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 (Text with EEA relevance)
Date: 2007-11-13
Institutions: Council of the European Union, European Parliament
Subjects: biotechnology, drug surveillance, labelling, market approval, marketing standard, medicinal product, qualitative analysis

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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

(Text with EEA relevance)

THE EUROPEAN PARLIAMENT AND THE COUNCIL OF THE EURO-
PEAN UNION,

Having regard to the Treaty establishing the European Commu-
nity, and in particular Article 95 thereof,

Having regard to the proposal from the Commission,

Having regard to the Opinion of the European Economic and
Social Committee (1),

After consulting the Committee of the Regions,

Acting in accordance with the procedure laid down in Article 251
of the Treaty (2),

Whereas:

(1)

(2)

New scientific progress in cellular and molecular biotech-
nology has led to the development of advanced therapies,
such as gene therapy, somatic cell therapy, and tissue engi-
neering. This nascent field of biomedicine offers new
opportunities for the treatment of diseases and dysfunc-
tions of the human body.

Insofar as advanced therapy products are presented as hav-
ing properties for treating or preventing diseases in human
beings, or that they may be used in or administered to
human beings with a view to restoring, correcting or modi-
fying physiological functions by exerting principally a
pharmacological, immunological or metabolic action, they
are biological medicinal products within the meaning of
Annex I to Directive 2001/83/EC of the European Parlia-
ment and of the Council of 6 November 2001 on the
Community code relating to medicinal products for human
use (3), read in conjunction with the definition of medici-
nal products in Article 1(2) thereof. Thus, the essential aim
of any rules governing their production, distribution and
use must be to safeguard public health.

(3)

For reasons of clarity, complex therapeutic products
require precise legal definitions. Gene therapy medicinal
products and somatic cell therapy medicinal products have

(1) OJ C 309, 16.12.2006, p. 15.
(2) Opinion of the European Parliament of 25 April 2007 (not yet pub-
lished in the Official Journal) and Council Decision of 30 October
2007.

(3) OJ L 311, 28.11.2001, p. 67. Directive as last amended by Regulation

(EC) No 1901/2006 (OJ L 378, 27.12.2006, p. 1).

(4)

(5)

(6)

been defined in Annex I to Directive 2001/83/EC, but a
legal definition of tissue engineered products remains to be
laid down. When products are based on viable cells or tis-
sues, the pharmacological, immunological or metabolic
action should be considered as the principal mode of
action. It should also be clarified that products which do
not meet the definition of a medicinal product, such as
products made exclusively of non-viable materials which
act primarily by physical means, cannot by definition be
advanced therapy medicinal products.

According to Directive 2001/83/EC and the Medical
Device Directives the basis for deciding which regulatory
regime is applicable to combinations of medicinal prod-
ucts and medical devices is the principal mode of action of
the combination product. However, the complexity of
combined advanced therapy medicinal products contain-
ing viable cells or tissues requires a specific approach. For
these products, whatever the role of the medical device, the
pharmacological, immunological or metabolic action of
these cells or tissues should be considered to be the prin-
cipal mode of action of the combination product. Such
combination products should always be regulated under
this Regulation.

Because of the novelty, complexity and technical specific-
ity of advanced therapy medicinal products, specially tai-
lored and harmonised rules are needed to ensure the free
movement of those products within the Community, and
the effective operation of the internal market in the bio-
technology sector.

This Regulation is a lex specialis, which introduces addi-
tional provisions
to those laid down in Directive
2001/83/EC. The scope of this Regulation should be to
regulate advanced therapy medicinal products which are
intended to be placed on the market in Member States and
either prepared industrially or manufactured by a method
involving an industrial process, in accordance with the
general scope of the Community pharmaceutical legisla-
tion laid down in Title II of Directive 2001/83/EC.
Advanced therapy medicinal products which are prepared
on a non-routine basis according to specific quality stan-
dards, and used within the same Member State in a hospi-
tal under the exclusive professional responsibility of a
medical practitioner, in order to comply with an individual
medical prescription for a custom-made product for an
individual patient, should be excluded from the scope of
this Regulation whilst at the same time ensuring that rel-
evant Community rules related to quality and safety are not
undermined.

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(7)

(8)

(9)

The regulation of advanced therapy medicinal products at
Community level should not interfere with decisions made
by Member States on whether to allow the use of any spe-
cific type of human cells, such as embryonic stem cells, or
animal cells. It should also not affect the application of
national legislation prohibiting or restricting the sale, sup-
ply or use of medicinal products containing, consisting of
or derived from these cells.

This Regulation respects the fundamental rights and
observes the principles reflected in the Charter of Funda-
mental Rights of the European Union and also takes into
account the Council of Europe Convention for the Protec-
tion of Human Rights and Dignity of the Human Being
with regard to the Application of Biology and Medicine:
Convention on Human Rights and Biomedicine.

All other modern biotechnology medicinal products cur-
rently regulated at Community level are already subject to
a centralised authorisation procedure, involving a single
scientific evaluation of the quality, safety and efficacy of
the product, which is carried out to the highest possible
standard by the European Medicines Agency as established
by Regulation (EC) No 726/2004 of the European Parlia-
ment and of the Council of 31 March 2004 laying down
Community procedures for the authorisation and supervi-
sion of medicinal products for human and veterinary
use (1) (hereinafter referred to as the Agency). This proce-
dure should also be compulsory for advanced therapy
medicinal products in order to overcome the scarcity of
expertise in the Community, ensure a high level of scien-
tific evaluation of these medicinal products in the Commu-
nity, preserve the confidence of patients and medical
professions in the evaluation and facilitate Community
market access for these innovative technologies.

(10)

The evaluation of advanced therapy medicinal products
often requires very specific expertise, which goes beyond
the traditional pharmaceutical field and covers areas bor-
dering on other sectors such as biotechnology and medi-
cal devices. For this reason, it is appropriate to create,
within the Agency, a Committee for Advanced Therapies,
which should be responsible for preparing a draft opinion
on the quality, safety and efficacy of each advanced therapy
medicinal product for final approval by the Agency’s Com-
mittee for Medicinal Products for Human Use. In addition,
the Committee for Advanced Therapies should be con-
sulted for the evaluation of any other medicinal product
which requires specific expertise falling within its area of
competence.

(11)

The Committee for Advanced Therapies should gather the
best available expertise on advanced therapy medicinal
products in the Community. The composition of the Com-
mittee for Advanced Therapies should ensure appropriate
coverage of the scientific areas relevant to advanced

therapies, including gene therapy, cell therapy, tissue engi-
neering, medical devices, pharmacovigilance and ethics.
Patient associations and clinicians with scientific experi-
ence of advanced therapy medicinal products should also
be represented.

(12)

To ensure scientific consistency and the efficiency of the
the Agency should ensure the coordination
system,
between the Committee for Advanced Therapies and its
other Committees, advisory groups and working parties,
notably the Committee for Medicinal Products for Human
Use, the Committee on Orphan Medicinal Products, and
the Scientific Advice Working Party.

(13) Advanced therapy medicinal products should be subject to
the same regulatory principles as other types of biotech-
nology medicinal products. However, technical require-
ments, in particular the type and amount of quality, pre-
clinical and clinical data necessary to demonstrate the
quality, safety and efficacy of the product, may be highly
specific. While those requirements are already laid down in
Annex I to Directive 2001/83/EC for gene therapy medici-
nal products and somatic cell therapy medicinal products,
they need to be established for tissue engineered products.
This should be done through a procedure that provides for
sufficient flexibility, so as to easily accommodate the rapid
evolution of science and technology.

(14) Directive 2004/23/EC of the European Parliament and of
the Council (2) sets standards of quality and safety for the
donation, procurement, testing, processing, preservation,
storage and distribution of human tissues and cells. This
Regulation should not derogate from the basic principles
laid down in Directive 2004/23/EC, but should supple-
ment them with additional requirements, where appropri-
ate. Where an advanced therapy medicinal product
contains human cells or tissues, Directive 2004/23/EC
should apply only as far as donation, procurement and
testing are concerned, since the further aspects are covered
by this Regulation.

(15) As regards the donation of human cells or tissues, prin-
ciples such as the anonymity of both donor and recipient,
altruism of the donor and solidarity between donor and
recipient should be respected. As a matter of principle,
human cells or tissues contained in advanced therapy
medicinal products should be procured from voluntary
and unpaid donation. Member States should be urged to
take all necessary steps to encourage a strong public and
non-profit sector involvement in the procurement of
human cells or tissues, as voluntary and unpaid cell and tis-
sue donations may contribute to high safety standards for
cells and tissues and therefore to the protection of human
health.

(1) OJ L 136, 30.4.2004, p. 1. Regulation as amended by Regulation (EC)

No 1901/2006.

(2) OJ L 102, 7.4.2004, p. 48.

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(16)

(17)

Clinical trials on advanced therapy medicinal products
should be conducted in accordance with the overarching
principles and the ethical requirements laid down in Direc-
tive 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 prac-
tice in the conduct of clinical trials on medicinal products
for human use (1). However, Commission Directive
2005/28/EC of 8 April 2005 laying down principles and
detailed guidelines for good clinical practice as regards
investigational medicinal products for human use, as well
as the requirements for authorisation of the manufactur-
ing or importation of such products (2) should be adapted
by laying down rules tailored to fully take into account the
specific technical characteristics of advanced therapy
medicinal products.

The manufacture of advanced therapy medicinal products
should be in compliance with the principles of good manu-
facturing practice, as set out in Commission Directive
2003/94/EC of 8 October 2003 laying down the principles
and guidelines of good manufacturing practice in respect
of medicinal products for human use and investigational
medicinal products for human use (3), and adapted, where
necessary, to reflect the specific nature of those products.
Furthermore, guidelines specific to advanced therapy
medicinal products should be drawn up, so as to properly
reflect the particular nature of their manufacturing process.

(18) Advanced therapy medicinal products may incorporate
medical devices or active implantable medical devices.
Those devices should meet the essential requirements laid
down in Council Directive 93/42/EEC of 14 June 1993
concerning medical devices (4) and Council Directive
90/385/EEC of 20 June 1990 on the approximation of the
laws of the Member States relating to active implantable
medical devices (5), respectively,
in order to ensure an
appropriate level of quality and safety. The results of the
assessment of the medical device part or the active implant-
able medical device part by a notified body in accordance
with those Directives should be recognised by the Agency
in the evaluation of a combined advanced therapy medici-
nal product carried out under this Regulation.

(19)

The requirements in Directive 2001/83/EC as regards the
summary of product characteristics, labelling and the pack-
age leaflet should be adapted to the technical specificities
of advanced therapy medicinal products by laying down

(1) OJ L 121, 1.5.2001, p. 34. Directive as amended by Regulation (EC)

No 1901/2006.

(2) OJ L 91, 9.4.2005, p. 13.
(3) OJ L 262, 14.10.2003, p. 22.
(4) OJ L 169, 12.7.1993, p. 1. Directive as last amended by Directive
2007/47/EC of the European Parliament and of the Council (OJ L 247,
21.9.2007, p. 21).

(5) OJ L 189, 20.7.1990, p. 17. Directive as last amended by Directive

2007/47/EC.

(20)

(21)

specific rules on those products. These rules should com-
ply fully with the patient’s right to know the origin of any
cells or tissues used in the preparation of advanced therapy
medicinal products, while respecting donor anonymity.

Follow-up of efficacy and adverse reactions is a crucial
aspect of the regulation of advanced therapy medicinal
products. The applicant should therefore detail in its mar-
keting authorisation application whether measures are
envisaged to ensure such follow-up and, if so, what those
measures are. Where justified on public health grounds,
the holder of the marketing authorisation should also be
required to put in place a suitable risk management system
to address risks related to advanced therapy medicinal
products.

The operation of this Regulation requires the establishment
of guidelines to be drawn up either by the Agency or by
the Commission. Open consultation with all interested
parties, in particular Member State authorities and the
industry, should be carried out in order to allow a pooling
of the limited expertise in this area and ensure proportion-
ality. The guidelines on good clinical practice and good
manufacturing practice should be laid down as soon as
possible, preferably during the first year after entry into
force and before the date of application of this Regulation.

(22) A system allowing complete traceability of the patient as
well as of the product and its starting materials is essential
to monitor the safety of advanced therapy medicinal prod-
ucts. The establishment and maintenance of that system
should be done in such a way as to ensure coherence and
compatibility with traceability requirements laid down in
Directive 2004/23/EC in respect of human tissues and
cells, and in Directive 2002/98/EC of the European Parlia-
ment and of the Council of 27 January 2003 setting stan-
dards of quality and safety for the collection, testing,
processing, storage and distribution of human blood and
blood components (6). The traceability system should also
respect the provisions laid down in Directive 95/46/EC of
the European Parliament and of the Council of 24 Octo-
ber 1995 on the protection of individuals with regard to
the processing of personal data and the free movement of
such data (7).

(23) As science evolves very rapidly in this field, undertakings
developing advanced therapy medicinal products should
be enabled to request scientific advice from the Agency,
including advice on post-authorisation activities. As an
incentive, the fee for that scientific advice should be kept
at a minimal level for small and medium-sized enterprises,
and should also be reduced for other applicants.

(6) OJ L 33, 8.2.2003, p. 30.
(7) OJ L 281, 23.11.1995, p. 31. Directive as amended by Regulation (EC)

No 1882/2003 (OJ L 284, 31.10.2003, p. 1).

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(24)

(25)

(26)

(27)

(28)

(29)

(30)

The Agency should be empowered to give scientific recom-
mendations on whether a given product based on genes,
cells or tissues meets the scientific criteria which define
advanced therapy medicinal products, in order to address,
as early as possible, questions of borderline with other
areas such as cosmetics or medical devices, which may
arise as science develops. The Committee for Advanced
Therapies, with its unique expertise, should have a promi-
nent role in the provision of such advice.

Studies necessary to demonstrate the quality and non-
clinical safety of advanced therapy medicinal products are
often carried out by small and medium-sized enterprises.
As an incentive to conduct those studies, a system of evalu-
ation and certification of the resulting data by the Agency,
independently of any marketing authorisation application,
should be introduced. Even though the certification would
not be legally binding, this system should also aim at facili-
tating the evaluation of any future application for clinical
trials and marketing authorisation application based on the
same data.

In order to take into account scientific and technical devel-
opments, the Commission should be empowered to adopt
any necessary changes regarding the technical require-
ments for applications for marketing authorisation of
advanced therapy medicinal products, the summary of
product characteristics, labelling, and the package leaflet.
The Commission should ensure that relevant information
on envisaged measures is made available to interested par-
ties without delay.

Provisions should be laid down to report on the implemen-
tation of this Regulation after experience has been gained,
with a particular attention to the different
types of
advanced therapy medicinal products authorised.

The opinions of the Scientific Committee for Medicinal
Products and Medical Devices concerning tissue engineer-
ing and that of the European Group on Ethics in Science
and New Technologies have been taken into account, as
well as international experience in this field.

The measures necessary for the implementation of this
Regulation should be adopted in accordance with Council
Decision 1999/468/EC of 28 June 1999 laying down the
procedures for the exercise of implementing powers con-
ferred on the Commission (1).

In particular, the Commission should be empowered to
adopt amendments to Annexes I to IV to this Regulation
and to Annex I to Directive 2001/83/EC. Since those mea-
sures are of general scope and are designed to amend non-
essential elements of this Regulation and of Directive
2001/83/EC, they must be adopted in accordance with the

(1) OJ L 184, 17.7.1999, p. 23. Decision as amended by Decision

2006/512/EC (OJ L 200, 22.7.2006, p. 11).

in
regulatory procedure with scrutiny provided for
Article 5a of Decision 1999/468/EC. Those measures are
essential for the proper operation of the whole regulatory
framework and should therefore be adopted as soon as
possible.

(31) Directive 2001/83/EC and Regulation (EC) No 726/2004

should therefore be amended accordingly,

HAVE ADOPTED THIS REGULATION:

CHAPTER 1

SUBJECT MATTER AND DEFINITIONS

Article 1

Subject matter

This Regulation lays down specific rules concerning the authori-
sation, supervision and pharmacovigilance of advanced therapy
medicinal products.

Article 2

Definitions

In addition to the definitions laid down in Article 1 of Direc-
1.
tive 2001/83/EC and in Article 3, points (a) to (l) and (o) to (q) of
Directive 2004/23/EC, the following definitions shall apply for
the purposes of this Regulation:

(a)

‘Advanced therapy medicinal product’ means any of the fol-
lowing medicinal products for human use:

— a gene therapy medicinal product as defined in Part IV

of Annex I to Directive 2001/83/EC,

— a somatic cell therapy medicinal product as defined in

Part IV of Annex I to Directive 2001/83/EC,

— a tissue engineered product as defined in point (b).

(b)

‘Tissue engineered product’ means a product that:

— contains or consists of engineered cells or tissues, and

— is presented as having properties for, or is used in or
administered to human beings with a view to regenerat-
ing, repairing or replacing a human tissue.

A tissue engineered product may contain cells or tissues of
human or animal origin, or both. The cells or tissues may be
viable or non-viable. It may also contain additional sub-
stances, such as cellular products, bio-molecules, bio-
materials, chemical substances, scaffolds or matrices.

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Products containing or consisting exclusively of non-viable
human or animal cells and/or tissues, which do not contain
any viable cells or tissues and which do not act principally by
pharmacological, immunological or metabolic action, shall
be excluded from this definition.

CHAPTER 2

MARKETING AUTHORISATION REQUIREMENTS

Article 3

(c) Cells or tissues shall be considered ‘engineered’ if they fulfil

Donation, procurement and testing

at least one of the following conditions:

— the cells or tissues have been subject to substantial
manipulation, so that biological characteristics, physi-
ological functions or structural properties relevant for
the intended regeneration, repair or replacement are
achieved. The manipulations listed in Annex I, in par-
ticular,
substantial
manipulations,

considered as

shall not be

— the cells or tissues are not intended to be used for the
same essential function or functions in the recipient as
in the donor.

(d)

‘Combined advanced therapy medicinal product’ means an
advanced therapy medicinal product that fulfils the follow-
ing conditions:

— it must incorporate, as an integral part of the product,
one or more medical devices within the meaning of
Article 1(2)(a) of Directive 93/42/EEC or one or more
active implantable medical devices within the meaning
of Article 1(2)(c) of Directive 90/385/EEC, and

— its cellular or tissue part must contain viable cells or tis-

sues, or

— its cellular or tissue part containing non-viable cells or
tissues must be liable to act upon the human body with
action that can be considered as primary to that of the
devices referred to.

2. Where a product contains viable cells or tissues, the phar-
macological, immunological or metabolic action of those cells or
tissues shall be considered as the principal mode of action of the
product.

3.
An advanced therapy medicinal product containing both
autologous (emanating from the patient himself) and allogeneic
(coming from another human being) cells or tissues shall be con-
sidered to be for allogeneic use.

4.
A product which may fall within the definition of a tissue
engineered product and within the definition of a somatic cell
therapy medicinal product shall be considered as a tissue engi-
neered product.

5.

A product which may fall within the definition of:

— a somatic cell therapy medicinal product or a tissue engi-

neered product, and

— a gene therapy medicinal product,

shall be considered as a gene therapy medicinal product.

Where an advanced therapy medicinal product contains human
cells or tissues, the donation, procurement and testing of those
cells or tissues shall be made in accordance with Directive
2004/23/EC.

Article 4

Clinical trials

1.
The rules set out in Article 6(7) and Article 9(4) and (6) of
Directive 2001/20/EC in respect of gene therapy and somatic cell
therapy medicinal products shall apply to tissue engineered
products.

2.
The Commission shall, after consulting the Agency, draw up
detailed guidelines on good clinical practice specific to advanced
therapy medicinal products.

Article 5

Good manufacturing practice

The Commission shall, after consulting the Agency, draw up
guidelines in line with the principles of good manufacturing prac-
tice and specific to advanced therapy medicinal products.

Article 6

Issues specific to medical devices

1.
A medical device which forms part of a combined advanced
therapy medicinal product shall meet the essential requirements
laid down in Annex I to Directive 93/42/EEC.

2.
An active implantable medical device which forms part of a
combined advanced therapy medicinal product shall meet the
essential requirements laid down in Annex 1 to Directive
90/385/EEC.

Article 7

Specific requirements for advanced therapy medicinal
products containing devices

In addition to the requirements laid down in Article 6(1) of Regu-
lation (EC) No 726/2004, applications for the authorisation of an
advanced therapy medicinal product containing medical devices,
bio-materials, scaffolds or matrices shall include a description of
the physical characteristics and performance of the product and a
description of the product design methods, in accordance with
Annex I to Directive 2001/83/EC.

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CHAPTER 3

MARKETING AUTHORISATION PROCEDURE

The Agency shall recognise the results of that assessment in its
evaluation of the medicinal product concerned.

Article 8

Evaluation procedure

The Committee for Medicinal Products for Human Use shall
1.
consult the Committee for Advanced Therapies on any scientific
assessment of advanced therapy medicinal products necessary to
draw up the scientific opinions referred to in Article 5(2) and (3)
of Regulation (EC) No 726/2004. The Committee for Advanced
Therapies shall also be consulted in the event of re-examination
of the opinion pursuant to Article 9(2) of Regulation (EC)
No 726/2004.

2. When preparing a draft opinion for final approval by the
Committee for Medicinal Products for Human Use, the Commit-
tee for Advanced Therapies shall endeavour to reach a scientific
consensus. If such consensus cannot be reached, the Committee
for Advanced Therapies shall adopt the position of the majority
of its members. The draft opinion shall mention the divergent
positions and the grounds on which they are based.

The draft opinion given by the Committee for Advanced
3.
Therapies under paragraph 1 shall be sent to the Chairman of the
Committee for Medicinal Products for Human Use in a timely
manner so as to ensure that the deadline laid down in Article 6(3)
or Article 9(2) of Regulation (EC) No 726/2004 can be met.

4. Where the scientific opinion on an advanced therapy
medicinal product drawn up by the Committee for Medicinal
Products for Human Use under Article 5(2) and (3) of Regulation
(EC) No 726/2004 is not in accordance with the draft opinion of
the Committee for Advanced Therapies, the Committee for
Medicinal Products for Human Use shall annex to its opinion a
detailed explanation of the scientific grounds for the differences.

The Agency shall draw up specific procedures for the appli-

5.
cation of paragraphs 1 to 4.

Article 9

Combined advanced therapy medicinal products

1. Where a combined advanced therapy medicinal product is
concerned, the whole product shall be subject to final evaluation
by the Agency.

The application for a marketing authorisation for a com-
2.
bined advanced therapy medicinal product shall include evidence
of conformity with the essential requirements referred to in
Article 6.

3.
The application for a marketing authorisation for a com-
bined advanced therapy medicinal product shall include, where
available, the results of the assessment by a notified body in accor-
dance with Directive 93/42/EEC or Directive 90/385/EEC of the
medical device part or active implantable medical device part.

The Agency may request the relevant notified body to transmit
any information related to the results of its assessment. The noti-
fied body shall transmit the information within a period of one
month.

If the application does not include the results of the assessment,
the Agency shall seek an opinion on the conformity of the device
part with Annex I to Directive 93/42/EEC or Annex 1 to Direc-
tive 90/385/EEC from a notified body identified in conjunction
with the applicant, unless the Committee for Advanced Therapies
advised by its experts for medical devices decides that involve-
ment of a notified body is not required.

CHAPTER 4

SUMMARY OF PRODUCT CHARACTERISTICS, LABELLING
AND PACKAGE LEAFLET

Article 10

Summary of product characteristics

By way of derogation from Article 11 of Directive 2001/83/EC,
the summary of the product characteristics for advanced therapy
medicinal products shall contain the information listed in
Annex II to this Regulation, in the order indicated therein.

Article 11

Labelling of outer/immediate packaging

By way of derogation from Articles 54 and 55(1) of Directive
2001/83/EC, the particulars listed in Annex III to this Regulation
shall appear on the outer packaging of advanced therapy medici-
nal products or, where there is no outer packaging, on the imme-
diate packaging.

Article 12

Special immediate packaging

In addition to the particulars mentioned in Article 55(2) and (3)
of Directive 2001/83/EC, the following particulars shall appear
on the immediate packaging of advanced therapy medicinal
products:

(a)

the unique donation and product codes, as referred to in
Article 8(2) of Directive 2004/23/EC;

(b)

in the case of advanced therapy medicinal products for
autologous use, the unique patient identifier and the state-
ment ‘For autologous use only’.

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Article 13

Package leaflet

Article 15

Traceability

By way of derogation from Article 59(1) of Directive
1.
2001/83/EC, the package leaflet for an advanced therapy medici-
nal product shall be drawn up in accordance with the summary
of product characteristics and shall include the information listed
in Annex IV to this Regulation, in the order indicated therein.

2.
The package leaflet shall reflect the results of consultations
with target patient groups to ensure that it is legible, clear and
easy to use.

CHAPTER 5

POST-AUTHORISATION REQUIREMENTS

Article 14

Post-authorisation follow-up of efficacy and adverse
reactions, and risk management

1.
In addition to the requirements for pharmacovigilance laid
down in Articles 21 to 29 of Regulation (EC) No 726/2004, the
applicant shall detail, in the marketing authorisation application,
the measures envisaged to ensure the follow-up of efficacy of
advanced therapy medicinal products and of adverse reactions
thereto.

2. Where there is particular cause for concern, the Commis-
sion shall, on the advice of the Agency, require as part of the mar-
keting authorisation that a risk management system designed to
identify, characterise, prevent or minimise risks related to
advanced therapy medicinal products, including an evaluation of
the effectiveness of that system, be set up, or that specific post-
marketing studies be carried out by the holder of the marketing
authorisation and submitted for review to the Agency.

The holder of a marketing authorisation for an advanced
1.
therapy medicinal product shall establish and maintain a system
ensuring that the individual product and its starting and raw
materials, including all substances coming into contact with the
cells or tissues it may contain, can be traced through the sourc-
ing, manufacturing, packaging, storage, transport and delivery to
the hospital, institution or private practice where the product is
used.

The hospital,

institution or private practice where the
2.
advanced therapy medicinal product is used shall establish and
maintain a system for patient and product traceability. That sys-
tem shall contain sufficient detail to allow linking of each prod-
uct to the patient who received it and vice versa.

3. Where an advanced therapy medicinal product contains
human cells or tissues, the marketing authorisation holder, as well
as the hospital, institution or private practice where the product
is used, shall ensure that the traceability systems established in
accordance with paragraphs 1 and 2 of this Article are comple-
mentary to, and compatible with, the requirements laid down in
Articles 8 and 14 of Directive 2004/23/EC as regards human cells
and tissues other than blood cells, and Articles 14 and 24 of
Directive 2002/98/EC as regards human blood cells.

4.
The marketing authorisation holder shall keep the data
referred to in paragraph 1 for a minimum of 30 years after the
expiry date of the product, or longer if required by the Commis-
sion as a term of the marketing authorisation.

In case of bankruptcy or liquidation of the marketing autho-
5.
risation holder, and in the event that the marketing authorisation
is not transferred to another legal entity, the data referred to in
paragraph 1 shall be transferred to the Agency.

In addition, the Agency may request submission of additional
reports evaluating the effectiveness of any risk management sys-
tem and the results of any such studies performed.

6.
In the event that the marketing authorisation is suspended,
revoked or withdrawn, the holder of the marketing authorisation
shall remain subject to the obligations laid down in paragraphs 1,
3 and 4.

Evaluation of the effectiveness of any risk management system
and the results of any studies performed shall be included in the
periodic safety update reports referred to in Article 24(3) of Regu-
lation (EC) No 726/2004.

7.
The Commission shall draw up detailed guidelines relating
to the application of paragraphs 1 to 6, in particular the type and
amount of data referred to in paragraph 1.

3.
The Agency shall forthwith inform the Commission if it
finds that the marketing authorisation holder has failed to com-
ply with the requirements referred to in paragraph 2.

The Agency shall draw up detailed guidelines relating to the

4.
application of paragraphs 1, 2 and 3.

CHAPTER 6

INCENTIVES

Article 16

Scientific advice

5.
If serious adverse events or reactions occur in relation to a
combined advanced therapy medicinal product, the Agency
shall inform the relevant national competent authorities respon-
implementing Directives 90/385/EEC, 93/42/EEC
sible for
and 2004/23/EC.

1.
The applicant or holder of a marketing authorisation may
request advice from the Agency on the design and conduct of
pharmacovigilance and of the risk management system referred to
in Article 14.

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By way of derogation from Article 8(1) of Council Regula-
2.
tion (EC) No 297/95 of 10 February 1995 on fees payable to the
European Agency for the Evaluation of Medicinal Products (1), a
90 % reduction for small and medium-sized enterprises and 65 %
for other applicants shall apply to the fee for scientific advice pay-
able to the Agency for any advice given in respect of advanced
therapy medicinal products pursuant to paragraph 1 of this
Article and Article 57(1)(n) of Regulation (EC) No 726/2004.

Paragraph 1 shall also apply to fees charged by the Agency
2.
for post-authorisation activities in the first year following the
granting of the marketing authorisation for the advanced therapy
medicinal product.

Paragraphs 1 and 2 shall apply during the transitional peri-

3.
ods laid down in Article 29.

Article 17

Scientific recommendation on advanced
therapy classification

1.
Any applicant developing a product based on genes, cells or
tissues may request a scientific recommendation of the Agency
with a view to determining whether the referred product falls, on
scientific grounds, within the definition of an advanced therapy
medicinal product. The Agency shall deliver this recommendation
after consultation with the Commission and within 60 days after
receipt of the request.

2.
The Agency shall publish summaries of the recommenda-
tions delivered in accordance with paragraph 1, after deletion of
all information of commercial confidential nature.

Article 18

Certification of quality and non-clinical data

CHAPTER 7

COMMITTEE FOR ADVANCED THERAPIES

Article 20

Committee for Advanced Therapies

A Committee for Advanced Therapies shall be established

1.
within the Agency.

2.
Save where otherwise provided in this Regulation, Regula-
tion (EC) No 726/2004 shall apply to the Committee for
Advanced Therapies.

3.
The Executive Director of the Agency shall ensure appro-
priate coordination between the Committee for Advanced Thera-
pies and the other Committees of the Agency, in particular the
Committee for Medicinal Products for Human Use and the Com-
mittee for Orphan Medicinal Products, their working parties and
any other scientific advisory groups.

Small and medium-sized enterprises developing an advanced
therapy medicinal product may submit to the Agency all relevant
quality and, where available, non-clinical data required in accor-
dance with modules 3 and 4 of Annex I to Directive 2001/83/EC,
for scientific evaluation and certification.

Article 21

Composition of the Committee for Advanced Therapies

The Committee for Advanced Therapies shall be composed

1.
of the following members:

The Commission shall lay down provisions for the evaluation and
certification of such data, in accordance with the regulatory pro-
cedure referred to in Article 26(2).

(a)

Article 19

Reduction of the fee for marketing authorisation

five members or co-opted members of the Committee for
Medicinal Products for Human Use from five Member States,
with alternates either proposed by their respective Member
State or, in the case of co-opted members of the Committee
for Medicinal Products for Human Use, identified by the lat-
ter on the advice of the corresponding co-opted member.
These five members with their alternates shall be appointed
by the Committee for Medicinal Products for Human Use;

1.
By way of derogation from Regulation (EC) No 297/95, the
fee for marketing authorisation shall be reduced by 50 % if the
applicant is a hospital or a small or medium-sized enterprise and
can prove that there is a particular public health interest in the
Community in the advanced therapy medicinal product
concerned.

(1) OJ L 35, 15.2.1995, p. 1. Regulation as last amended by Regulation

(EC) No 1905/2005 (OJ L 304, 23.11.2005, p. 1).

(b) one member and one alternate appointed by each Member
State whose national competent authority is not represented
among the members and alternates appointed by the Com-
mittee for Medicinal Products for Human Use;

(c)

two members and two alternates appointed by the Commis-
sion, on the basis of a public call for expressions of interest
and after consulting the European Parliament, in order to
represent clinicians;

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(d)

two members and two alternates appointed by the Commis-
sion, on the basis of a public call for expressions of interest
and after consulting the European Parliament, in order to
represent patients’ associations.

The alternates shall represent and vote for the members in their
absence.

All members of the Committee for Advanced Therapies
2.
shall be chosen for their scientific qualification or experience in
respect of advanced therapy medicinal products. For the purposes
of paragraph 1(b), the Member States shall cooperate, under the
coordination of the Executive Director of the Agency, in order to
ensure that the final composition of the Committee for Advanced
Therapies provides appropriate and balanced coverage of the sci-
entific areas relevant to advanced therapies, including medical
devices, tissue engineering, gene therapy, cell therapy, biotechnol-
ogy, surgery, pharmacovigilance, risk management and ethics.

At least two members and two alternates of the Committee for
Advanced Therapies shall have scientific expertise in medical
devices.

3.
The members of the Committee for Advanced Therapies
shall be appointed for a renewable period of three years. At meet-
ings of the Committee for Advanced Therapies, they may be
accompanied by experts.

4.
The Committee for Advanced Therapies shall elect its Chair-
man from among its members for a term of three years, renew-
able once.

5.
The names and scientific qualifications of all members shall
be made public by the Agency, in particular on the Agency’s
website.

Article 22

Conflicts of interest

In addition to the requirements laid down in Article 63 of Regu-
lation (EC) No 726/2004, members and alternates of the Com-
mittee for Advanced Therapies shall have no financial or other
interests in the biotechnology sector and medical device sector
that could affect their impartiality. All indirect interests that could
relate to these sectors shall be entered in the register referred to in
Article 63(2) of Regulation (EC) No 726/2004.

Human Use and to advise the latter on any data generated in
the development of such a product;

(b)

to provide advice, pursuant to Article 17, on whether a prod-
uct falls within the definition of an advanced therapy medici-
nal product;

(c) at the request of the Committee for Medicinal Products for
Human Use, to advise on any medicinal product which may
require, for the evaluation of its quality, safety or efficacy,
expertise in one of
the scientific areas referred to in
Article 21(2);

(d)

to provide advice on any question related to advanced
therapy medicinal products, at the request of the Executive
Director of the Agency or the Commission;

(e)

to assist scientifically in the elaboration of any documents
related to the fulfilment of the objectives of this Regulation;

(f)

at the Commission’s request, to provide scientific expertise
and advice for any Community initiative related to the devel-
opment of innovative medicines and therapies which requires
expertise in one of
the scientific areas referred to in
Article 21(2);

(g)

to contribute to the scientific advice procedures referred to in
Article 16 of this Regulation and in Article 57(1)(n) of Regu-
lation (EC) No 726/2004.

CHAPTER 8

GENERAL AND FINAL PROVISIONS

Article 24

Adaptation of Annexes

The Commission shall, after consulting the Agency and in accor-
dance with the regulatory procedure with scrutiny referred to in
Article 26(3), amend Annexes I to IV in order to adapt them to
scientific and technical evolution.

Article 25

Report and review

Article 23

Tasks of the Committee for Advanced Therapies

The Committee for Advanced Therapies shall have the following
tasks:

(a)

to formulate a draft opinion on the quality, safety and effi-
cacy of an advanced therapy medicinal product for final
approval by the Committee for Medicinal Products for

By 30 December 2012, the Commission shall publish a general
report on the application of this Regulation, which shall include
comprehensive information on the different types of advanced
therapy medicinal products
to this
Regulation.

authorised pursuant

In this report, the Commission shall assess the impact of techni-
cal progress on the application of this Regulation. It shall also
review the scope of this Regulation, including in particular the
regulatory framework for combined advanced therapy medicinal
products.

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Article 26

Committee procedure

Article 28

Amendments to Directive 2001/83/EC

1.
The Commission shall be assisted by the Standing Commit-
tee on Medicinal Products for Human Use set up by Article 121(1)
of Directive 2001/83/EC.

2. Where reference is made to this paragraph, Articles 5 and 7
of Decision 1999/468/EC shall apply, having regard to the pro-
visions of Article 8 thereof.

The period laid down in Article 5(6) of Decision 1999/468/EC
shall be set at three months.

3. Where reference is made to this paragraph, Article 5a(1)
to (4) and Article 7 of Decision 1999/468/EC shall apply, having
regard to the provisions of Article 8 thereof.

Article 27

Amendments to Regulation (EC) No 726/2004

Regulation (EC) No 726/2004 is hereby amended as follows:

1.

in the first subparagraph of Article 13(1), the first sentence
shall be replaced by the following:

‘Without prejudice to Article 4(4) and (5) of Directive
2001/83/EC, a marketing authorisation which has been
granted in accordance with this Regulation shall be valid
throughout the Community.’;

2. Article 56 shall be amended as follows:

(a)

in paragraph 1, the following point shall be inserted:

‘(da) the Committee for Advanced Therapies;’

(b)

in the first sentence of the first subparagraph of para-
graph 2, the words ‘paragraph 1(a) to (d)’ shall be
replaced by ‘paragraph 1(a) to (da)’;

3.

the Annex shall be amended as follows:

(a)

the following point shall be inserted:

‘1a. Advanced therapy medicinal products as defined
in Article 2 of Regulation (EC) No 1394/2007 of
the European Parliament and of the Council of
13 November 2007 on advanced therapy medicinal
products (*).

(*) OJ L 324, 10.12.2007, p. 121’;

(b)

In point 3, the second subparagraph shall be replaced by
the following:

‘After 20 May 2008, the Commission, having consulted
the Agency, may present any appropriate proposal to
amend this point and the European Parliament and the
Council shall take a decision thereon in accordance with
the Treaty.’

Directive 2001/83/EC is hereby amended as follows:

1.

in Article 1, the following point shall be inserted:

‘4a. Advanced therapy medicinal product:

A product as defined in Article 2 of Regulation (EC)
No 1394/2007 of the European Parliament and of the
Council of 13 November 2007 on advanced therapy
medicinal products (*).

(*) OJ L 324, 10.12.2007, p. 121’;

2.

in Article 3, the following point shall be added:

‘7.

Any advanced therapy medicinal product, as defined in
Regulation (EC) No 1394/2007, which is prepared on
a non-routine basis according to specific quality stan-
dards, and used within the same Member State in a
hospital under the exclusive professional responsibil-
ity of a medical practitioner, in order to comply with
an individual medical prescription for a custom-made
product for an individual patient.

Manufacturing of these products shall be authorised by
the competent authority of the Member State. Member
States shall ensure that national traceability and phar-
macovigilance requirements as well as the specific
quality standards referred to in this paragraph are
equivalent to those provided for at Community level in
respect of advanced therapy medicinal products for
which authorisation is required pursuant to Regulation
(EC) No 726/2004 of the European Parliament and of
the Council of 31 March 2004 laying down Commu-
nity procedures for the authorisation and supervision
of medicinal products for human and veterinary use
and establishing a European Medicines Agency (*).

(*) OJ L 136, 30.4.2004, p. 1. Regulation as amended by
Regulation (EC) No 1901/2006 (OJ L 378, 27.12.2006,
p. 1).’;

3.

in Article 4, the following paragraph shall be added:

‘5.
This Directive and all Regulations referred to therein
shall not affect the application of national legislation prohib-
iting 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 these cells, on
grounds not dealt with in the aforementioned Community
legislation. The Member States shall communicate the
national legislation concerned to the Commission. The Com-
mission shall make this information publicly available in a
register.’;

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4.

in Article 6(1), the first subparagraph shall be replaced by the
following:

‘No medicinal product may be placed on the market of a
Member State unless a marketing authorisation has been
issued by the competent authorities of that Member State in
accordance with this Directive or an authorisation has been
granted in accordance with Regulation (EC) No 726/2004,
read in conjunction with Regulation (EC) No 1394/2007.’

Tissue engineered products which were legally on the Com-
2.
munity market in accordance with national or Community legis-
lation on 30 December 2008 shall comply with this Regulation
no later than 30 December 2012.

By way of derogation from Article 3(1) of Regulation (EC)
3.
No 297/95, no fee shall be payable to the Agency in respect of
applications submitted for the authorisation of the advanced
therapy medicinal products mentioned in paragraphs 1 and 2 of
this Article.

Article 29

Transitional period

Article 30

Entry into force

1.
Advanced therapy medicinal products, other than tissue
engineered products, which were legally on the Community mar-
ket in accordance with national or Community legislation on
30 December 2008, shall comply with this Regulation no later
than 30 December 2011.

This Regulation shall enter into force on the 20th day following
its publication in the Official Journal of the European Union.

It shall apply from 30 December 2008.

This Regulation shall be binding in its entirety and directly applicable in all Member States.

Done at Strasbourg, 13 November 2007.

For the European Parliament
The President
H.-G. PÖTTERING

For the Council
The President
M. LOBO ANTUNES

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ANNEX I

Manipulations referred to in the first indent of Article 2(1)(c)

— cutting,

— grinding,

— shaping,

— centrifugation,

— soaking in antibiotic or antimicrobial solutions,

— sterilization,

— irradiation,

— cell separation, concentration or purification,

— filtering,

— lyophilization,

— freezing,

— cryopreservation,

— vitrification.

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ANNEX II

Summary of product characteristics referred to in Article 10

1.

2.

Name of the medicinal product.

Composition of the product:

2.1. general description of the product, if necessary with explanatory drawings and pictures,

2.2. qualitative and quantitative composition in terms of the active substances and other constituents of the product, knowl-
edge of which is essential for proper use, administration or implantation of the product. Where the product contains
cells or tissues, a detailed description of these cells or tissues and of their specific origin, including the species of ani-
mal in cases of non-human origin, shall be provided,

For a list of excipients, see point 6.1.

3.

4.

Pharmaceutical form.

Clinical particulars:

4.1.

therapeutic indications,

4.2. posology and detailed instructions for use, application, implantation or administration for adults and, where neces-

sary, for children or other special populations, if necessary with explanatory drawings and pictures,

4.3. contra-indications,

4.4.

special warnings and precautions for use, including any special precautions to be taken by persons handling such prod-
ucts and administering them to or implanting them in patients, together with any precautions to be taken by the
patient,

4.5.

interaction with other medicinal products and other forms of interactions,

4.6. use during pregnancy and lactation,

4.7. effects on ability to drive and to use machines,

4.8. undesirable effects,

4.9. overdose (symptoms, emergency procedures).

5.

Pharmacological properties:

5.1. pharmacodynamic properties,

5.2. pharmacokinetic properties,

5.3. preclinical safety data.

6.

Quality particulars:

6.1.

list of excipients, including preservative systems,

6.2.

incompatibilities,

6.3.

shelf life, when necessary after reconstitution of the medicinal product or when the immediate packaging is opened
for the first time,

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6.4.

special precautions for storage,

6.5. nature and contents of container and special equipment for use, administration or implantation, if necessary with

explanatory drawings and pictures,

6.6.

special precautions and instructions for handling and disposal of a used advanced therapy medicinal product or waste
materials derived from such product, if appropriate and, if necessary, with explanatory drawings and pictures.

7. Marketing authorisation holder.

8. Marketing authorisation number(s).

9.

Date of the first authorisation or renewal of the authorisation.

10. Date of revision of the text.

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ANNEX III

Labelling of outer/immediate packaging referred to in Article 11

(a) The name of the medicinal product and, if appropriate, an indication of whether it is intended for babies, children or
adults; the international non-proprietary name (INN) shall be included, or, if the product has no INN, the common
name;

(b) A description of the active substance(s) expressed qualitatively and quantitatively, including, where the product con-
tains cells or tissues, the statement ‘This product contains cells of human/animal [as appropriate{] origin’ together with
a short description of these cells or tissues and of their specific origin, including the species of animal in cases of non-
human origin;

(c) The pharmaceutical form and, if applicable, the contents by weight, by volume or by number of doses of the product;

(d) A list of excipients, including preservative systems;

(e) The method of use, application, administration or implantation and, if necessary, the route of administration. If appli-

cable, space shall be provided for the prescribed dose to be indicated;

(f) A special warning that the medicinal product must be stored out of the reach and sight of children;

(g) Any special warning necessary for the particular medicinal product;

(h) The expiry date in clear terms (month and year; and day if applicable);

(i)

Special storage precautions, if any;

(j)

Specific precautions relating to the disposal of unused medicinal products or waste derived from medicinal products,
where appropriate, as well as reference to any appropriate collection system in place;

(k) The name and address of the marketing authorisation holder and, where applicable, the name of the representative

appointed by the holder to represent him;

(l) Marketing authorisation number(s);

(m) The manufacturer’s batch number and the unique donation and product codes referred to in Article 8(2) of Directive

2004/23/EC;

(n)

In the case of advanced therapy medicinal products for autologous use, the unique patient identifier and the statement
‘For autologous use only’.

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ANNEX IV

Package leaflet referred to in Article 13

(a)

For the identification of the advanced therapy medicinal product:

(i)

the name of the advanced therapy medicinal product and, if appropriate, an indication of whether it is intended
for babies, children or adults. The common name shall be included;

(ii)

the therapeutic group or type of activity in terms easily understandable for the patient;

(iii) where the product contains cells or tissues, a description of those cells or tissues and of their specific origin, includ-

ing the species of animal in cases of non-human origin;

(iv) where the product contains medical devices or active implantable medical devices, a description of those devices

and their specific origin;

(b) The therapeutic indications;

(c) A list of information which is necessary before the medicinal product is taken or used, including:

(i)

contra-indications;

(ii)

appropriate precautions for use;

(iii)

forms of interaction with other medicinal products and other forms of interaction (e.g. alcohol, tobacco, food-
stuffs) which may affect the action of the medicinal product;

(iv)

special warnings;

(v)

if appropriate, possible effects on the ability to drive vehicles or to operate machinery;

(vi)

the excipients, knowledge of which is important for the safe and effective use of the medicinal product and which
are included in the detailed guidance published pursuant to Article 65 of Directive 2001/83/EC.

The list shall also take into account the particular condition of certain categories of users, such as children, pregnant or
breastfeeding women, the elderly, persons with specific pathological conditions;

(d) The necessary and usual instructions for proper use, and in particular:

(i)

the posology;

(ii)

the method of use, application, administration or implantation and, if necessary, the route of administration;

and, as appropriate, depending on the nature of the product:

(iii)

the frequency of administration, specifying if necessary the appropriate time at which the medicinal product may
or must be administered;

(iv)

the duration of treatment, where it should be limited;

(v)

the action to be taken in case of an overdose (such as symptoms, emergency procedures);

(vi)

information on what to do when one or more doses have not been taken;

(vii) a specific recommendation to consult the doctor or the pharmacist, as appropriate, for any clarification on the

use of the product;

(e) A description of the adverse reactions which may occur under normal use of the medicinal product and, if necessary,
the action to be taken in such a case; the patient should be expressly asked to communicate any adverse reaction which
is not mentioned in the package leaflet to his doctor or pharmacist;

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(f) A reference to the expiry date indicated on the label, with:

(i)

a warning against using the product after that date;

(ii) where appropriate, special storage precautions;

(iii)

if necessary, a warning concerning certain visible signs of deterioration;

(iv)

the full qualitative and quantitative composition;

(v)

the name and address of the marketing authorisation holder and, where applicable, the name of his appointed rep-
resentatives in the Member States;

(vi)

the name and address of the manufacturer;

(g) The date on which the package leaflet was last revised.