1 This request for a preliminary ruling concerns the interpretation of Article 1(2)(b) 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 2001 L 311, p. 67), as amended by Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2004 (OJ 2004 L 136, p. 34) (‘Directive 2001/83’).
2 The request has been made in proceedings between, on the one hand, Cassella-med GmbH & Co. KG (‘Cassella-med’) and MCM Klosterfrau Vertriebsgesellschaft mbH (‘MCM Klosterfrau’) and, on the other hand, Verband Sozialer Wettbewerb eV (‘VSW’) concerning the marketing by Cassella-med of two products, ‘Femannose’ and ‘Femannose N’, as medical devices for the prevention and treatment of certain urinary tract infections, and advertising by MCM Klosterfrau to promote the second of those products.
3 Article 1(2)(a) of Council Directive 93/42/EEC of 14 June 1993 concerning medical devices (OJ 1993 L 169, p. 1), as amended by Directive 2007/47/EC of the European Parliament and of the Council of 5 September 2007 (OJ 2007 L 247, p. 21) (‘Directive 93/42’), provided: ‘2. For the purposes of this Directive, the following definitions shall apply: (a) “medical device” means any instrument, apparatus, appliance, software, material or other article, whether used alone or in combination, including the software intended by its manufacturer to be used specifically for diagnostic and/or therapeutic purposes and necessary for its proper application, intended by the manufacturer to be used for human beings for the purpose of: - diagnosis, prevention, monitoring, treatment or alleviation of disease, - diagnosis, monitoring, treatment, alleviation of or compensation for an injury or handicap, - investigation, replacement or modification of the anatomy or of a physiological process, - control of conception, and which does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means, but which may be assisted in its function by such means’.
4 Article 1(5)(c) of Directive 93/42 provided: ‘This Directive shall not apply to: … (c) medicinal products covered by [Directive 2001/83]. In deciding whether a product falls under that Directive or this Directive, particular account shall be taken of the principal mode of action of the product’.
5 That directive was repealed with effect, as regards, inter alia, Article 1 thereof, from 26 May 2021 by Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC (OJ 2017 L 117, p. 1), as amended by Regulation (EU) 2020/561 of the European Parliament and of the Council of 23 April 2020 amending Regulation (EU) 2017/745 on medical devices, as regards the dates of application of certain of its provisions (OJ 2020 L 130, p. 18) (‘Regulation 2017/745’).
6 Article 1(2) of Directive 2001/83 provides: ‘For the purposes of this Directive, the following terms shall bear the following meanings: … 2. Medicinal product: (a) Any substance or combination of substances presented as having properties for treating or preventing disease in human beings; or (b) 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 medical diagnosis’.
7 Article 2(2) of that directive provides: ‘In cases of doubt, where, taking into account all its characteristics, a product may fall within the definition of a “medicinal product” and within the definition of a product covered by other Community legislation the provisions of this Directive shall apply.’
8 Recital 7 of Directive 2004/27 states: ‘Particularly as a result of scientific and technical progress, the definitions and scope of [Directive 2001/83] should be clarified in order to achieve high standards for the quality, safety and efficacy of medicinal products for human use. In order to take account both of the emergence of new therapies and of the growing number of so-called “borderline” products between the medicinal product sector and other sectors, the definition of “medicinal product” should be modified so as to avoid any doubt as to the applicable legislation when a product, whilst fully falling within the definition of a medicinal product, may also fall within the definition of other regulated products. This definition should specify the type of action that the medicinal product may exert on physiological functions. …’
9 Article 1(6) of Regulation 2017/745 provides: ‘This Regulation does not apply to: … (b) medicinal products as defined in point 2 of Article 1 of [Directive 2001/83]. In deciding whether a product falls under [Directive 2001/83] or under this Regulation, particular account shall be taken of the principal mode of action of the product; …’
10 Article 2 of that regulation reads as follows: ‘For the purposes of this Regulation, the following definitions apply: (1) “medical device” means any instrument, apparatus, appliance, software, implant, reagent, material or other article intended by the manufacturer to be used, alone or in combination, for human beings for one or more of the following specific medical purposes: - diagnosis, prevention, monitoring, prediction, prognosis, treatment or alleviation of disease, - diagnosis, monitoring, treatment, alleviation of, or compensation for, an injury or disability, - investigation, replacement or modification of the anatomy or of a physiological or pathological process or state, - providing information by means of in vitro examination of specimens derived from the human body, including organ, blood and tissue donations, and which does not achieve its principal intended action by pharmacological, immunological or metabolic means, in or on the human body, but which may be assisted in its function by such means. …’
11 That regulation became applicable on 26 May 2021, in accordance with Article 123(2) thereof.
12 Cassella-med marketed the product Femannose, the main constituents of which were D-mannose and cranberry extract, as a medical device ‘for the treatment and prevention of cystitis (bladder infection) and other urinary tract infections’. Since October 2017, it has marketed a product under the name ‘Femannose N’ which, unlike Femannose, does not contain cranberry extract and the packaging of which includes the following statement: ‘for the prevention and to support the treatment of cystitis (bladder infection) and other urinary tract infections’.
13 MCM Klosterfrau operates a website on which the product Femannose was advertised until October 2017.
14 VSW, an association the object of which, according to its statutes, includes defending the commercial interests of its members, many of whom market medicinal products and medical devices, brought an action before the Landgericht Köln (Regional Court, Cologne, Germany) against Cassella-med and MCM Klosterfrau for an injunction against the marketing and advertising of Femannose and Femannose N as medical devices.
15 According to VSW, those products are not medical devices but medicinal products, and it is common ground that no marketing authorisation has been granted in respect of those products.
16 By a judgment of 15 January 2020, the Landgericht Köln (Regional Court, Cologne) upheld that action.
17 The appeal brought against that judgment by Cassella-med and MCM Klosterfrau was dismissed by the Oberlandesgericht Köln (Higher Regional Court, Cologne, Germany) in a judgment of 23 December 2020.
18 The latter court found that the products at issue in the main proceedings were medicinal products by function, for the purposes of Article 1(2)(b) of Directive 2001/83, the pharmacological action of which is exerted by D-mannose. In reaching that conclusion, the Oberlandesgericht Köln (Higher Regional Court, Cologne) referred to the findings of an expert appointed by the court (‘the court-appointed expert’), according to whom the active substance D-mannose attaches in urine to the adhesin FimH that is present on Escherichia coli bacteria, thereby preventing the bacteria from adhering to certain structures in the bladder wall, which constitutes an intervention in the physiological processes of that bacterium and in the pathophysiological processes of the urinary tract infection.
19 That court referred to the guidance document adopted by the European Commission’s Directorate-General for Enterprise and Industry, entitled ‘Medical devices: Guidance document - Borderline products, drug-delivery products and medical devices incorporating, as an integral part, an ancillary medicinal substance or an ancillary human blood derivative - MEDDEV 2.1/3 rev. 3’ (‘the Meddev Guidance’), which defines ‘pharmacological means’, for the purposes of Article 1(2)(a) of Directive 93/42, in particular, as an interaction between the molecules of the substance in question and a cellular constituent, usually referred to as a receptor, which blocks the response to another agent.
20 Having taken the view that the effect of the D-mannose on FimH adhesins was to block the response to another agent, as referred to in that definition, the Oberlandesgericht Köln (Higher Regional Court, Cologne) considered that that active substance exerted a pharmacological action, within the meaning of Article 1(2)(b) of Directive 2001/83, and stated that the question whether the binding of the D-mannose to the bacterium is reversible was not relevant.
21 Cassella-med and MCM Klosterfrau brought an appeal on a point of law against the judgment of 23 December 2020 before the Bundesgerichtshof (Federal Court of Justice, Germany), which is the referring court.
22 Before the referring court, Cassella-med and MCM Klosterfrau claim, in particular, that reversible physical binding between an active substance and a cellular constituent establishes only an interdependence, which is insufficient for the purpose of establishing the chemical-pharmacological interaction required by the definition referred to in paragraph 19 above.
23 They also maintain that, in order to be able to find that the response of ‘another agent’ is blocked, for the purposes of that definition, the blocked substance must be an ‘agent’, that is to say, a substance intended to exert a specific (harmful) effect on a target cell and, moreover, as is apparent from the use of the term ‘another’, the blocked agent must be different from the cellular constituent involved in the interaction. In their view, neither of those two conditions is satisfied in the present case.
24 Furthermore, Cassella-med and MCM Klosterfrau contest the view of the Oberlandesgericht Köln (Higher Regional Court, Cologne) that, if used as intended, the products at issue appreciably restore, correct or modify physiological functions, within the meaning of Article 1(2)(b) of Directive 2001/83. They contend that the influence on physiological functions which is inherent in a therapeutic or preventive action is not, in itself, sufficient for classification as a medicinal product by function to be recognised. The intended therapeutic purpose must be achieved by significant interference with the physiological functions of the human body that may be classified as ‘pharmacological’, which is not the case with respect to D-mannose.
25 The referring court considers that the outcome of the dispute pending before it depends on the answer to the question whether the products concerned exert a pharmacological action and whether they are capable of significantly affecting physiological functions in human beings, and should therefore be classified as medicinal products by function, within the meaning of Article 1(2)(b) of Directive 2001/83.
26 As regards, in particular, the pharmacological action of those products, the referring court states that, according to the court-appointed expert, the binding of D-mannose to bacteria is via hydrogen bonds, which, contrary to what is argued by the appellants in the main proceedings, should not be regarded as a purely mechanical or physical action. In that sense, such binding by means of hydrogen bonds could constitute an ‘interaction’, for the purposes of the definition referred to in paragraph 19 above, which would cause the main effect of the substance at issue in the main proceedings. However, the referring court considers that that issue calls for clarification by the Court of Justice.
27 The referring court also states that, according to the case-law from the judgment of 6 September 2012, Chemische Fabrik Kreussler (C‑308/11, EU:C:2012:548, paragraphs 31 and 32), a substance the molecules of which do not interact with a human cellular constituent may nevertheless, by means of its interaction with other cellular constituents present within the user’s organism, such as bacteria, viruses or parasites, have the effect of restoring, correcting or modifying physiological functions in human beings.
28 Furthermore, according to that court, there is nothing in the Meddev Guidance to indicate that the binding of the substance in question to a cellular constituent must be permanent, which would suggest that the view taken by the Oberlandesgericht Köln (Higher Regional Court, Cologne) in the appeal, according to which, if such an interaction exists, the question of the reversibility of the adhesion to a cellular constituent is irrelevant, is correct. However, that point also requires clarification by the Court of Justice.
29 The referring court indicates that it will also be required to address the question whether the mode of action of D-mannose may be regarded as ‘blocking the response to another agent’, for the purposes of the definition referred to in paragraph 19 above.
30 In that regard, first, the referring court considers that if the understanding advocated by the appellants in the main proceedings, according to which an agent is a substance intended to exert a specific action on a target cell, were accepted, it could justifiably be countered that glycoproteins on the cell membranes of the urinary tract cannot be regarded as being agents, since no action emanates from them. Nevertheless, the referring court considers that the broad understanding of the concept of ‘agent’ adopted by the Oberlandesgericht Köln (Higher Regional Court, Cologne) in the appeal appears convincing. There are many factors that militate in favour of such an interpretation of that concept, which should be understood generally as describing a binding partner without specifying the material or structural nature of that binding partner. The referring court indicates that many medicinal products work in such a way as to block the response of a cellular constituent to parts of the human body. That is so in the case of beta blockers and ‘attachment inhibitors’, in the context of human immunodeficiency virus (HIV) infection therapy, cited as examples by the court-appointed expert.
31 Second, according to the referring court, the Oberlandesgericht Köln (Higher Regional Court, Cologne) found on appeal that D-mannose blocked the binding of the adhesin FimH on the bacterium (receptor) to certain structures on the bladder wall (another agent), which, according to that court, comes within the relevant definition. Thus, even according to the understanding of the Oberlandesgericht Köln (Higher Regional Court, Cologne), the blocked agent is different from the cellular constituent involved in the interaction concerned.
32 In those circumstances, the Bundesgerichtshof (Federal Court of Justice) decided to stay the proceedings and to refer the following question to the Court of Justice for a preliminary ruling: ‘Is there a pharmacological action within the meaning of the first case in Article 1(2)(b) of Directive 2001/83 where the substance in question (in this case: D-mannose), by means of a reversible binding to bacteria via hydrogen bonds, prevents the bacteria from adhering to human cells (in this case: the bladder wall)?’
33 By its question, the referring court asks, in essence, whether Article 1(2)(b) of Directive 2001/83 must be interpreted as meaning that a substance which, by means of a reversible binding to bacteria, prevents the bacteria from adhering to human cells must be regarded as exerting a ‘pharmacological action’ within the meaning of that provision.
34 As a preliminary point, it should be recalled, first, that under Article 1(2)(b) of Directive 2001/83, 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 medical diagnosis is regarded as a ‘medicinal product by function’ (judgment of 13 October 2022, M2Beauté Cosmetics, C‑616/20, EU:C:2022:781, paragraph 28).
35 Second, it follows from Article 1(2)(a) of Directive 93/42 that a substance intended to be used for human beings for the purpose, inter alia, of diagnosis, prevention, monitoring, treatment or alleviation of disease must be classified as a ‘medical device’, provided that that substance does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means.
36 Accordingly, a substance cannot be classified as a ‘medical device’, within the meaning of that provision, if its principal intended action in or on the human body is achieved by pharmacological means (see, to that effect, judgment of 19 January 2023, Bundesrepublik Deutschland (Nasal drops), C‑495/21 and C‑496/21, EU:C:2023:34, paragraph 37 and the case-law cited).
37 While the expressions ‘pharmacological action’, within the meaning of Directive 2001/83, and ‘action [achieved] by pharmacological … means’, within the meaning of Directive 93/42, are not defined by those directives, they nevertheless refer to the same type of action, that is to say, pharmacological action, and must therefore be interpreted uniformly.
38 In that regard, it has consistently been held that, for the purpose of interpreting a provision of EU law, it is necessary to consider not only its wording, in accordance with its usual meaning in everyday language, but also its context and the objectives of the legislation of which it forms part (see, to that effect, judgment of 13 October 2022, M2Beauté Cosmetics, C‑616/20, EU:C:2022:781, paragraph 40 and the case-law cited).
39 In accordance with its usual meaning, ‘pharmacological action’ designates the effects of a substance on a living organism, notably for therapeutic or preventive purposes.
40 That definition is supported by the guidance documents drawn up by a group of experts from the national authorities, the Commission’s services and industry trade associations. Although not legally binding, those documents may provide useful information for the interpretation of the relevant provisions of EU law and therefore contribute to ensuring that those provisions are applied uniformly (see, to that effect, judgment of 6 September 2012, Chemische Fabrik Kreussler, C‑308/11, EU:C:2012:548, paragraph 25).
41 In the present case, the Meddev Guidance is of particular relevance to the determination of the scope of the concept of ‘pharmacological action’. As the title and foreword indicate, that guidance was drawn up under the aegis of the Commission for the purposes of the application of EU directives on medical devices and aims, in particular, as set out in section A of that document, to help the competent authorities to distinguish such devices from medicinal products.
42 According to point A.2.1.1 of that document, headed ‘Definition of medical device’, ‘pharmacological means’, within the meaning of Article 1(2)(a) of Directive 93/42, is to be understood as an interaction between the molecules of the substance in question and a cellular constituent, usually referred to as a receptor, which either results in a direct response, or which blocks the response to another agent.
43 That definition of ‘pharmacological means’ was subsequently clarified in the guidance document entitled ‘MDCG 2022 - 5 Rev. 1 - Guidance on borderline between medical devices and medicinal products under Regulation (EU) 2017/745 on medical devices (“MDCG Guidance”)’ (‘the MDCG Guidance’).
44 It is apparent from footnote 6 to the MDCG Guidance, drawn up in connection with Regulation 2017/745, that the definitions set out in that document, which include the definition of ‘pharmacological means’, are aimed at adding more precision to the definitions of the identical concepts set out in the Meddev Guidance drawn up in connection with Directive 93/42.
45 According to the MDCG Guidance, that concept corresponds to an interaction, typically at a molecular level, between a substance or its metabolites and a constituent of the human body which results in initiation, enhancement, reduction or blockade of physiological functions or pathological processes.
46 It must, moreover, in the first place, be pointed out that the Court of Justice has previously found, in the context of the interpretation of Article 1(2)(b) of Directive 2001/83, that a substance the molecules of which do not interact with a human cellular constituent may nevertheless, by means of its interaction with other cellular constituents present within the user’s organism, such as bacteria, viruses or parasites, have the effect of restoring, correcting or modifying physiological functions in human beings, as referred to in that provision (see, to that effect, judgment of 6 September 2012, Chemische Fabrik Kreussler, C‑308/11, EU:C:2012:548, paragraph 31). The MDCG Guidance states, in the same vein, that ‘constituents of the human body’ may include any cellular constituent, including pathogens present on or within the body.
47 In the second place, it should be noted that the type of interaction required is defined relatively broadly in the Meddev Guidance and MDCG Guidance, that is to say, ‘between the molecules’ or ‘typically at a molecular level’, so that it cannot, a priori, be required, as MCM Klosterfrau maintains in its written observations, that such an interaction should give rise to a modification of the molecular structure of the cellular constituent in question.
48 That conclusion is reinforced by the case-law of the Court of Justice, according to which the concept of ‘medicinal product’, within the meaning of Directive 2001/83, is to be broadly construed (see, to that effect, judgment of 20 September 2007, Antroposana and Others, C‑84/06, EU:C:2007:535, paragraph 31 and the case-law cited).
49 It should also be noted that point 1.2.2 of the MDCG Guidance expressly mentions bonding by means of a hydrogen bond as an example of an ‘interaction’, for the purposes of the definition of ‘pharmacological means’, thereby supporting the interpretation according to which the binding of a substance to the cellular constituent in question by means of a hydrogen bond constitutes an interaction that falls within the definition of ‘pharmacological means’.
50 In the third place, it does not follow either from Directives 2001/83 and 93/42 or from the Meddev Guidance and MDCG Guidance that the molecules of the substance concerned should necessarily have to interact with a cellular constituent by means of a binding that is permanent, and therefore it cannot be ruled out that a substance whose binding to a cellular constituent is reversible may be regarded as exerting a pharmacological action, within the meaning of Article 1(2)(b) of Directive 2001/83, particularly in the light of the requirement that the concept of ‘medicinal product’, for the purposes of that directive, be broadly construed, as noted in paragraph 48 above.
51 In the fourth place, the criterion, from the definition of ‘pharmacological means’ in the Meddev Guidance, according to which the interaction must give rise, in particular, to a blocking of the response to another agent, must be read, as is apparent from paragraph 44 above, in the light of the definition of that concept that appears in the MDCG Guidance. According to the latter definition, the interaction between the substance concerned and the cellular constituent present within the user’s organism must result in ‘initiation, enhancement, reduction or blockade of physiological functions or pathological processes’.
52 It is common ground that the process by which a substance attaches to a bacterium and thereby prevents that bacterium from adhering to a human cellular constituent must be regarded as a ‘blockade of pathological processes’.
53 It follows from the above considerations that a substance which, by means of a reversible binding to bacteria, prevents the bacteria from adhering to human cells must be regarded as exerting a ‘pharmacological action’ within the meaning of Article 1(2)(b) of Directive 2001/83.
54 That interpretation is supported both by the context of that provision and by the objectives of Directive 2001/83.
55 As regards the context of Article 1(2)(b) of Directive 2001/83, it should be borne in mind that Article 2(2) of that directive provides that, in cases of doubt as to the correct classification of a product that may fall within the definition of a ‘medicinal product’, as referred to in that directive, and within the definition of a product covered by other EU legislation, priority must be given to the application of that directive.
56 As the Court has noted, Directive 2004/27, which introduced Article 2(2) into Directive 2001/83, states in recital 7 that, ‘in order to take account both of the emergence of new therapies and of the growing number of so-called “borderline” products between the medicinal product sector and other sectors, the definition of “medicinal product” should be modified so as to avoid any doubt as to the applicable legislation when a product, whilst fully falling within the definition of a medicinal product, may also fall within the definition of other regulated products’ (see, to that effect, judgment of 19 January 2023, Bundesrepublik Deutschland (Nasal drops), C‑495/21 and C‑496/21, EU:C:2023:34, paragraph 30).
57 Therefore, a product that falls within the definition of a ‘medicinal product’, as referred to in Article 1(2)(a) or (b) of Directive 2001/83, is covered by the legal regime established by that directive and accordingly may not be classified as a ‘medical device’, within the meaning of Directive 93/42 (judgment of 19 January 2023, Bundesrepublik Deutschland (Nasal drops), C‑495/21 and C‑496/21, EU:C:2023:34, paragraph 34 and the case-law cited).
58 As regards, lastly, the objectives of Directive 2001/83, it should be noted that that directive is aimed at ensuring a high level of protection of human health (judgment of 13 October 2022, M2Beauté Cosmetics, C‑616/20, EU:C:2022:781, paragraph 41), which is also the objective of Article 168 TFEU. From that perspective, as is apparent from recital 7 of Directive 2004/27, the scope of Directive 2001/83 must be interpreted in such a way as to ensure high standards for the quality, safety and efficacy of medicinal products for human use.
59 In those circumstances, not only would a narrow interpretation of ‘pharmacological action’ within the meaning of Article 1(2)(b) of Directive 2001/83, such as an interpretation excluding interactions consisting, as in the present case, in a reversible binding of a substance to bacteria by means of a hydrogen bond, run counter to the case-law cited in paragraph 48 above, it would also be such as to jeopardise the objective pursued by that directive (see, to that effect, judgment of 13 October 2022, M2Beauté Cosmetics, C‑616/20, EU:C:2022:781, paragraph 41).
60 Having regard to all of the above considerations, the answer to the question raised is that Article 1(2)(b) of Directive 2001/83 must be interpreted as meaning that a substance which, by means of a reversible binding to bacteria, prevents the bacteria from adhering to human cells must be regarded as exerting a ‘pharmacological action’ within the meaning of that provision.
61 Since these proceedings are, for the parties to the main proceedings, a step in the action pending before the referring court, the decision on costs is a matter for that court. Costs incurred in submitting observations to the Court, other than the costs of those parties, are not recoverable.