II
(Information)
INFORMATION FROM EUROPEAN UNION INSTITUTIONS, BODIES, OFFICES
AND AGENCIES
EUROPEAN COMMISSION
Communication from the Commission — Detailed guidance on the request to the competent
authorities for authorisation of a clinical trial on a medicinal product for human use, the
notification of substantial amendments and the declaration of the end of the trial (CT-1)
(2010/C 82/01)
1. INTRODUCTION
1.1. Legal basis
1. This detailed guidance is based on Article 9(8) of Directive
2001/20/EC of the European Parliament and of the
Council of 4 April 2001 on the approximation of the
laws, regulations and administrative provisions of the
Member States relating to the implementation of good
clinical practice in the conduct of clinical trials on
medicinal products for human use (
1
) (hereinafter
Directive 2001/20/EC), which establishes that:
‘In consultation with Member States, the Commission
shall draw up and publish detailed guidance on:
(a) the format and contents of the request referred to in
paragraph 2 (i.e. submission of a valid request for
authorisation to the competent authority of the
Member State in which the sponsor plans to
conduct the clinical trial) as well as the documentation
to be submitted to support that request, on the quality
and manufacture of the investigational medicinal
product, any toxicological and pharmacological tests,
the protocol and clinical information on the investi
gational medicinal product including the investigator’s
brochure;
(b) the presentation and content of the proposed
amendment referred to in point (a) of Article 10 on
substantial amendments made to the protocol;
(c) the declaration of the end of the clinical trial.’
2. This guidance does address aspects related to Ethics
Committees only insofar as the provisions contained in
Directive 2001/20/EC are identical with regard to both
the national competent authority and the Ethics
Committee. This means that the following sections in
this guidance also apply to Ethics Committees:
— Procedural aspects of notification of ‘substantial
amendments’ (Sections 3.1 to 3.3, and 3.5 to 3.8); and
— Declaration of the end of the trial (Section 4).
Regarding the other aspects, reference is made to the
separate Commission guidance based on Article 8 of
Directive 2001/20/EC.
3. According to Article 3(1) of Directive 2001/20/EC, all
national requirements as regards clinical trials have to
be consistent with the procedures and timescales set out
in Directive 2001/20/EC, such as the procedures and
timescales for authorisation of a clinical trial, notification
of a substantial amendment, and declaration of the end of
the clinical trial. This document provides guidance on
these aspects.
4. EU Member States, contracting States of the European
Economic Area (EEA) (
2
) and persons who request auth
orisation of a clinical trial (applicants), notify substantial
amendments, and declare the end of a clinical trial in the
EU should consider this guidance when applying Directive
2001/20/EC.
EN
30.3.2010 Official Journal of the European Union C 82/1
(
1
) OJ L 121, 1.5.2001, p. 34.
(
2
) For the purposes of this document, references to the EU, EU Member
States or Member States should be understood to include the EEA or
EEA contracting States, unless indicated otherwise.
1.2. Scope
5. This guidance addresses the requests for authorisation,
amendments, and declaration of the end of clinical trials
within the scope of Directive 2001/20/CE. Directive
2001/20/EC applies to all clinical trials as defined in
Article 2(a) of this Directive. As regards the term
‘medicinal products’, this refers to medicinal products
for human use as defined in Article 1(2) of Directive
2001/83/EC of the European Parliament and of the
Council of 6 November 2001 on the Community code
relating to medicinal products for human use (
1
) (here
inafter Directive 2001/83/EC). This includes medicinal
products where the pharmacological, immunological, or
metabolic action of the product is still uncertain and
being explored.
6. This includes also medicinal products which are
specifically addressed in the EU law on pharmaceuticals,
such as advanced therapy medicinal products (
2
) or
medicinal products derived from human blood or
human plasma as defined in Article 1(10) of Directive
2001/83/EC.
7. Directive 2001/20/EC also applies to interventional
clinical trials with medicinal products for the paediatric
population and interventional clinical trials with medicinal
products manufactured or reconstituted in a (hospital)
pharmacy and intended to be supplied directly to the
clinical trials participants.
8. The exclusions contained in Article 3 of Directive
2001/83/EC are not relevant as regards the scope of
Directive 2001/20/EC and of this guidance.
9. Directive 2001/20/EC does not apply to:
— medical devices, active implantable medical devices,
and in vitro diagnostic medical devices as defined in
Community legislation (
3
), (
4
), (
5
),
— cosmetic products as defined in Community
legislation (
6
),
— food as defined in Community legislation (
7
).
10. To draw the ‘borderline’ between these sectoral legislations
(e.g. medicinal products/food, medicinal products/cosmetic
products, medicinal products/medical devices), the estab
lished criteria as set out in the case law of the European
Court of Justice apply and reference is made to the
relevant guidelines (
8
).
1.3. Definitions
11. The definitions contained in Directive 2001/20/EC, its
implementing acts and relevant guidance documents in
the current version apply also for this guidance. With
regard to implementing guidelines, the following
guidance documents in particular provide valuable
additional definitions:
— Guidance on Investigational Medicinal Products (IMPs)
and other medicinal products used in Clinical Trials
(on the term ‘investigational medicinal products’) (
9
),
— Annex 13 to the Guidelines on good manufacturing
practice — Manufacture of investigational medicinal
products (
10
),
— Commission Guidelines on Pharmacovigilance for
Medicinal Products for Human Use (on the term
‘non-interventional trial’) (
11
), and
— Questions and Answers Document on the Clinical
Trials Directive (
12
).
EN
C 82/2 Official Journal of the European Union 30.3.2010
(
1
) OJ L 311, 28.11.2001, p. 67.
(
2
) As defined in Article 2(1)(a) of 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
2001/83/EC and Regulation (EC) No 726/2004 (OJ L 324,
10.12.2007, p. 121) (hereinafter Regulation (EC) No 1394/2007).
(
3
) Council Directive 93/42/EEC of 14 June 1993 concerning medical
devices (OJ L 169, 12.7.1993, p. 1).
(
4
) Council Directive 90/385/EEC of 20 June 1990 on the approxi
mation of the laws of the Member States relating to active
implantable medical devices (OJ L 189, 20.7.1990, p. 17).
(
5
) Directive 98/79/EC of the European Parliament and of the Council
of 27 October 1998 on in vitro diagnostic medical devices
(OJ L 331, 7.12.1998, p. 1).
(
6
) Council Directive 76/768/EEC of 27 July 1976 on the approxi
mation of the laws of the Member States relating to cosmetic
products (OJ L 262, 27.9.1976, p. 169).
(
7
) Regulation (EC) No 178/2002 of the European Parliament and of
the Council of 28 January 2002 laying down the general principles
and requirements of food law, establishing the European Food
Safety Authority and laying down procedures in matters of food
safety (OJ L 31, 1.2.2002, p. 1), as amended.
(
8
) cf., for example, http://ec.europa.eu/enterprise/sectors/cosmetics/
cosmetic-products/borderline-products/index_en.htm
(
9
) http://ec.europa.eu/enterprise/sectors/pharmaceuticals/documents/
eudralex/vol-10/index_en.htm
(
10
) http://ec.europa.eu/enterprise/sectors/pharmaceuticals/documents/
eudralex/vol-10/index_en.htm
(
11
) Volume 9A of The Rules Governing Medicinal Products in the European
Union (Sept. 2008), Part 1, Point 7.1. (p. 90).
(
12
) http://ec.europa.eu/enterprise/sectors/pharmaceuticals/documents/
eudralex/vol-10/index_en.htm
12. For the purposes of this guidance, ‘Member State
concerned’ means the Member State where the clinical
trial is intended to be performed. For a given clinical
trial there may be several Member States concerned
(multinational clinical trials). ‘ICH country’ means a third
country which is party to the International Conference on
Harmonisation of Technical Requirements for Registration
of Pharmaceuticals for Human Use, i.e. Japan and the US.
2. REQUEST FOR A CLINICAL TRIAL AUTHORISATION
2.1. Procedural aspects
2.1.1. Legal basis
13. Article 9(1), second subparagraph, and (2) of Directive
2001/20/EC reads as follows:
‘The sponsor may not start a clinical trial until the Ethics
Committee has issued a favourable opinion and inasmuch
as the competent authority of the Member State
concerned has not informed the sponsor of any grounds
for non-acceptance. …
Before commencing any clinical trial, the sponsor shall be
required to submit a valid request for authorisation to the
competent authority of the Member State in which the
sponsor plans to conduct the clinical trial (
1
).
___________
(
1
) cf. also recital 11 of Directive 2001/20/EC: “As a rule,
authorisation should be implicit, i.e. if there has been a
vote in favour by the Ethics Committee and the
competent authority has not objected within a given
period, it should be possible to begin the clinical
trials.” ’
2.1.2. Request for authorisation, applicable timelines, tacit
authorisation
14. The applicant submits a request for authorisation of a
clinical trial to the national competent authority of the
Member State concerned.
15. In accordance with Article 9(4) of Directive 2001/20/EC,
consideration of a valid request for authorisation by the
national competent authority shall be carried out as
rapidly as possible and may not exceed 60 calendar days.
16. Validation of the request for authorisation is included in
the period of 60 calendar days. Day 0 is the day of receipt
of the request. If the request is valid, and by day 60 no
ground for non-acceptance has been raised, the clinical
trial is authorised by the national competent authority
of the Member State concerned (tacit authorisation (
1
)).
17. However, Article 9(4), (5) and (6) of Directive 2001/20/EC
sets out important exceptions to the rules on timelines
and tacit authorisation as regards certain medicinal
products, including medicinal products the active
ingredient of which is a biological product of human or
animal origin, or contains biological components of
human or animal origin, or the manufacturing of which
requires such components. Exceptions also apply to
medicinal products for gene therapy, somatic cell
therapy including xenogenic cell therapy and all
medicinal products containing genetically modified
organisms.
2.1.3. Scope of authorisation
18. The authorisation of a clinical trial by the national
competent authority is valid for a clinical trial
conducted in that Member State. This authorisation is
not to be considered as scientific advice on the devel
opment programme of the investigational medicinal
product (IMP) tested.
2.1.4. Follow-up to request for authorisation
2.1.4.1. A p p l i c a t i o n i s n o t v a l i d
19. If an application is not valid, the national competent
authority should inform the applicant of this within the
first 10 calendar days of the period referred to in Section
2.1.2. The reasons should be given.
2.1.4.2. C h a n g e s t o t h e s u b m i t t e d t o d o c u
m e n t a t i o n d u r i n g t h e e v a l u a t i o n
p h a s e
20. Following the submission of a request for authorisation,
the submitted documentation may change. This may
happen either:
— following information by the national competent
authority that the application is not valid (see
Section 2.1.4.1). In this case, the time limit set out
in Article 9(4) of Directive 2001/20/EC starts again
when a valid request has been received;
— at the initiative of the applicant. In practice, the
applicant may have an interest in changing
submitted documentation. This may happen as a
consequence of grounds for non-acceptance by the
national competent authority of another Member
State or a third country concerned if the applicant
wants to ensure that the documentation submitted
in all Member States/third countries concerned is
identical. In this case, the time limit set out in
Article 9(4) of Directive 2001/20/EC starts again; or
— following notification of grounds for non-acceptance
by the competent authority of the Member State
concerned: in this case Article 9(3) of Directive
2001/20/EC applies.
EN
30.3.2010 Official Journal of the European Union C 82/3
(
1
) The term ‘authorisation’ will be used throughout this document.
2.1.4.3. W i t h d r a w a l s
21. Unexpected events or additional information may require
the applicant to withdraw a request for authorisation
before the national competent authority has reached its
decision on authorisation. The applicant should inform
the national competent authority of the Member State
concerned as soon as he becomes aware that he intends
to withdraw the application. The initial contact should be
by fax or e-mail and include the EudraCT number and
other trial identification. Where the initial contact is by
telephone, this should be followed up, for reasons of
traceability, by fax or e-mail. The initial contact should
be followed as soon as possible by a formal letter of
withdrawal providing a brief description of the reasons.
22. If the applicant wishes to resubmit the application, he
must identify the application as a resubmission in the
cover letter (resubmission letter) and in the dedicated
field of the clinical trial application form. The initial
EudraCT number is used with a letter after the number
sequence: A for first resubmission, B for second
resubmission, and so on.
2.1.5. Interface with other authorisation requirements
23. The applicant should make applications to fulfil other
requirements that relate to clinical trials with IMPs
where applicable. For example, if the IMP is a genetically
modified organism (GMO) it may be necessary to obtain
permission from the relevant competent authority in the
Member State concerned for its contained use or
deliberate release in accordance with Council Directive
90/219/EEC of 23 April 1990 on the contained use of
genetically modified micro-organisms (
1
) or 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 (
2
).
2.1.6. Other issues
24. The application dossier should be submitted as electronic
version only, i.e. via telematics system (if nationally
available), e-mail, or a posted CD-ROM. If documentation
is sent by paper, it should be limited to the signed cover
letter only.
25. The Commission encourages national competent
authorities to accept the English language in their
communication with applicants and for documentation
which is not destined for the public or the clinical trial
participant, such as scientific documentation.
2.2. Allocation of EudraCT number
26. Before submitting an application to the national
competent authority, the applicant should obtain a
unique EudraCT number from the EudraCT Community
Clinical Trial System (
3
) by the procedure described in the
current version of the Detailed guidance on the European
clinical trials database (
4
). This number identifies the
protocol for a trial, whether conducted at a single site
or at multiple sites in one or more Member States. To
obtain the EudraCT number automatically from the
database the applicant will need to provide a few items
of information (
5
).
2.3. Cover letter
27. The applicant should submit a signed cover letter with the
application. Its subject line should contain the EudraCT
number and the invariable sponsor protocol number (if
available) with the title of the trial.
28. In the cover letter, the applicant should draw attention to
peculiarities of the trial.
29. However, in the cover letter it is not necessary to
reproduce information which is already contained in the
clinical trial application form, with the following
exceptions:
— specific features of the trial population, such as clinical
trial participants not able to give informed consent or
minors;
— whether the trial involves the first administration of a
new active substance to humans;
— whether there is scientific advice related to the trial or
IMP given by the European Medicines Agency (the
Agency) or the national competent authority of a
Member State or third country; and
— whether the trial is part or is intended to be part of a
Paediatric Investigation Plan (PIP) as referred to in Title
II, Chapter 3 of Regulation (EC) No 1901/2006 of the
European Parliament and of the Council of
12 December 2006 on medicinal products for
paediatric use (
6
). If the Agency has already issued a
Decision on the PIP, the cover letter should contain
the link to the Decision of the Agency on its website
(see also Section 2.9).
EN
C 82/4 Official Journal of the European Union 30.3.2010
(
1
) OJ L 117, 8.5.1990, p. 1.
(
2
) OJ L 106, 17.4.2001, p. 1.
(
3
) https://eudract.ema.europa.eu/
(
4
) EudraLex, Volume 10; http://ec.europa.eu/enterprise/sectors/
pharmaceuticals/documents/eudralex/vol-10/index_en.htm
(
5
) Note that paediatric clinical trials included in an agreed PIP and
performed in a third country have to be entered into EudraCT as
well (cf. point 2.2.1. of Commission Communication 2009/C28/01).
(
6
) OJ L 378, 27.11.2006, p. 1.
30. In the cover letter, the applicant should highlight whether
the IMP or NIMP is a narcotic and psychotropic.
31. The applicant should indicate where the relevant
information is contained in the application dossier.
32. The applicant should set out precisely in the cover letter
where in the application dossier the reference safety
information is contained for assessing whether an
adverse reaction is a suspected unexpected serious
adverse reaction (SUSAR).
33. In the case of a resubmission letter (see Section 2.1.4.3),
the applicant should highlight the changes as compared to
the previous submission.
2.4. Clinical trial application form
34. For clinical trials falling within the scope of the Directive
2001/20/EC, there is a unique, EU-wide clinical trial appli
cation form provided for and published in Volume 10 of
EudraLex — The Rules Governing Medicinal Products in
the European Union (
1
).
35. Some of the information in the form, such as information
related to the applicant and the name of the investigators,
will be relevant in one Member State only.
36. The applicant’s signature will confirm that the sponsor is
satisfied that:
— the information provided is complete,
— the attached documents contain an accurate account
of the information available,
— the clinical trial will be conducted in accordance with
the protocol, and
— the clinical trial will be conducted, and SUSARs and
result-related information will be reported, in
accordance with the applicable legislation.
37. If the form is submitted in paper form (cf. Section 2.1.6),
the applicant should save the full clinical trial application
form data set as an XML file using the utilities feature and
submit an electronic copy of this XML file on a CD-ROM.
38. More information about the clinical trial application form,
and how to fill it in, is available in the current version of
these documents:
— Detailed guidance on the European clinical trials
database (
2
),
— EudraCT User Manual (
3
), and
— EudraCT Frequently Asked Questions (
4
).
39. In addition, the Agency operates a help desk to support
applicants who have questions related to EudraCT (
5
).
40. Certain information contained in the clinical trial appli
cation form will be made public, following its entry into
EudraCT by the national competent authority of the
Member State concerned. This is done by rendering
certain data fields contained in EudraCT public in
accordance with the applicable guidelines published by
the Commission (
6
).
2.5. Protocol
41. According to Article 2(h), first sentence, of Directive
2001/20/EC, the protocol is ‘a document that describes
the objective(s), design, methodology, statistical
considerations and organisation of a trial.’
42. The protocol should be identified by the title, the
sponsor’s protocol code number specific for all versions
of it (if available), a date and number of version that will
be updated when it is amended, and a short title or name
assigned to it.
43. For the content and format of the protocol, reference is
made to Section 6 of the Community guideline on Good
Clinical Practice (CPMP/ICH/135/95) (
7
). In particular, the
protocol should include:
— a clear and unambiguous definition of the end of the
trial in question. In most cases this will be the date of
the last visit of the last patient undergoing the trial.
Any exceptions to this should be justified in the
protocol; and
EN
30.3.2010 Official Journal of the European Union C 82/5
(
1
) http://ec.europa.eu/enterprise/sectors/pharmaceuticals/documents/
eudralex/vol-10/index_en.htm
(
2
) http://ec.europa.eu/enterprise/sectors/pharmaceuticals/documents/
eudralex/vol-10/index_en.htm
(
3
) http://eudract.ema.europa.eu/document.html
(
4
) http://eudract.ema.europa.eu/document.html
(
5
+44 2075237523; Fax +44 2074188669.
(
6
) EudraLex, Volume 10, Chapter V (http://ec.europa.eu/enterprise/
sectors/pharmaceuticals/documents/eudralex/vol-10/index_en.htm).
(
7
) http://ec.europa.eu/enterprise/sectors/pharmaceuticals/documents/
eudralex/vol-10/index_en.htm
— a description of the plan for the provision of any
additional care for the trial participants once their
participation in the trial has ended, where it differs
from what is normally expected according to the
medical condition of the clinical trial participant.
44. The protocol should clearly address sub-studies conducted
at all trial sites or only at specific sites.
45. The protocol should also contain the relevant information
for the assessment of the clinical trial by the Ethics
Committee. To this end, the protocol should include the
following information:
— a discussion of the relevance of the clinical trial and its
design to allow assessment in view of Article 6(3)(a) of
Directive 2001/20/EC,
— an evaluation of the anticipated benefits and risks as
required in Article 3(2)(a) of Directive 2001/20/EC (cf.
Article 6(3)(b) of Directive 2001/20/EC),
— a justification for including participants who are
incapable of giving informed consent or other
special populations, such as minors (cf.
Article 6(3)(g) of Directive 2001/20/EC), and
— a detailed description of the recruitment and informed
consent procedure, especially when participants are
incapable of giving informed consent (cf.
Article 6(3)(k) of Directive 2001/20/EC).
46. More details are provided in the separate Commission
guidance based on Article 8 of Directive 2001/20/EC.
47. A sponsor may wish to conduct a clinical trial with an
active substance that is available in the European Union
with different trade names in a number of medicines with
marketing authorisations in the Member State concerned.
This may be the case, for example, in order to address
local clinical practice at each clinical trial site in the
Member State concerned. In this case the protocol may
define the treatment in terms of the active substance or
Anatomical Therapeutic Chemical (ATC) code (level 3-5)
only and not specify the trade name of each product.
48. With regard to notification of adverse events, the protocol
— may identify serious adverse events which do not
require immediate reporting by the investigator (cf.
Article 16(1) of Directive 2001/20/EC), and
— shall identify adverse events or laboratory anomalies
critical to safety evaluations to be reported to the
sponsor (cf. Article 16(2) of Directive 2001/20/EC).
49. In certain cases, issues of unblinding of IMPs might need
to be addressed in the protocol. For details, reference is
made to the guidelines on adverse reaction reporting
published in Volume 10 of EudraLex — The Rules
Governing Medicinal Products in the European Union (
1
).
50. Regarding first-in-human clinical trials, additional
guidance is provided in the Guideline on strategies to
identify and mitigate risks for first-in-human clinical
trials with investigational medicinal products (
2
).
51. The protocol should be accompanied by a synopsis of the
protocol.
52. The protocol should be signed by the sponsor and:
— the overall coordinating investigator for a multi-centre
(incl. multinational) trial, or
— the principal investigator in a single-site trial.
2.6. Investigator’s brochure
53. According to Article 2(g) of Directive 2001/20/EC, the
investigator’s brochure (IB) is ‘a compilation of the
clinical and non-clinical data on the investigational
medicinal product or products which are relevant to the
study of the product or products in human subjects.’
54. A request for trial authorisation has to be accompanied by
an IB or a document used in place of the IB (see below).
Its purpose is to provide the investigators and others
involved in the trial with the information to facilitate
their understanding of the rationale for, and their
compliance with, key features of the protocol, such as
the dose, dose frequency/interval, methods of
administration, and safety monitoring procedures.
EN
C 82/6 Official Journal of the European Union 30.3.2010
(
1
) http://ec.europa.eu/enterprise/sectors/pharmaceuticals/documents/
eudralex/vol-10/index_en.htm
(
2
) EMEA/CHMP/SWP/28367/07 (see http://www.ema.europa.eu/pdfs/
human/swp/2836707enfin.pdf).
55. The content, format and procedures for updating the IB
have to comply with Article 8(1) of Commission Directive
2005/28/EC laying down principles and detailed
guidelines for good clinical practice as regards investi
gational medicinal products for human use, as well as
the requirements for authorisation of the manufacturing
or importation of such products (
1
) (hereinafter Directive
2005/28/EC) and with the Community guideline on Good
Clinical Practice (CPMP/ICH/135/95). It should be
prepared from all available information and evidence
that supports the rationale for the proposed clinical trial
and the safe use of the IMP in the trial and be presented
in the form of summaries.
56. The approved summary of product characteristics (SmPC)
may be used in place of the IB if the IMP is authorised in
any Member State or ICH country and is used according
to the terms of the marketing authorisation. Regarding
ICH countries, the document equivalent to the SmPC is
used. If the conditions of use in the clinical trial differ
from those authorised, the SmPC should be supplemented
with a summary of relevant non-clinical and clinical data
that support the use of the IMP in the clinical trial. Where
the IMP is identified in the protocol only by its active
substance, the sponsor should elect one SmPC as
equivalent to the IB for all medicinal products that
contain that active substance and are used at any
clinical trial site.
57. For a multinational trial where the medicinal product to
be used in each Member State is the one authorised at
national level and the SmPC varies among Member States,
the sponsor should chose one SmPC to replace the IB for
the whole clinical trial. This SmPC should be the one best
suited to ensure patient safety.
58. The IB as last amended and approved by the national
competent authority or equivalent document (e.g. SmPC
for marketed products) serves as the reference safety
information for the assessment of the expectedness of
any adverse reaction that might occur during the clinical
trial.
2.7. IMP dossier
59. Article 2(d) of Directive 2001/20/EC defines an IMP as
follows:
‘A pharmaceutical form of an active substance or placebo
being tested or used as a reference in a clinical trial,
including products already with a marketing authorisation
but used or assembled (formulated or packaged) in a way
different from the authorised form, or when used for an
unauthorised indication, or when used to gain further
information about the authorised form.’
60. The IMP dossier (IMPD) gives information related to the
quality of any IMP (i.e. including reference product and
placebo), manufacture and control of the IMP, and data
from non-clinical studies and from its clinical use.
However, in many cases where the IMP has a marketing
authorisation, an IMPD is not required. Reference is made
to Section 2.7.1 (regarding compliance with Good Manu
facturing Practice, GMP) and Section 2.7.3 (regarding
data).
2.7.1. GMP compliance
61. As regards GMP compliance, in the following cases no
documentation needs to be submitted:
— the IMP has a marketing authorisation in the EU or in
an ICH country, is not modified, and is manufactured
in the EU, or
— the IMP is not manufactured in the EU, but has a
marketing authorisation in the EU, and is not
modified.
62. If the IMP does not have a marketing authorisation in the
EU or an ICH country and is not manufactured in the EU,
the following documentation should be submitted:
— a copy of the importation authorisation as referred to
in Article 13(1) of Directive 2001/20/EC, and
— a certification by the qualified person (QP) in the EU
that the manufacturing complies with GMP at least
equivalent to the GMP in the EU. Regarding this
certification, there are specific arrangements provided
for in the Mutual Recognition Agreements between
the EU and third countries (
2
).
63. In all other cases, to document compliance with GMP as
set out in Directive 2003/94/EC and the implementing
detailed guideline for IMPs (
3
), the applicant should
submit a copy of the manufacturing/importing author
isation as referred to in Article 13(1) of Directive
2001/20/EC stating the scope of the manufacturing/
importation authorisation.
2.7.2. Data related to the IMP
2.7.2.1. I n t r o d u c t o r y r e m a r k s
64. Regarding data, the IMPD can be replaced by other docu
mentation which may be submitted alone or with a
simplified IMPD. The details for this ‘simplified IMPD’
are set out in Section 2.7.3.
EN
30.3.2010 Official Journal of the European Union C 82/7
(
1
) OJ L 91, 9.4.2005, p. 13.
(
2
) More information is available here: http://www.ema.europa.eu/
Inspections/docs/000204en.pdf
(
3
) Annex 13 to Volume 4 of EudraLex — The Rules Governing
Medicinal Products in the European Union (http://ec.europa.eu/
enterprise/sectors/pharmaceuticals/documents/eudralex/vol-10/index_
en.htm).
65. The IMPD should be prefaced with a detailed table of
contents and a glossary of terms.
66. The information in the IMPD should be concise. The
IMPD should not be unnecessarily voluminous. It is
preferable to present data in tabular form accompanied
by brief narrative highlighting the main salient points.
67. Regarding various specific types of IMPs, guidance is also
given by the Agency, and made available in Volume 3 of
EudraLex — The Rules Governing Medicinal Products in
the European Union (
1
).
2.7.2.2. Q u a l i t y d a t a
68. Quality data should be submitted in a logical structure,
such as the headings of the current version of the
Guideline on the requirements to the chemical and
pharmaceutical quality documentation concerning investi
gational medicinal products in clinical trials (
2
). This
document also contains guidance for quality of placebos.
69. As regards biotechnological IMPs, reference is made to the
Guideline on virus safety evaluation of biotechnological
investigational medicinal products, as amended (
3
).
70. In exceptional cases, where impurities are not justified by
the specification or when unexpected impurities (not
covered by specification) are detected, the certificate of
analysis for test products should be attached. Applicants
should assess the need to submit a TSE Certificate.
2.7.2.3. N o n - c l i n i c a l p h a r m a c o l o g y a n d
t o x i c o l o g y d a t a
71. The applicant should also provide summaries of non-
clinical pharmacology and toxicology data for any IMP
used in the clinical trial. He should also provide a
reference list of studies conducted and appropriate
literature references. Full data from the studies and
copies of the references should be made available on
request. Wherever appropriate it is preferable to present
data in tabular form accompanied by a brief narrative
highlighting the main salient points. The summaries of
the studies conducted should allow an assessment of the
adequacy of the study and whether the study has been
conducted according to an acceptable protocol.
72. Non-clinical pharmacology and toxicology data should be
submitted in a logical structure, such as the headings of
the current version of Module 4 of the Common
Technical Document (
4
), or of the eCTD format.
73. Reference is made to the specific Community guidelines
contained in Volume 3 of EudraLex (
5
), and especially the
Note for guidance on non-clinical safety studies for the
conduct of human clinical trials and marketing author
isation for pharmaceuticals, as amended (CPMP/
ICH/286/95).
74. This section should provide a critical analysis of the data,
including justification for omissions of data, and an
assessment of the safety of the product in the context
of the proposed clinical trial rather than a mere factual
summary of the studies conducted.
75. The protocols should meet the requirements of Good
Laboratory Practice (GLP) guidelines where appropriate.
The applicant should provide a statement of the GLP
status of all studies.
76. The test material used in the toxicity studies should be
representative of that proposed for clinical trial use in
terms of qualitative and quantitative impurity profiles.
The preparation of the test material should be subject to
the controls necessary to ensure this and thus support the
validity of the study.
2.7.2.4. P r e v i o u s c l i n i c a l t r i a l a n d h u m a n
e x p e r i e n c e d a t a
77. Clinical trial and human experience data should be
submitted in a logical structure, such as the headings of
the current version of Module 5 of the Common
Technical Document (
6
), or of the eCTD format.
78. This section should provide summaries of all available
data from previous clinical trials and human experience
with the proposed IMPs.
79. All studies should have been conducted in accordance
with the principles of Good Clinical Practice (GCP). To
this end, the applicant should submit the following:
— a statement of the GCP compliance of the clinical
trials referred to,
EN
C 82/8 Official Journal of the European Union 30.3.2010
(
1
) http://ec.europa.eu/enterprise/sectors/pharmaceuticals/documents/
eudralex/vol-10/index_en.htm
(
2
) CHMP/QWP/185401/2004 final (http://ec.europa.eu/enterprise/
sectors/pharmaceuticals/documents/eudralex/vol-10/index_en.htm).
(
3
) Ref. EMEA/CHMP/BWP/398498/2005 (http://www.ema.europa.eu/
pdfs/human/bwp/39849805enfin.pdf).
(
4
) http://ec.europa.eu/enterprise/sectors/pharmaceuticals/files/eudralex/
vol-2/b/update_200805/ctd_05-2008_en.pdf
(
5
) http://ec.europa.eu/enterprise/sectors/pharmaceuticals/documents/
eudralex/vol-3/index_en.htm
(
6
) http://ec.europa.eu/enterprise/sectors/pharmaceuticals/files/eudralex/
vol-2/b/update_200805/ctd_05-2008_en.pdf
— where a clinical trial referred to has been performed in
third countries, a reference to the entry of this clinical
trial in a public register, if available. Where a clinical
trial is not published in a register, this should be
explained and justified.
80. There are no specific requirements for data from clinical
studies that must be provided before a clinical trial au
thorisation can be granted. Rather, this is to be assessed
on a case-by-case basis. In this respect, guidance is
provided in the guideline General considerations for
clinical trials (CPMP/ICH/291/95) (
1
).
2.7.2.5. O v e r a l l r i s k a n d b e n e f i t
a s s e s s m e n t
81. This section should provide a brief integrated summary
that critically analyses the non-clinical and clinical data in
relation to the potential risks and benefits of the proposed
trial unless this information is already provided in the
protocol. In the latter case, the applicant should cross-
refer to the relevant section in the protocol. The text
should identify any studies that were terminated
prematurely and discuss the reasons. Any evaluation of
foreseeable risks and anticipated benefits for studies on
minors or incapacitated adults should take account of
the provisions set out in Articles 3 to 5 of Directive
2001/20/EC.
82. Where appropriate, the sponsor should discuss safety
margins in terms of relative systemic exposure to the
IMP, preferably based on area under the curve (AUC)
data, or peak concentration (C
max
) data, whichever is
considered more relevant, rather than in terms of
applied dose. The sponsor should also discuss the
clinical relevance of any findings in the non-clinical and
clinical studies along with any recommendations for
further monitoring of effects and safety in the clinical
trials.
2.7.3. Simplified IMPD by referring to other documentation
83. The applicant has the possibility to refer to other docu
mentation which may be submitted alone or with a
simplified IMPD to contain the information as set out
in Table 1.
2.7.3.1. P o s s i b i l i t y t o r e f e r t o t h e I B
84. The applicant may either provide a stand-alone IMPD or
cross-refer to the IB for the preclinical and clinical parts of
the IMPD. In the latter case, the summaries of pre-clinical
information and clinical information should include data,
preferably in tables, providing sufficient detail to allow
assessors to reach a decision about the potential toxicity
of the IMP and the safety of its use in the proposed trial.
If there is some special aspect of the preclinical data or
clinical data that requires a detailed expert explanation or
discussion beyond what would usually be included in the
IB, the applicant should submit the preclinical and clinical
information as part of the IMPD.
2.7.3.2. P o s s i b i l i t y t o r e f e r t o t h e S m P C o r
t o t h e a s s e s s m e n t o f t h e I M P D i n
a n o t h e r c l i n i c a l t r i a l s a p p l i c a t i o n
85. The applicant may submit the current version of the
SmPC (or, as regards ICH countries, the documentation
equivalent to the SmPC) as the IMPD if an IMP has a
marketing authorisation in any Member State or in an
ICH country. The exact requirements are detailed in
Table 1.
86. Moreover, the IMPD may have been submitted previously
by the same applicant or by another applicant and held
by the national competent authority of the Member State
concerned. In these cases applicants are allowed to cross-
refer to the previous submission. If the submission was
made by another applicant, a letter from that applicant
should be submitted authorising the national competent
authority to cross-refer to that data. The exact
requirements are detailed in Table 1.
87. Table 1
Content of simplified IMPD
Types of previous assessment
Quality data Non-clinical data Clinical data
The IMP has an MA in any EU Member State or
ICH country and is used in the trial:
— within the conditions of the SmPC SmPC
— outside the conditions of the SmPC
SmPC If appropriate If appropriate
— after modification (e.g. blinding) P+A SmPC SmPC
EN
30.3.2010 Official Journal of the European Union C 82/9
(
1
) http://www.ema.europa.eu/htms/human/ich/ichefficacy.htm
Types of previous assessment Quality data Non-clinical data Clinical data
Another pharmaceutical form or strength of the
IMP has an MA in any EU Member State or ICH
country and the IMP is supplied by the MA
holder
SmPC+P+A Yes Yes
The IMP has no MA in any EU Member State or
ICH country but the active substance is part of a
medicinal product with an MA in an EU Member
State and
— is supplied by the same manufacturer SmPC+P+A Yes Yes
— is supplied by another manufacturer SmPC+S+P+A Yes Yes
The IMP was subject to a previous CTA and
authorised in the Member State concerned (
1
)
and has not been modified and
— no new data is available since last
amendment to the CTA
Reference to previous submission
— new data is available since last amendment to
the CTA
New data New data New data
— is used under different conditions If appropriate If appropriate If appropriate
(S: Data relating to the active substance; P: Data relating to the IMP; A: Appendices to the current version of the
Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational
medicinal products in clinical trials (
2
).)
(
1
) The sponsor should provide a letter of authorisation to cross-refer to the data submitted by another applicant.
(
2
) CHMP/QWP/185401/2004 final (http://ec.europa.eu/enterprise/sectors/pharmaceuticals/documents/eudralex/vol-10/index_en.
htm).
88. If the applicant is the MA holder and he has submitted an
application to vary the SmPC, which has not yet been
authorised, and which is relevant for the assessment of
the IMPD in terms of patient safety, the nature of the
variation and the reason for it should be explained.
89. If the IMP is defined in the protocol in terms of active
substance or ATC code (see above, Section 2.5), the
applicant may replace the IMPD by one representative
SmPC for each active substance/active substance
pertaining to that ATC group. Alternatively, he may
provide a collated document containing information
equivalent to that in the representative SmPCs for each
active substance that could be used as an IMP in the
clinical trial.
2.7.4. IMPD in cases of placebo
90. If the IMP is a placebo, the information requirements can
be reduced in line with the requirements set out in
Table 2.
91. Table 2
IMPD in cases of placebo
IMPD in for placebo Quality data Non-clinical data Clinical data
The IMP is a placebo P+A No No
The IMP is a placebo and the placebo has the
same composition as the tested IMP, is manu
factured by the same manufacturer, and is not
sterile
No No No
EN
C 82/10 Official Journal of the European Union 30.3.2010
IMPD in for placebo Quality data Non-clinical data Clinical data
The IMP is a placebo and has been submitted in
a previous CTA in the Member State concerned
No No No
(S: Data relating to the active substance; P: Data relating to the IMP; A: Appendices to the current version of the
Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational
medicinal products in clinical trials (
1
).)
(
1
) CHMP/QWP/185401/2004 final (http://ec.europa.eu/enterprise/sectors/pharmaceuticals/documents/eudralex/vol-10/index_en.
htm).
2.8. Non-investigational medicinal products used in
the trial
92. Medicinal products used in the context of a clinical trial
and not falling within the definition of an IMP are non-
investigational medicinal products (NIMPs). The
‘borderline’ between IMPs and NIMPs is described in the
Guidance on Investigational Medicinal Products (IMPs) and
other medicinal products used in Clinical Trials (
1
).
93. It is strongly recommended that NIMPs with marketing
authorisation in the Member State concerned are used.
When this is not possible, the next choice should be
NIMPs with marketing authorisation in another Member
State. When this is not possible, the next choice should be
NIMPs with marketing authorisation in an ICH country or
a third country having a mutual recognition agreement
with the EU (MRA country) (
2
). When this is not
possible, the next choice should be NIMPs with a
marketing authorisation in another third country.
Otherwise, a NIMP with no marketing authorisation
may be used.
94. For the requirements of the NIMP dossier, reference is
made to the applicable guideline published in EudraLex
— The Rules Governing Medicinal Products in the
European Union, Volume 10 (
3
).
2.9. Other documents to be submitted, Overview
95. The following additional documents should be contained
in the application dossier submitted to the national
competent authority of the Member State concerned:
1. A copy of the opinion of the Ethics Committee of the
Member State concerned, whether the application has
been submitted in parallel or in sequence, as soon as it
is available, unless the Ethics Committee informs the
applicant that it has copied its opinion to the national
competent authority of the Member State concerned. A
submission of this document subsequently to the
submission of a request for authorisation is not to
be considered as a change of the documentation as
referred to in Section 2.1.4.2.
2. If available, a copy of the summary of scientific advice
from any Member State or the Agency with regard to
the clinical trial. A submission of this document
subsequently to the submission of a request for auth
orisation is not to be considered as a change of the
documentation as referred to in Section 2.1.4.2.
3. If the clinical trial is part of an agreed PIP, a copy of
the Agency’s Decision on the agreement on the PIP,
and the opinion of the Paediatric Committee, unless
these documents are fully accessible via the internet. In
the latter case, the link to this documentation in the
cover letter is sufficient (see Section 2.3). A submission
of this document subsequently to the submission of a
request for authorisation is not to be considered as a
change of the documentation as referred to in Section
2.1.4.2.
4. The content of the labelling of the IMP.
5. In case of fees, proof of payment.
96. Table 3 contains the final overview of the documentation
to be submitted.
Table 3
List of documentation to be provided to the national
competent authority of the Member State concerned in
accordance with this detailed guidance
— Cover letter with the contents set out in Section 2.3,
— Clinical trial application form,
— Protocol with the contents set out in Section 2.5,
— IB, or document replacing the IB, as set out in Section 2.6,
— IMPD/simplified IMPD, as set out in Sections 2.7 and 2.7.3,
— NIMP dossier as set out in Section 2.8,
— The additional pieces of documentation as set out in
Section 2.9.
2.10. Additional national requirements for
documents
97. The national requirements for the content of the clinical
trial application dossier can be more comprehensive than
the list of documentation set out in Section 2.9 in the
following two cases:
EN
30.3.2010 Official Journal of the European Union C 82/11
(
1
) cf. http://ec.europa.eu/enterprise/sectors/pharmaceuticals/documents/
eudralex/vol-10/index_en.htm
(
2
) These third countries are Australia, Canada, Japan, New Zealand and
Switzerland.
(
3
) cf. http://ec.europa.eu/enterprise/sectors/pharmaceuticals/documents/
eudralex/vol-10/index_en.htm
2.10.1. Documents relating to information relevant for Ethics
Committees but exceptionally considered by national
competent authorities in accordance with Article 6(4)
of Directive 2001/20/EC
98. Documents relating to information which is, according to
Article 6(2) of the Directive 2001/20/EC, only assessed by
the Ethics Committee should not be submitted to the
national competent authority of the Member State
concerned.
99. However, if a Member State has decided, in accordance
with Article 6(4) of Directive 2001/20/EC, that its
national competent authority is responsible for
considering:
— the provisions for indemnity or compensation,
— insurance or indemnity to cover the liability of the
investigator/sponsor,
— compensation and rewards of investigators and clinical
trial participants, or
— the agreement between the sponsor and the clinical
trial sites.
The relevant documentation should be submitted to the
national competent authority of this Member State.
100. Member States who decide to extend the scope of
assessment of the national competent authority are
under an obligation to notify the Commission, the other
Member States, and the Agency of this. Those Member
States are listed on the ‘clinical trials website’ of the
European Commission (
1
).
2.10.2. Documents relating to information on a more compre
hensive protection of the clinical trial participant in
accordance with Article 3(1) of Directive 2001/20/EC
101. Some Member States may have national provisions on the
protection of clinical trial subjects in place which are
more comprehensive than the provisions of the
Directive 2001/20/EC (cf. Article 3(1) of Directive
2001/20/EC).
102. In order for the national competent authority to assess
compliance with these national provisions (hereinafter
referred to as ‘underlying national provisions’), Member
States may require additional information in the clinical
trial application dossier.
103. However, Member States may only request this additional
information if the underlying national provision is
compliant with Directive 2001/20/EC. This requires in
particular, that the underlying national provision:
— is clearly aimed at a more comprehensive protection
of the clinical trial subject than the provisions of
Directive 2001/20/EC,
— is appropriate and proportionate in view of the aim
pursued,
— is consistent with the procedures set out in Directive
2001/20/EC, and
— is consistent with the timescales set out in Directive
2001/20/EC.
104. The Commission is going to ensure compliance of
underlying national provisions with these requirements.
3. NOTIFICATION OF AMENDMENTS AND RELATED
MEASURES
3.1. Legal basis and scope
105. Article 10(a) of Directive 2001/20/EC reads as follows:
‘After the commencement of the clinical trial, the sponsor
may make amendments to the protocol. If those
amendments are substantial and are likely to have an
impact on the safety of the trial subjects or to change
the interpretation of the scientific documents in support
of the conduct of the trial, or if they are otherwise
significant, the sponsor shall notify the competent
authorities of the Member State or Member States
concerned of the reasons for, and content of, these
amendments and shall inform the ethics committee or
committees concerned in accordance with Articles 6
(Ethics Committee) and 9 (Commencement of clinical
trial).’
106. In view of the identical legal consequences of an
amendment that is ‘substantial and likely to have an
impact on the safety of the trial subjects or to change
the interpretation of the scientific documents in support
of the conduct of the trial’ and an amendment that is
‘otherwise significant’, the term ‘substantial amendment’
used in this guidance refers to both types of amendments.
EN
C 82/12 Official Journal of the European Union 30.3.2010
(
1
) http://ec.europa.eu/enterprise/sectors/pharmaceuticals/human-use/
clinical-trials/index_en.htm
107. Notification/submission of information (
1
) is only obli
gatory if the amendment is a substantial amendment.
Directive 2001/20/EC does not require notification, nor
immediate submission of information of non-substantial
amendments. Neither national competent authorities of
the Member State concerned, nor its Ethics Committee
can oblige the sponsor to submit non-substantial
amendments. In this regard, the rules for non-substantial
amendments (cf. Section 3.6) apply.
3.2. The notion of ‘amendment’
108. The following changes do not count as an ‘amendment’ as
referred to in Article 10(a) of Directive 2001/20/EC:
— a change to the documentation submitted to the
national competent authority during the ongoing
assessment of the request for authorisation by the
national competent authority (for these aspects see
Section 2.1.4.2), and
— a change to the documentation submitted to the
Ethics Committee during the ongoing assessment of
the request for authorisation by the Ethics Committee.
109. Article 10(a) of Directive 2001/20/EC refers only to
amendments to the approved protocol. This is to be
understood as encompassing all documentation
submitted in the context of the approved protocol.
110. The annual safety report (ASR) in accordance with
Article 17(2) of Directive 2001/20/EC is not per se an
amendment and thus does not have to be notified as a
substantial amendment to the national competent
authority of the Member State concerned. However, the
sponsor has to verify whether the data presented in the
ASR requires a change to the documentation submitted
with the request for authorisation of a clinical trial. If this
amendment is substantial, the rules for notification of
substantial amendments apply to these changes.
111. A change of the contact person or in the contact details
of the contact person (e.g. a change of e-mail or postal
address) is not considered as an amendment, if the
sponsor and legal representative remain identical.
However, the sponsor should ensure that the national
competent authority of the Member State concerned is
aware of this change as soon as possible, in order to
allow the national competent authority to exercise its
supervisory function.
3.3. The notion of ‘substantial’
112. Amendments to the trial are regarded as ‘substantial’
where they are likely to have a significant impact on:
— the safety or physical or mental integrity of the clinical
trial participants, or
— the scientific value of the trial.
113. In all cases, an amendment is only to be regarded as
‘substantial’ when one or both of the above criteria are
met.
114. It is up to the sponsor to assess whether an amendment is
to be regarded as ‘substantial’. This assessment is to be
made on a case-by-case basis in view of the above criteria.
While the responsibility for this assessment lies with the
sponsor, in cases where the sponsor consults the national
competent authority advice should be given without delay
and free of charge.
115. In applying these criteria, however, care has to be taken to
avoid over-reporting. In particular, not every change to
the clinical trial application form is by default to be
considered as a ‘substantial’ amendment.
116. The annual update of the IB in accordance with Article 8
of Directive 2005/28/EC is not per se a substantial
amendment. However, the sponsor has to verify whether
the update relates to changes which are to be considered
as substantial. In that case, the rules for notification of
substantial amendments apply to the change.
117. The sponsor should assess also whether the combination
of substantial amendments lead to changes of the clinical
trial to an extent that it has to be considered as a
completely new clinical trial, which would then be
subject to a new authorisation procedure.
3.4. Examples
118. In view of these criteria the following examples should
serve as guidance for the case-by-case decision of the
sponsor. These examples relate only to the aspects
assessed by the national competent authority of the
Member State concerned. For aspects considered by the
Ethics Committee, reference is made to the Commission
guidance based on Article 8 of Directive 2001/20/EC.
3.4.1. Amendments as regards the clinical trials protocol
119. With regard to the protocol, the following is a non-
exhaustive list of amendments that are typically
‘substantial’:
(a) change of main objective of the clinical trial;
EN
30.3.2010 Official Journal of the European Union C 82/13
(
1
) Directive 2001/20/EC distinguishes between notification of the
national competent authority and information of the Ethics
Committee. For the purposes of this guidance, both submissions
will be referred to as ‘notification’.
(b) change of primary or secondary endpoint which is
likely to have a significant impact on the safety or
scientific value of the clinical trial;
(c) use of a new measurement for the primary endpoint;
(d) new toxicological or pharmacological data or new
interpretation of toxicological or pharmacological
data which is likely to impact on the risk/benefit
assessment;
(e) a change in the definition of the end of the trial, even
if the trial has in practice already ended;
(f) addition of a trial arm or placebo group;
(g) change of inclusion or exclusion criteria, such as
changes to age range, if these changes are likely to
have a significant impact on the safety or scientific
value of the clinical trial;
(h) reducing the number of monitoring visits;
(i) change of a diagnostic or medical monitoring
procedure which is likely to have a significant
impact on the safety or scientific value of the
clinical trial;
(j) withdrawal of an independent data monitoring board;
(k) change of IMPs;
(l) change of dosing of IMPs;
(m) change of mode of administration of IMPs;
(n) a change of study design which is likely to have a
significant impact on primary or major secondary
statistical analysis or the risk/benefit assessment.
120. With regard to the protocol, the following is a non-
exhaustive list of amendments that are typically not
‘substantial’:
(a) changes to the identification of the trial (e.g. change of
title, etc.);
(b) the addition/deletion of exploratory/tertiary endpoints;
(c) a minor increase in the duration of the trial (< 10 %
of the overall time of the trial);
(d) an increase in duration of > 10 % of the overall time
of the trial, provided that:
— the exposure to treatment with the IMP is not
extended,
— the definition of the end of the trial is unchanged,
and
— monitoring arrangements are unchanged;
(e) a change in the number of clinical trial participants
per trial site, if the total number of participants in the
Member State concerned is identical or the increase/
decrease is insignificant in view of the absolute
number of participants;
(f) a change in the number of clinical trial participants in
the Member State concerned, if the total number of
participants is identical or the increase/decrease is
insignificant in view of the absolute number of
participants;
(g) a change in the documentation used by the research
team for recording study data (e.g. case report form or
data collection form);
(h) additional safety monitoring which is not part of an
urgent safety measure but is taken on a precautionary
basis;
(i) minor clarifications to the protocol;
(j) correction of typographical errors.
3.4.2. Amendments as regards the IMPD
121. With regard to changes in the IMPD, guidance is
contained in Chapter 8 of the Guideline on the
requirements to the chemical and pharmaceutical quality
documentation concerning investigational medicinal
products in clinical trials (
1
).
3.4.3. Amendments as regards the IB
122. With regard to the IB, the following is a non-exhaustive
list of amendments that are typically ‘substantial’:
EN
C 82/14 Official Journal of the European Union 30.3.2010
(
1
) CHMP/QWP/185401/2004 final (http://ec.europa.eu/enterprise/
sectors/pharmaceuticals/documents/eudralex/vol-10/index_en.htm).
(a) new toxicological or pharmacological data or new
interpretation of toxicological or pharmacological
data of relevance for the investigator;
(b) changes to the reference safety information for the
annual safety report.
3.4.4. Amendments as regards other initial documents
supporting the request for authorisation of the clinical
trial
123. With regard to other initial documents, the following is a
non-exhaustive list of amendments that are typically
‘substantial’:
(a) a change of sponsor or the sponsor’s legal
representative;
(b) the revocation or suspension of the IMP’s marketing
authorisation.
124. With regard to other initial documents, the following is a
list of amendments that are typically not ‘substantial’:
(a) any change of persons other than the sponsor or his
legal representative, for example applicant, clinical
research associates (CRAs) who monitor the clinical
trial for the investigator, and clinical research organ
isations (CROs) (note that the responsibility vis-à-vis
the national competent authority for the clinical trial
is always with the sponsor or his legal representative);
(b) any change in the contact details of persons referred
to in the documentation (see, however, Section 3.2 as
regards contact details of the contact person);
(c) changes to the internal organisation of the sponsor or
of the persons to whom certain tasks have been
delegated;
(d) changes in the logistical arrangements for storing/
transporting samples;
(e) change of technical equipment;
(f) addition or deletion per se of another Member State
or third country concerned.
3.5. Who should be notified?
125. Substantial amendments may relate to information
relevant for assessment by the national competent
authority, the Ethics Committee, or both.
126. For substantial amendments to information that is
assessed only by the national competent authority of
the Member State concerned, the sponsor should only
notify the amendment to the national competent
authority.
127. For substantial amendments to information that is
assessed, according to Directive 2001/20/EC, only by
the Ethics Committee of the Member State concerned,
the sponsor should only notify the amendment to the
Ethics Committee. This is in particular of relevance for
the information relating to:
— the clinical trial site (Article 6(3)(f) of Directive
2001/20/EC),
— the written information to be given to the clinical trial
participant in order to obtain informed consent
(Article 6(3)(g) of Directive 2001/20/EC), and
— the investigator (Article 6(3)(d) of Directive
2001/20/EC).
128. These aspects are addressed in the separate Commission
guidance based on Article 8 of Directive 2001/20/EC.
129. In the case of substantial amendments that affect
information assessed by both the national competent
authority and the Ethics Committee of the Member
State concerned, the sponsor should submit the
notifications in parallel.
130. There is no need to notify ‘for information only’
substantial amendments to one body (national
competent authority or Ethics Committee), if this
information is assessed by the respective other body.
131. In practice, it is necessary that the national competent
authority and the Ethics Committee in the Member State
concerned communicate with each other in order to
ensure the exchange of expertise or information. This
may be in particular relevant, for example, for:
— assessing scientific information requiring specific
expertise,
— ensuring effective inspections of clinical trials sites,
and
— updating relevant information in EudraCT.
EN
30.3.2010 Official Journal of the European Union C 82/15
3.6. Non-substantial amendments
132. The sponsor does not have to notify non-substantial
amendments to the national competent authority or the
Ethics Committee. However, non-substantial amendments
should be recorded and contained in the documentation
when it is subsequently submitted, for example in the
subsequent notification of a substantial amendment. This
is of particular relevance for the Clinical Trial Application
Form: This form should be updated in its entirety at the
occasion of a substantial amendment. Documentation of
non-substantial amendments should also be available on
request for inspection at the trial site or the sponsor
premises as appropriate.
3.7. Format and content of notification
133. The notification of a substantial amendment should
include the following:
(a) a signed cover letter, including:
— in its subject line the EudraCT number and the
sponsor protocol number (if available) with the
title of the trial and the sponsor’s amendment
code number allowing unique identification of
the substantial amendment. Care should be taken
to use the code number consistently;
— identification of the applicant;
— identification of the amendment (sponsor’s
substantial amendment code number (
1
) and
date). One amendment could refer to several
changes in the protocol or scientific supporting
documents;
— a highlighted indication of any special issues
related to the amendment and indication where
the relevant information or text is in the original
application dossier;
— identification of any information not contained in
the Amendment Notification Form that might
impact on the risk to trial participants;
— where applicable, a list of all affected clinical trials
with EudraCT numbers and respective amendment
code numbers (see above);
(b) the Amendment Notification Form, as amended,
which is published in Volume 10 of EudraLex —
The Rules Governing Medicinal Products in the
European Union (
2
). Only this Amendment
Notification Form should be used;
(c) a description of the amendment:
— an extract from the amended documents showing
previous and new wording in track changes, as
well as the extract only showing the new wording;
— notwithstanding the previous point, if the changes
are so widespread or far-reaching that they justify
an entire new version of the document, a new
version of the entire document. In this case, an
additional table should list the amendments to the
documents. In this list, identical changes can be
grouped.
The new version should be identified with the date
and an updated version number.
(d) supporting information including, where applicable:
— summaries of data,
— an updated overall risk/benefit assessment,
— possible consequences for subjects already
included in the trial,
— possible consequences for the evaluation of the
results;
(e) if a substantial amendment involves changes to entries
on the clinical trial application form, a revised copy of
the XML file incorporating amended data. If the form
is not submitted via a telematics system, the fields
affected by the substantial amendment should be
highlighted in the revised form (
3
).
134. Where a substantial amendment affects more than one
clinical trial of the same sponsor and the same IMP, the
sponsor may make a single notification to the national
competent authority/Ethics Committee of the Member
State concerned. The cover letter and the notification
should contain a list of all clinical trials affected with
their EudraCT numbers and respective amendment code
numbers. If the substantial amendment involves changes
to several clinical trial application forms, all forms should
be updated (see Section 3.7).
EN
C 82/16 Official Journal of the European Union 30.3.2010
(
1
) The code number identifies the amendment and refers to all the
documents submitted. The sponsor decides which code to be used.
Section E1 of the amendment form should be completed with the
date and version of the new amendment to which this form relates.
(
2
) http://ec.europa.eu/enterprise/sectors/pharmaceuticals/documents/
eudralex/vol-10/index_en.htm
(
3
) Section A4 of the CTA form should contain the version and date of
the protocol originally authorised and this should not be changed
when the protocol is later amended. Section B4 of the amendment
form should contain the version and date of the currently authorised
protocol. Note that Section H of the CTA form does not need to be
changed, as it concerns the status of the CTA application to the
Ethics Committee at the time of the CTA submission to the CA.
3.8. Time for response, implementation
135. Article 10(a), second and third subparagraph, of Directive
2001/20/EC reads as follows:
‘On the basis of the details referred to in Article 6(3) and
in accordance with Article 7, the Ethics Committee shall
give an opinion within a maximum of 35 days of the date
of receipt of the proposed amendment in good and due
form. If this opinion is unfavourable, the sponsor may not
implement the amendment to the protocol.
If the opinion of the Ethics Committee is favourable and
the competent authorities of the Member States have
raised no grounds for non-acceptance of the …
substantial amendments, the sponsor shall proceed to
conduct the clinical trial following the amended
protocol. Should this not be the case, the sponsor shall
either take account of the grounds for non-acceptance and
adapt the proposed amendment to the protocol
accordingly or withdraw the proposed amendment.’
136. Accordingly, the Ethics Committee has to give within 35
calendar days an opinion on a valid submission of a
proposed substantial amendment. If a submission is not
considered as valid by the Ethics Committee, the Ethics
Committee should inform the applicant of this within the
first 10 calendar days of this 35-day period. The reasons
should be given.
137. With regard to the national competent authority, no
deadline is set in Directive 2001/20/EC., and in view of
the approval time for requests for authorisation, the
national competent authority are invited to respond
within 35 calendar days of receipt of the valid notification
of an amendment. Validation of the submission is
included in this period. If a submission is not valid (for
example, the dossier does not contain the documentation
required according to this guidance), the national
competent authority are invited to inform the applicant
of this within the first 10 calendar days of this 35-day
period. The reasons should be given. This response time
may be extended if such extension is justified in view of
the nature of the substantial amendment, for example if
the national competent authority has to consult an expert
group or committee. In such cases, the national
competent authority should notify the sponsor of the
duration of the extension and its reasons. If the national
competent authority states that it raises no grounds for
non-acceptance, the sponsor can implement the changes,
even if fewer than 35 days have elapsed since the filing of
the substantial amendment.
138. For amendments submitted to either the Ethics Committee
alone or to the national competent authority alone, the
sponsor may implement the amendment when the Ethics
Committee opinion is favourable or the competent
national authority has raised no grounds for non-
acceptance.
139. Up until then, the trial can continue on the basis of the
original documentation, unless the rules for urgent safety
measures apply.
140. Applicants should be aware that these procedures are
intended to ensure rapid and efficient processing of
substantial amendments. Against this background, unsatis
factory documentation is likely to lead to non-acceptance
of the substantial amendment. Non-acceptance does not
prejudice the applicant’s right to resubmission.
141. Upon approval, it is the sponsor’s responsibility to ensure
communication of the changes to the investigators.
3.9. Notification of urgent safety measures
142. Article 10(b) of Directive 2001/20/EC reads as follows:
‘Without prejudice to point (a), in the light of the circum
stances, notably the occurrence of any new event relating
to the conduct of the trial or the development of the
investigational medicinal product where the new event is
likely to affect the safety of the subjects, the sponsor and
the investigator shall take appropriate urgent safety
measures to protect the subjects against any immediate
hazard. The sponsor shall forthwith inform the
competent authorities of those new events and the
measures taken and shall ensure that the Ethics
Committee is notified at the same time.’
143. Examples of urgent safety measures are if, for reasons of
safety of the clinical trial participants, a trial is temporarily
halted (see Section 3.10) or additional monitoring
measures are set up.
144. Urgent safety measures may be taken without prior notifi
cation to the national competent authority. However, the
sponsor must inform ex post the national competent
authority and the Ethics Committee of the Member
State concerned of the new events, the measures taken
and the plan for further action as soon as possible.
Where the initial contact is by telephone, this should be
followed up, for reasons of traceability, by fax or e-mail. It
should be followed by a written report.
145. The ex post notification of urgent safety measures is
independent of the obligation to:
EN
30.3.2010 Official Journal of the European Union C 82/17
— notify substantial amendments (see above),
— notify early termination of the trial within 15 days in
accordance with Article 10(c) of Directive 2001/20/EC
(see below, Section 4.2.2), and
— notify adverse events and serious adverse reactions in
accordance with Articles 16 and 17 of Directive
2001/20/EC.
3.10. Temporary halt of a trial
146. A temporary halt of a trial is a stoppage of the trial which
is not envisaged in the approved protocol and where there
is an intention to resume it.
147. A temporary halt can be:
— a substantial amendment, or
— part of an urgent safety measure as referred to in
Article 10(b) of Directive 2001/20/EC. In this case,
the notification of the temporary halt of a trial
should be made immediately and, at the latest, in
accordance with the deadline set out in Article 10(c),
second sentence, of Directive 2001/20/EC, within 15
days from when the trial is temporarily halted.
148. The reasons and scope, e.g. stopping recruitment or inter
rupting treatment of subjects already included, should be
clearly explained in the notification (in case of substantial
amendment, see Section 3.7) or in the ex post information
(in case of urgent safety measures, see Section 3.9).
149. The restart of the trial should be treated as a substantial
amendment providing evidence that it is safe to restart the
trial.
150. If the sponsor decides not to recommence a temporarily
halted trial he should notify the national competent
authority of the Member States concerned within 15
days of his decision in accordance with Article 10(c),
second sentence, of Directive 2001/20/EC (see
Section 4.2).
3.11. Suspension/prohibition of a clinical trial by the
national competent authority in case of doubts about
safety or scientific validity
151. Article 12(1) of Directive 2001/20/EC reads as follows:
‘Where a Member State has objective grounds for
considering that the conditions in the request for
authorisation referred to in Article 9(2) are no longer met
or has information raising doubts about the safety or
scientific validity of the clinical trial, it may suspend or
prohibit the clinical trial and shall notify the sponsor
thereof.
Before the Member State reaches its decision it shall,
except where there is imminent risk, ask the sponsor
and/or the investigator for their opinion, to be delivered
within one week.
In this case, the competent authority concerned shall
forthwith inform the other competent authorities, the
Ethics Committee concerned, the Agency and the
Commission of its decision to suspend or prohibit the
trial and of the reasons for the decision.’
152. If the trial is terminated following a suspension, the rules
on end of trial notification apply (see below, Section 4.2).
3.12. Non-compliance with the applicable rules on
clinical trials
153. Article 12(2) of Directive 2001/20/EC reads as follows:
‘Where a competent authority has objective grounds for
considering that the sponsor or the investigator or any
other person involved in the conduct of the trial no
longer meets the obligations laid down, it shall
forthwith inform him thereof, indicating the course of
action which he must take to remedy this state of
affairs. The competent authority concerned shall
forthwith inform the Ethics Committee, the other
competent authorities and the Commission of this
course of action.’
154. The ‘course of action’ of the national competent authority
should have a timetable for its implementation and a date
when the sponsor should report back to the national
competent authority on the progress and completion of
its implementation.
155. The sponsor should ensure that the ‘course of action’ set
by the national competent authority is immediately imple
mented and report to the national competent authority of
the Member State concerned on the progress in and
completion of its implementation in accordance with
the timetable set.
156. The national competent authority must inform the other
national competent authorities, the Ethics Committee of
the Member State concerned and the Commission of the
‘course of action’.
EN
C 82/18 Official Journal of the European Union 30.3.2010
4. DECLARATION OF THE END OF A CLINICAL TRIAL
4.1. Legal basis and scope
157. Article 10(c) of Directive 2001/20/EC reads as follows:
‘Within 90 days of the end of a clinical trial the sponsor
shall notify the competent authorities of the Member State
or Member States concerned and the Ethics Committee
that the clinical trial has ended. If the trial has to be
terminated early, this period shall be reduced to 15 days
and the reasons clearly explained.’
158. ‘End of the trial’ is not defined in Directive 2001/20/EC.
The definition of the end of the trial should be provided
in the protocol (for guidance, see Section 2.5). For
changes to the definition see under Section 3.4.1.
4.2. Procedure for declaring the end of the trial
4.2.1. General rules
159. The sponsor has to make an end of trial declaration when
the complete trial has ended in all Member States/third
countries concerned. The end of the clinical trial is defined
in the protocol (see Section 4.1).
160. This declaration has to be made to the national competent
authority and the Ethics Committee of all Member States
concerned within 90 days of the end of the clinical trial.
To this end, the form published in Volume 10 of
EudraLex — The Rules Governing Medicinal Products in
the European Union (
1
) should be used.
161. The notified Member States are responsible for entering
this information into the EudraCT database.
4.2.2. Shortened deadline for early termination
162. An earlier end of the clinical trial which is not based on
grounds of safety, but on other grounds, such as faster
recruitment than anticipated, is not considered as ‘early
termination’.
163. In the case of early termination, the sponsor must notify
the end of the trial to the national competent authority
and the Ethics Committee of the Member State concerned
immediately and at the latest within 15 days after the trial
is halted, clearly explain the reasons, and describe follow-
up measures, if any, taken for safety reasons.
4.3. Clinical trial summary report
164. The clinical trial summary report is part of the end of trial
notification, albeit usually submitted only subsequently to
the end of trial notification. The sponsor should provide
this summary report within one year of the end of the
complete trial for non-paediatric clinical trials. For
paediatric clinical trials, the timelines are set out in the
Commission Communication 2009/C28/01. Regarding
the arrangements for submitting the clinical trial
summary report, its format, content, and its accessibility
for the public, reference is made to the Commission
Communications 2009/C28/01 and 2008/C168/02 and
their implementing technical guidance documents (
2
).
EN
30.3.2010 Official Journal of the European Union C 82/19
(
1
) http://ec.europa.eu/enterprise/sectors/pharmaceuticals/documents/
eudralex/vol-10/index_en.htm
(
2
) http://ec.europa.eu/enterprise/sectors/pharmaceuticals/documents/
eudralex/vol-10/index_en.htm
