“(4) Trade in medicinal products within the Community is hindered by disparities between certain national provisions, in particular between provisions relating to medicinal products (excluding substances or combinations of substances which are foods, animal feeding stuffs or toilet preparations), and such disparities directly affect the functioning of the internal market. … (8) Standards and protocols for the performance of tests and trials on medicinal products are an effective means of control of these products and hence of protecting public health and can facilitate the movement of these products by laying down uniform rules applicable to tests and trials, the compilation of dossiers and the examination of applications. … (11) The adoption of the same standards and protocols by all the Member States will enable the competent authorities to arrive at their decisions on the basis of uniform tests and by reference to uniform criteria and will therefore help to avoid differences in evaluation.”
“24. The sequence of steps for an application under the centralised procedure are as follows. At phase one, full copies of the application file (“the dossier”) are sent to the rapporteur and a co-rapporteur designated by the competent EMA scientific committee. They co-ordinate the EMA’s assessment of the medicinal product and prepare draft assessment reports. Once the draft reports are prepared they are sent to the CHMP, whose comments or objections are communicated to the applicant through the EMA. The rapporteur and co-rapporteur then assess the applicant’s replies and submit them for discussion to the CHMP. Taking into account the conclusions of this debate the rapporteur and co-rapporteur prepare a final assessment report. Once the final assessment report is completed, the CHMP gives a favourable or unfavourable opinion as to whether to grant the authorisation based on its assessment of the risk-benefit balance. When the opinion is favourable, it shall include the draft summary of the product’s characteristics (“SmPC”), the package leaflet and the texts proposed for the various packaging materials. The time limit for the evaluation procedure is 210 days. 25. The second phase of the procedure, the decision-making process, starts with the EMA forwarding copies of the CHMP opinion and the final assessment report to the Commission within fifteen days. During the decision-making process, the Commission services verify that the grant of the MA would comply with EU law, including the common regulatory framework. The Commission has fifteen days to prepare a draft decision. 26. The draft decision is then sent to the Standing Committee for its opinion. Member States have fifteen days to return their linguistic comments and 22 days for scientific and technical objections. This procedure is conducted in writing but if a duly justified objection is raised by one or more Member States, the Standing Committee will convene a plenary meeting to discuss it. 27. If the opinion of the Standing Committee is favourable, the draft decision is adopted by the Commission. The applicant is then notified of the decision.”
“DEFINITIONS Article 1 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 substances 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 diagnosis. … 3a. Active Substance Any substance or mixture of substances intended to be used in the manufacture of a medicinal product and that, when used in its production, becomes an active ingredient of that product intended to exert a pharmacological, immunological or metabolic action with a view to restoring, correcting or modifying physiological functions or to make a diagnosis. 3b. Excipient Any constituent of a medicinal product other than the active substance and the packaging material. [Articles 3a and 3b inserted by the Falsified Medicines Directive, 2012/26/EU] … MARKETING AUTHORISATION Article 6 1. No medicinal product may be placed on the market of a Member State unless a marketing authorisation has been issued by the competent authorities of that Member State in accordance with this Directive or an authorisation has been granted in accordance with [the Regulation] … When a medicinal product has been granted an initial marketing authorisation in accordance with the first subparagraph, any additional strengths, pharmaceutical forms, administrative routes, presentation, as well as any variations and extensions shall also be granted an authorisation in accordance with the first subparagraph or be included in the initial marketing authorisation. All these marketing authorisations shall be considered as belonging to the same global marketing authorisation, in particular for the purpose of the application of Article 10.1. [This subparagraph inserted by Directive 2004/27/EC] … Article 8 1. In order to obtain an authorisation to place a medicinal product in the market …, an application shall be made to the competent authority of the Member State concerned. … 3. The application shall be accompanied by [the dossier] … … Article 10 1. By way of derogation from Article 8.3(i) [the requirement to file a dossier], the applicant shall not be required to provide the results if pre-clinical tests and of clinical trials if he can demonstrate that the medicinal product is a generic of a reference medicinal product which is or has been authorised under Article 6 for not less than eight years in a Member State or in the Community A generic medicinal product authorised pursuant to this provision shall not be placed on the market until ten years have elapsed from the initial authorisation of the reference product. … The ten-year period referred to in the second subparagraph shall be extended to a maximum of eleven years if, during the first eight years of those ten years, the marketing authorisation holder obtains an authorisation for one or more new therapeutic indications which, during the scientific evaluation prior to their authorisation, are held to bring a significant clinical benefit in comparison with existing therapies. [This is the fourth subparagraph of Article 10(1)] 2. For the purposes of this Article: (a) “reference medicinal product” shall mean a medicinal product authorised under Article 6, in accordance with the provisions of Article 8. (b) “generic medicinal product” shall mean a medicinal product which has the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference medicinal product, and whose bioequivalence with the reference medicinal product has been demonstrated …. The different salts, esters, isomers, mixtures of isomers, complexes or derivatives of an active substance shall be considered to be the same active substance, unless they differ significantly in properties with regard to safety and/or efficacy. In such cases, additional information providing proof of the safety and/or efficacy of the various salts, esters or derivatives of an authorised active substance must be supplied by the applicant. … … Article 10b In the case of medicinal products containing active substances used in the composition of authorised medicinal products but not hitherto used in combination for therapeutic purposes, the results of pre-clinical tests or new clinical trials relating to that combination shall be provided in accordance with Article 8.3(i), but it shall not be necessary to provide scientific researches relating to each individual active substance. Article 10c Following the grant of a marketing authorisation, the authorisation holder may allow use to be made of the pharmaceutical, pre-clinical and clinical documentation contained in the file on the medicinal product, with a view to examining subsequent applications relating to other medicinal products possessing the same qualitative and quantitative composition in terms of active substances and the same pharmaceutical form. [Articles 29ff set out a procedure for dealing with situations where a Member State cannot approve an application because in its view there would be a serious risk to public health.] ANNEX 1 Standard Marketing Authorisation Dossier Requirements … 1.2 Application Form The Medicinal product, which is the subject of the application, shall be identified by name and name of the active substance(s), together with the pharmaceutical form, the route of administration, the strength and the final presentation, including packaging. … Specific Marketing Authorisation Dossiers and Requirements … 3. Additional Data Required in Specific Situations Where the active substance of an essentially similar medicinal product contains the same therapeutic moiety as the original authorised product associated with a different salt-ester complex derivative evidence that there is no change in the pharmacokinetics of the moiety, pharmacodynamics and/or in toxicity which could change the safety/efficacy profile shall be demonstrated. Should this not be the case, this association shall be considered a new active substance.”
“The Commission representatives called the Committee attention to the fact that in cases where a marketing authorisation application relates to a product which contains a change of an existing substance, the issue whether it is a new active substance in accordance with Notice to Applicants, should be addressed and clarified during the marketing authorisation procedure, and lead subsequently to a harmonised approach across the Community.”
“Clinical Development should correspond to the intended claim … Particular attention should be given to the doses of each active substance in the fixed combination medicinal product, with each dose combination being scientifically justified and clinically relevant. The proposed combination should always be based on valid therapeutic principles. Also, the combined safety (and efficacy) profile of all active substances in the fixed combination medicinal product should be considered.”
“2.3 Notion of ‘global marketing authorisation’ Article 6(1) second subparagraph of Directive 2001/83/EC provides that when a medicinal product has been granted an initial marketing authorisation, any additional strengths, pharmaceutical forms, administration routes, presentations as well as any variations and extensions must also be granted an authorisation or be included in the initial marketing authorisation. All these marketing authorisations are considered as belonging to the same global marketing authorisation, in particular for the purpose of the application of Article 10 of the directive, which lays down rules on data exclusivity and market protection and on the so-called European Reference Product. Thus, the global marketing authorisation contains the initial authorisation and all variations and extensions thereof, as well as any additional strengths, pharmaceutical form, administration routes or presentations authorised through separate procedures, including in different Member States within the EU, and under a different name, granted to the marketing authorisation holder of the initial authorisation. Where a product is initially authorised nationally and, subsequently, an additional strength, pharmaceutical form, administration route or presentation is authorised through the centralised procedure, this is also part of the same global marketing authorisation. To determine the notion of same marketing authorisation holder or applicant in this context, see section 2.8. 1. If the medicinal product being assessed contains a modification of an existing active substance, it should be clarified during the marketing authorisation procedure whether the product contains a new active substance or not. This clarification impacts on the existence or not of a global marketing authorisation if the medicinal products belong to the same marketing authorisation holder. Request for a new active substance claim should be submitted within the initial marketing authorisation application for medicinal product containing the modified substance and will not be considered retroactively. This assessment is to be done in accordance with the definition of a new active substance provided in Annex I at the end of this Chapter and the conclusion should be reflected at least in the assessment report. If the assessment report does not indicate that the product contains a new active substance, it will be considered that the product at stake contains the same active substance and belongs to the global marketing authorisation of the already authorised medicinal product(s) as described in Article 6(1) of Directive 2001/83/EC. Example: Active substance A in MP 1 → active substance A’ in MP 2 2. If the medicinal product being assessed contains within the same pharmaceutical form a combination of active substances, it will form a new and unique medicinal product requiring a separate marketing authorisation, regardless whether all of the active substances contained therein were already authorised in a medicinal product or not. In its application for the new combination, the applicant must demonstrate that each active substance has a documented therapeutic contribution within the combination and therefore all compounds are different active substance. The authorisation for this new combination medicinal product is not considered to fall within the scope of the global marketing authorisations of the already authorised medicinal product(s) as described in Article 6(1) of Directive 2001/83/EC. Examples: Active substance A in MP1, active substance B in MP2 → Active substances A+B in MP3 Active substances A+B in MP1, Active substances C+D in MP2 → Active substances A+C in MP3 Active substances A+B in MP1, Active substance C in MP2 → Active substances A+C in MP3 Active substances A+B in MP1 → Active substance A+C in MP2 3. If the medicinal product being assessed contains only one active substance which was part of an authorised combination product, the new medicinal product will form a new and unique medicinal product requiring a separate marketing authorisation. Considering that during the assessment procedure of the already authorised combination product, the marketing authorisation holder had demonstrated that each substance of the fixed combination has a documented therapeutic contribution within the combination and therefore all compounds are different active substances, the authorisation for the new medicinal product is not considered to fall within the scope of the global marketing authorisations of the already authorised combination medicinal product as described in Article 6(1) of Directive 2001/83/EC. Example: Active substances A+B in MP1 → Active substance A in MP2 The implications of the notion of global marketing authorisation for the purpose of the application of rules on data exclusivity and market protection are referred to in section 6 below. Multiple applications of the same marketing authorisation holder are covered by the notion of ‘global marketing authorisation’. [My comment: section 2.8 deals with the concept of “applicant” and “marketing authorisation holder”
“32. As the Advocate General stated in points 100 and 101 of his Opinion, not only would such an interpretation run counter to the very wording of Articles 28 and 29 of Directive 2001/83, but it would render those provisions redundant. If a Member State which was asked to recognise an authorisation already granted by another Member State could make that recognition subject to a second assessment of all or part of the application for authorisation, that would deprive the mutual recognition procedure established by the Community legislature of all meaning and seriously compromise the attainment of the objectives of Directive 2001/83 such as, in particular, the free movement of medicinal products in the internal market, referred to in paragraph 25 above. 33. The reply to the first question must therefore be that Article 28 of Directive 2001/83 precludes a Member State to which an application is made for mutual recognition of a marketing authorisation of a medicinal product for human use granted by another Member State under the abridged procedure provided for in Article 10(1)(a)(iii) of that directive from refusing that application on the ground that the medicinal product in question is not essentially similar to the reference product.”
“29. Firstly, the applicant submits that a decision to grant or refuse marketing authorisation would not have contained a decision about whether eszopiclone is or is not a new active substance. That implies that the Commission’s position as regards the notion of new active substance and the legal test applied by the Committee to determine whether an active substance may be regarded as new could not be subject to review by the Court. 30. In that regard, the Commission does not dispute that, if the decision to grant marketing authorisation had been adopted in favour of the applicant, the operative part of that decision would have been limited to the grant of that authorisation and would not have dealt with the question whether eszopiclone is or is not a new active substance. According to the Commission, the operative part of the decision would have contained a simple reference to the Committee’s opinion. 31. However, that does not mean that that question cannot be subject to review by the Court. The Committee’s opinion that eszopiclone cannot be regarded as a new active substance must be regarded as a preparatory act to the decision to grant the marketing authorisation which the Commission is to adopt under Regulation No 726/2004. In accordance with the case-law, whilst measures of a purely preparatory character may not themselves be the subject of an action for annulment, any legal defects therein may be relied upon in an action directed against the definitive act for which they represent a preparatory step (IBM v Commission, paragraph 15 above, paragraph 12). 32. Accordingly, if the applicant had not withdrawn its application for marketing authorisation, it would have been able to challenge, by an action against the Commission’s decision granting marketing authorisation, both the Committee’s refusal to recognise eszopiclone as a new active substance and the legal test applied by that Committee to reach that conclusion. Accordingly, it cannot rightfully be claimed that the refusal to recognise eszopiclone as a new active substance, as decided upon by the Committee and confirmed by the Commission, could not be subject to any review in the event of an action against the decision to grant the marketing authorisation, adopted by virtue of Regulation No 726/2004.”
“30. All four medicinal products concerned in the present case have been authorised through the centralised procedure, provided for initially in Regulation No 2309/93 and subsequently in Regulation No 726/2004. 31. It is undisputed that the GMA concept applies to nationally authorised products under Directive 2001/83 in the same way as products authorised in the centralised procedure under Regulation No 726/2004 and, previously, Regulation No 2309/93. 32. Pursuant to the second subparagraph of Article 6(1) of Directive 2001/83, the initial marketing authorisation as well as those pertaining to the developments of the initial medicinal product shall be considered as belonging to the same GMA, in particular for the purpose of using the abridged procedure upon the expiration of the applicable regulatory data protection period, as specified in Article 10(1) of Directive 2001/83 and, in the present case, in Article 13(4) of Regulation 2309/93. 33. In the light of the connection established in Article 6(1) of Directive 2001/83 between the regulatory data protection period and the GMA, the latter notion is instrumental in the determination of the conditions under which applicants in the abridged procedure may rely on the data contained in the file of the reference medicinal product. Pursuant to Article 10(2)(a) of Directive 2001/83, a reference medicinal product is defined as ‘a medicinal product authorised under Article 6, in accordance with the provisions of Article 8’. 34. It follows from the second subparagraph of Article 6(1) of Directive 2001/83 that only one regulatory data protection period is associated with the GMA. That regulatory data protection period applies to the data related to the initial medicinal product as well as to the data submitted in respect of developments based on it. 35. The second subparagraph of Article 6(1) of Directive 2001/83 lists the developments of the initial medicinal product that constitute variables that would fall, if developed, under the GMA concept. These variables are: additional strengths, pharmaceutical forms, administration routes, presentations, and any variations and extensions. 36. By contrast, the second subparagraph of Article 6(1) of Directive 2001/83 does not specify the constitutive elements by which a GMA can be identified, and by which a specific GMA can be distinguished from another GMA. … 43. Secondly, the most important element of a medicinal product is its active substance. A marketing authorisation granted for a medicinal product that is based on a different active substance to the initial medicinal product can hardly be seen to be a development considering the language of second subparagraph of Article 6(1) of Directive 2001/83. Further, if a difference in active substance does not lead to a different GMA, it would be difficult to perceive what kind of innovation would provide the applicant with a different regulatory data protection period. 44. The conclusion that the active substance (or a combination of active substances) is a constitutive element of the GMA is also confirmed in the Commission’s Notice to Applicants: ‘If the medicinal product being assessed contains a modification of an existing active substance, it should be clarified … whether the product contains a new active substance or not. This clarification impacts on the existence or not of a global marketing authorisation if the medicinal products belong to the same marketing authorisation holder. 45. The examples provided by the Commission on changes to the initial medicinal product that do not fall within the same GMA all concern scenarios under which there is a change to the active substance (or combination of active substances) in the initial medicinal products. This is the case for, first, fixed combination products pursuant to Article 10b of Directive 2001/83; second, the separation of the substance from a previous combination of active substances or, third, a modification of an existing active substance that amounts to a new active substance. 46. It thus follows that the notion of GMA is based on identity of the marketing authorisation holder and of the active substance(s). If the marketing authorisation holder or the active substance changes, the same GMA no longer applies. … 59. By contrast, Directive 2001/83 provides for rather broad possibilities as to data that may be referred to in the abridged procedure. Article 10(1) of Directive 2001/83 expressly connects the regulatory data protection period with the GMA notion, irrespective of the fact that that notion covers various developments of the initial product, in relation to which separate data have to be supplied at different points over the course of time. The starting point of the 10-year data protection period is thus determined by the granting of the marketing authorisation for the initial medicinal product. There is no rule on the protection of separate subsequent studies, as acknowledged in the Generics case.”
“78. There is, however, a deeper layer to the assessment of ‘a potential serious risk to public health’. Since what is being requested is the authorisation of a generic product, that process relies on the extant data of the reference product. Now if the data protection period has not yet lapsed, then there is no data to be relied on. If the relevant data cannot yet be consulted, it is logically impossible to conduct any scientific assessment of the generic medicinal product at issue. 79. I therefore agree in substance with arguments advanced by the Governments of Belgium and the United Kingdom in their submissions. The impossibility of referring to the data of a reference medicinal product logically hampers, in my view, the evaluation of a public health risk of the generic product. In this manner, the agreement as to the expiration of the data exclusivity period is, in a way, a preliminary, but indispensable, part of the approval process. 80. In the light of the abovementioned, I consider, in response to the first preliminary question posed, that Article 28(5) and Article 29(1) of Directive 2001/83 should be interpreted as meaning that the competent authority of the concerned Member State, acting in the decentralised procedure for marketing authorisation for a generic medicinal product, is not competent, when issuing the national marketing authorisation pursuant to Article 28(5) of Directive 2001/83, to determine unilaterally the time from which the data exclusivity period for the reference medicinal product begins to run. However, that authority takes part in that assessment at an earlier stage in the decentralised procedure pursuant to Article 28(3) and (4) of Directive 2001/83. The participation of the competent authority of the concerned Member State in the approval process thus makes that authority co-responsible for the documents approved in that procedure.”
“Based on the review of data on the quality, non-clinical and clinical properties of the active substance, the rapporteurs consider that DMF contained in Tecfidera is not to be qualified as a new active substance as from the submitted data it does not appear to differ significantly in properties with regard to safety and/or efficacy from the currently authorised product Fumaderm …”
“In laymen’s terms, they do this [sc. demonstrate pharmacological activity] by activating a particular pathway (called the “Nrf2” transcriptional pathway), which activates the immune system promoting cellular defence to potentially toxic stimuli. Once the pathway is activated, genes will be expressed (switched on) and proteins synthesised (produced) which are protective in relation to certain kinds of harm such as inflammatory and oxidative stress.”
“The CHMP’s assessment of NAS status represented an exceptional and novel case, where a medicinal product containing active substance A and active substance B had already been authorised, and authorisation was subsequently sought for a different medicinal product containing solely active substance A. The assessment of NAS in that precise situation had not arisen before, to my knowledge.”
“Dimethyl fumarate (DMF), the active substance of "Tecfidera - Dimethyl fumarate”, is part of the composition of the authorised medicinal product Fumaderm which consist [sic] of DMF and calcium salt of ethyl fumarate, magnesium salt of ethyl hydrogen fumarate and zinc salt of ethyl hydrogen fumarate (MEF salts), belonging to the same marketing authorisation holder. The Committee for Medicinal Products for Human Use concluded that MEF and DMF are both active and are not the same active substance since they do not share the same therapeutic moiety. Therefore it is considered that Tecfidera containing DMF is different from Fumaderm the other already authorised medicinal product composed of DMF and MEF salts. Therefore "Tecfidera - Dimethyl fumarate”, the application of which was based on Article 8(3) of Directive 2001/83/EC, and the already authorised medicinal product Fumaderm do not belong to the same global marketing authorisation as described in Article 6(1) of Directive 2001/83/EC.” (italics mine) The sentence I have italicised is a somewhat compressed summary of what the CHMP decided in full. Insofar as there may be any doubt, recital (3) should be read and understood in the light of the CHMP report. In any event, I do not read recital (3) as stating that the sole issue determined by the CHMP was that of therapeutic moiety: the Commission stated, entirely correctly, that it had been concluded by the CHMP “that MEF and DMF are both active …”
“The evidence for the three salts of MEF, of which the calcium salt comprises 89% of the MEF content of Fumaderm mite and 92% of the MEF content of Fumaderm [I believe that he has omitted “forte”], is that they do not have convincing evidence of relevant pharmacological activity when tested in vitro at concentrations that are relevant in vivo … Both MEF and DMF have similar pharmacological activity in vitro, though DMF is generally more active. There is no evidence from clinical trials for sufficient efficacy of MEF as oral monotherapy to justify its inclusion at the doses used in Fumaderm. There is an absence of data to show that MEF makes a significant additional contribution to the DMF component of Fumaderm. DMF is rapidly hydrolysed in the wall of the small intestine and may act through its metabolite MMF and possibly other yet unidentified metabolites, perhaps adducts with GSH. The better physico-chemical properties of DMF compared to MEF, in terms of lipid solubility, may account for the greater potency of DMF with oral dosing in humans.”
“I have had a look. I think Teva has presented data to demonstrate the esters are less active than DMT [her acronym for DMF] but not that they have no activity. The non-inferiority study (Mrowietz) shows that DMT alone is not >15% worse than the DMT + esters. The point estimates in the main favour Fumaderm. Speed of onset data not presented. The other study is v small but again point estimates appear to favour FAC-EC (combination tablet). So some additional activity possible – whether clinically important is another matter.”
“… although doubts are being raised with regards to the activity of MEF in Fumaderm, a number of elements had been given in the EPAR for Tecfidera that remain. Conclusion: differences are noted between DMF on its own and associated with fumurate salts hence the conclusion for Tecfidera remains, although as Sue mentions the importance of these differences could be questioned.”
“… that the EC decision on Tecfidera clearly states that MEF and DMF are not the same active substance and Tecfidera does not belong to the same GMA as Fumaderm. Generic applications relating to Tecfidera are therefore not yet possible.”
“[t]he position on the data exclusivity enjoyed by Tecfidera, as set out in the EPAR and the recital to the Commission Decision granting the MA, remains the current position.”
“shall be considered as belonging”
“127. However, as may be seen from the settled case-law, only the enacting terms of a decision are capable of producing legal effects and, consequently, of adversely affecting a person’s legal interests, regardless of the grounds on which the decision is based. By contrast, the assessments made in the recitals in the preamble to a decision are not in themselves capable of forming the subject of an application for annulment and can be subject to review by the Community judicature only to the extent that, as grounds for an act adversely affecting a person’s interests, they constitute the essential basis for the enacting terms of that act … It should also be pointed out that, in principle, the enacting terms of an act are inextricably linked to the statement of reasons for them in the recitals, so that, if they had to be interpreted, account must be taken of the reasons which led to the adoption. … 129. Although the Commission none the less comments, obiter, in the recitals in the preamble to the contested decision on aspects of the NAP to which it does not object, those recitals cannot produce binding legal effects or constitute the necessary basis for the enacting terms of the decision, given that Article 9(3) of Directive 2003/87 does not give the Commission the power to determine, in a legally binding manner, the lawfulness of a rule contained in a NAP. Moreover, in those circumstances, the recitals also cannot provide useful information for the interpretation of the enacting terms of the contested decision within the meaning of the case-law cited in paragraph 127 …”
“3a. Active Substance Any substance or mixture of substances intended to be used in the manufacture of a medicinal product and that, when used in its production, becomes an active ingredient of that product intended to exert a pharmacological, immunological or metabolic action with a view to restoring, correcting or modifying physiological functions or to make a diagnosis.”