Proposal for a Regulation of the European Parliament and of the Council on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 {SEC(2005) 1444}
Date: 2005-11-16
Institutions: European Commission
Subjects: European Medicines Agency, approximation of laws, drug surveillance, marketing, medicinal product, pharmaceutical legislation, public health, veterinary drug

COMMISSION OF THE EUROPEAN COMMUNITIES 

Brussels, 16.11.2005 
COM(2005) 567 final 

2005/0227 (COD) 

Proposal for a 

REGULATION OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL 

on advanced therapy medicinal products and amending Directive 2001/83/EC and 
Regulation (EC) No 726/2004 

{SEC(2005) 1444} 

(presented by the Commission) 

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EXPLANATORY MEMORANDUM  

1. 

INTRODUCTION AND BACKGROUND 

The current picture 

The advancement of science in the fields of biology, biotechnology and medicine, has fuelled 
the  development  of  promising  gene-  and  cell-based  approaches  for  the  prevention  and 
treatment  of  diseases  or  dysfunctions  of  the  human  body.  A  number  of  gene  therapy  and 
somatic  cell  therapy  products  are  already  being  tested  at  clinical  level  for  the  treatment  of 
inherited  diseases,  cancer,  diabetes,  Parkinson's  disease  and  other  neurodegenerative 
disorders. 

In  addition,  a  new  biotechnology  area  has  emerged:  tissue  engineering,  which  combines 
various  aspects  of  medicine,  cell  and  molecular  biology,  materials  science  and  engineering, 
for the purpose of regenerating, repairing or replacing human tissues. Current applications of 
this  nascent  field  of  “regenerative  medicine”  include  treatment  for  skin,  cartilage  and  bone 
diseases or injuries. More complex products are already in development, and could reach the 
Community market in a near future1. 

Advanced therapies: a coherent ensemble 

These  three  kinds  of  advanced  therapies  (gene  therapy,  somatic  cell  therapy,  and  tissue 
engineering) are expected to have a major impact on public health, by improving the quality 
of  life  of  patients  and  changing  medical  practice  significantly.  Moreover,  they  constitute  a 
coherent  ensemble  insofar  as  they  share  several  key  scientific,  regulatory  and  economic 
features: 

–  They are based on complex, highly innovative manufacturing processes. The specificity of 

the product precisely lies in the process. 

–  Regulatory  and  scientific  expertise  for  the  evaluation  of  advanced  therapies  is  scarce: 
pooling of that expertise at Community level is therefore essential to ensure a high level of 
public health protection. 

–  Traceability  from  the  donor  to  the  patient,  long-term  patient  follow-up  and  a  thorough 
post-authorisation  risk  management  strategy  are  crucial  aspects  to  be  addressed  when 
evaluating advanced therapies. 

–  Advanced therapy products are usually developed by innovative small and medium-sized 
enterprises,  highly-specialised  divisions  of  larger  operators  in  the  Life  Science  sector 
(biotechnology, medical devices and pharmaceuticals), hospitals or tissue banks. They are 
subject to rapid and often radical innovation. 

1 

See  Bock,  A.K.,  Ibarreta,  D.,  Rodriguez-Cerezo,  E.:  ‘Human  tissue-engineered  products  -  Today's 
markets and future prospects’, Joint Research Centre - Institute for Prospective Technological Studies 
(European Commission), EUR 21000 EN, October 2003. 

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The current regulatory gap and its implications on public health 

Despite  these  common  elements,  the  regulatory  picture  for  advanced  therapies  remains 
incomplete. In particular, while products intended for gene and somatic cell therapy have been 
classified as medicinal products and regulated as such in the Community2, tissue-engineered 
products  currently  lie  outside  of  any  Community  legislative  framework.  This  leads  to 
divergent,  national  approaches  as  to  their  legal  classification  and  authorisation,  thereby 
impairing the free movement of tissue engineered products in the Community, and hindering 
patients’ access to these innovative therapies. 

There is therefore a need to bridge the regulatory gap by addressing all advanced therapies -
including in particular tissue engineering- within a single, integrated framework, fully taking 
into  account  their  scientific  and  technical  characteristics  as  well  as  the  specificities  of  the 
economic operators concerned. 

2. 

JUSTIFICATION 

2.1. 

Objectives 

The  overall  policy  objective  is  to  improve  patients’  safe  access  to  advanced  therapies  by 
increasing the research, development and authorisation of gene therapy, somatic cell therapy, 
and tissue engineered products. 

More specifically, the main objectives are: 

–  To  guarantee  a  high  level  of  health  protection  for  European  patients  treated  with 

advanced therapy products; 

–  To  harmonise  market  access  and  to  improve  the  functioning  of  the  internal  market  by 
establishing  a  tailored  and  comprehensive  regulatory  framework  for  the  authorisation, 
supervision and post-authorisation vigilance of advanced therapy products; 

–  To foster the competitiveness of European undertakings operating in this field; 

–  To provide overall legal certainty, while allowing for sufficient flexibility at technical 

level, in order to keep the pace with the evolution of science and technology. 

2.2. 

Scope, legal basis and procedure 

Scope 

The proposal covers all advanced therapy products (gene therapy medicinal products, somatic 
cell  therapy  medicinal  products,  and  tissue  engineered  products)  falling  within  the  global 
scope of the pharmaceutical legislation (Article 2(1) of Directive 2001/83/EC3), i.e. intended 

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Part  IV  of  Annex  I  to  Directive  2001/83/EC,  as  amended  by  Directive  2003/63/EC,  OJ  L159, 
27.6.2003,  p.46.  See  also  ‘Commission  Communication  on  the  Community  marketing  authorisation 
procedures for medicinal products’, 98/C 229/03, OJ C 229/4, 22.7.1998. 
OJ L 311, 28.11.2001, p. 67 

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to be placed on the market in Member States and either prepared industrially or manufactured 
by a method involving an industrial process. 

Legal basis and procedure 

The  proposal  is  based  on  Article  95  of  the  EC  Treaty.  Article  95,  which  prescribes  the  co-
decision procedure described in Article 251, is the legal basis for achieving the aims set out in 
Article 14 of the Treaty, which includes the free movement of goods (Article 14(2)), in this 
case advanced therapy medicinal products for human use. 

While  taking  account  of  the  fact  that  any  regulation  on  the  manufacture  and  distribution  of 
medicinal products must be fundamentally aimed at safeguarding public health, this aim must 
be achieved by means that do not impede the free movement of medicinal products within the 
Community. Since the Amsterdam Treaty came into force, all legislative provisions adopted 
by the European Parliament and the Council in this field have been adopted on the basis of 
that  Article,  since  the  differences  between  the  national  legislative,  regulatory  and 
administrative  provisions  on  medicinal  products  tend  to  hinder  intra-Community  trade  and 
therefore  directly  affect  the  operation  of  the  internal  market.  Action  to  promote  the 
development and authorisation of advanced therapy medicinal products is hence justified at a 
European level, with a view to preventing or eliminating these obstacles. 

Given the particularities of advanced therapy products, it is essential to provide a robust and 
comprehensive  regulatory  framework,  which  is  directly  applicable  in  all  Member  States.  A 
Regulation is therefore considered as the most appropriate legal instrument. It should indeed 
ensure uniform and timely application of the provisions, for the benefit of all actors, including 
patients,  industry  and  other  stakeholders  involved  in  this  emerging  sector.  In  addition,  the 
‘centralised’ marketing authorisation procedure is also laid down in a Regulation (Regulation 
(EC) No 726/2004)4. 

2.3. 

Subsidiarity and proportionality 

The  proposal  builds  on  the  experience  gained  with  the  existing  regulatory  framework  for 
medicines in Europe. On the basis of the available evidence, it is concluded that it is unlikely 
that  the  current  public  health  issue  regarding  advanced  therapy  medicinal  products,  in 
particular  tissue  engineered  products,  will  be  resolved  in  the  EU  until  a  specific  legislative 
system is put in place. 

Community  action  allows  the  best  possible  use  of  the  instruments  set  up  in  Community 
legislation  (in  particular  in  the  pharmaceutical  sector)  to  complete  the  internal  market.  In 
addition,  authorisation  and  availability  of  innovative  therapies  is  a  Europe-wide  issue. 
Nevertheless,  Member  States  will  have  a  crucial  role  in  the  fulfilment  of  the  proposal’s 
objectives. 

The proposed rules aim at harmonising an area in which application of existing Community 
legislation and additional national measures have proven insufficient. However, the proposal 
will create additional regulatory requirements only when this appears necessary to achieve the 
intended objectives. In this respect, the scope of the proposal has been carefully designed and 
discussed with all stakeholders, in order to avoid imposing an unnecessary regulatory burden 

4 

OJ L 136, 30.4.2004, p. 1 

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on  certain  economic  operators  (e.g.  hospitals,  universities  and  research  community).  The 
proposal does not go beyond what is necessary to achieve the objectives pursued. 

2.4. 

Legislative and administrative simplification 

The proposed approach is based on a single, integrated regulatory framework for all advanced 
therapy products. The aim of this strategy is to avoid any re-drafting of already-existing and 
applicable  concepts,  while  focusing  exclusively  on  the  key  regulatory  and  technical 
specificities of the field.  

The approach is based on 3 levels: 

(1) 

A  Regulation  on  Advanced  Therapy  Medicinal  Products,  which  lays  down  tailored 
regulatory principles for the evaluation and authorisation of these products: marketing 
authorisation  procedure,  post-authorisation  vigilance, 
traceability,  etc.  Such 
Regulation builds on already-existing legislation, in particular: 

–  Directive 2004/23/EC, which lays down quality and safety standards in respect of 
human tissues and cells5. It is important to bear in mind that these standards would 
apply  to  the  donation,  procurement  and  testing  of  human  tissues  and  cells 
contained in advanced therapy products; 

–  Regulation  (EC)  No  726/2004,  which  establishes  the  so-called  ‘centralised 
procedure’  and  the  role/structure  of  the  European  Medicines  Agency  (EMEA, 
hereinafter “the Agency”); 

–  Directive 2001/83/EC on medicinal products; 

–  Council Directive 93/42/EEC concerning medical devices6 and Council Directive 

90/385/EEC on active implantable medical devices7. 

(2) 

(3) 

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Technical  requirements.  It  is  well  acknowledged  that  advanced  therapy  products  are 
neither  medical  devices  nor  conventional  medicines:  therefore,  the  technical 
requirements necessary to demonstrate their quality, safety and efficacy (e.g. the type 
of pre-clinical and clinical data required) will be highly specific, and should depend on 
the  level  of  risks  associated  with  these  products.  As  regards  gene  and  somatic  cell 
therapy  products,  those  high-level  requirements  are  already  laid  down  in  Annex  I  to 
Directive  2001/83/EC8 
further 
complemented by guidelines9. In order to provide for the same level of flexibility, it is 
proposed to follow a similar approach regarding tissue engineered products, i.e. to lay 
down the main technical requirements that are specific to these products in Annex I to 
Directive 2001/83/EC, and to further complement them with guidelines. 

‘comitology’)  and 

is  amendable  by 

(which 

Detailed  guidelines.  As  for  gene  and  somatic cell therapy products,  it is proposed to 
through 
establish  detailed 

tissue  engineered  products 

technical  guidance  for 

OJ L 102, 7.4.2004, p. 48 
OJ L 169, 12.7.1993, p. 1 
OJ L 189, 20.7.1990, p. 17 
Annex I to Directive 2001/83/EC, as amended by Directive 2003/63/EC, OJ L 159, 27.6.2003, p. 46. 
See http://www.emea.eu.int/htms/human/itf/itfguide.htm  

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guidelines. The fact that expertise is still scarce in this fast-growing, fast-evolving area 
highlights  the  importance  of  extensive  and  thorough  consultation  with  all  interested 
parties for the drafting of these guidelines. 

It  is  important  to  note  that  the  current,  existing  requirements  for  gene  therapy  medicinal 
products  and  somatic  cell  therapy  medicinal  products  are  not  affected  by  the  proposal.  The 
only  main  change  related  to  these  products  concerns  the  introduction  of  a  new  Committee 
(Committee for Advanced Therapies). 

2.5. 

Consistency with other Community policies 

As described in Section 2.4, the proposed Regulation is consistent with Community policy in 
the  field  of  public  health  (e.g.  quality  and  safety  of  human  tissues  and  cells)  and  medical 
devices. Consistency will also be sought with other activities related to health and consumer 
protection, as well as in the area of research and development. 

2.6. 

Outside consultation 

All interested parties (patients associations, industry, hospitals, research community…) have 
been  widely  consulted  on  this  proposal,  through  various  means: internet-based consultation, 
workshops,  bilateral  meetings,  interviews.  Details  on  the  consultations  conducted  by  the 
Commission are included in the Impact Assessment attached to the proposal. 

2.7. 

Evaluation of the proposal: Impact Assessment 

The proposed Regulation has been the subject of a Commission Impact Assessment, which is 
attached to the proposal. 

3. 

PRESENTATION: KEY ELEMENTS OF THE PROPOSAL 

3.1. 

Definitions and Scope 

Definitions 

Advanced therapy products are defined as medicinal products being either: 

–  gene therapy medicinal products, as defined in Annex I to Directive 2001/83/EC; or 

–  somatic cell therapy medicinal products, as defined in Annex I to Directive 2001/83/EC; or 

–  tissue engineered products, as defined in the proposal. 

Products which do not qualify as advanced therapy medicinal products, even if based on or 
consisting of tissues and cells, will not be regulated under this framework. 

It must be acknowledged that even the best possible definition of advanced therapy medicinal 
products  may  not  fully  eliminate  the  risk  of  grey  areas,  given  the  highly  innovative  and 
rapidly  evolving  nature  of  the  advanced  therapies  sector.  To  address  this,  the  proposal 
foresees the possibility for applicants to request a scientific recommendation from the EMEA 
on  the  classification  of  any  product  based  on  cells  or  tissues,  with  a  view  to  resolving 
borderline issues. 

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Within  the  Community  legislation  on  pharmaceuticals,  products  intended  for  gene  therapy 
and  somatic  cell  therapy  are  already  classified  as  biological  medicinal  products.  Tissue 
engineered products are also considered from a legal viewpoint as medicinal products for at 
least one of the following reasons: 

–  They are presented as having properties for treating or preventing disease in human beings; 

–  They are used in or administered to human beings with a view to restoring, correcting or 
modifying  physiological  functions  by  exerting  a  pharmacological,  immunological  or 
metabolic action; 

–  In accordance with the jurisprudence of the European Court of Justice (ECJ) on the matter, 

they are capable of having a significant effect on the actual functioning of the body10. 

Furthermore, the existence of health risks is traditionally one of the criteria employed by the 
ECJ  for  classifying  a  product  as  medicinal11.  It  follows  from  the  aim  of  health  protection 
pursued  by  the  Community  pharmaceutical  legislation  that  products  presenting  potential 
health  risks  (as  is  clear  for  advanced  therapy  medicinal  products)  should  be  covered  by  the 
rigorous requirements of that legislation in case of doubt as to their classification12. 

However, this does not mean that advanced therapy medicinal products will be subject to the 
same  technical  requirements  as  ‘conventional’  medicines.  On  the  contrary,  the  type  and 
amount of pre-clinical/clinical data necessary to demonstrate their quality, safety and efficacy 
should be highly specific, fully taking into account their biological, functional and structural 
characteristics. 

Scope 

The  proposal  addresses  all  advanced  therapy  medicinal  products  falling  within  the  general 
scope of the Community legislation on medicinal products13, i.e. “intended to be placed on the 
market  in  Member  States  and  either  prepared  industrially  or  manufactured  by  a  method 
involving an industrial process”. Products which are both prepared in full and used in a single 
hospital,  in  accordance  with  a  medical  prescription  for  an  individual  patient,  are  excluded 
from  the  scope  of  the  proposal.  Detailed  examples  related  to  this  aspect  of  the  proposal  are 
provided in the Impact Assessment. 

3.2.  Marketing Authorisation Procedure 

General principles 

Experience  gained  in  the  area  of  modern  biotechnology,  where  scientific  expertise  is  often 
limited,  highlights  the  necessity  to  establish  centralised  procedures  for  the  authorisation  of 
biotechnology-derived therapeutic products. This pooling of expertise from all Member States 

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See cases 227/82, Van Bennekom [1983] ECR 3883 ; C-369/88, Delattre [1991] ECR I-1487 ; C-60/89, 
Monteil  and  Samanni  [1991]  ECR  I-1547 ;  C-112/89,  Upjohn  [1991]  ECR  I-1703 ;  C-290/90, 
Commission v Federal Republic of Germany [1992] ECR I-3317 ; C-219/91, Ter Voort [1992] ECR I-
5485. 
Monteil  and  Samanni,  paragraph  29;  Delattre,  paragraph  35;  Commission  v.  Federal  Republic  of 
Germany, paragraph 17. 
See also Article 2(2) of Directive 2001/83/EC, as amended by Directive 2004/27/EC. 
Article 2(1) of Directive 2001/83/EC, as amended by Directive 2004/27/EC. 

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enables to guarantee a high level of scientific evaluation across the European Union, and thus 
to preserve the confidence of patients and medical practitioners in their evaluation. This is all 
the more important for advanced therapy medicinal products, which often result from highly 
innovative, not-yet-well-established processes and technologies. 

The principle of a compulsory Community marketing authorisation is already established for 
gene therapy medicinal products and somatic cell therapy medicinal products resulting from 
any  biotechnology  process  referred  to  in  the  Annex  to  Regulation  (EC)  No  726/2004.  It  is 
proposed  to  apply  the  same  principle  of  a  compulsory,  ‘centralised’  Community  marketing 
authorisation  to  all  advanced  therapy  medicinal  products,  including  tissue  engineered 
products, in order to ensure the effective operation of the internal market in the biotechnology 
sector, and to enable undertakings to benefit from direct access to the Community market. As 
for  other  ‘centrally-authorised’  products,  the  scientific  evaluation  would  be  carried  out  by 
Member States experts, within the network coordinated by the EMEA. 

Committee for Advanced Therapies (CAT) 

Within the EMEA, the Committee for Medicinal Products for Human Use (CHMP) holds the 
responsibility  for  drawing  up  the  Agency’s  opinion  on  any  scientific  matter  concerning  the 
evaluation  of  medicinal  products  for  human  use,  and  for  ensuring  consistency  in  the  risk-
benefit assessment of all categories of medicinal products. 

Nevertheless,  the  assessment  of  advanced  therapy  medicinal  products  often  requires  very 
specific  expertise,  which  goes  beyond  the  traditional  pharmaceutical  field  and  covers 
borderline  areas  related  to  other  sectors,  such  as  biotechnology  or  medical  devices.  For  this 
reason,  it  is  proposed  to  create,  within  the  EMEA,  a  Committee  for  Advanced  Therapies 
(CAT),  which  the  CHMP  should  consult  on  the  assessment  of  data  related  to  advanced 
therapy  medicinal  products,  whilst  retaining  responsibility  for  the  final  scientific  opinions 
issued. 

Thus, the main task of the CAT will be to advise scientifically on any data related to advanced 
therapy medicinal products. 

The  CAT  will  work  in  close  cooperation  with,  and  under  the  general  supervision  of,  the 
CHMP. A clearly-defined procedure, with strict deadlines, is established in order to avoid any 
delays  in  the  marketing  authorisation  of  these  products.  The  composition  of  this  new 
Committee  should  reflect  the  multidisciplinary  nature  of  the  field  and  ensure  appropriate 
coverage  of  the  scientific  areas  relevant  to  advanced  therapies.  Patient  associations  and 
medical  surgeons  with  scientific  experience  of  advanced  therapy  medicinal  products  should 
also be represented. 

Evaluation procedure 

The CHMP will consult the CAT for any evaluation of advanced therapy medicinal products. 
A  number  of  mechanisms  are  foreseen  in  the  proposal  to  avoid  divergent  opinions  between 
the CHMP and the CAT. The CAT may also be consulted for other medicinal products which, 
although not classified as advanced therapy medicinal products, may require specific, CAT-
related expertise for the evaluation of their quality, safety or efficacy. 

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3.3.  Marketing Authorisation Requirements 

General principles 

Broadly speaking, advanced therapy medicinal products are biotechnology-derived products. 
They should therefore be subject to the same overarching regulatory principles as other types 
of  biotechnology-derived  medicines,  such  as  products  developed  by  means  of  recombinant 
DNA technology. 

Technical requirements 

‘Conventional pharmaceutical’ technical requirements are not directly relevant for advanced 
therapy  medicinal  products,  due  to  their  specific  structural,  functional  and  biological 
properties.  Special  considerations  related  to  the  viability  or  proliferation  of  cells,  to  the 
clinical circumstances where the products are used, or to their particular mode of action, may 
be required. 

In  respect  of  gene  and  cell  therapy,  the  type  and  amount  of  quality-related,  pre-clinical  and 
clinical  data  necessary  to  demonstrate  the  quality,  safety  and  efficacy  of  the  products  are 
already laid down in Annex I to Directive 2001/83/EC and through EMEA guidelines. 

It is proposed to follow the same approach for tissue engineered products: to amend Annex I 
to Directive 2001/83/EC in order to lay down technical requirements that are specific to these 
particular products, and to further complement those requirements with guidelines, drawn up 
in consultation with all interested parties. 

Other requirements 

Directive  2004/23/EC  lays  down  standards  of  quality  and  safety  for  the  donation, 
procurement, testing, processing, preservation, storage and distribution of human tissues and 
cells.  As  for  human  tissues  and  cells  contained  in  advanced  therapy  medicinal  products, 
Directive  2004/23/EC  should  apply  only  as  far  as  donation,  procurement  and  testing  are 
concerned, since the further aspects are regulated by the proposed Regulation. 

Advanced  therapy  medicinal  products  may  also  include,  as  an  integral  part  of  the  product, 
medical devices or active implantable medical devices, as defined in Directive 93/42/EEC and 
Directive 90/385/EEC, respectively. In that case, the ‘device’ part should meet the essential 
requirements laid down in those Directives. The EMEA, through the CAT, would provide a 
‘one-stop shop’ system, by evaluating all aspects (including ‘device’ aspects) of the product. 
However, if the device part has already been evaluated and certified by a notified body, this 
certification  should  be  fully  taken  into  account  by  the  CAT  for  the  final  evaluation  of  the 
concerned product. 

3.4. 

Post-authorisation issues 

By their very nature, advanced therapy medicinal products can stay in the human body for a 
longer  time  than  ‘conventional’  medicines.  Thus,  long-term  patient  follow-up  and  post-
authorisation monitoring are crucial aspects of these products. It is hence essential to ensure, 
where  justified  on  public  health  grounds,  that  the  applicant  puts  in  place  a  suitable  risk 
management system, in order to address these critical issues. 

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Likewise, a system allowing complete traceability of the patient, as well as the product and its 
starting materials, is essential to monitor the safety of advanced therapy medicinal products in 
a long-term perspective, and should therefore be required. This traceability system should be 
compatible with the requirements laid down in Directive 2004/23/EC as regards the donation, 
procurement  and  testing  of  human  tissues  and  cells,  including  the  aspects  related  to  data 
protection, confidentiality, and anonymity of both donor and recipient. 

3.5. 

Ethical aspects 

General principles 

The  proposed  Regulation  respects  fundamental  human  rights  and  observes  the  principles 
reflected  in  the  Charter  of  Fundamental  Rights  of  the  European  Union14.  It  also  takes  into 
account, as appropriate, the Convention for the protection of human rights and dignity of the 
human being with regard to the application of biology and medicine: Convention on human 
rights and biomedicine (‘Oviedo’ Convention15). 

The  issue  of  embryonic  stem  cells  was  extensively  debated  during  the  adoption  of  the 
Directive on the quality and safety of human tissues and cells (Directive 2004/23/EC). In this 
context,  the  legislators  have  recognised  that  there  is,  to  date,  no  consensus  among  Member 
States upon which harmonised decisions at EU level could be taken on the use or prohibition 
of  embryonic  stem  cells.  Thus,  regulating  such  use  or  prohibition  should  remain  a  national 
responsibility. If, however, any particular use of these cells is authorised in a given Member 
State, it should be ensured that all provisions necessary to protect public health and guarantee 
respect  for  fundamental  rights  are  effectively  applied,  in  a  harmonised  way  throughout  the 
Community16. 

It is suggested to  follow  the same logic in this proposal. The proposed  Regulation does  not 
interfere  with  national  legislation  prohibiting  or  restricting  the  use  of  any  specific  type  of 
human or animal cells, or the sale, supply or use of medicinal products based on such cells. 
Explicit provisions have been introduced in the proposal to clarify this point. 

Voluntary and unpaid donation 

As  outlined  in  Directive  2004/23/EC,  human  tissue-  and  cell-  based  products  should  be 
founded  on  the  philosophy  of  voluntary  and  unpaid  donation,  anonymity  of  both  donor  and 
recipient,  altruism  of  the  donor  and  solidarity  between  donor  and  recipient.  Voluntary  and 
unpaid tissue and cell donations are a factor which may contribute to high safety standards for 
tissues and cells, and hence to the protection of human health. 

3.6. 

Competitiveness aspects 

The  fact  that  advanced  therapy  medicinal  products  fall  under  the  overall  regulatory 
framework  for  medicinal  products 
incentives  and 
competitiveness-related  provisions  of  this  framework  directly  apply  to  these  products.  This 
includes: 

that  all  already-existing 

implies 

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OJ C 364, 18.12.2000, p. 1. 
http://conventions.coe.int/treaty/en/treaties/html/164.htm 
Recital (12) and Article 4(3) of Directive 2004/23/EC. 

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–  Direct and harmonised access to the Community market through a Community marketing 

authorisation, without prejudice to national prohibitions as referred to in section 3.5; 

–  A harmonised data protection period (the so-called ‘8+2+1’ rule)17; 

–  The possibility to be designated as an orphan medicinal product18; 

–  The possibility of an accelerated assessment procedure19; 

–  The  option  to  get  conditional  marketing  authorisations  or  marketing  authorisations  in 

exceptional circumstances20; 

–  Specific financial incentives and administrative assistance in respect of small and medium-

sized enterprises (SMEs)21. 

Besides, the proposal foresees additional, specific incentives: 

–  a  90%  fee  reduction  for  the  provision  of  scientific  advice  by  the  EMEA  in  respect  of 

advanced therapies, regardless of the economic size of the applicant; 

–  A system of early evaluation and certification of quality and non-clinical safety data by the 
Agency,  independently  of  any  marketing  authorisation  application,  for  SMEs  developing 
advanced therapy medicinal products. This system is designed to help SMEs which focus 
on  the  early  development  aspects,  but  do  not  conduct  the  subsequent  clinical  trials 
themselves. The certification of ‘early-development’ data by the Agency should provide an 
important selling argument to those companies who wish to license out their technology to 
bigger undertakings. 

17 
18 
19 
20 
21 

Article 14(11) of Regulation (EC) No 726/2004. 
Regulation (EC) No 141/2000, OJ L 18, 22/1/2000, p. 1 
Article 14(9) of Regulation (EC) No 726/2004. 
Article 14(7) and 14(8) of Regulation (EC) No 726/2004. 
Article 70(2) of Regulation (EC) No 726/2004. 

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2005/0227 (COD) 

Proposal for a 

REGULATION OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL 

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 EUROPEAN UNION, 

Having  regard  to  the  Treaty  establishing  the  European  Community,  and  in  particular 
Article 95 thereof, 

Having regard to the proposal from the Commission22, 

Having regard to the opinion of the European Economic and Social Committee23, 

Having regard to the opinion of the Committee of the Regions24, 

Acting in accordance with the procedure laid down in Article 251 of the Treaty25, 

Whereas: 

(1) 

(2) 

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

Insofar  as  these  advanced  therapy  products  are  presented  as  having  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  modifying 
physiological  functions  by  exerting  a  pharmacological,  immunological  or  metabolic 
action, they are biological medicinal products within the meaning of Article 1(2) and 
Annex I to 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 
use26. Thus, the essential aim of any rules governing their production, distribution and 
use must be to safeguard public health. 

22 
23 
24 
25 
26 

OJ C , , p. . 
OJ C , , p. . 
OJ C , , p. . 
OJ C , , p. . 
OJ L 311, 28.11.2001, p. 67. Directive as last amended by Directive 2004/27/EC (OJ L 136, 30.4.2004, 
p. 34). 

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(3) 

(4) 

(5) 

(6) 

(7) 

(8) 

(9) 

For  reasons  of  clarity,  complex  therapeutic  products  need  precise  legal  definitions. 
Gene  therapy  medicinal  products  and  somatic  cell  therapy  medicinal  products  have 
been  defined  in  Annex  I  to  Directive  2001/83/EC,  but  a  a  legal  definition  of  tissue 
engineered products remains to be laid down. 

Because  of  the  novelty,  complexity  and  technical  specificity  of  advanced  therapy 
medicinal  products,  specially  tailored  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 biotechnology sector. 

Advanced  therapy  medicinal  products  should  be  regulated  in  so  far  as  they  are 
intended to be placed on the market in Member States and either prepared industrially 
or  manufactured  by  a  method  involving  an  industrial process,  within  the  meaning  of 
Article 2(1) of Directive 2001/83/EC. Advanced therapy medicinal products which are 
both prepared in full and used in a hospital, in accordance with a medical prescription 
for  an  individual  patient,  should  thus  be  excluded  from  the  scope  of  the  present 
Regulation. 

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 
specific 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, 
supply  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  Fundamental  Rights  of  the  European  Union27  and  takes  also  into 
account the Convention for the protection 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 currently 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  (hereinafter 
“the  Agency”).  This  procedure  should  also  be  compulsory  for  advanced  therapy 
medicinal products in order to overcome the scarcity of Community expertise, ensure 
a  high  level  of  scientific  evaluation  of  these  medicinal  products  in  the  Community, 
preserve  the  confidence  of  patients  and  medical  professions  in  the  evaluation,  and 
facilitate Community market access for these innovative technologies. 

The  evaluation  of  advanced  therapy  medicinal  products  often  requires  very  specific 
expertise, which goes beyond the traditional pharmaceutical field and covers areas on 
the  borderline  to  other  sectors  such  as  biotechnology  and  medical  devices.  For  this 
reason,  it  is  appropriate  to  create,  within  the  Agency,  a  Committee  for  Advanced 
Therapies,  which  the  Committee  for  Medicinal  Products  for  Human  Use  of  the 
Agency  should  consult  on  the  assessment  of  data  related  to  advanced  therapy 
medicinal  products,  before  issuing  its  final  scientific  opinion.  In  addition,  the 

27 

OJ C 364, 18.12.2000, p. 1. 

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Committee for Advanced Therapies may be consulted for the evaluation of any other 
medicinal  product  which  requires  specific  expertise  falling  within  its  area  of 
competence. 

(10)  The Committee for Advanced Therapies should gather the best available Community 
expertise on advanced therapy medicinal products. The composition of the Committee 
for  Advanced  Therapies  should  ensure  appropriate  coverage  of  the  scientific  areas 
relevant  to  advanced  therapies,  including  gene  therapy,  cell  therapy,  tissue-
engineering, medical devices, pharmacovigilance and ethics. Patient associations and 
surgeons  with  scientific  experience  of  advanced  therapy  medicinal  products  should 
also be represented. 

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

(12)  Advanced  therapy  medicinal  products  should  be  subject  to  the  same  regulatory 
principles  as  other  types  of  biotechnology  medicinal  products.  However,  technical 
requirements,  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  medicinal  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. 

(13)  Directive  2004/23/EC  of  the  European  Parliament  and  of  the  Council  of  31  March 
200428  lays  down  standards  of  quality  and  safety  for  the  donation,  procurement, 
testing, processing, preservation, storage and distribution  of human tissues and cells. 
The proposed Regulation does not derogate from the basic principles laid down in this 
Directive,  but  supplements  them  with  additional  requirements  where  appropriate. 
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. 

(14)  As  a  matter  of  principle,  human  cells  or  tissues  contained  in  advanced  therapy 
medicinal products should be procured from voluntary and unpaid donation. Voluntary 
and unpaid tissue and cell donations are a factor which may contribute to high safety 
standards for tissues and cells and therefore to the protection of human health. 

(15)  Clinical  trials  on  advanced  therapy  medicinal  products  should  be  conducted  in 
accordance with the overarching principles and the ethical requirements laid down in 
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 

28 

OJ L 102, 7.4.2004, p. 48. 

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of  clinical  trials  on  medicinal  products  for  human  use29.  However,  tailored  rules 
should  be  laid  down,  adapting  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 
manufacturing or importation of such products30, in order to fully take into account the 
specific technical characteristics of advanced therapy medicinal products. 

(16)  The  manufacture  of  advanced  therapy  medicinal  products  should  be  in  compliance 
with the principles of good manufacturing 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  use31.  Furthermore,  guidelines  specific 
to advanced therapy medicinal products should be drawn up, so as to properly reflect 
the particular nature of their manufacturing process. 

(17)  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 
devices32 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  devices33, 
respectively, in order to ensure an appropriate level of quality and safety. 

(18)  Specific rules should be laid down, adapting the requirements in Directive 2001/83/EC 
as regards the summary of product characteristics, labelling and package leaflet to the 
technical specificities of advanced therapy medicinal products. 

(19)  Long-term  patient  follow-up  and  pharmacovigilance  are  crucial  aspects  of  advanced 
therapy medicinal products. Where justified on public health grounds, the holder of the 
marketing  authorisation  should  therefore  be  required  to  put  in  place  a  suitable  risk 
management system to address those aspects. 

(20)  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 
products. 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 Parliament and of the Council of 27 January 2003 setting 
standards  of  quality  and  safety  for  the  collection,  testing,  processing,  storage  and 
distribution  of  human  blood  and  blood  components  and  amending  Directive 
2001/83/EC34. 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 October 1995 

29 
30 
31 
32 

33 

34 

OJ L 121, 1.5.2001, p. 34. 
OJ L 91, 9.4.2005, p. 13. 
OJ L 262, 14.10.2003, p. 22. 
OJ L 169, 12.7.1993, p. 1. Directive as last amended by European Parliament and Council Regulation 
(EC) No 1882/2003 (OJ L 284, 31.10.2003, p. 1). 
OJ L 189, 20.7.1990, p. 17. Directive as last amended by European Parliament and Council Regulation 
(EC) No 1882/2003 (OJ L 284, 31.10.2003, p. 1). 
OJ L 33, 8.2.2003, p. 30. 

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on the protection of individuals with regard to the processing of personal data and the 
free movement of such data35. 

(21)  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. 

(22)  The  Agency  should  be  empowered  to  give  scientific  recommendations  on  whether  a 
given  product  based  on  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. 

(23)  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  evaluation  and 
certification  of  the  resulting  data  by  the  Agency,  independently  of  any  marketing 
authorisation  application,  should  be  introduced.  This  system  should  also  aim  at 
facilitating the evaluation of any future marketing authorisation application based on 
the same data. 

(24) 

In  order  to  take  into  account  scientific  and  technical  developments,  the  Commission 
should  be  empowered  to  adopt  any  necessary  changes  regarding  the  technical 
requirements  for  applications  for  marketing  authorisation  of  advanced  therapy 
medicinal  products,  the  summary  of  product  characteristics,  labelling,  and  package 
leaflet. 

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

(26)  The opinions of the Scientific Committee for Medicinal Products and Medical Devices 
concerning  tissue  engineering  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. 

(27)  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 conferred on the Commission36. 

(28)  Directive 2001/83/EC and Regulation (EC) No 726/2004 of the European Parliament 
and  of  the  Council  of  31  March  2004  laying  down  Community  procedures  for  the 
authorisation and supervision of medicinal products for human and veterinary use and 
establishing  a  European  Medicines  Agency37  should 
therefore  be  amended 
accordingly, 

35 

36 
37 

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). 
OJ L 184, 17.7.1999, p. 23. 
OJ L 136, 30.4.2004, p. 1 

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HAVE ADOPTED THIS REGULATION: 

CHAPTER 1 
SUBJECT MATTER AND DEFINITIONS 

Article 1 

Subject matter 

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

Article 2 

Definitions 

1. 

In addition to the definitions laid down in Article 1 of Directive 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  following  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,  regenerating,  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  substances,  such  as  cellular  products,  bio-molecules,  bio-materials, 
chemical substances, scaffolds or matrices; 

(c) 

engineered cells or tissues means cells or tissues which fulfil at least one of the 
points listed in Annex I; 

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(d) 

 combined  advanced  therapy  medicinal  product  means  an  advanced  therapy 
medicinal product that fulfils the following 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; 

its cellular or tissue part must be liable to act upon the human body with 
action  that  cannot  be  considered  as  ancillary  to  that  of  the  devices 
referred to. 

2. 

3. 

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

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 engineered product. 

CHAPTER 2 
MARKETING AUTHORISATION REQUIREMENTS 

Article 3 

Donation, procurement and testing 

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  the 
provisions laid down in Directive 2004/23/EC. 

Article 4 

Clinical Trials 

1. 

2. 

3. 

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

The Commission shall, in accordance with the procedure referred to in Article 26(2), 
amend Directive 2005/28/EC in order to take account of the specific characteristics 
of advanced therapy medicinal products. 

The Commission shall draw up detailed guidelines on good clinical practice specific 
to advanced therapy medicinal products. 

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Article 5 

Good Manufacturing Practice 

Detailed guidelines in line with the principles of good manufacturing practice and specific to 
advanced therapy medicinal products shall be published by the Commission. 

Article 6 

Issues specific to medical devices 

1. 

2. 

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. 

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 tissue engineered products 

In  addition  to  the  requirements  laid  down  in  Article  6(1)  of  Regulation  (EC)  No  726/2004, 
applications for the authorisation of a tissue engineered product 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. 

Article 8 

Technical requirements 

The Commission shall, in accordance with the procedure referred to in Article 26(2) of this 
Regulation,  amend  Annex  I  to  Directive  2001/83/EC  in  order  to  lay  down  technical 
requirements that are specific to tissue engineered products, in particular those referred to in 
Article 7, with a view to taking account of scientific and technical evolution. 

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CHAPTER 3 
MARKETING AUTHORISATION PROCEDURE 

Article 9 

Evaluation procedure 

1. 

2. 

3. 

4. 

The Committee for  Medicinal Products  for Human Use of the European Medicines 
Agency,  hereinafter  “the  Agency”,  shall  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  case  of  re-examination  of  the  opinion  pursuant  to  Article  9(2)  of 
Regulation (EC) No 726/2004. 

The rapporteur or co-rapporteur appointed by the Committee for Medicinal Products 
for  Human  Use  pursuant  to  Article  62  of  Regulation  (EC)  No  726/2004  shall  be  a 
member  of  the  Committee  for  Advanced  Therapies.  This  member  shall  also  act  as 
rapporteur or co-rapporteur for the Committee for Advanced Therapies. 

The advice given by the Committee for Advanced 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)  of 
Regulation (EC) No 726/2004 can be met. 

Where the scientific opinion on an advanced therapy medicinal product drawn up by 
the Committee for Medicinal Products for Human Use under Article 5, paragraphs 2 
and  3  of  Regulation  (EC)  No  726/2004  is  not in accordance with the advice 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. 

5. 

The  Agency  shall  draw  up  specific  procedures  for  the  application  of  paragraphs  1 
to 4. 

Article 10 

Combined advanced therapy medicinal products 

1. 

2. 

Where  a  combined  advanced  therapy  medicinal  product  is  concerned,  the  whole 
product,  including  any  medical  device  or  any  active  implantable  medical  device 
incorporated in the medicinal product, shall be evaluated by the Agency. 

Where  the  medical  device  or  active  implantable  medical  device  which  is  part  of  a 
combined  advanced  therapy  medicinal  product  has  already  been  assessed  by  a 
notified body in accordance with Directive 93/42/EEC or Directive 90/385/EEC, the 

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Agency  shall  take  account  of  the  results  of  that  assessment  in  its  evaluation  of  the 
medicinal product concerned. 

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

CHAPTER 4 
SUMMARY OF PRODUCT CHARACTERISTICS, LABELLING AND PACKAGE 
LEAFLET 

Article 11 

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, in the order indicated therein. 

Article 12 

Outer/immediate packaging 

By  way  of  derogation  from  Articles  54  and  55(1)  of  Directive  2001/83/EC,  the  particulars 
listed  in  Annex  III  shall  appear  on  the  outer  packaging  of  advanced  therapy  medicinal 
products or, where there is no outer packaging, on the immediate packaging. 

Article 13 

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  packagings  of  advanced  therapy 
medicinal products: 

(a) 

(b) 

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

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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Article 14 

Package leaflet 

1. 

2. 

1. 

2. 

3. 

4. 

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

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 15 

Post-authorisation Risk Management 

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. 

Where there is particular cause for concern, the Commission may, on the advice of 
the  Agency,  require  as  part  of  the  marketing  authorisation  that  a  risk  management 
system  designed  to  identify,  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. 

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

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 Regulation (EC) No 726/2004. 

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

The  Agency  shall  draw  up  detailed  guidelines  relating  to  the  application  of 
paragraphs 1, 2 and 3. 

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Article 16 

Traceability 

1. 

2. 

3. 

4. 

5. 

6. 

7. 

The holder of a marketing authorisation for an advanced 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 
tissues  or  cells  it  may  contain,  can  be  traced  through  the  sourcing,  manufacturing, 
packaging, transport and delivery to the hospital, institution or private practice where 
the product is used. 

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

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  the  first  and  second  paragraphs  are  complementary  to,  and 
compatible with, the requirements laid down in Article 8 and Article 14 of Directive 
2004/23/EC as regards human cells and tissues other than blood cells, and Article 14 
and Article 24 of Directive 2002/98/EC as regards human blood cells. 

The  marketing  authorisation  holder  shall  keep  the  data  referred  to  in  the  first 
paragraph  for  a  minimum  of  30  years  after  placing  the  product  on  the  market,  or 
longer if required by the Commission as a term of the marketing authorisation. 

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

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 the first, third and fourth paragraph. 

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. 

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CHAPTER 6 
INCENTIVES 

Article 17 

Scientific Advice 

1. 

2. 

1. 

2. 

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 15. 

By  way  of  derogation  from  Article  8(1)  of  Regulation  (EC)  No  297/95,  a  90% 
reduction shall apply to the fee payable to the Agency for any advice referred to in 
paragraph  1  and  in  Article  57(1)(n)  of  Regulation  (EC)  No  726/2004  in  respect  of 
advanced therapy medicinal products. 

Article 18 

Scientific recommendation on advanced therapy classification 

Any applicant developing a product based on 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. 

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

Article 19 

Certification of quality and non-clinical data 

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

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

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CHAPTER 7 
COMMITTEE FOR ADVANCED THERAPIES 

Article 20 

Committee for Advanced Therapies 

1. 

2. 

3. 

A Committee for Advanced Therapies is established within the Agency. 

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

The  Executive  Director  of  the  Agency  shall  ensure  appropriate  co-ordination 
between  the  Committee  for  Advanced  Therapies  and  the  other  Committees  of  the 
Agency, in particular the Committee for Medicinal Products for Human Use and the 
Committee  for  Orphan  Medicinal  Products,  their  working  parties  and  any  other 
scientific advisory groups. 

Article 21 

Composition of the Committee for Advanced Therapies 

1. 

The  Committee  for  Advanced  Therapies  shall  be  composed  of  the  following 
members: 

(a) 

(b) 

(c) 

five members and five alternates of the Committee for Medicinal Products for 
Human Use, appointed by the latter; 

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 Committee for Medicinal Products for Human Use; 

four members appointed by the Commission, on the basis of a public call for 
expressions of interest, two of them to represent surgeons and two of them to 
represent patients associations. 

2. 

3. 

All  members  of  the  Committee  for  Advanced  Therapies  shall  be  chosen  for  their 
scientific  qualification  or  experience  in  respect  of  advanced  therapy  medicinal 
products.  For  the  purposes  of  point  (b)  of  paragraph  1,  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 
appropriately and in a balanced way covers the scientific areas relevant to advanced 
therapies, including medical devices, tissue-engineering, gene therapy, cell therapy, 
biotechnology, pharmacovigilance, risk management and ethics. 

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

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4. 

5. 

1. 

2. 

The  Committee  for  Advanced  Therapies  shall  elect  its  Chairman  from  among  its 
members for a term of three years renewable once. 

The  names  and  scientific  qualifications  of  the  members  shall  be  published  by  the 
Agency. 

Article 22 

Conflicts of Interest 

Members of the Committee for Advanced Therapies and its experts shall undertake 
to  act  in  the  public  interest  and  in  an  independent  manner.  They  shall  not  have 
financial  or  other  interests  in  the  pharmaceutical  sector,  medical  device  sector  or 
biotechnology sector that could affect their impartiality. 

All  indirect  interests  that  could  relate  to  the  pharmaceutical  sector,  medical  device 
sector  or  biotechnology  sector  shall  be  entered  in  the  register  referred  to  in  Article 
63(2) of Regulation (EC) No 726/2004. 

Article 23 

Tasks of the Committee for Advanced Therapies 

The Committee for Advanced Therapies shall have the following tasks: 

(a) 

(b) 

(c) 

(d) 

(e) 

to  advise  the  Committee  for  Medicinal  Products  for  Human  Use  on  any  data 
generated  in  the  development  of  an  advanced  therapy  medicinal  product,  for 
the formulation of an opinion on its quality, safety and efficacy; 

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); 

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; 

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

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

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CHAPTER 8 
GENERAL AND FINAL PROVISIONS 

Article 24 

Adaptation of Annexes 

The  Commission  shall,  in  accordance  with  procedure  referred  to  in  Article  26(2),  amend 
Annexes I to IV in order to adapt them to scientific and technical evolution. 

Article 25 

Reporting 

Within 5 years of entry into force of this Regulation, the Commission shall publish a general 
report  on  its  application,  which  shall  include  comprehensive  information  on  the  different 
types of advanced therapy medicinal products authorised pursuant to this Regulation. 

Article 26 

Committee procedure 

1. 

2. 

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

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

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

Article 27 

Amendments to Regulation (EC) No 726/2004 

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

(1) 

Article 56 is amended as follows: 

(a) 

In paragraph 1, the following point (d)a is inserted: 

“(d)a  the Committee for Advanced Therapies;” 

(b) 

In paragraph 2, in the first sentence of the first subparagraph, “paragraph 1(a) 
to (d)” is replaced by “paragraph 1(a) to (d)a”. 

(2) 

In the Annex, the following point 1a is inserted: 

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“1a. Advanced therapy medicinal products, as defined in Regulation (EC) No […/of 
the  European  Parliament  and  of  the  Council  (Regulation  on  Advanced  Therapy 
Medicinal Products)*]. 

_______________________________________________________- 

* 

OJ L […], […], p. […].” 

Article 28 

Amendments to Directive 2001/83/EC 

Directive 2001/83/EC is amended as follows: 

(1) 

In Article 3, the following paragraph 7 is added: 

“7.  Any  advanced  therapy  medicinal  product,  as  defined  in  Regulation  (EC)  No 
[…/of  the  European  Parliament  and  of  the  Council  (Regulation  on  Advanced 
Therapy Medicinal Products)*], which is both prepared in full and used in a hospital, 
in accordance with a medical prescription for an individual patient. 

_______________________________________________________- 

* 

OJ L […], […], p. […].” 

(2) 

In Article 4, the following paragraph 5 is added: 

“5.  This  Directive  and  all  Regulations  referred  to  therein  shall  not  affect  the 
application  of  national  legislation  prohibiting  or  restricting  the  use  of  any  specific 
type  of  human  or  animal  cells,  or  the  sale,  supply  or  use  of  medicinal  products 
containing,  consisting  of  or  derived  from  these  cells.  The  Member  States  shall 
communicate the national legislation concerned to the Commission.” 

(3) 

In Article 6, the first subparagraph of paragraph 1 is 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  of  the  European  Parliament  and  of 
the  Council*,  read  in  conjunction  with  Regulation  (EC)  No  […/of  the  European 
Parliament  and  of  the  Council  (Regulation  on  Advanced  Therapy  Medicinal 
Products)**]. 

_______________________________________________________- 

* 

OJ L 136, 30.4.2004, p. 1 

**  OJ L […], […], p. […].” 

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Article 29 

Transitional period 

1. 

2. 

Advanced therapy medicinal products which were legally on the Community market 
in accordance with national or Community legislation at the time of entry into force 
of  this  Regulation  shall  comply  with  this  Regulation  no  later  than  2  years  after  its 
entry into force. 

By way of derogation from Article 3(1) of Regulation (EC) 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 paragraph 1. 

Article 30 

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

It shall apply from [3 months after entry into force] 

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

Done at Brussels, 

For the European Parliament 
The President 

For the Council 
The President 

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ANNEX I 
Points referred to in Article 2(1)(c) 

Cells  or  tissues  shall  be  considered  ‘engineered’  if  they  fulfil  at  least  one  of  the  following 
points: 

(1) 

The cells or tissues have been subject to substantial manipulation, so that their original 
biological characteristics, physiological functions or structural properties relevant for 
the intended regeneration, repair or replacement, are altered. 

The following manipulations are not considered as substantial manipulations: 

–  cutting; 

–  grinding; 

–  shaping; 

–  centrifugation; 

–  soaking in antibiotic or antimicrobial solutions; 

–  sterilization; 

–  irradiation; 

–  cell separation, concentration or purification; 

–  filtering; 

–  lyophilization; 

–  freezing; 

–  cryopreservation; 

–  vitrification. 

(2) 

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

(3) 

The cells or tissues form part of a combined advanced therapy medicinal product. 

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ANNEX II 
Summary of Product Characteristics 

1. Name of the medicinal product. 

2. 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,  knowledge  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 shall 
be provided. 

3. Pharmaceutical form. 

4. Clinical particulars: 

4.1. therapeutic indications, 

4.2.  dosage  and  detailed 
implantation  or 
administration  for  adults  and,  where  necessary,  for  children  or  other  special 
populations, if necessary with explanatory drawings and pictures, 

instructions  for  use,  application, 

4.3. contra-indications, 

4.4. special warnings and precautions for use, including any special precautions to be 
taken  by  persons  handling  such  products  and  administering  or  implanting  them  to 
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 and pharmacokinetic properties, if applicable. 

5.2. preclinical safety data. 

6. Quality particulars: 

6.1. list of preservative systems and excipients, if applicable 

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6.2. major incompatibilities, if applicable 

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

6.4. special precautions for storage, 

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

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. 

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 

(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  contains  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; 

(c) The pharmaceutical form; 

(d) A list of preservative systems and excipients, if applicable; 

(e) The method of use, application, administration or implantation and, if necessary, the route 
of  administration.  If  applicable,  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) The number of the authorization for placing the medicinal product on the market; 

(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 

(a) For the identification of the advanced therapy medicinal product: 

(i) the name of the advanced therapy medicinal product and an indication of whether 
it is intended for babies, children or adults. The common name shall be included if 
the product contains only one active substance and if its name is an invented name; 

(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; 

(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,  foodstuffs)  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 dosage, 

(ii) a summary of 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; 

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(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; 

(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 representatives in the Member States; 

(vi) the name and address of the manufacturer; 

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

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LEGISLATIVE FINANCIAL STATEMENT 

Policy area: Internal Market (Art. 95 TEC). 

Activities: The following policies are concerned: 

–  To  guarantee  a  high  level  of  health  protection  for  European  patients  treated  with  advanced 

therapies; 

–  To facilitate market access for advanced therapy products and the functioning of the internal 

market in this sector; 

–  To foster the competitiveness of European undertakings in this field, in particular small and 

medium-sized enterprises; 

TITLE OF ACTION: Regulation of the European Parliament and of the Council on advanced 
therapy  medicinal  products  and  amending  Directive  2001/83/EC  and  Regulation 
(EC) No 726/2004 

1. 

BUDGET LINE(S) + HEADING(S) 

02 04 02 01 – European Medicines Agency — Subsidy under Titles 1 and 2 

02 04 02 02 – European Medicines Agency — Subsidy under Title 3 

2. 

OVERALL FIGURES  

2.1. 

Total allocation for action (Part B): 

The proposal has an impact on the EMEA, but not directly on the allocations for 
action  of  the  Community  budget.  A  detailed  calculation  of  the  impact  on  the 
EMEA is annexed. 

2.2. 

Period of application: 

The  assumption  is  that  the  proposed  Regulation  would  apply  from  the  end  of 
2007.  The  impact  has  been  calculated  for  2008-2012;  the  impact  for  2007  is 
assumed to be negligible. 

2.3. 

Overall multiannual estimate of expenditure: 

None (see Section 10 for the estimated impact on the EMEA) 

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2.4. 

Compatibility with financial programming and financial perspective 

[X]  Proposal may entail reprogramming of the relevant heading in the financial 

perspective. 

2.5. 

Financial impact on revenue: 

[X]  Proposal has no financial implications on Community revenue 

3. 

BUDGET CHARACTERISTICS 

Type of expenditure 

New 

EFTA 
contribution 

Contributions 
form applicant 
countries 

Non-comp  Differentiat

NO 

YES 

NO 

ed 

Heading in 
financial 
perspective 

No 3 (1a) 

4. 

LEGAL BASIS  

–  Treaty establishing the European Community and notably Article 95. 

–  Regulation  (EC)  No  726/2004  of  the  European  Parliament  and  of  the  Council  of  30 
May 2004, laying down Community procedures for the authorisation and supervision 
of  medicinal  products  for  human  and  veterinary  use  and  establishing  a  European 
Medicines Agency (OJ L136, 30.4.2004, p. 1). 

–  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 (OJ L311, 
28.11.2001, p.67, as amended by OJ L136, 30.4.2004, p.34) 

–  Council Regulation (EC) No 297/95 of 10 February 1995 concerning fees payable to 
the European Agency for the Evaluation of Medicinal Products (OJ L035, 15.2.1995, 
p. 1, as amended by Council Regulation (EC) No 2743/98 of 14 December 1998, OJ 
L345, 19.12.98, p. 3 and by Commission Regulation (EC) No 494/2003 of 18 March 
2003, OJ L73, 19.3.2003, p. 6; see also COM(2005)106). 

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5. 

DESCRIPTION AND GROUNDS 

5.1. 

Need for Community intervention 

5.1.1.  Objectives pursued 

The main objectives of the proposal are: 

–  To  guarantee  a  high  level  of  health  protection  for  European  patients  treated  with 

advanced therapy products; 

–  To facilitate market access for advanced therapy products; 

–  To foster the competitiveness of European undertakings operating in this field; 

–  To provide overall legal certainty. 

The  proposal  contributes  to  the  three  strategic  goals  of  the  Community  legislation  on 
medicinal products: 

(1) 

(2) 

(3) 

Ensuring that public health is adequately protected across the Community; 

Supporting the achievement of the internal market in the pharmaceutical sector; 

Improving  the  competitiveness  of  the  EU  pharmaceutical  and  biotechnology 
industry. 

5.1.2.  Measures taken in connection with ex ante evaluation  

An Impact Assessment was conducted on the Commission’s proposal. It draws on: 

–  Experience  with  the  existing  EU  legislation  on  medicinal  products,  medical  devices 

and human tissues and cells; 

–  Experience with gene and somatic cell therapy products at the EMEA; 

–  Extensive consultation with all stakeholders; 

–  Two  studies  on  human  tissue  engineering  conducted  by  the  Institute  for  Prospective 

Technological Studies (IPTS); 

–  Experience  with  legislation  on  human  cells,  tissues,  and  cellular  and  tissue-based 

products (HCT/Ps) in the United States (US); and 

–  Published literature on regenerative medicine in general. 

There  has  been  extensive  consultation  with  all  stakeholders  in  preparing  the  proposed 
Regulation. This included: 

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–  Workshops and roundtable meetings; 

–  Stakeholders interviews; 

–  Public consultations on the internet. 

Feedback from all stakeholders was carefully taken in consideration for the refinement of 
the proposal. 

5.1.3.  Measures taken following ex post evaluation 

As  regards  gene  and  somatic  cell  therapy,  the  proposal  draws  on  experience  with  the 
existing  legislation  on  medicines,  medical  devices  and  human  tissues  and  cells, 
experience  with  gene  and  somatic  cell  therapy  products  at  the  EMEA,  and  experience 
with legislation on HCT/Ps in the US. 

As  regards  tissue  engineering,  there  is  so  far  no  Community  framework  covering  these 
products.  Therefore,  no  ex-post  evaluation  could  be  conducted  at  Community  level. 
Nevertheless,  experience  at  national  level,  in  particular  in  the  United  Kingdom,  France 
and Germany, was carefully analyzed and taken in consideration. 

5.2. 

Action envisaged and budget intervention arrangements 

Achievement of these objectives and results can easily be measured, for instance in terms 
of: 

–  Number of marketing authorisation applications for advanced therapy products. 

–  Number of requests for conditional marketing authorisations. 

–  Number  of  requests  for  accelerated  assessment  of  marketing  authorisation 

applications. 

–  Number of requests for scientific advice. 

–  Number of marketing authorisation applications granted. 

–  Percentage of applications coming from SMEs. 

–  Number  of  requests  for  post-marketing  studies,  post-authorisation  plans  and  risk 

management systems and the delivery against those plans. 

5.3.  Methods of implementation 

Centralised Management, indirectly by delegation to a body set up by the Communities 
as referred to in Art. 185 of the Financial Regulation (EMEA). 

EN 

39 

   EN 

 
6. 

FINANCIAL IMPACT 

–  The proposed Regulation has direct implications on the European Medicines Agency. 

(See Section 10). 

–  Advanced therapies represent a young sector, which is developing rapidly in Europe. 
Consequently,  there  are  rather  broad  corridors  of  possible  developments.  The 
regulatory  framework  is  only  one  of  the  factors  influencing  the  future  of  this  area. 
Only limited and static information is available in this fast-moving field. The figures 
provided here should hence be regarded as estimates only. 

6.1. 

Total financial impact on Part B - (over the entire programming period) 

6.1.1.  Financial intervention 

None (see Section 10 for the estimated impact on the EMEA) 

6.1.2.  Technical and administrative assistance, support expenditure and IT expenditure 

(commitment appropriations) 

None (see Section 10 for the estimated impact on the EMEA) 

6.2. 

Calculation  of  costs  by  measure  envisaged  in  Part  B  (over  the  entire 
programming period) 

None (see Section 10 for the estimated impact on the EMEA) 

7. 

IMPACT ON STAFF AND ADMINISTRATIVE EXPENDITURE  

7.1. 

Impact on human resources 

None (see Section 10 for the estimated impact on the EMEA) 

7.2. 

Overall financial impact of human resources 

None (see Section 10 for the estimated impact on the EMEA) 

7.3. 

Other administrative expenditure deriving from the action 

None (see Section 10 for the estimated impact on the EMEA) 

8. 

FOLLOW-UP AND EVALUATION 

8.1. 

Follow-up arrangements 

Most  of  the  effects  of  the  proposal  lend  themselves  to  direct  measurement.  Besides, 
Articles 67 to 70 of Regulation (EC) No 726/2004 lay down financial provisions for the 

EN 

40 

   EN 

 
annual preparation, execution, monitoring and reporting of the EMEA budget, including 
revenues from fees paid by undertakings and costs entailed for the evaluation, supervision 
and  post-authorisation  vigilance  of  medicinal  products.  Adequate  monitoring  data 
regarding  advanced  therapies  will  be  collected  in  the  context  of  the  implementation  of 
these Articles and the provisions laid down in this proposal. 

8.2. 

Arrangements and schedule for the planned evaluation 

The EMEA will provide annually an analysis of the experience acquired as a result of the 
application of this Regulation, through its Annual Report. 

9. 

ANTI-FRAUD MEASURES 

The  European  Medicines  Agency  has  specific  budgetary  control  mechanisms  and 
procedures.  The  Management  Board,  which  comprises  representatives  of  the  Member 
States, the Commission and the European Parliament, adopts the budget (Article 66(f) of 
Regulation  (EC)  No  726/2004),  as  well  as  the  internal  financial  provisions  (Article 
66(g)). The European Court of Auditors examines the execution of the budget each year 
(Article 68.3).  

The provisions of Regulation (EC) No 1073/1999 of the European Parliament and of the 
Council  of  25  May  1999  concerning  investigations  conducted  by  the  European  Anti-
Fraud Office (OLAF) apply to the EMEA without restriction. A decision concerning co-
operation with the OLAF was already adopted on 1 June 1999 (EMEA/D/15007/99). 

Finally,  the  Quality  Management  System  applied  by  the  Agency  supports  a  continuous 
review,  whose  objective  is  to  ensure  that  the  correct  procedures  are  followed  and  that 
these procedures  are pertinent and efficient. Several internal audits are undertaken each 
year as part of this process. 

10.  ANNEX:  DETAILED  CALCULATION  OF  THE  PROPOSAL’S  FINANCIAL 

IMPACT ON THE EMEA REVENUES AND COSTS 

Introduction 

The proposal entails various impacts on the EMEA, notably through: 

(1) 

The creation of a new Committee and the related infrastructure; 

(2) 

New applications submitted through the centralised procedure, for which 
applicants will have to pay a fee. 

Costs related to point (1) can be estimated by analogy with already existing Committees. 

Costs and revenues related to point (2) are more difficult to predict, as they will depend 
on  external  factors  (e.g.  development  of  the  sector,  venture  capital  investment  in  the 
field...) which lie outside the scope of the proposal. 

EN 

41 

   EN 

 
Methodology 

Assumptions on the revenues 

–  Fees amounts payable by applicants are normally based on average fees for 2004, as 
provided by the EMEA and based on Council Regulation (EC) No 297/9538. Inflation 
is not taken into account. 

–  The success rate for the marketing authorisation applications is assumed to be around 

80%. 

–  The different types of services provided by the Agency are listed (e.g. evaluation of a 
marketing authorisation application, variations, scientific advice etc.). A distinction is 
made  between  designated  orphan  medicinal  products,  to  which  additional,  specific 
fees  reductions  apply39,  and  other  medicines.  The  fee  for  inspections  is  a  flat-rate 
inspection fee, travel expenses are excluded. 

–  The calculation takes into account special fees reductions and deferrals for SMEs, as 
provided for in the Commission Regulation implementing Article 70(2) of Regulation 
(EC) No726/2004. The main provisions are: 

–  Deferral  of  the  marketing  authorisation  application  fee  until  the  end  of  the 
evaluation procedure. The fee for an application submitted in year N is hence 
allocated to the revenues of year N+1; 

–  90% reduction on scientific advice fee, inspection fee, and scientific services 
fee.  The  fee  reduction  on  scientific  advice  also  applies  to  non-SMEs 
undertakings; 

–  100% reduction on administrative service fee; 

–  100%  fee  reduction  on  scientific  advice  fee  and  scientific  service  fee  for 

designated orphan medicinal products; 

–  Conditional fee exemption for the marketing authorisation: if scientific advice 
has  been  requested  and  used  prior  to  the  submission  of  a  marketing 
authorisation application, the fee for that application would be due only if the 
outcome is positive. 

–  The average fee for scientific services is estimated at 100 000 Euros. 

38 

39 

OJ L035, 15.2.1995, p. 1, as amended by Council Regulation (EC) No 2743/98 of 14 December 
1998,  OJ  L345,  19.12.98,  p.  3  and  by  Commission  Regulation  (EC)  No  494/2003  of  18  March 
2003, OJ L73, 19.3.2003, p. 6. See also COM(2005)106. 
See Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 
1999 on orphan medicinal products (OJ L18, 22.1.2000, p.1) and http://www.emea.eu.int.  

EN 

42 

   EN 

 
                                                 
–  During the first two years, a number of applications may have to be evaluated free of 
charge.  The  figures  vary  from  4  applications  (2008:2;  2009:2)  in  the  conservative 
scenario,  to  11  (2008:6;  2009:5)  in  the  optimistic  scenario.  The  evaluation  of  these 
applications  does  not  entail  revenues,  but  does  entail  costs  (e.g.  payment  of 
rapporteurs,  additional  experts,  etc.).  Post-authorisation  services  related  to  these 
applications entail the same revenues and costs as other applications. 

Assumptions on the costs 

The following costs are assumed: 

–  CAT Members costs, based on 750 Euros per member per day, 2 days per meeting, 11 

meetings per year; 

–  Secretariat  costs,  based  on  1,5  to  2  Administrator  FTEs  (FTE:  Full-time  Equivalent 
Employee) and 1.5 to 3 Senior Assistant FTEs. Staff costs are usual EMEA standards, 
including overhead; 

–  Additional experts costs, on a ad-hoc basis depending on the number and novelty of 
applications  to  be  evaluated  by  the  Agency;  and  based  on  750  Euros  per  expert  per 
day, 2 days per meeting, 11 meetings per year; 

–  Meeting management and conference services costs, based on ~2500Euros per day per 

meeting, 2 days per meeting, 11 meetings per year; 

–  Evaluation  costs,  i.e.  payment  of  the  rapporteurs  and  co-rapporteurs,  estimated  to 
∼45% of the total fee revenues. This is in line with the usual evaluation costs for other 
types of medicinal products, as provided by the EMEA for the 2003-2005 period40. 

–  IT developments, databases and other costs related to the management of the dossiers 
and their maintenance at the Agency. At a given year N, those costs are assumed to be 
proportional  to  (1+ln(AN/AN-1)),  where  AN  is  the  number  of  marketing  authorisation 
applications in year N and AN-1 is the number of marketing authorisation applications 
in year N-1. 

–  EMEA workshops, trainings and missions related to the field. Given the pace at which 
science  evolves  in  this  area,  these  costs  may  not  be  negligible.  A  10%  increase  per 
year is assumed. 

As of 2007, the EMEA would most likely have to set up a task force to prepare the work 
and  the  procedures  laid  down  in  the  proposal.  It  is  assumed  that  this  would  require  1 
Administrator FTE and 1 Senior Assistant FTE, but only through internal redeployment. 
These 2007 costs are hence assumed to be negligible. 

40 

See also Annex 7 of the EMEA 2004 Annual report. 

EN 

43 

   EN 

 
                                                 
Assumptions on the scenarios 

Three scenarios (conservative, average, optimistic) are provided: 

–  Conservative  scenario:  the  field  of  advanced  therapies  would  develop  very  slowly. 
SMEs  would  mostly  apply  for  scientific  advice,  with  almost  no  marketing 
authorisation  applications  in  the  first  three  years.  A  few  dossiers  would  nevertheless 
be submitted to the Agency by non-SMEs applicants. 

–  Optimistic  scenario,  based  on  an  exponential  development  of  the  field.  A  significant 
number  of  applications,  both  at  scientific  advice  and  marketing  authorisation  level, 
would be submitted by SMEs and non-SMEs. 

–  Average scenario, based on a moderate development of the industry. A stationary state 

would be reached by 2011-2012. 

Results 

The results are given in Figure 1. Detailed figures are given in Tables 1, 2 and 3. 

2 500 000

2 000 000

1 500 000

1 000 000

500 000

0

-500 000

-1 000 000

-1 500 000

-2 000 000

-2 500 000

2008

2009

2010

2011

2012

Figure 1: Advanced Therapies: Revenues – Costs. The X-axis represents the years. The Y-axis represents 
the  difference  between  the  estimated  revenues  and  costs,  in  Euros.  The  three  scenarios  are  outlined: 
conservative (triangle dots), average (square dots), and optimistic (bullet dots). 

The figures suggest that: 

–  During  the  first  three  years,  the  financial  impact  is  overall  negative  in  the  three 
scenarios.  This  is  essentially  due  to  the  costs  entailed  for  the  applications  evaluated 

EN 

44 

   EN 

 
 
free  of  charge  under  the  2-years  ‘Transitional  period’  foreseen  in  the  proposal. 
However,  the  maximum  annual  deficit  is  capped  below  ∼1.8  million  Euros  in  2008 
and  below  ∼1.3  million  Euros  in  2009  and  2010.  In  the  optimistic  scenario, 
equilibrium is reached in 2010 already. 

–  During  the  2010-2012  period,  the  financial  impact  in  the  conservative  scenario 
remains  around  -1  million  Euros  per  year.  In  the  optimistic  scenario,  the  impact 
increases  from  ∼+250  000  Euros  surplus  in  2010  to  ∼+2.1  million  Euros  surplus  in 
2012.  In  the  average  scenario,  the  financial  impact  reaches  equilibrium  in  2011  and 
stabilizes around ∼+250 000 Euros surplus. 

–  Two financial incentives foreseen in the proposal may have a significant impact on the 
EMEA, by entailing costs without directly generating revenues: the 90% fee reduction 
on  scientific  advice,  and  the  2-years  transitional  period  of  free-of-charge  assessment 
by  the  EMEA  of  products  which  were  authorised  before  the  entry  into  force  of  the 
Regulation. These two measures appear justified: 

–  to  support  the  growth  of  this  emerging  sector  and  thus  the  development  of 

new products and treatments for patients; 

–  to facilitate a smooth transition from the current regulatory picture to the one 
laid  down  in  this  Regulation,  by  alleviating  the  financial  pressure  put  on 
applicants during this period. 

–  Whatever the scenario, the financial impact of the proposal is not negligible. It should 
therefore be fully taken into account in the budgetary procedures, when reviewing the 
Community contribution to the EMEA for the 2008-2012 period. This impact should 
not be considered alone but in a broader context, together with all other legislation that 
may  have  an  impact  on  the  EMEA  budget,  such  as  the  Commission  Regulation 
implementing Article 70(2) of Regulation (EC) No 726/2004. 

EN 

45 

   EN 

 
Revenues 

Applications from transitional period 

New Applications 
SMEs 
Marketing Authorisation Applications - Non Orphan 

Positive outcome  
Negative outcome, no Scientific Advice 
Negative outcome with Scientific Advice 

Marketing Authorisation Applications - Orphan 

Positive outcome  
Negative outcome without Scientific Advice 
Negative outcome with Scientific Advice 

Variations 
Inspections 
Annual Fee 
Scientific Advice 

Scientific Services 

Non Orphan 
Orphan 

Non Orphan 
Orphan 

Administrative Services 

Non-SMEs 
Marketing Authorisation Applications - Non Orphan 
Marketing Authorisation Applications - Orphan 
Variations 
Inspections 
Annual Fee 
Scientific Advice 

Scientific Services 

Administrative Services 

Non Orphan 
Orphan 

Non Orphan 
Orphan 

Total Revenues (A) 
Marketing Authorisations Applications 
Marketing Authorisations granted 

Fee 

232.000 

Special Fee 
reductions & 
deferrals 
Free of charge 

2008 

Nº  
applica-
tions 
4.0 

Financial 
Impact 

0 

2009 

Nº  
applica-
tions 
4.0 

Financial 
Impact 

0 

2010 

Nº  
applica-
tions 

Financial 
Impact 

2011 

Nº  
applica-
tions 

Financial 
Impact 

2012 

Nº  
applica-
tions 

Financial 
Impact 

232.000 
232.000 
232.000 
232.000 
116.000 
116.000 
116.000 
116.000 
50.000 
17.400 
80.000 

52.200 
52.200 

100.000 
100.000 
5.800 

232.000 
116.000 
50.000 
17.400 
80.000 

52.200 
52.200 

100.000 
100.000 
5.800 

Deferral 
0% 
0% 
100% 
Deferral 
0% 
0% 
100% 
0% 
90% 
0% 

90% 
100% 

90% 
100% 
100% 

0% 
0% 
0% 
0% 
0% 

90% 
100% 

0% 
0% 
0% 

1.0 
0 
0 
0 
0 
0 
0 
0 
0 
3.8 
0 

4.0 
2.0 

4.0 
0 
0 

1.0 
0 
0 
1.0 
0 

4.0 
2.0 

5.0 
0 
0 

6 
4.8 

2008 

0 
+0 
+0 
+0 
+0 
+0 
+0 
+0 
+0 
+6.525 
+0 

+20.880 
+0 

+40.000 
+0 
+0 

+232.000 
+0 
+0 
+17.400 
+0 

+20.880 
+0 

+500.000 
+0 
+0 

1.0 
1.0 
0 
0 
0 
0 
0 
0 
2.0 
4.0 
2.4 

10.0 
4.0 

6.0 
1.0 
0 

1.0 
0 
2.0 
3.0 
2.4 

10.0 
2.0 

8.0 
2.0 
0 

0 
+232.000 
+0 
+0 
+0 
+0 
+0 
+0 
+100.000 
+6.960 
+192.000 

+52.200 
+0 

+60.000 
+0 
+0 

+232.000 
+0 
+100.000 
+52.200 
+192.000 

+52.200 
+0 

+800.000 
+200.000 
+0 

837.685 

2.271.560 

6 
4.8 

2009 

3.0 
1.0 
0 
0 
1.0 
0 
0 
0 
3.7 
5.0 
4.8 

15.0 
4.0 

8.0 
3.0 
1.0 

3.0 
0 
3.7 
3.9 
4.8 

15.0 
3.0 

10.0 
2.0 
2.0 

7 
5.6 

0 
+232.000 
+0 
+0 
+0 
+0 
+0 
+0 
+183.333 
+8.700 
+384.000 

+78.300 
+0 

+80.000 
+0 
+0 

+696.000 
+0 
+183.333 
+67.860 
+384.000 

+78.300 
+0 

+1.000.000 
+200.000 
+11.600 

3.587.427 

4.0 
3.0 
0 
0 
1.0 
1.0 
0 
0 
5.4 
6.5 
7.6 

18.0 
5.0 

12.0 
4.0 
2.0 

5.0 
2.0 
5.4 
8.2 
7.6 

18.0 
3.0 

12.0 
3.0 
3.0 

12 
9.6 

0 
+696.000 
+0 
+0 
+0 
+116.000 
+0 
+0 
+269.444 
+11.310 
+608.000 

+93.960 
+0 

+120.000 
+0 
+0 

+1.160.000 
+232.000 
+269.444 
+142.158 
+640.000 

+93.960 
+0 

+1.200.000 
+300.000 
+17.400 

5.937.677 

5.0 
3.0 
1.0 
0 
2.0 
1.0 
0 
0 
8.5 
9.0 
12.4 

20.0 
5.0 

12.0 
4.0 
3.0 

5.0 
1.0 
8.5 
8.5 
12.4 

20.0 
4.0 

13.0 
3.0 
3.0 

13 
10.4 

0 
+696.000 
+232.000 
+0 
+0 
+116.000 
+0 
+0 
+424.537 
+15.573 
+992.000 

+104.400 
+0 

+120.000 
+0 
+0 

+1.160.000 
+116.000 
+424.537 
+147.047 
+992.000 

+104.400 
+0 

+1.300.000 
+300.000 
+17.400 

7.261.894 

Costs 

Cost 

# FTEs 

Impact 

# FTEs 

Evaluation costs (payment to (co-)rapporteurs 

Committee for Advanced Therapies 
CAT member costs 
Secretariat costs 

Administrator Staff 
Senior Assistant Staff 

150000 
126000 

Additional experts costs 
Meeting management , and conference services 
IT developments & databases costs 
EMEA Workshops, trainings, missions 

31 

1.5 
1.5 
3 

 -1.350.473 

-511.500 

-225.000 
-189.000 
-49.500 
-55.000 
-80.000 
-50.000 

31 

1.5 
1.5 
3 

EN 

46 
EN 

Financial 
Impact 
 -2.319.750 

2010 

# FTEs 

2011 

# FTEs 

Financial 
Impact 
 -3.170.847 

Financial 
Impact 
 -4.442.376 

2012 

# FTEs 

Financial 
Impact 
 -5.218.403 

31 

2.0 
2.0 
3.5 

-511.500 

-225.000 
-189.000 
-49.500 
-55.000 
-80.000 
-55.000 

31 

2.0 
2.0 
6.0 

-511.500 

-300.000 
-252.000 
-57.750 
-55.000 
-92.332 
-60.500 

31 

2.0 
3.0 
6.5 

-511.500 

-300.000 
-252.000 
-99.000 
-55.000 
-142.099 
-66.550 

-511.500 

-300.000 
-378.000 
-107.250 
-55.000 
-153.473 
-73.205 

 
 
 
  
  
  
  
  
  
  
  
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
  
Total Costs (B) 

Total Impact (A+B) 

-2.510.473 

-1.672.788 

-3.484.750 

-1.213.190 

-4.499.929 

-5.868.525 

-6.796.831 

-912.502 

69 152 

465.064 

Table 1: (Average Scenario) Financial impact of the proposal on the EMEA. Financial figures are given in Euros. Figures should be regarded as indicative estimates only.

EN 

47 
EN 

 
 
 
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
  
Table 2: (Conservative Scenario) Financial impact of the proposal on the EMEA. Financial figures are given in Euros. Figures should be regarded as indicative estimates only. 

Revenues 

Applications from transitional period 

New Applications 
SMEs 
Marketing Authorisation Applications - Non Orphan 

Positive outcome  
Negative outcome, no Scientific Advice 
Negative outcome with Scientific Advice 

Marketing Authorisation Applications - Orphan 

Positive outcome  
Negative outcome without Scientific Advice 
Negative outcome with Scientific Advice 

Variations 
Inspections 
Annual Fee 
Scientific Advice 

Scientific Services 

Non Orphan 
Orphan 

Non Orphan 
Orphan 

Administrative Services 

Non-SMEs 
Marketing Authorisation Applications - Non Orphan 
Marketing Authorisation Applications - Orphan 
Variations 
Inspections 
Annual Fee 
Scientific Advice 

Scientific Services 

Administrative Services 

Non Orphan 
Orphan 

Non Orphan 
Orphan 

Total Revenues (A) 
Marketing Authorisations Applications 
Marketing Authorisations granted 

Fee 

232.000 

Special Fee 
reductions & 
deferrals 
Free of charge 

2008 

Nº  
applica-
tions 
2,0 

Financial 
Impact 

0 

2009 

Nº  
applica-
tions 
2,0 

Financial 
Impact 

0 

2010 

Nº  
applica-
tions 

Financial 
Impact 

2011 

Nº  
applica-
tions 

Financial 
Impact 

2012 

Nº  
applica-
tions 

Financial 
Impact 

232.000 
232.000 
232.000 
232.000 
116.000 
116.000 
116.000 
116.000 
50.000 
17.400 
80.000 

52.200 
52.200 

100.000 
100.000 
5.800 

232.000 
116.000 
50.000 
17.400 
80.000 

52.200 
52.200 

100.000 
100.000 
5.800 

Deferral 
0% 
0% 
100% 
Deferral 
0% 
0% 
100% 
0% 
90% 
0% 

90% 
100% 

90% 
100% 
100% 

0% 
0% 
0% 
0% 
0% 

90% 
100% 

0% 
0% 
0% 

0 
0 
0 
0 
0 
0 
0 
0 
0 
1,5 
0 

2,0 
0 

3,0 
0 
0 

0 
0 
0 
0 
0 

3,0 
0 

3,0 
0 
0 

2,0 
1,6 

0 
+0 
+0 
+0 
+0 
+0 
+0 
+0 
+0 
+2.610 
+0 

+10.440 
+0 

+30.000 
+0 
+0 

+0 
+0 
+0 
+0 
+0 

+15.660 
+0 

+300.000 
+0 
+0 

358.710 

0 
0 
0 
0 
0 
0 
0 
0 
0,7 
1,5 
0,8 

4 
1,0 

3,0 

0 

1,0 
0 
0,7 
2,0 
0,8 

5,0 
1,0 

4,0 
1,0 
0 

3,0 
2,4 

0 
+0 
+0 
+0 
+0 
+0 
+0 
+0 
+33.333 
+2.610 
+64.000 

+20.880 
+0 

+30.000 
+0 
+0 

+232.000 
+0 
+33.333 
+34.800 
+64.0000 

+26.100 
+0 

+400.000 
+100.000 
+0 

1.041.057 

1 
0 
0 
0 
1 
0 
0 
0 
1,6 
1,5 
2,0 

8,0 
2,0 

5,0 
1,0 
0 

1,0 
0 
1,6 
2,0 
2,0 

8,0 
1,0 

4,0 
1 
0 

3,0 
2,4 

0 
+0 
+0 
+0 
+0 
+0 
+0 
+0 
+77.778 
+2.610 
+160.000 

+41.760 
+0 

+50.000 
+0 
+0 

+232.000 
+0 
+77.778 
+34.800 
+160.000 

+41.760 
+0 

+400.000 
+100.000 
+0 

1.378.486 

1,0 
1,0 
0 
0 
1,0 
1,0 
0 
0 
2,3 
1,5 
3,2 

11,0 
2,0 

7,0 
1,0 
1,0 

2,0 
0,0 
2,3 
1,5 
3,2 

10,0 
2,0 

5,0 
1,0 
1,0 

4,0 
3,2 

0 
+232.000 
+0 
+0 
+0 
+116.000 
+0 
+0 
+114.815 
+2.610 
+256.000 

+57.420 
+0 

+70.000 
+0 
+0 

+464.000 
+0 
+114.815 
+26.100 
+256.000 

+52.200 
+0 

+500.000 
+100.000 
+5.800 

2.367.760 

1,0 
1,0 
0 
0,0 
1,0 
1,0 
0 
0 
3,2 
1,5 
4,8 

14,0 
3,0 

7,0 
2,0 
1,0 

3,0 
0 
3,2 
3,0 
4,8 

15,0 
3,0 

6,0 
1,0 
2,0 

5,0 
4,0 

0 
+232.000 
+0 
+0 
+0 
+116.000 
+0 
+0 
+162.346 
+2.610 
+384.000 

+73.080 
+0 

+70.000 
+0 
+0 

+696.000 
0 
+162.346 
+52.200 
+384.000 

+78.300 
+0 

+600.000 
+100.000 
+11.600 

3.124.481 

Evaluation costs (payment to (co-)rapporteurs 

-607.995 

Costs 

Cost 

# FTEs 

Impact 

# FTEs 

2008 

2009 

Financial 
Impact 
 -1.046.595 

2010 

# FTEs 

Financial 
Impact 
 -1.443.715 

2011 

# FTEs 

2012 

# FTEs 

Financial 
Impact 
 -1.945.093 

Financial 
Impact 
 -2.546.726 

Committee for Advanced Therapies 
CAT member costs 
Secretariat costs 

Administrator Staff 
Senior Assistant Staff 

150000 
126000 

Additional experts costs 
Meeting management , and conference services 
IT developments & databases costs 

31,0 

1,5 
1,5 
1,0 

-511.500 

31,0 

-511.500 

31,0 

-511.500 

31,0 

-511.500 

31,0 

-511.500 

-225.000 
-189.000 
-16.5000 
-55.000 
-50.000 

1,5 
1,5 
1,5 

2,0 
2,0 
1,5 

-225.000 
-189.000 
-24.750 
-55.000 
-70.273 

2,0 
2,0 
2,0 

-300.000 
-252.000 
-24.750 
-55.000 
-70.273 

2,0 
3,0 
2,5 

-300.000 
-252.000 
-33.000 
-55.000 
-90.490 

-300.000 
-378.000 
-41.250 
-55.000 
-110.682 

EN 

48 
EN 

 
 
 
  
  
  
  
  
  
  
  
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
EMEA Workshops, trainings, missions 

-40.000 

-44.000 

-48.400 

-53.240 

-58.564 

Total Costs (B) 

Total Impact (A+B) 

-1.694.995 

-1.336.285 

-2.166.118 

-1.125.062 

-2.705.638 

-1.327.153 

-3.240.323 

-4.001.722 

-872.563 

-877.241 

EN 

49 
EN 

 
 
 
  
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
  
Table 3: (Optimistic Scenario) Financial impact of the proposal on the EMEA. Financial figures are given in Euros. Figures should be regarded as indicative estimates only. 

Fee 

232.000 

Special Fee 
reductions & 
deferrals 
Free of charge 

2008 

Nº  
applica-
tions 
6,0 

Financial 
Impact 

0 

2009 

Nº  
applica-
tions 
5,0 

Financial 
Impact 

0 

2010 

Nº  
applica-
tions 

Financial 
Impact 

2011 

Nº  
applica-
tions 

Financial 
Impact 

2012 

Nº  
applica-
tions 

Revenues 

Applications from transitional period 

New Applications 
SMEs 
Marketing Authorisation Applications - Non Orphan 

Positive outcome  
Negative outcome, no Scientific Advice 
Negative outcome with Scientific Advice 

Marketing Authorisation Applications - Orphan 

Positive outcome  
Negative outcome without Scientific Advice 
Negative outcome with Scientific Advice 

Variations 
Inspections 
Annual Fee 
Scientific Advice 

Scientific Services 

Non Orphan 
Orphan 

Non Orphan 
Orphan 

Administrative Services 

Non-SMEs 
Marketing Authorisation Applications - Non Orphan 
Marketing Authorisation Applications - Orphan 
Variations 
Inspections 
Annual Fee 
Scientific Advice 

Scientific Services 

Administrative Services 

Non Orphan 
Orphan 

Non Orphan 
Orphan 

Total Revenues (A) 
Marketing Authorisations Applications 
Marketing Authorisations granted 

232.000 
232.000 
232.000 
232.000 
116.000 
116.000 
116.000 
116.000 
50.000 
17.400 
80.000 

52.200 
52.200 

100.000 
100.000 
5.800 

232.000 
116.000 
50.000 
17.400 
80.000 

52.200 
52.200 

100.000 
100.000 
5.800 

Deferral 
0% 
0% 
100% 
Deferral 
0% 
0% 
100% 
0% 
90% 
0% 

90% 
100% 

90% 
100% 
100% 

0% 
0% 
0% 
0% 
0% 

90% 
100% 

0% 
0% 
0% 

2,0 
0 
0 
0 
0 
0 
0 
0 
0 
6,0 
0 

8,0 
3,0 

5,0 
1,0 
0 

3,0 
0 
0 
2,3 
0 

8,0 
2,0 

7,0 
1,0 
0 

0 
+0 
+0 
+0 
+0 
+0 
+0 
+0 
+0 
+10.440 
+0 

+41.760 
+0 

+50.000 
+0 
+0 

+696.000 
+0 
+0 
+39.150 
+0 

+41.760 
+0 

+700.000 
+100.000 
+0 

1.679.110 

11,0 
8,8 

2008 

2,0 
2,0 
0 
0 
1,0 
0 
0 
0 
3,7 
6,0 
4,4 

15,0 
5,0 

8,0 
2,0 
0 

5,0 
1,0 
3,7 
4,5 
4,4 

15,0 
4,0 

10,0 
2,0 
1,0 

14,0 
11,2 

2009 

0 
+464.000 
+0 
+0 
+0 
+0 
+0 
+0 
+183.333 
+10.440 
+352.000 

+78.300 
+0 

+80.000 
+0 
+0 

+1.160.000 
+116.000 
+183.333 
+78.300 
+352..000 

+78.300 
+0 

+1.000.000 
+200.000 
+5.800 

4.341.807 

4,0 
1,0 
0 
1,0 
1,0 
1,0 
0 
0 
7,7 
3,8 
10,0 

20,0 
6,0 

9,0 
3,0 
2,0 

7,0 
1,0 
7,7 
7,0 
10,0 

18,0 
6,0 

12,0 
4,0 
2,0 

13,0 
10,4 

0 
+232.000 
+0 
+0 
+0 
+116.000 
+0 
+0 
+386.111 
+6.525 
+800.000 

+104.400 
+0 

+90000 
+0 
+0 

+1.624.00 
+116.000 
+386.111 
+121.800 
+800.000 

+93.960 
+0 

+1.200.000 
+400.000 
+11.600 

6.488.507 

7,0 
3,0 
0 
1,0 
2,0 
1,0 
0 
0 
10,8 
6,8 
15,2 

25,0 
8,0 

13,0 
5,0 
3,0 

8,0 
2,0 
10,8 
10,0 
15,2 

22,0 
7,0 

13,0 
4,0 
3,0 

19,0 
15,2 

0 
+696.000 
+0 
+0 
+0 
+116.000 
+0 
+0 
+538.426 
+11.745 
+1.216.000 

+130.500 
+0 

+130.000 
+0 
+0 

+1.856.000 
+232.000 
+538.426 
+174.000 
+1.216.000 

+114.840 
+0 

+1.300.000 
+400.00 
+17.400 

8.687.337 

7,0 
6,0 
1,0 
0 
3,0 
2,0 
0 
0 
15,3 
7,5 
22,8 

30,0 
10,0 

14,0 
7,0 
4,0 

7,0 
2,0 
15,3 
10,0 
22,8 

25,0 
8,0 

13,0 
5,0 
5,0 

19,0 
15,2 

Financial 
Impact 

0 

0 
+1.392.000 
+232.000 
+0 
+0 
+232.000 
+0 
+0 
+765.355 
+13.050 
+1.824.000 

+156.600 
+0 

+140.000 
+0 
+0 

+1.624.000 
+232.000 
+765.355 
+174.000 
+1.824.000 

+130.500 
+0 

+1.300.000 
+50.000 
+29.000 

11.333.860 

Evaluation costs (payment to (co-)rapporteurs 

 -2.336.288 

Costs 

Cost 

# FTEs 

Impact 

# FTEs 

2010 

# FTEs 

Financial 
Impact 
 -3.829.935 

Financial 
Impact 
 -4.849.413 

2011 

# FTEs 

Financial 
Impact 
 -6.531.976 

2012 

# FTEs 

Financial 
Impact 
 -7.683.304 

Committee for Advanced Therapies 
CAT member costs 
Secretariat costs 

Administrator Staff 
Senior Assistant Staff 

150000 
126000 

Additional experts costs 
Meeting management , and conference services 
IT developments & databases costs 

31.0 

1.5 
1.5 
4.0 

-511.500 

31.0 

-511.500 

31.0 

-511.500 

31.0 

-511.500 

31.0 

-511.500 

-225.000 
-189.000 
-66.000 
-55.000 
-100.000 

1.5 
1.5 
5.1 

2.0 
2.0 
4.7 

-225.000 
-189.000 
-84.000 
-55.000 
-124.116 

2.0 
2.0 
6.9 

-300.000 
-252.000 
-78.000 
-55.000 
-114.918 

2.0 
3.0 
6.9 

-300.000 
-252.000 
-114.000 
-55.000 
-158.528 

-300.000 
-378.000 
-114.000 
-55.000 
-158.528 

EN 

50 
EN 

 
 
 
  
  
  
  
  
  
  
  
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
EMEA Workshops, trainings, missions 

-70.000 

-77.000 

-84.700 

-93.170 

-102.487 

Total Costs (B) 

Total Impact (A+B) 

-3.552.788 

-1.873.678 

-5.095.551 

-6.245.531 

-8.016.174 

-9.302.820 

-753.745 

242.977 

671.163 

2.031.040 

EN 

51 
EN