information per MSC
25
K. Recruitment arrangement (same placeholder in CTIS)
K1_ Recruitment arrangements
K2_ Recruitment material description
L. Subject information sheet, informed consent form, other subject information material
(same placeholder in CTIS)
L1_ SIS and ICF description (e.g. SIS and ICF adults, SIS and ICF 12-16 yr)
L2_ Other subject information material description (e.g. information leaflet adults)
M. Suitability investigator (same placeholder in CTIS)
M1_ CV Investigator name investigator and clinical trial site (use abbreviations)
M2_ DoI Investigator name investigator and clinical trial site (use abbrevations)
N. Suitability facilities (same placeholder in CTIS)
N1_ Site suitability form name clinical trial site
O. Proof of Insurance or indemnification (same placeholder in CTIS)
O1_ Trial participant insurance certificate
O2_ Proof of coverage sponsor or investigator name sponsor/trial site (if not covered by O1)
P. Financial and other arrangements (same placeholder in CTIS)
P1_ Compensation trial participants, investigator, funding and other arrangements
R. Compliance with national requirements on data protection (same placeholder in CTIS)
R1_ Compliance on the collection and use of personal data
S. Compliance with use of biological samples (same placeholder in CTIS)
S1_ Compliance on the collection, use and storage of biological samples
25
See information on language requirements from each MS in Annex II and on websites with national requirements part II per MSC in
annex III of Q&A CTR [2]
Clinical Trials Regulation (EU) No 536/2014 in practice
28
Annex 2. Calendar for the initial authorisation of a CT
The clock starts running the day after the application is submitted and follows the Central
European Time (CET). Each phase - validation, assessment and decision - has its own
maximum timelines for both MSCs and sponsors. The timelines are set in calendar days and
are visible in CTIS, taking timelines ending on weekends and national holidays into
consideration as provided for in Regulation (EEC, Euratom) No 1182/71 for the calculation of
due dates in the system. If a sponsor exceeds the legal timelines when replying to a Request for
information (RFI), the application will lapse.
The maximum calendar periods for the part I and part II assessment of the initial application
for authorisation of a CT are 10 days for validation, extensible for up to 15 days, 45 for the
assessment, extensible for up to 31 days and 5 days for every MSC to notify the decision to the
sponsor. Substantial modifications have the same calendar, shortening the validation period to
6 days and the assessment to 38 days.
Diagram bellow represents the calendar for the initial application showing also the internal sub-
periods for RMS exchange of information with the MSC on part I in case of a multinational
CT.
The CTR foresees extending the assessment by a maximum further 50 days for clinical trials
involving an advanced therapy investigational medicinal product or a medicinal product defined
in point 1 of the Annex to Regulation (EC) No 726/2004, for the purpose of consulting with
experts. The reporting Member State will communicate the sponsor any extension in the
assessment period during the validation.
Clinical Trials Regulation (EU) No 536/2014 in practice
29
Annex 3. Overview notifications CTR
After the trial has been authorised, the sponsor must notify each MSC through the CTIS about
the following information:
Notification
Definition
Timeline
Date, start clinical trial
First act of recruitment of a
potential subject for a specific
clinical trial, unless defined
differently in the protocol
< 15 days of this date
Date, first visit of first
subject
< 15 days of this date
Date, end of recruitment
< 15 days of this date
Restart of recruitment
< 15 days of this date
Date, end clinical trial in
MSC
The last visit of the last subject, or
at a later point in time as defined in
the protocol
< 15 days of this date
Date, end clinical trial in
all MSCs
The last visit of the last subject, or
at a later point in time as defined in
the protocol
< 15 days of this date
Date, end clinical trial in
all MSCs and in all 3
rd
countries (global end)
The last visit of the last subject, or
at a later point in time as defined in
the protocol
< 15 days of this date
Temporary halt of
clinical trial in all MSC
for reasons not affecting
benefit-risk balance
An interruption not provided in the
protocol of the conduct of a clinical
trial by the sponsor with the
intention of the sponsor to resume
it
26
< 15 days (include
reason)
Resume clinical trial after
temporary halt (see row
above)
< 15 days from the restart
in all MSC
Early termination clinical
trial for reasons not
affecting benefit-risk
balance
The premature end of a clinical
trial due to any reason before the
conditions specified in the protocol
are complied with
< 15 days (include reason
and when appropriate the
follow-up measures for
the subjects)
Temporary halt or early
termination for reasons of
safety
An interruption not provided in the
protocol of the conduct of a clinical
trial by the sponsor with the
intention of the sponsor to resume
it
< 15 days (include reason
and specify follow-up
measures)
Serious breaches
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.
Without undue delay but
not later than 7 days of
becoming aware of the
breach
26
In case the protocol foresee criteria for an early end of the CT, should these criteria occur, the sponsor has to notify the early
termination of the CT. Early termination notifications related to CT with complex design also apply to sub-studies and are clarified in the
Q&A on Complex CT in Eudralex volume 10 [41].
Clinical Trials Regulation (EU) No 536/2014 in practice
30
Unexpected events, not
being SUSARs, which
affect the benefit-risk
balance
Without undue delay but
not later than 15 days of
becoming aware of the
event
Urgent safety measures
because of an unexpected
event as referred to in
previous row
Without undue delay but
not later than 7 days from
the date the measures
have been taken
Summary of intermediate
trial results (if foreseen in
protocol)
Within one year of the
intermediate data
analysis date
Summary of results
(Annex IV CTR)
Within one year from the
end of a clinical trial
Summary of results
understandable for
laypersons (Annex V
CTR)
Within one year from the
end of a clinical trial
Clinical study report
(only applicable for cases
where the clinical trial
was intended to be used
for obtaining a marketing
authorisation for the
investigational medicinal
product)
Within 30 days after the
day the marketing
authorisation has been
granted, the procedure
for granting the
marketing authorisation
has been completed, or
the applicant for
marketing authorisation
has withdrawn the
application.