REPORT FROM THE COMMISSION TO THE EUROPEAN PARLIAMENT AND THE COUNCIL in accordance with Article 25 of Regulation (EC) No 1394/2007 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
Date: 2014-03-28
Institutions: European Commission
Subjects: drug surveillance, genetic engineering, health care, market approval, marketing standard, medicinal product













EUR-Lex - 52014DC0188 - EN











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52014DC0188

REPORT FROM THE COMMISSION TO THE EUROPEAN PARLIAMENT AND THE COUNCIL in accordance with Article 25 of Regulation (EC) No 1394/2007 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 /* COM/2014/0188 final */









REPORT FROM THE COMMISSION TO THE
EUROPEAN PARLIAMENT AND THE COUNCIL
in accordance with Article 25 of
Regulation (EC) No 1394/2007 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)
1.           Introduction
Scientific progress has brought about a new
type of medicinal products based on gene therapy,
somatic-cell therapy or tissue engineering.  To provide
for a common framework for the marketing of so-called advanced therapy
medicinal products (hereinafter "ATMPs"), Regulation (EC) No
1394/2007 of the European Parliament and of the Council on advanced therapy
medicinal products (hereinafter "ATMP Regulation") was adopted in
2007[1]
The ATMP Regulation was designed to ensure a
high level of human health protection as well as the free movement of ATMPs in
the EU.  The cornerstone of the Regulation is that a marketing authorisation
must be obtained prior to the marketing of ATMPs.  In turn, the marketing
authorisation can only be granted if, after a scientific assessment of the
quality, efficacy and safety profile, it is demonstrated that the benefits
outweigh the risks.  The application for a marketing authorisation must be
submitted to the European Medicines Agency (hereinafter "Agency") and
the final decision is taken by the Commission.  This procedure ensures that
these products are assessed by a specialised body (the Committee for Advanced
Therapies; hereinafter "CAT") and that the marketing authorisation is
valid in all the EU Member States.
The ATMP Regulation empowered the Agency to
make scientific recommendations as to whether a given product should be
considered an ATMP (hereinafter "classifications").  Additionally, it
provided for a new instrument, the so-called certification procedure, designed
as an incentive for small and medium sized enterprises (hereinafter
"SMEs") that were involved in the first stages of the development of
ATMPs but lacked the resources to conduct clinical trials.  Specifically, the
certification that the quality and preclinical aspects of the development are
in conformity with the relevant regulatory requirements was expected to help
SMEs attract capital and to facilitate the transfer of research activities to
entities with the capacity to market medicinal products.
The ATMP Regulation applies since 30 December
2008.  However, a transitional period was foreseen for ATMPs that were already
in the EU market when the Regulation was adopted.  Specifically, gene therapy and
somatic cell therapy were required to comply with the Regulation by 30 December
2011, while tissue-engineered products were required to comply with the new
requirements by 30 December 2012.
By means of this Report, prepared in compliance
with Article 25 of the ATMP Regulation, the Commission takes stock of the
situation of ATMPs in the EU and analyses the impact of the Regulation on
advanced therapies.  The report takes account of the outcome of the public
consultation on the application of the ATMP Regulation conducted by the
Commission services (hereafter "public consultation").[2]  
2.           Research and Development
Activities on Advanced Therapies in the EU: The current landscape
There is significant research in advanced
therapies in the EU.  Specifically, up to 250 distinct ATMPs were reported in
the EudraCT[3]
during the period 2004-2010.  
The majority of research in advanced therapies
is conducted by small companies and entities that operate on a non-for-profit
basis.  Thus, almost 70% of sponsors for clinical trials on ATMPs reported in
EudraCT are non-for-profit organisations or SME's; big pharmaceutical companies
accounting for less than 2% of all sponsorships.    Likewise, the majority of
applications for scientific advice to the CAT are also submitted by SMEs (see
Section 3.5).  
The translation of research activities into
medicinal products available to patients is generally challenging.  Only a
small fraction of the molecules investigated as potential medicinal products
eventually obtain a marketing authorisation. The majority of the molecules
investigated do not even make it to the stage of testing in humans for a
variety of reasons (e.g. that the assumed activity of the molecule or
the mechanism of action is not confirmed, or that pre-clinical studies
demonstrate that the safety profile is not acceptable).  In addition, it is
estimated that, on average, less than a quarter of the molecules that are
tested in clinical trials obtain a marketing authorisation.    Typically, the
path from identification of an active substance to the authorisation of the
medicinal product can take more than ten years.
Due to the specific characteristics of advanced
therapies, developers of ATMPs are confronted with additional difficulties. 
For example, the variability of the source materials makes it difficult to
demonstrate the homogeneity of the product.  Likewise, the small batch sizes
which are typically available and short shelf-lives thereof (ranging from few
hours to few days) can render extensive testing impossible.  Moreover, the
realisation of randomized controlled clinical trials may not always be
feasible, for instance, if the administration of the product requires a
surgical procedure (i.e. the majority of tissue engineering products),
or where no alternative treatments are available.
In addition, the development of ATMPs is
further hindered by the fact that researchers usually lack appropriate funding
and regulatory expertise to successfully navigate through the marketing
authorisation procedures. In turn, the uncertainties in the return for
investment are a major deterrent to investors.
3.           Overview of the
application of the ATMP Regulation from 1 January 2009 to 30 June 2013
The regulation of ATMPs has been an important
step to protect patients from scientifically unsound treatments.  In addition,
the ATMP Regulation has created a common framework for the assessment of
advanced therapies in the EU.  
We are still at the early days of the
development of advanced therapies and only four ATMPs have been granted a marketing
authorisation.  However, the much higher activity of the CAT in the area of
scientific advice and classification, as well as the high number of clinical
trials involving ATMPs, is a signal of a dynamic research sector.
3.1.        A specialised body and adapted
regulatory framework
The establishment of the CAT, as provided for
in Article 20 of the Regulation, has been a chief milestone in the
implementation of the ATMP Regulation.  This committee gathers some of the best
available experts in the EU to assess the quality, safety and efficacy of
ATMPs.  It held its first meeting in January 2009.  In addition, a
collaboration group between the CAT and the notified bodies for medical devices
was set up in November 2010 as an advisory group to the CAT on combined ATMPs.[4]
The ATMP Regulation empowered the Commission to
adopt specific requirements regarding the content of marketing authorisation
applications, good manufacturing practices, good clinical practice, and the
traceability of ATMPs.   An amendment to the Part IV of the Annex to Directive
2001/83/EC adopted on 14 September 2009 adapted some of the requirements in
terms of the content of marketing authorisation applications for ATMPs.[5] In addition, a revised
Guideline on good manufacturing practice containing specific adaptions for
ATMPs applies since 31 January 2013.[6]
However, the adoption of specific requirements regarding good clinical practice
and traceability is still pending as additional experience was deemed necessary
to better understand the type of adaptations required.[7]  
Specific provisions governing the certification
procedure were adopted by means of Commission Regulation (EC) No 668/2009 of 24
July 2009.[8]
3.2.        Marketing authorisations
Ten marketing authorisation applications for
ATMPs had been submitted to the Agency by 30 June 2013.  Five of them concerned
products that were previously on the EU market.
Out of the ten marketing authorisation
applications, four have successfully completed the procedure and have been
granted a marketing authorisation by the Commission:
-           ChondroCelect,
a tissue engineered product indicated for repairing single symptomatic
cartilage defects of the femoral condyle of the knee in adults;[9] 
-           Glybera,
a gene therapy medicinal product indicated for adult patients diagnosed with
familial lipoprotein lipase deficiency (LPLD) and suffering from severe or
multiple pancreatitis attacks despite dietary fat restrictions;[10]
-           MACI,
a combined ATMP indicated for the repair of symptomatic, full-thickness
cartilage defects of the knee (grade III and IV of the Modified Outerbridge
Scale) of 3-20 cm2 in skeletally mature adult patients.[11]
-           Provenge,
a somatic cell therapy medicinal product indicated for the treatment of
asymptomatic or minimally symptomatic metastatic (non-visceral) castrate
resistant prostate cancer in male adults in whom chemotherapy is not yet
clinically indicated.[12]
In contrast, four marketing authorisation
applications have failed.  One of these applications corresponded to a product
that was on the market prior to the entry into force of the ATMP Regulation.
Two marketing authorisation applications were
under assessment by the CAT on 30 June 2013.
3.3.        Classifications
The CAT had received 87 requests and it had
issued 81 classification recommendations by 30 June 2013.[13]  Almost half of all
classification requests received originated from SMEs and an additional 15% of
the requests came from the non-for-profit sector.  Classification requests from
large pharmaceutical companies represented approximately 5% of all submissions.
3.4.        Certifications
Only three certification requests had been
submitted to the Agency by 30 June 2013.  Two of the requests concerned
exclusively quality data, while the third request related to quality and
non-clinical data.  The CAT granted the certification in all three cases.  
3.5.        Scientific advice
By 30 June 2013, the Agency had
provided scientific advice regarding ATMPs on 93 occasions; the advice
referring to 65 different products.  Over 60% of the requests for scientific
advice had been submitted by SMEs and an additional 6% was from academia. 
Requests from big pharmaceutical companies represented less than 10% of all
requests.  
Additionally, it is noted that seven out of the
ten applicants for marketing authorisation had previously requested scientific
advice.  
4.           Analysis

The contribution of the ATMP Regulation to
public health could be measured against two parameters: (1) the extent to which
new ATMPs have become available in the EU; and (2) the extent to which
authorised ATMPs are efficacious and safe.
While there are no indications suggesting that
the requirements of the ATMP Regulation are not sufficiently robust to ensure
the good quality, efficacy and safety profile of authorised products, it needs
to be considered if the high level of public health protection that the
Regulation was designed to achieve is being undermined by the marketing of
products exhibiting the characteristics of ATMPs marketed outside the framework
of the ATMP Regulation (e.g. under the regulatory framework applicable
to tissues and cells, medical devices, or others). 
Additionally, it needs to be considered if
there is room to facilitate that more ATMPs can become available to patients. 
4.1.        The impact of the ATMP on
the availability of existing ATMPs
4.1.1      Advanced therapies available in the EU prior to the ATMP
Regulation 
It has been difficult to obtain precise figures
about the number of advanced therapy medicinal products that were on the EU
market prior to the entry into force of the ATMP Regulation.  This may be
partially explained by the intrinsic difficulties linked to the application of
the definition of "ATMP" (see Section 4.3).  
Member States have reported 31 ATMPs as being
legally on the EU market prior to the entry into force of the ATMP Regulation.[14] This figure must be taken with caution as, on the one hand, the
same product may have been reported by more than one Member State and, on the other hand, not all Member States have been able to report.  Even among the
reporting Member States, it is not excluded that the reported figures are
incomplete as some products may have been put on the market as tissues/cells or
medical devices despite having the potential to fall under the definition of
ATMP.  
It is worth noting that a number of Member States
have indicated that no ATMP was available in their territory prior to the entry
into force of the ATMP Regulation, the non-availability of these products being
more common in the smaller Member States.
4.1.2      Advanced therapies after the entry into force of the ATMP
Regulation 
The low number of marketing authorisation
applications received by the Agency (see Section 3.2) shows that a significant
number of developers of ATMPs that were on the market prior to the entry into
force of the ATMP Regulation did not apply for a marketing authorisation.   
According to data reported by the Member
States, approximately 60 derogations from the obligation to obtain a marketing
authorisation prior to the marketing of advanced therapies had been granted
until April 2012.[15]  Derogations were granted under Article 3(7) of Directive 2001/83
(so-called "hospital exemption") as well as under other provisions of
the Directive, notably Article 5.[16]  
It follows that the effects of the entry into
force of the ATMP Regulation on the availability of previously available
treatments is difficult to establish in practice:
On the one hand, a significant number of
existing ATMPs continue to be used in the absence of a marketing authorisation
under derogations granted by Member States (the hospital exemption or
otherwise).  
On the other hand, the majority of the ATMPs
that have been reported by the Member States as being marketed in their
territories before the ATMP Regulation entered into force were
chondrocyte-containing products (16 out of 31).  As the marketing authorisation
under the ATMP Regulation is valid in all Member States and given that two
marketing authorisations have been granted for chondrocyte-containing products,
the application of the ATMP Regulation may have actually led to wider coverage
of the EU territory for these products.
4.2.        Hospital exemption 
The ATMP Regulation gives Member States the
power to authorise the use of custom-made ATMPs prepared on non-routine basis
in the absence of a marketing authorisation, provided that the product is used
for individual patients in a hospital and under the professional responsibility
of a medical practitioner.[17] The so-called hospital exemption requires the application of
national requirements on quality, traceability, and pharmacovigilance
equivalent to those required for authorised medicinal products.
The hospital exemption enables patients to
receive an ATMP under controlled conditions in cases where no authorised
medicinal product is available.  Additionally, it facilitates research and
development in advanced therapies by non-profit organisations (such as academia
and hospitals) and it can be a valuable tool to obtain information prior to
seeking a marketing authorisation.
However, the experience accumulated since the
entry into force of the Regulation shows that there is a risk that a too broad
use of the hospital exemption may deter the submission of marketing
authorisation applications.  Specifically, ATMPs with a marketing authorisation
face higher developmental and maintenance costs than ATMPs that are made
available through the hospital exemption, as the marketing authorisation is
linked to stricter data requirements and post-marketing obligations. 
Developers seeking a marketing authorisation are therefore put in a competitive
disadvantage vis-à-vis those that market the products through the hospital
exemption.   
If the hospital exemption became the normal
route to market advanced therapies, there would be detrimental consequences for
public health.  First, clinical trials remain the main means to obtain reliable
information about the efficacy and safety profile of a medicinal product and
the systematic administration of complex medicinal products to patients in the
absence of appropriate clinical trials could put patients at risk.  Secondly,
the collection of data on efficacy and safety of the treatment would be
seriously undermined as each site would only generate information on a small
number of patients and there would be no transmission of information to the
authorities of another Member State where the same type of product may be used
under the hospital exemption also.  Additionally, the treatment would not be
available to all patients across the EU.
It is therefore necessary to find a balance
between the need to ensure that ATMPs are made available to patients only after
the quality, efficacy and safety thereof has been adequately demonstrated, and
the need to facilitate early access for new treatments in case of unmet medical
needs.  
The lack of harmonisation regarding the
conditions required by Member States for the application of the exemption has
also been identified as a concern in the public consultation.  The usage that
is made of this derogation is very different across Member States, partly
because of different approaches as to the meaning of "non-routine". 
For example, while the concept of "non-routine" is narrowly construed
in some Member States where a maximum number of patients is fixed, in others
there is no limit and the derogation is applied case by case.  
Clarification of the conditions under which the
hospital exemption is possible and of the requirements attached could
contribute to improving the functioning of the internal market in advanced
therapies.  In this context, appropriate consideration should be given to the
reporting of results, particularly negative results, so that patients are not
unnecessarily exposed to unsafe/ineffective treatments. 
Other issues that could benefit from additional
clarification include: 
- the role of derogatory provisions of
Directive 2001/83/EC other than the hospital exemption (in particular Article
5(1) thereof) in the context of ATMPs, and 
- the role of data generated from the use of a
product under the hospital exemption in the context of an application for a
marketing authorisation.  
4.3.        Scope of the Regulation
and classification of ATMPs
4.3.1.     Scope of the ATMP Regulation 
Three types of medicinal products are
considered ATMPs:  gene therapies, somatic cell therapies, and tissue
engineered products.  The assessment whether a product falls under any of these
categories may involve complex scientific judgements.  Specifically, the
question whether a manipulation of a living material is to be considered as
substantial may be difficult to answer.  Even the question whether the cells or
tissues are intended to fulfil the same function in the donor and in the
recipient can be challenging in some cases (e.g. bone marrow material). 

Experience in the application of the
definitions of the various categories of ATMPs by the CAT shows that some
aspects of the definition could be further clarified to ensure a better match
of the legal definitions with the underlying scientific reality. 
Additionally, advanced therapies being a field
subject to rapid scientific progress, it is necessary to keep the definitions
of gene therapies, somatic cell therapies, and tissue engineered products under
continuous review.  New innovative products, which are not clearly captured by
existing provisions, are emerging.  For instance, the development of devices
which allow the collection of cells or tissues, the processing thereof in a
closed environment and its reinjection into the donor within the same procedure
raises questions as to how these treatments should be regulated (particularly in
case of non-homologous use). 
4.3.2.     Classification 
An increasing number of innovative biological
products exhibits characteristics that could potentially fall under various
regulatory regimes (e.g. medicines, medical devices, cosmetics, or
tissues and cells).   Clarity on the regime that is applicable to new products
is essential to achieve an adequate level of public health protection. 
Moreover, developers also need a clear understanding of the regulatory
framework that will apply to their products so that the development process can
be adapted to the relevant requirements.
However, cases have been reported where the
competent authorities of the Member States had reached divergent conclusions as
to whether a product should be considered as ATMP or not.  The disparities that
exist across the EU regarding the classification of ATMPs have also been
identified as a concern in the public consultation undertaken by the Commission
services in preparation of this report. 
The possibility that the same product may be
subject to different requirements across the EU implies that the level of
public health protection is different according to the place of residence of
the patient.  That the same product can be marketed under different regulatory
regimes is not only undesirable from a public health standpoint but it also
undermines the incentives to develop ATMPs.  First, the uncertainty as to the
market potential for a product discourages investments.  Secondly, divergent
classification of the same product distorts competition between developers.
Finally, the application of different regulatory requirements across the EU
hinders the free movement of these products.
The ATMP Regulation gave the Agency the task of
providing scientific recommendations on advanced therapy classifications.  The
advice is provided free of charge and it is non-binding.  
The classification mechanism provided for in
the ATMP Regulation has shown two strengths.  First, a centralised assessment
ensures a single view point throughout the EU and provides certainty. 
Secondly, that the service is provided at no cost has prompted small companies
to use this mechanism (see Section 3.3).  In the Commission's view, this is a
positive outcome as it can help ensure that the development process of these products
is designed at an early phase in a way that maximises the chances of obtaining
a marketing authorisation.  
However, the current classification mechanism
also exhibits some weaknesses.  First, the conclusion of the CAT that a product
is an ATMP may be disregarded by a developer that decides to market the product
without generating efficacy and safety data, and/or without complying with the
quality and pharmacovigilance requirements that are typical of medicinal
products.  Another limitation of the current system is that the competent
authorities of the Member States do not have the possibility to seek the view
of the CAT when they are confronted with the question whether a product should
be considered as ATMP.  
4.4.        Requirements for the
marketing authorisation of ATMPs
4.4.1.     General considerations 
The ATMP Regulation builds on the procedures,
concepts, and requirements designed for chemical-based medicinal products. 
However, ATMPs present very different characteristics.  Additionally, in
contrast to chemical-based medicinal products, research in advanced therapies
is -for the most part- conducted by academia, non-for-profit organisations, and
SMEs, which only have limited financial resources and often lack exposure to
the regulatory system that governs medicines. 
Commission Directive 2009/120/EC provides for
adapted requirements in terms of the information that applicants must provide
when applying for a marketing authorisation of an ATMP.  The possibility to
apply a risk-based approach to determine the extent of quality, non-clinical
and clinical data is also envisaged.  
However, the public consultation shows that it
is widely felt that additional flexibility should be applied, particularly in
the area of quality, with a view to ensure that the marketing authorisation
application requirements take due consideration of scientific progress and
specific characteristics of ATMPs.  This view has been shared by respondents
representing industry, patients, hospitals, academia and non-for-profit
organisations. 
In addition to possible specific adaptations of
quality or efficacy/safety data requirements, it has been suggested that, to
allow advanced therapies to kick off, alternative approaches to reduce
regulatory costs should also be explored.  Thus, several respondents in the
public consultation suggested the introduction of a marketing authorisation
granted on the basis of limited data to be used in a restricted setting,
particularly in cases of unmet medical needs.  The
data collected on the uses in the restrictive settings could be subsequently
used to expand the marketing authorisation up to the point of becoming a
standard authorisation.  
4.4.2.     The case of autologous ATMPs
In the case of autologous products the
cells/tissues are harvested from a patient, then treated or expanded, and
finally they are introduced back into the same patient.  The starting material
(i.e. the cells/tissues) is different for each patient and, as a
consequence, the manufacturing process of these products has specific features
as compared with other medicinal products.  
Nevertheless, not all autologous products face
the same manufacturing challenges.  In this regard, it is appropriate to
distinguish two different scenarios.  On the one hand, there are autologous
products where the patient’s cells/tissues are transported to a pharmaceutical
company and the final medicinal product is delivered back to the hospital for
implantation/injection in the same patient. ChondroCelect, MACI and Provenge,
which received a centralised marketing authorisation, are examples of such
autologous ATMPs. On the other hand, there are cases where the patient’s
cells/tissues are manipulated in the hospital (e.g. by means of medical
devices that are developed for cell separation and manipulation) prior to
re-administration to the same patient. 
In the public consultation some respondents
considered that autologous ATMPs should not be regulated as medicines. While
this approach would reduce the developmental costs associated with the use of
these products, in the Commission's view, the need to ensure an adequate level
of public health protection should prevail over economic considerations.  
The regulation of these products as medicines
ensures that the risk-benefit thereof has been found positive by an independent
and highly-specialised body, that patients are followed-up after treatment, and
that the lasting effects of the treatment can be known to health care
professionals (in terms not only of safety but also of efficacy).  
However, it is important that the requirements
that apply to autologous products are proportionate and adapted to the specific
characteristics thereof.  Requiring autologous products that are manufactured
at the hospital prior to the administration to the patient to comply with the quality
controls and manufacturing requirements of standardised chemical-based
medicinal products would prevent the development of these treatments in
practice as a batch release certification would be required per treatment and a
manufacturing license would be required per hospital.
4.4.3.     The case of combined ATMPs
A combined ATMP is an ATMP that contains viable
cells or tissues and that incorporates one or more medical device(s) as an
integral part of the product.  ATMPs incorporating a device but containing
non-viable cells or tissues are also combined ATMPs if the action of the
cells/tissues on the human body is primary to that of the device.
Under the current rules, the final scientific
assessment of the combined ATMP is undertaken by the CAT.  However, for the
device part, the Agency is to rely on the assessment of the notified bodies (if
available).  If no assessment is available from the notified bodies, the Agency
is in principle required to consult one, unless the CAT considers it is not
necessary.
The public consultation showed that the
separate assessment of the medical device and the medicinal product is widely
perceived as an excessive burden when the device is not marketed separately. 
Thus, there was strong support to the principle of a single assessment (by the
CAT) for ATMPs where the device is an integral part of the product (i.e.
all combined ATMPs).  Additionally, the public consultation showed that
stakeholders have difficulties to understand the interaction between the Agency
and the notified bodies in practice.
The risk has also been identified that the
current framework gives incentives to developers to use medical devices already
licensed (even if for a use different to the intended use in the combined ATMP)
rather than developing new, better targeted devices.  This course of action may
be prompted by the perception that choosing a device with the CE-mark will
facilitate the regulatory procedure.   
4.5.        Marketing
authorisation procedure
The ATMP Regulation requires that marketing
authorisation applications for advanced therapies are submitted to the Agency. 
The scientific evaluation thereof involves up to five committees. 
Specifically:
(i)      the
CAT assesses the marketing authorisation application and gives its opinion to
the Committee for Medicinal Products for Human Use ("CHMP");
(ii)     the
CHMP adopts an opinion which is transmitted to the Commission;
(iii)    the
Pharmacovigilance Risk Assessment Committee ("PRAC") provides
recommendations to the CHMP on pharmacovigilance matters;
(iv)    the
Paediatric Committee ("PDCO") intervenes on aspects related with the
obligations imposed under Regulation (EC) No 1901/2006 of the European
Parliament and of the Council;[18] and
 (v)    the
Committee on Orphan Medicinal Products ("COMP") provides scientific opinions
to the Commission on aspects related to the application of the orphan
incentives (this committee is only involved therefore if the applicant seeks
orphan status).
The current marketing authorisation procedure
has proven complex to manage in practice and it is also challenging for
prospective applicants, which are typically entities with no exposure to the
centralised procedure of marketing authorisations.  In this regard, the public
consultation showed that the procedure for evaluation of ATMPs at the Agency is
perceived as too cumbersome, particularly for SMEs and non-for-profit
organisations. 
In sum, the experience acquired since the entry
into force of the ATMP Regulation shows that there is room for streamlining the
procedure for the evaluation of ATMPs. Simplification of this procedure should
not only bring benefits for prospective applicants but should also ensure that
there is a robust assessment of these complex products and clear allocation of
responsibility within the Agency for this task.
4.6.        Certification 
The certification of the quality and
non-clinical data by the Agency was a novel instrument designed to help SME's
attract investments/obtain revenue for the development of ATMPs.  By analogy with the reductions applied in the case of scientific
advice, the Agency applied a fee reduction of 90% to certification requests
submitted by SMEs.[19]
However, the very low number of certifications
applications received is a disappointing outcome.  The low usage of the
certification procedure may be partially explained by the exclusion of
non-commercial entities from the certification scheme.  Expanding the category
of applicants that could apply for a certification could therefore help
increase the value of this instrument.
Additionally, the outcome of the public
consultation and the enquiry carried out by EMA[20] suggests that the value of the certification could increase if some
changes were made, such as a clarification of the link between the
certification and the marketing authorisation procedure, or the extension of
the certification scheme to cover other parts of the dossier (i.e.
clinical aspects).  
4.7.        Scientific advice
Early contacts between developers of ATMPs and
the authorities are important to ensure that the development activities are designed
in the best possible way to maximise the chances of obtaining a marketing
authorisation.  Understanding at an initial stage of development the
requirements that are necessary to demonstrate the efficacy and safety of the
product is particularly important for developers that are not familiar with
marketing authorisation procedures.
As an incentive to prompt developers of ATMPs
to discuss the development of their products with the Agency, the ATMP
Regulation provided for significant fee reductions for requests for scientific
advice.  The discount went up to 90% in the case of SMEs. 
The large number of requests for scientific
advice that have been received by the Agency in the period under consideration
in this report is a positive development that can contribute to the successful
translation of research into medicinal products.  Of particular relevance is
that the majority of the requests for scientific advice emanated from SMEs (see
Section 3.5).  The heavy discount applied to SMEs has proven therefore effective.
In contrast, the exclusion of certain
non-profit organisations from the fee incentives has been identified in the
public consultation as a shortcoming.  The
low percentage of requests for scientific advice from academia (6%) suggests
that a fee reduction analogous to that applied to SMEs could encourage
researchers working in an academic (or other non-for-profit setting) to seek
scientific advice from the Agency.
4.8.        Fee incentives regarding
marketing authorisation application and post-marketing obligations
Fees linked to the application for marketing
authorisation and post-marketing activities (during the first year after the
granting of the authorisation) were reduced by 50% for SMEs and hospitals if
there was a public health interest in the concerned ATMP.  These fee reductions
were however limited in time and no longer apply. 
It is difficult to make general conclusions on
the impact of these fee incentives as only two marketing authorisations had
been granted during the term of validity thereof.  However, in general terms,
the costs linked to post-marketing activities can be very significant,
particularly if a large number of post-marketing obligations is imposed.  
These costs can be unaffordable for small companies, particularly until such time
as the medicinal product is capable of generating income (i.e. pending
the agreement of the national bodies competent for reimbursement procedures).  

5.           Conclusions
Advanced therapies have the potential to bring
major benefits to patients.  However, there are still many unknowns and it is
therefore important to put in place adequate controls to prevent detrimental
consequences for public health.  
The ATMP Regulation protects patients by
requiring that an independent review of the ATMP is done by the best available
experts in the EU according to high standards of quality, efficacy and safety
before the product is made available to patients.  
However, too burdensome requirements could have
detrimental consequences for public health as it could prevent the appearance
of valid treatments for unmet medical needs.  Regulation in this area should
contribute to creating conditions that facilitate the appearance of new
medicinal products, while ensuring a high level of public health protection. 
It is likewise important that the regulatory framework is adapted to rapid
scientific progress.
On the basis of the experience accumulated
since the entry into force of the ATMP Regulation, some possibilities to help
the translation of research into ATMPs available to patients across the EU
while maintaining a high level of public health protection can be identified,
including:
-        clarification
of the scope of the ATMP Regulation by fine-tuning the current definitions of
ATMPs and by reflecting on the appropriate regulatory framework for new
innovative products that many not be captured by existing provisions;
-        considering
measures to avoid disparities in the classification of ATMPs in the EU;
-        clarification
of the conditions for the application of the hospital exemption, as well as the
role of data obtained therefrom in the context of marketing authorisation
procedures;
-        revising
the requirements for the authorisation of ATMPs with a view to ensure that
applicable requirements are proportionate and well-adapted to the specific
characteristics thereof, having specific consideration to autologous products; 
-        streamlining
the marketing authorisation procedures;
-        extending
the certification procedure and clarification of the link between the
certification and the marketing authorisation procedure; 
-        creating
a more favourable environment for ATMP developers working in an academic or
non-for-profit setting, including by promoting early contacts with the
authorities through the application of the fee reduction for scientific advice
and by extending the certification scheme to these developers;
-        considering
possible fee incentives to reduce the financial impact of post-marketing
obligations.
[1]               Regulation (EC) No 1394/2007 of the European
Parliament and of the Council of 13 November 2007 on advanced therapy medicinal
products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 (OJ
L324, 10.12.2007, p.121).
[2]               http://ec.europa.eu/health/files/advtherapies/2013_05_pc_atmp/2013_04_03_pc_summary.pdf
[3]               Database of all clinical trials that have started in
the EU after 1 May 2004. 
[4]               http://www.ema.europa.eu/docs/en_GB/document_library/Other/2010/12/WC500099532.pdf

[5]               Commission Directive 2009/120/EC amending Directive
2001/83/EC of the European Parliament and of the Council on the Community code
relating to medicinal products for human use as regards advanced therapy
medicinal products (OJ L 242, 15.9.2009, p.3). 
[6]               http://ec.europa.eu/health/files/eudralex/vol-4/vol4-an2__2012-06_en.pdf
[7]               Some recommendations regarding good clinical practice
for ATMPs have been however published by the Commission services (http://ec.europa.eu/health/files/eudralex/vol-10/2009_11_03_guideline.pdf)

[8]               Commission Regulation (EC) No 668/2009 implementing
Regulation (EC) No 1394/2007 of the European Parliament and of the Council with
regard to the evaluation and certification of quality and non-clinical data
relating to advanced therapy medicinal products developed by micro, small and
medium-sized enterprises (OJ L 194, 25.07.2009, p.7).
[9]               Marketing authorisation granted by Commission
Decision C (2009) 7726 of 5 October 2009.
[10]             Marketing authorisation granted by Commission Decision
C (2012) 7708 of 25 October 2012.
[11]             Marketing authorisation granted by Commission Decision
C (2013) 4190 of 27 June 2013.
[12]             Marketing authorisation granted by Commission Decision C
(2013) 5841 of 6 September 2013.
[13]             The classification procedure was on-going for the
remaining six applications.
[14]             Pooled data from surveys conducted by EMA in 2007 and 2009.
[15]             http://ec.europa.eu/health/files/advtherapies/2013_05_pc_atmp/07_2_pc_atmp_2013.pdf
[16]             Article 5(1) of Directive 2001/83 provides that a Member State may exclude from the provisions of the Directive medicinal products supplied
in response to a bona fide unsolicited order, formulated in accordance with the
specifications of an authorised health-care professional and for use by an
individual patient under his direct personal responsibility.
[17]             Article 28(2) of the ATMP Regulation which, in turn,
amended Article 3 of Directive 2001/83.
[18]             Regulation (EC) No 1901/2006 of the European Parliament
and of the Council on medicinal products for paediatric use and amending
Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and
Regulation (EC) No 726/2004 (OJ L378, 27.12.2006, p.1).
[19]          http://www.ema.europa.eu/docs/en_GB/document_library/Other/2013/07/WC500146978.pdf
[20]             http://www.ema.europa.eu/docs/en_GB/document_library/Other/2013/02/WC500138476.pdf