# Access to Advanced Therapy Medicinal Products in the EU: Where Do We Stand?

Aurélie Mahalatchimy

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Aurélie Mahalatchimy. Access to Advanced Therapy Medicinal Products in the EU: Where Do We Stand?. European Journal of Health Law, 2011, 18, pp.305 - 317. 10.1163/157180911x574146. hal-05365949

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Access to advanced therapy medicinal products in the EU: where do we stand?

A. Mahalatchimy*, **

New scientific progresses in cellular and molecular biotechnology always give rise to much expectancy. Indeed, they make patients access to new treatments possible, either more efficient or non-existent hitherto. As they led to the development of advanced therapies, they became entirely legally framed in European Union (EU) law following the Regulation (EC) N°1394/2007¹ and its implementing texts. Halfway between medicine and biotechnology, advanced therapies generate an actual effervescence at scientific level as well as political, judicial, ethical, societal and economical levels.

The EU created a new category of medicinal products called “Advanced Therapy Medicinal Products” (ATMP). ATMP are biological medicinal products for human use defined as “Any substance or combination of substances presented as having properties for treating or preventing disease in human beings; or any substance or combination of substances which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medicinal diagnosis.”<fnref n="2" /> They are based

<footnote n="1">¹ Regulation (EC) N° 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) N°726/2004, OJ L 324, 10.12.2007, p.121.</footnote>

<footnote n="2">² Article 1 § 2 and Annex I of Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use, OJ L 311,</footnote>
on genes (gene therapy), cells (cell therapy) and/or tissues (tissue engineered) from human or animal origin. While gene therapy and cell therapy have been regulated as medicinal products under the Community general legal framework since 2003³, tissue-engineered products (TEP's) lied outside any EU legislation. In order to bridge this regulatory gap, the EU institutions agreed on a new regulation addressing all advanced therapies, including tissue engineering within a coherent and single framework. On November 13th, 2007, the European Parliament and the Council adopted the regulation (EC) n. 1394/2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 ("the ATMP Regulation")<fnref n="4" />. It applied from 30 December 2008⁵.

Thus, ATMP are covered by the general Community pharmaceutical legislation as they are medicinal products. But they are also submitted to the ATMP Regulation which is a *lex specialis* setting up a judicial system stricter than the one enforceable to other medicinal products.

EU law defines and regulates four types of medicinal products as ATMP. Firstly, gene therapy medicinal products means “a biological medicinal product which has the following characteristics: it contains an active substance which contains or consists of a

<footnote>28/11/2001, p. 0067-0128; as lastly amended by Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2004 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use, OJ L 136, 30/04/2004, p. 34-57.</footnote>

<footnote n="3">³ Commission Directive 2003/63/EC of 25 June 2003 amending directive 2001/83/EC, OJ L 159 of 27/06/2003 p. 46</footnote>

<footnote n="4">⁴ Cf. Supra n. 1</footnote>

<footnote n="5">⁵ However, article 29 of the ATMP Regulation provides a transitional period. Advanced therapy medicinal products “which were legally on the Community market in accordance with national or Community legislation on 30 December 2008”, shall comply with this Regulation no later than 30 December 2012 for tissue engineered products and no later than 30 December 2011 for the others. This period is important because it implies no treatment interruption. However, the expression “legally on the market” is raising problems. Indeed, there are differences of what is “legally on the market” or not according to the Member States.</footnote>
recombinant nucleic acid used in or administered to human beings with a view of regulating, repairing, replacing adding or deleting a genetic sequence; its therapeutic, prophylactic or diagnostic effect relates directly to the recombinant nucleic acid sequence it contains, or the product of genetic expression of this sequence. Gene therapy medicinal products shall not include vaccines against infectious diseases”<fnref n="6" />. Secondly, somatic cell therapy medicinal products means a biological medicinal product which “contains or consists of cells or tissues that have been subject to substantial manipulation so that biological characteristics, physiological functions or structural properties relevant for the intended clinical use have been altered, or of cells or tissues that are not intended to be used for the same essential function (s) in the recipient and the donor; [and] is presented as having properties for, or is used in or administered to human beings with a view to treating, preventing or diagnosing a disease through the pharmacological, immunological or metabolic action of its cells or tissues”<fnref n="7" />. Thirdly, a tissue engineered product contains or consists of engineered cells or tissues (of human or animal origin or both, viable or non viable), and is presented as having properties for human beings to regenerate, repair or replace a human tissue<fnref n="8" />. Fourthly, combined advanced therapy medicinal product means an ATMP which “incorporates, as an integral part of the product, one or more medical devices [...], and its cellular or tissue part must contain viable cells or tissues, or its cellular or tissue part containing non-viable cells or tissues must be liable to act upon

<footnote n="6">⁶ Annex, Part IV, 2.1 of Commission Directive 2009/120/EC of 14 September 2009 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, Official Journal L 242 15/9/2009, p. 3 - 12.</footnote>

<footnote n="7">⁷ Annex, Part IV, 2.2 of Commission Directive 2009/120/EC of 14 September 2009 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, Official Journal L 242 15/9/2009, p. 3 - 12.</footnote>

<footnote n="8">⁸ Article 2.1 (b) of Regulation (EC) 1394/2007, supra note 1</footnote>
the human body with action that can be considered as primary to that of the devices referred to"<fnref n="9" />.

Four ATMP characteristics can be identified. Firstly, ATMP could lead to revolutionary treatments for a number of serious diseases<fnref n="10" /> such as cancer<fnref n="11" />, rheumatoid arthritis<fnref n="12" />, Crohn's disease<fnref n="13" /> or acute myeloid leukaemia<fnref n="14" />. For such serious diseases, ATMP will enhance the level of medical care. Secondly, ATMP have a strong therapeutic potential as far as they give the opportunity to target directly causes of the diseases instead of tackling their symptoms only. They are not only new; they also imply a new way of treatment. Thirdly, their technical specificities make them complex. For instance, they have the capacity, and even sometimes the function, to stay within the human body for years while they are based on living materials which can grow; they have a short shelf-life; once administered it is not possible to take them away; they still bear a significant level of medical uncertainty. That is why the EU retained a risk-based

<footnote n="9">⁹ Article 2.1 (d) of Regulation (EC) 1394/2007, supra note 1</footnote>

<footnote n="10">¹⁰ http://www.ema.europa.eu/htms/human/advanced_therapies/recommendations.htm</footnote>

<footnote n="11">¹¹ For instance, the Committee for Advanced Therapy recognized as a gene therapy medicinal product "a product consisting of a *Salmonella typhi* strain genetically modified to secrete a fusion protein of the prostate specific antigen (PSA) and a protein leading to an increased antigenicity, intended for the treatment of prostate cancer": http://www.ema.europa.eu/pdfs/human/cat/10968110en.pdf</footnote>

<footnote n="12">¹² For instance, the Committee for Advanced Therapy recognized as a somatic cell therapy medicinal product "a product consisting of autologous tolerogenic dendritic cells derived from peripheral blood monocytes, intended for the treatment of rheumatoid arthritis": http://www.ema.europa.eu/pdfs/human/cat/66775809en.pdf</footnote>

<footnote n="13">¹³ For instance, the Committee for Advanced Therapy recognized as a somatic cell therapy medicinal product "an autologous cell therapy product, intended for the treatment of Crohn's disease": http://www.ema.europa.eu/pdfs/human/cat/3891010en.pdf</footnote>

<footnote n="14">¹⁴ For instance, the Committee for Advanced Therapy recognized as a somatic cell therapy medicinal product "a product consisting of allogenic natural killer cells activated with a lysate from a cell line which is established from a patient with acute monoblastic leukaemia, intended for the treatment of acute myeloid leukaemia": http://www.ema.europa.eu/pdfs/human/cat/3891010en.pdf</footnote>
approach<fnref n="15" /> to take into account these technical specificities. Fourthly, their costs are very high notably due to several years for research.

The EU provides a complete legal framework from research to marketing authorisation of ATMP. Considering their ability to enhance the level of human health protection and the competitiveness of EU companies, the EU aims to enable the widest accessibility to these new medicinal products. What about the access to ATMP in the EU?

It is first necessary to give two precisions. Regarding the notion of “ATMP access”, two complementary levels need to be considered: ATMP access to the market and patients’ access to ATMP, once they are on the market. Patients’ access to ATMP and more precisely ATMP access to the market depends of succession of actions more or less encouraged for ATMP marketing: research, clinical trials, and manufacture. In this study, the notion of “market access” is strictly considered, i.e. as the final step of this action chain. Indeed, the question of access to therapies by patients at the step of clinical trials and the case of the numerous gene and cell therapies that are single patient treatments and as such not covered by the ATMP Regulation are not considered in this study. Furthermore, it shall be specified that this is a general forecasting study without factual data as the new Regulation on ATMP is very recent, the European Medicines Agency (EMA) did not authorised any ATMP to be placed on the EU market yet. Indeed, according to the last information available from the Monthly report from the Committee

<footnote n="15">¹⁵ On 17 December 2009, the EMEA released for consultation the “development of a guideline on the risk-based approach according to annex I, part IV of Directive 2001/83/EC applied to advanced therapy medicinal products”:
CHMP/CPWP/708420/09:</footnote>

<footnote>http://www.ema.europa.eu/pdfs/human/cpwp/70842009en.pdf</footnote>
for Advanced Therapy<fnref n="16" /> (CAT) February meeting<fnref n="17" />, the CAT gave one positive draft opinion on the initial evaluation of Marketing Authorisation Application (MAA) for an ATMP, one negative draft opinion, one evaluation is ongoing and one application was withdrawn.

The EU explicitly chooses and acts through the harmonisation method to foster ATMP market access (II). However, there are still many limitations to this harmonisation for patients to access ATMP in the EU (III).

## I. An explicit will: the harmonisation of ATMP market access

This explicit will to harmonise ATMP market access is visible regarding EU objectives (A) as well as the means used (B).

### A. EU Objectives

Article 152 EC Treaty provides the European Community (EC) shall ensure a “high level of human protection [...] in the definition and implementation of all Community policies and activities”<fnref n="18" />. Thus, the EU shall take into account consequences in public health when developing any other policy<fnref n="19" />. The EC has a specific competence regarding public health even if it is only complementary regarding Member States

<footnote n="16">¹⁶ The CAT is the sixth Committee within the EMEA. It was established in accordance with Regulation (CE) n. 1394/2007 on ATMP to provide notably assessment and recommendations regarding ATMP: http://www.ema.europa.eu/htms/general/contacts/CAT/CAT.html</footnote>

<footnote n="17">¹⁷ http://www.ema.europa.eu/pdfs/human/cat/10968110en.pdf</footnote>

<footnote n="18">¹⁸ Article 152 EC Treaty</footnote>

<footnote n="19">¹⁹ T. K. HERVEY and J.V. McHALE, “Health Law and the European Union”, Cambridge University Press, 2004, p. 469.</footnote>
competency<fnref n="20" />. Thus, the principle of subsidiarity applies: "In areas which do not fall within its exclusive competence, the Community shall take action, in accordance with the principle of subsidiarity, only if and in so far as the objectives of the proposed action cannot be sufficiently achieved by the Member States and can therefore, by reason of the scale or effects of the proposed action, be better achieved by the Community"<fnref n="21" />. The choice of this principle can be explained by the Member States divergences on sensitive ethical questions. Indeed, "Legislation in force in Member States concerning the use of certain types of cells, such as embryonic stem cells, varies considerably"<fnref n="22" />.

Since 1992, the EC developed an actual strategy for public health. In this context, several documents can be mentioned: the Communication of the Commission of 16 May 2000 which defines a strategy of the European Community on health<fnref n="23" />; the amended proposal for a decision of the European Parliament and of the Council establishing a second Programme of Community action in the field of Health (2007-2013)<fnref n="24" />; the White Paper of the European Commission, 23 October 2007, "together for health: a strategic approach for the EU 2008-2013"<fnref n="25" />.

<footnote n="20">²⁰ V. MICHEL, « La compétence de la Communauté en matière de santé publique », RAE-LEA, 2003-2004/2, p. 157.</footnote>

<footnote n="21">²¹ Article 5 al. 2 EC Treaty</footnote>

<footnote n="22">²² Committee on Legal Affairs, Report of the European Parliament, 7 February 2007, on the 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 (COM(2005)0567-C6-0401/2005-2005/0227(COD)), A6-0031/2007 final, p. 73; See also F. BELLIVIER, L. BRUNET, M. A. HERMITTE et autres, « Les limitations légales de la recherche génétique et de la commercialisation de ses résultats : le droit français. », Revue Internationale de Droit Comparé, 01/01/06, n. 2, p. 275-318 and ; C-M ROMEO CASABONA, la recherche et la thérapie avec des cellules souches embryonnaires. Quel est le cadre juridique pour l'Europe ?, Revue Générale de droit Médical, 1er Mars 2003, n.9, p.151-166.</footnote>

<footnote n="23">²³ COM (2000) 285 final</footnote>

<footnote n="24">²⁴ 24/05/2006, COM (2006) 234 final</footnote>

<footnote n="25">²⁵ COM (2007) 630 final</footnote>
The EC is more and more interested in biomedicine. S. Hennette-Vauchez
highlights the particularities of this emerging judicial corpus: the biomedicine EC law<fnref n="26" />.

Moreover, the new Regulation on ATMP is in line with different EU Strategies:
the health strategy aforementioned, the strategy on life sciences and biotechnology<fnref n="27" /> and
the economic strategy of the EU. The ATMP Regulation aims to promote the patients
access to ATMP while ensuring their security and fostering competitiveness of European
pharmaceutical undertakings.

Finally, the overall policy objective of the ATMP Regulation 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”<fnref n="28" />.
More specifically and explicitly, among the main objectives of the ATMP Regulation are
the guarantee of a high level of health protection for European patients treated with
ATMP and the harmonisation of ATMP market access.

B. EU means

One of the positive effects of the ATMP Regulation is to clarify the existing legal
framework, and to remedy to the lack of frame regarding tissue engineered products.
Therefore, every interested person, and notably the European patient, can benefit from an

<footnote n="26">²⁶ S. Hennette-Vauchez, L'émergence d'un droit communautaire de la biomédecine, RTD eur. 45 (1), Janv.-mars 2009</footnote>

<footnote n="27">²⁷ Communication from the Commission to the European Parliament, the Council, the Economic and Social Committee and the Committee of the Regions, “Life sciences and biotechnology- A strategy for Europe”, COM (2002)27</footnote>

<footnote n="28">²⁸ European Commission 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, COM(2005)0567, 16/11/2005, Explanatory Memorandum, 2.1, p. 3.</footnote>
easier access to the specific law regarding these medicinal products by referring to the ATMP Regulation. It has been essential to obviate the market division and to bridge the regulatory gap<sup>29</sup>. The European Commission, in its impact assessment<sup>30</sup>, envisaged every usable legal tool and chose the most appropriate one after discussion with interested parties. The regulation appears to be the best tool available for the harmonisation of EC law. Article 249 EC Treaty specifies the characteristics of an EC regulation. Firstly, it has a general application. A regulation is not enforceable to specific and identifiable recipients but to categories regarded "abstractly" in their entirety. Secondly, it is binding in its entirety. Compared to Directives which are binding only for the result, regulations need not to be transposed in national law. It is also binding as compared to opinions or recommendations which are not. "In its entirety" means that Member States cannot enforce it partially. Thirdly, it produces automatically legal effects in the Member States and it has to be enforced by them. Two kinds of direct effect are commonly recognised. Vertical direct effect creates rights and obligations for Member States whereas horizontal direct effect creates rights and obligations for individuals.

Furthermore, several possibilities were considered before adopting the ATMP Regulation as a unique and coherent framework for ATMP: to extend the scope of Directive 93/42/EEC on medical devices, to propose a separate regulation based on principles of "new approach"<sup>31</sup>, to set up a specific regulatory framework based on a

<footnote n="29"><sup>29</sup> Bock, A.K., D., Rodriguez-Cerezo, E.: "Human tissue-engineered products-Today's markets and future prospects", Joint Research Centre- Institute for Prospective Technological Studies (European Commission), Technical Report EUR 21000 EN- ftp://ftp.jrc.es/pub/EURdoc/eur21000en.pdf</footnote>

<footnote n="30"><sup>30</sup> Commission staff working document- Annex to the proposal for a regulation on advanced therapy medicinal products impact assessment - COM (2005) 567 final/ SEC/2005/1444/</footnote>

<footnote n="31"><sup>31</sup> The new approach aims "to recast technical harmonisation in Europe on a new basis by only harmonising the essential requirements of products and by applying the "general reference to standards" formula and the principle of mutual recognition in order to eliminate technical obstacles to the free movement of goods",</footnote>
semi-centralised procedure<fnref n="32" />, to establish a mechanism in which the Community and the Member States would share the responsibility of granting marketing authorisations.

Finally, the “advanced therapies approach” has been retained. Instead of creating a completely new legal framework designed only for tissue engineered products, the European Commission chose a more global and integrated approach, built on already-existing legislation, in particular regulation (EC) No 726/2004³³, directives 93/42/EEC<fnref n="34" />, 2001/83/EC<fnref n="35" /> and 2004/23/EC<fnref n="36" />. This approach addresses all advanced therapies- gene therapy, somatic cell therapy, tissue engineering- within a single and coherent framework, while taking into account their regulatory and technical specificities. “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”<fnref n="37" />.

Europa,

http://europa.eu/legislation_summaries/internal_market/single_market_for goods/technical_harmonisation/ l21001a_en.htm

<footnote n="32">³² “Applications for authorization [...] would be submitted to and processed by the competent authorities of the Member States, passed on to a central scientific committee for evaluation, and eventually approved by the Community”, Commission staff working document- Annex to the proposal for a regulation on advanced therapy medicinal products impact assessment – COM (2005) 567 final/ SEC/2005/1444/.</footnote>

<footnote n="33">³³ 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 Agency, OJ L 136, 30/04/2004 P. 0001 - 0033</footnote>

<footnote n="34">³⁴ Directive 93/42/EEC of the Council concerning medical devices, OJ L169, 12.7.1993, p.1</footnote>

<footnote n="35">³⁵ Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use, OJ L311, 28.11.2001, p. 67. Directive as amended by Commission Directive 2003/63/EC, OJ L159, 27.06.2003, p 46, and Directive 2004/27/EC, OJ L136, 30.4.2004, p.34.</footnote>

<footnote n="36">³⁶ Directive 2004/23/EC of the European Parliament and of the Council on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells, OJ L102; 7.4.2004, p. 48.</footnote>

<footnote n="37">³⁷ Commission staff working document- Annex to the proposal for a regulation on advanced therapy medicinal products impact assessment – COM (2005) 567 final/ SEC/2005/1444/.</footnote>
## II. A practical reality: the limitations of the harmonisation of ATMP market access

It is commonly recognised that the accessibility to treatment or to medicinal products depends on geographical accessibility, temporal accessibility and financial accessibility. If this is also true for ATMP, their limited accessibility comes primarily from the limitations of EU law itself. Limitations are due to the ATMP qualification (A), the EC method of harmonisation (B) and Member States choices (C).

### A. Limitations regarding ATMP qualification

To benefit from the harmonisation measures of ATMP access, a medicinal product has to be covered by the scope of the ATMP Regulation. Thus, the access to products which are outside this scope is not regulated in EU law.

To enter in the scope of the ATMP Regulation, a medicinal product has to fulfil cumulative conditions. On the one hand, it has to comply with the EC definitions of Gene therapy medical products, somatic cell therapy medicinal products, tissue engineered product or combined advanced therapy medicinal product. On the other hand, the medicinal product shall be “intended to be placed on the market in Member States and either prepared industrially or manufactured by a method involving an industrial process”<fnref n="38" />. The notion of “industrial process” appeared vague. Thus, the EU Commission tried to clarify it without real success: “This should cover, inter alia: any ‘mass

<footnote n="38">³⁸ Article 2 para. 1 of Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use, OJ L311, 28.11.2001, p. 67 as amended by article 1, 2) of Directive 2004/27/EC, OJ L136, 30.4.2004, p.34; see also whereas (6) of Regulation (CE) N. 1394/2007.</footnote>
production' of advanced therapy products for allogeneic use or, any ATMP for autologous use which, although being patient-specific by definition, is manufactured in accordance with a standardised and industrial process”<fnref n="39" />. If these two conditions are fulfilled, the medicinal product falls, in principle, within the scope of the ATMP Regulation.

However, the ATMP Regulation provides an hospital exemption: ATMP which are “prepared on a non-routine basis according to specific quality standards, and used within the same Member State in a hospital under the exclusive responsibility of a medical practitioner, in order to comply with an individual medical prescription for a custom-made product for an individual patient”<fnref n="40" /> are not covered by the ATMP Regulation.

## B. Limitations regarding the EC method of harmonisation

Even though the EC regulation is used, Member States keep a margin of freedom in the field of ATMP. The harmonisation provided by the ATMP Regulation is only partial. Indeed, the partial harmonisation can give rise to differences where Member States choose to apply rules stricter than those provided by the ATMP Regulation or by the directive 2004/23/EC on tissues and cells<fnref n="41" />. For instance, in some countries,

<footnote n="39">³⁹ Commission staff working document- Annex to the proposal for a regulation on advanced therapy medicinal products impact assessment - COM (2005) 567 final/SEC/2005/1444/</footnote>

<footnote n="40">⁴⁰ Whereas (6) and article 28, 2) of Regulation (CE) n. 1394/2007</footnote>

<footnote n="41">⁴¹ Directive 2004/23/EC of the European Parliament and of the Council on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells, OJ L102; 7.4.2004, p. 48.</footnote>
enterprises can only access raw materials (genes, cells ...) if they register as tissue bank.

This is not required by EC law and can entail inequalities.

Moreover, the ATMP Regulation itself by restricting its own scope includes limitations for the harmonisation of ATMP market access. According to whereas (7), the ATMP Regulation 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 with “the application of national legislation prohibiting or restricting the sale, supply or use of medicinal products containing, consisting of or derived from these cells”. Ethical controversies which have postponed the ATMP Regulation adoption are excluded as there are considered to be outside the EU competence although several ethical principles have been reaffirmed. Even though the difficult question of the sharing of competences between the Community and its Member States regarding ethical questions appeared it will not be developed in this study.<fnref n="42" />

Furthermore, ATMP are goods and the ATMP Regulation provides a partial harmonisation. Thus, once a marketing authorisation is obtained, the EC principle of free movement of goods applies to ATMP as well as its exceptions. Thus, Member States can invoke the exceptions of article 30 of the EC Treaty<fnref n="43" /> and/or the mandatory requirements primarily recognised by the “Cassis de Dijon” case-law<fnref n="44" />. However, if Member States have the possibility to restrict the free movement of ATMP, the European Court of

<footnote n="42">⁴² See M. Blanquet et N. De Grove-Valdeyron, « Les enjeux et les apports du règlement communautaire concernant les médicaments de thérapie innovante », RAE 2006/4, p. 687.</footnote>

<footnote n="43">⁴³ Article 30 of the EC Treaty provides prohibitions or restrictions on imports or/and exports of goods can be justified on grounds of public morality, public policy or public security; the protection of health and life of humans, animals or plants; the protection of national treasures possessing artistic, historic or archaeological value; or the protection of industrial and commercial property.</footnote>

<footnote n="44">⁴⁴ European Court of Justice, 20 February 1979, Rewe- Zentral AG v. Bundesmonopolverwaltung fur Branntwein, C.120/78, Rec. 1979, p. 649. For example, consumers’ protection could be invoked.</footnote>
Justice (ECJ) is in charge of the good implementation and interpretation of EC law. Thus, it can make sure the conditions of necessity, non discrimination and proportionality of the restricting national measure are respected.<fnref n="45" />

### C. Limitations regarding Member States choices

If Member States would invoke the protection of public health or ethical questions to limit the access to ATMP, the main reason might well be the high price of ATMP. Thus, mechanisms used by Member States to limit the access to high prices medicinal products should be applied to ATMP.

Firstly, the legal deadline of 180 days between marketing authorisation obtaining and reimbursement provided by the transparency directive<fnref n="46" /> is not very respected. However, the European Court of Justice will accept a legal action for non respect of the directive requirements disposals.

Secondly, the main limitation comes from the heterogeneity of Member States health systems as they are competent to regulate this field contrarily to the Community. They are free to choose their own system of pricing with enterprises and their agreement to pay medical expenses. They are using different methods such as the assessment of the therapeutic value, the inscription on list with reference pricing, or the economical assessment included most of the time the “cost/efficacy balance”. Member States could also limit the conditions of medical prescriptions: the more conditions are numerous and

<footnote n="45">⁴⁵ ECJ, 30 November 1995, Gebhard / Consiglio dell'Ordine degli Avvocati e Procuratori di Milano, C-55/94, Rec.1995, p. I-4165</footnote>

<footnote n="46">⁴⁶ Directive 89/105/ECC of 21 December 1988 relating to the transparency of measures regulating the pricing of medicinal products for human use and their inclusion in the scope of national health insurance systems, OJ L 40 of 11.02.1989, p.8.</footnote>
strict, the less medicinal products are prescribed. Most of the time prescriptions are one
of the conditions to be reimbursed by organisms of national solidarity or private
organisms. For patients, the best financial accessibility comes from a total
reimbursement. The reimbursement rate and the origin of funding influence the quality of
the financial accessibility. The accessibility is almost maximal when the treatment is
100% reimbursed. The funding of patients' reimbursement is more or less fast according
to the country and its origin: hospital, local, national, specific to a medicinal product or a
disease...

However, Member States have always to conciliate the objective of public health
protection and agreement to pay medical expenses with the obligation to control public
expenses which are variable according to each Member State. Furthermore, enterprises
often start negotiations with Member States able to pay a higher price for medicinal
products as this price will often be the reference price for negotiations with other States.

Thus, it would be interesting to create a European working group to assess the
therapeutic value of ATMP and to agree on reference price with marketing authorisation
holder: prices would be lower; the transparency directive delay could be respected. The
return on investment would be shorter for enterprises and the patients' access to ATMP
would be faster.<fnref n="47" />

Conclusion

Although the EU provides legal incentives to harmonise ATMP access there are still
many limitations. These limitations come from two main problems: the sharing of
competences between the EU and its Member States and the "limited" financial resources

<footnote n="47">⁴⁷ Eurordis (European Organisation for rare diseases) proposal for orphan drugs, http://www.eurordis.org/</footnote>
of Member States. On the one hand, the EU initially had a purely economical competence
Member States consider it is justified not to extend EU competencies regarding public
health, ethical questions and social protection systems. On the other hand, reimbursement
of ATMP depends on availability of public resources and their distribution within each
Member State according to the position given to health in the scale of social values
mainly through the organisation of the health systems.

These limitations entail, between others, inequalities to ATMP access for patients.
Would it be possible for the EU to go further with the aim to provide an equal access to
ATMP through an equal access to treatments for EU patients? With the adoption of the
Lisbon Treaty<fnref n="48" />, the EU Charter of Fundamental Rights<fnref n="49" /> obtained the value of primary
law. It provides a “right of access to preventive health care” and a general principle of
non discrimination with an open-ended list of prohibited grounds<fnref n="50" />. This general principle
is broader than article 13 EC Treaty<fnref n="51" /> as it also adds new grounds for non discrimination:
colour, social origin, genetic features, language, political or any other opinion,
membership of a national minority, property and birth. However, the interpretation of
these articles regarding the ATMP access will depend on the European Court of Justice
(ECJ). Although a clear tendency of the ECJ to increase patients’ rights as regards
patients’ mobility can be highlighted<fnref n="52" />, the recognition of a binding right of equal access

<footnote n="48">⁴⁸ http://europa.eu/lisbon_treaty/index_fr.htm</footnote>

<footnote n="49">⁴⁹ OJ C 364, 18/12/2000, p. 01</footnote>

<footnote n="50">⁵⁰ Article 21 of the EU Charter</footnote>

<footnote n="51">⁵¹ Article 12 of the European Community (EC) Treaty provides a direct prohibition against discrimination on grounds of nationality; while article 13 EC Treaty enables the Community to take action against discrimination based on sex, racial or ethnic origin, religion or belief, disability, age or sexual orientation.</footnote>

<footnote n="52">⁵² Without being exhaustive, it seems interesting to point out the ECJ notably recognised, in the Kohll and Decker Case law [ECJ, 28 April 1998, Kholl, C-158/96, and ECJ, 28 April 1998, Decker, C-120/95], a patient's right to access to medical treatment in another Member State without prior authorisation and to be reimbursed in accordance with the tariffs of the state in which the patient is insured. [See Jean-Louis</footnote>
to ATMP or treatment at EU level would be unrealistic. Beyond the political difficulties,
the differences of levels of public resources and standard of living in each country remain
the main problem. That is why “Inequalities will always exist within and between
countries. The EU has a role to address areas where change can be made and where
added value is achievable”<fnref n="53" />.

* The work presented in this article was supported by THERACELS (The medical uses of human stem cells faced to administrative regulation), ANR Project N°ANR-08-JCJC-0048-01, and the RISET EU project (Reprogramming the Immune System for the Establishment of Tolerance) EC Contract n° LSH-CT-2005-512090:

<http://www.risetfp6.org/cgi-bin/WebObjects/Awo3.woa>

* Inserm, « Epidemiology and analyses in public health: risks, chronic diseases and disability », and University Paul Sabatier Toulouse III, UMR 558, Faculté de Médecine-37,
allées Jules Guesde
31073 Toulouse Cedex 7, France

Clergerie et Chrysoula Karathanasi, “La mobilité des patients et le remboursement des dépenses médicales dans l'Union européenne”, *Revue de droit sanitaire et social* 2009 (2009), pp. 463-479
Moreover, the European Commission presented a proposal for a Directive on the application of patients’ right in cross border healthcare. It takes up most of the development of the ECJ and aims to establish “a general framework for the provision of safe, high quality and efficient cross-border healthcare”. However, it does not really recognised patients’ rights. [European Commission, proposal for a directive of the European Parliament and of the Council on the application of patients’ rights in cross-border healthcare, 2 July 2008, COM (2008) 414 final].

<footnote n="53">⁵³ Commission staff working document accompanying the White paper: together for health: a strategic approach for the EU 2008-2013 {COM(2007) 630 final} {SEC(2007) 1374} {SEC(2007) 1375}, SEC/2007/1376</footnote>
** PACTE Politique- Organisations Department UMR 5194, Institut d'Etudes
Politiques/F-38040 Grenoble cedex 9

Correspondence: mahalat@cict.fr