Generics (UK) Ltd (t/a Mylan), R (On the Application Of) v Secretary Of State For Health (acting as The Licensing Authority)

This is a renewed application for permission to challenge the decision of the Medicines and Healthcare products Regulatory Agency (“MHRA”) contained in its letter dated 27 November 2017 (“the MHRA Decision”), refusing to validate and/or revisit the Claimant’s application for a generic Marketing Authorisation with Tecfidera as the Reference Medicinal Product until 4 February 2022.

The MHRA carries out the licensing functions of the Secretary of State for Health and Social Care under the EU common regulatory framework for the authorisation and marketing of medicinal products (referred to as the “CRF”). No medicinal product can be placed on the market within the EU without a marketing authorisation (“MA”).

The Claimant wishes to market a generic dimethylfumarate (“DMF”) medicine for the treatment of multiple sclerosis, relying on another mono-DMF medicine, Tecfidera, as the reference medicinal product.

On 23 December 2016 the Claimant made a generic application, seeking to rely on Tecfidera, owned by the Interested Party, Biogen, which was authorised under the centralised procedure in the CRF, by the European Commission in its Implementing Decision dated 30 January 2014 (“the Commission Decision”).

The Commission Decision, which took account of the scientific opinion of the Committee for Medicinal Products for Human Use (“CHMP”), is clear that Tecfidera does not form part of the same global marketing authorisation (“GMA”) as Fumaderm and this is also reflected in the post-opinion note of the CHMP.

The CHMP considered whether MEF and DMF are different active substances. The following points were considered in reaching its decision.

“(a)

MEF and DMF are different esters of fumaric acid

From the CHMP’s point of view, it is evident that DMF and the MEF salts contain the same backbone structure of fumaric acid (FA). They are also clearly different esters of fumaric acid (FA).

(b)

Fumaric acid is not an active substance and therefore it follows that it is the esters themselves that give the activity in MEF and DMF

DMF and its metabolite MMF have been shown to be pharmacologically active. It has also been established that fumaric acid is not a therapeutic moiety of DMF and is pharmacologically inactive. In-vitro and in-vivo non-clinical data including Nrf2-dependent gene expression together with published clinical data suggesting the pharmacological activity of MEF in psoriasis lead to the conclusion that DMF and MEF are both active.

(c)

The esters are different pharmaceutically (physiochemical properties) and do not inter-convert or follow the same metabolic path in-vivo.

… DMF and MEF are different pharmaceutically.

… there is no metabolic inter-conversion between MMF and MEF or conversion of MEF to DMF or MMF in liver microsomes or hepatocytes from rats and humans. Both substances, DMF and MEF, show different levels of glutathione (GSH) conjugation reactions.

Taking into consideration the above, the CHMP concluded that MEF and DMF are both active and not the same active substance since they do not share the same therapeutic moiety (cf Part II(3) of the Annex to Directive 2001/83/EC as amended)…

Based on the review of data on the quality, non-clinical and clinical properties of both DMF and MEF, the CHMP considered that, the active substance of Tecfidera, dimethyl fumarate, is not the same as Fumaderm as MEF and DMF are considered pharmacologically active agents which contain different therapeutic moieties.”

The CHMP’s conclusion that DMF and MEF salts were each active substances in their own right and did not share the same therapeutic moiety was adopted by the Standing Committee on Medicinal Products for Human Use (“the Standing Committee”), and formed the basis for its conclusion that Fumaderm and Tecfidera did not belong to the same GMA.

These findings were reflected in Recital 3 to the Commission Decision which states:

“Dimethyl fumarate (DMF) , the active substance of ‘Tecfidera – Dimethyl fumarate’, is part of the composition of the authorised medicinal product Fumaderm which consist of DMF and calcium 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.”

The CHMP’s initial conclusion that Tecfidera contained a new active substance (“NAS”) was amended, and clarified by the postscript on page 126 of the European Public Assessment Report. It had been corrected following the referral that had been made to the Standing Committee as part of the challenge brought by the UK at the time, and did not form the basis of the Commission Decision.

On 3 January 2017 the MHRA refused to validate the Claimant’s generic application as it did not satisfy one of the conditions set out in the CRF, namely the expiry of the data exclusivity period. The application was subsequently withdrawn on 25 May 2017.

On 18 September 2017 the Claimant made a further approach to the European Medicines Agency (“EMA”) and the MHRA to revisit its decision based on “new evidence”, which consisted of two scientific reports prepared by Professor Christopher Schofield and Professor Michael Eddleston.

This evidence is now set out in materially identical form in (1) an expert report dated 18 December 2017 prepared by Professor Schofield concerning the chemical structures and similarities of the relevant active substances, DMF/MMF and MEF; and (2) an expert report dated 18 December 2017 prepared by Professor Eddleston concerning the evidence available as to the comparative safety of DMF and MEF (Amended Statement of Facts and Grounds (“ASFG”), at para 28, and see paras 29-32).

It is the Claimant’s case on the basis of their evidence that Tecfidera consists only of the same active substance as another Biogen product, Fumaderm, previously authorised in the EU more than ten years ago and for which data exclusivity has expired. If the Claimant is correct, then Tecfidera should not have been granted an independent MA; but instead should be included in the same (older) GMA as Fumaderm. Thus the question which the Commission considered in 2014, and which was before the MHRA in 2017 is whether Tecfidera could rely upon a fresh period of data exclusivity under Article 10(1) of the Directive or whether it should be considered to fall within the GMA of an existing medicinal product, Fumaderm. The Claimant contends that Tecfidera differs from Fumaderm in that it concerned a new therapeutic indication i.e. the treatment of multiple sclerosis, and because it contains only DMF and not MEF.

By letter dated 6 October 2017 the EMA informed the Claimant that it refused to consider the new evidence, observing that there was no pending regulatory procedure before it relating to the reassessment of Tecfidera, in the context of which the Claimant’s letter of 18 September 2017 could be treated as a third-party intervention.

Following receipt of that letter from the EMA, the Claimant’s solicitors wrote on 13 October 2017 to the MHRA asking whether in the circumstances the MHRA “would confirm whether or not it would reject an abridged marketing authorisation application that references Tecfidera due to NAS [New Active Substance] status”. The MHRA replied on 9 November 2017 that it was “somewhat perplexed” by the request since Tecfidera has not been authorised as a NAS and therefore does not have that professed “status”; and that should the Claimant decide to make such an application the reliance on Tecfidera as the reference medicinal product will need to be validated in accordance with the Directive. In this regard the MHRA referred to the Claimant’s earlier application in December 2016 and its decision in response. By letter dated 14 November 2017 the Claimant’s solicitors submitted that the MHRA had all the relevant information before it, in particular the Claimant’s application dated December 2016, as well as “the additional and more recent scientific evidence supplied by Mylan in September 2017”, and that in the circumstances to submit a new abridged application would be an entirely duplicative process; rather the MHRA was invited “to revisit its decision to refuse Mylan’s application and to confirm that Tecfidera does not currently benefit from an exclusivity period”. They responded with the MHRA Decision, concluding that there was no point in the Claimant resubmitting an abridged application as until the expiry of the exclusivity period, the outcome would not be any different.

The relief sought by the Claimant in this judicial review claim is a reference to the Court of Justice of the European Union (“CJEU”) for a preliminary ruling that the Commission Decision is invalid; and once the CJEU has determined that matter an order from this court quashing the MHRA’s Decision, and declaratory relief that Tecfidera is entitled to no, or no further, period of data protection.

The Claimant advances two grounds of challenge.

The Claimant describes these judicial review proceedings as “an avowed and necessary collateral attack on the reasoning contained in and the validity of” the Commission Decision (ASFG at para 7); and Mr Alan Maclean QC, for the Claimant, describes the Claimant’s claim as “a frontal challenge to the validity of the EU act upon which the MHRA relies”, namely the Commission Decision (Skeleton argument, para 21). It is contended that such a collateral challenge may be made where direct action is not available.

Article 263(4) TFEU, as amended, provides that “any … legal person may, … institute proceedings against an act addressed to that person or which is of direct and individual concern to them, and against a regulatory act which is of direct concern to them and does not entail implementing measures”.

Mr Maclean submits that the restricted standing rules prevent the Claimant from bringing a direct action against the Commission Decision or the EMA’s decision in 2017 to refuse to reconsider its analysis. That, he submits, is so because the Commission Decision is not a “regulatory act” within the meaning of Article 263(4); alternatively, even if it is such an act, the Claimant does not satisfy the “direct concern” or “implementing measures” requirements for an Article 263 action.

Mr Maclean contends that the Commission Decision was not a regulatory act. It was an individual decision addressed to the applicant, Biogen, for marketing authorisation. Article 288 of the Treaty states that “a decision which specifies those to whom it is addressed should be binding only on them”. In Microban International Ltd v European Commission Case T-262/10 the General Court was concerned with a decision addressed to Member States setting up a regulatory framework. At paragraph 21 of the judgment the court recalled that the meaning of a “regulatory act” for the purposes of the fourth paragraph of Article 263 must be understood as covering “all acts of general application apart from legislative acts” (see Inuit Tapiritt Kanatami and others v Parliament and Council Case 583/11P). Mr Maclean says there is no case where a decision on marketing authorisation is held to be a regulatory act. He submits that where, as here, the Claimant would “not unquestionably” have had a right of challenge to the Commission Decision by the Article 263 route, it is not prevented from going to the national court to apply for a reference (A and Others v Minister van Buitenlandse Zaken Case C-158/14 at para 69).

I do not agree. I am satisfied, having regard to Article 263(4), that the Commission Decision is a regulatory act of general application and that it is of “direct concern” to the Claimant.

As Mr Maclean accepts, the term “regulatory act” covers “all acts of general application”, and a decision is of general application if “it applies to objectively determined situations and it produces legal effects with respect to categories of persons envisaged in general and in the abstract” (Microban).

In R (Teva B.V.) v Secretary of State for Health acting as the Licensing Authority and Biogen IDEC Ltd [2018] EWHC 228 (Admin), in parallel proceedings brought by another generic manufacturer, Teva also sought to challenge the MHRA’s reliance on the CHMP’s scientific evaluation and the recitals in the Commission Decision concerning the scope of the GMA and the extent of the data exclusivity period conferred on Tecfidera. Jay J dismissed the application.

In Teva Jay J considered that the Commission Decision should be regarded as a regulatory act and also that it was of direct concern to Teva, notwithstanding that it was not named in, and was not an addressee of, the Commission Decision (at para 121). The same reasoning applies to the Claimant which, for these purposes, is in materially the same position.

In Ferracci v European Commission Case T-219/13, a case concerning State Aid, the General Court at para 53 said:

“Having regard to the nature of the power conferred on the Commission under the Treaty provisions on State aid, such a decision, even if it has only a single addressee, reflects the scope of the national instruments under investigation by the Commission, whether in order to grant the necessary authorisation for an aid measure to be applied or to set out the consequences if it is found to be illegal or incompatible with the internal market. In fact, the instruments in question have a general scope, since the operators to which they apply are defined in a general and abstract manner.”

A parallel situation exists in the present case where a decision taken by the Commission is binding in all states, having been taken by a centralised machinery.

Further I consider that the requirement of direct concern under Article 263(4) is satisfied. The result of the Decision is that the Claimant cannot rely on the Tecfidera dossier in its application for an MA and is prevented from marketing its generic equivalent in the EU until the data exclusivity period has expired. Plainly, in my view, the Commission Decision is of direct concern to the Claimant. The Claimant recognises this is so by this claim (see para 13 above) which it is said “raises significant questions about the remedies available to generic companies to challenge the legality of European Commission decisions not addressed to them, but which have a wide-ranging effect across the EU” (Claimant’s skeleton argument, para 3).

The Claimant did not avail itself of the opportunity to bring a challenge against the Commission Decision within the two month limitation period prescribed in Article 263.

In addition the Claimant had, and has, other alternative remedies. As Ms Anneli Howard, for the MHRA, submits, the Claimant could have challenged the EMA’s refusal of 6 October 2017 to review the CHMP’s Opinion by a direct action before the General Court pursuant to Article 265 or it could have sought to annul the EMA’s decision under Article 263, however it chose not to do so.

Further Ms Jemima Stratford QC, for Biogen, makes the point that where scientific evidence is placed before the EMA or Commission, those bodies are in turn entitled to request the opinion of the CHMP under Article 5(3) of Regulation 726/2004 (which is applicable with respect to Tecfidera); and Article 5(2) empowers the CHMP to consider such fresh scientific evidence even once an MA has been granted. Accordingly the Claimant could and should have made such a challenge following the EMA’s refusal of 6 October 2017.

There are other avenues open to the Claimant. The MHRA suggests further additional alternative remedies that could have been pursued. The Claimant could have sought a centralised authorisation from the Commission for its own DMF generic under Article 3 of the Regulation and then challenged any refusal by the Commission to validate its application before the General Court. Mr Maclean does not accept that this is an appropriate remedy because it would require the preparation of a separate dossier to be submitted to the EMA which would involve additional costs and further delay; moreover it would not assist the Claimant before the legality of the Commission Decision has been determined by the CJEU.

Alternatively the Claimant could have invoked the administrative remedy provided in Article 31 of the Directive whereby it could, as part of its own generic application (or alternatively have asked the Commission or the HMRA to) refer a concern of “EU interest” regarding the scope of the GMA or the extent of the data exclusivity period to the CHMP for an expert opinion. Mr Maclean submits that this would also require the Claimant to make a separate application under the Decentralised Procedure or the Mutual Recognition Procedures, involving similar duplication of cost and delay, and would not achieve for the Claimant the desired effect. It may well take longer than would a direct challenge under Article 263, but I do not accept, having regard to the work that has already been done by the Claimant, that there would be substantial additional work or costs.

Mr Maclean criticises all the suggested alternative remedies, other than a challenge to the Commission Decision as a regulatory act under Article 263(4), on the ground that they will involve starting some other process, whereas the Claimant is seeking to challenge the underlying decision taken in 2014.

In summary, a direct appeal against the Commission Decision under Article 263(4) would plainly have been the most effective way in which the Claimant could have challenged the entitlement of Tecfidera to a period of data exclusivity; having failed to take that route, an alternative effective way open to the Claimant was to challenge the EMA’s refusal to review the CHMP Opinion. I reject Mr Maclean’s contention that seeking a centralised authorisation from the Commission or invoking the remedy provided in Article 31 of the Directive do not also provide effective ways in which the Claimant can challenge the Commission Decision.

For the reasons I have given, I consider this application should be refused on the basis that the Claimant had, and still has, alternative remedies.

I am further of the view that the application should be refused on the ground of delay. Instead of challenging the MHRA decision of 3 January 2017, the Claimant withdrew its application on 25 May 2017 only to request the MHRA to revisit its decision in September 2017 (and again in November 2017). Mr Maclean contends that the assertion that the claim was brought out of time fails to have regard to the material change in circumstances following the Claimant’s receipt of expert scientific evidence which identifies at least arguable flaws in the Commission Decision. The problem with this argument is that it is not suggested that the scientific evidence submitted in September 2017 could not have been commissioned and was not available at the time the application was made in December 2016. The January 2017 decision should have been challenged promptly; it was not.

In the light of the conclusions I have reached on alternative remedies and delay, I can deal with the substantive grounds of challenge shortly.

The Claimant’s pleaded case is that the MHRA has erred in its conclusion that “Tecfidera is not part of the same GMA as Fumaderm since they contain different active substances – namely DMF in isolation in Tecfidera which is not the same as DMF in combination with MEF salts in Fumaderm”. It is said that the MHRA’s conclusion is plainly a product of the fact that it considers itself bound to so conclude by the reasoning contained in the Commission Decision, and in particular Recital (3) thereof.

However, as Ms Howard and Ms Stratford observe, the Claimant accepts that the MHRA was bound by the Commission Decision and that it could not call into question the scientific evaluation carried out by the CHMP and the EMA. That being so, there is no basis for alleging that the MHRA’s refusal to validate the Claimant’s application was wrong in law.

Nevertheless the Claimant contends that the reasoning of the MHRA is not legally or factually sustainable, in particular, because (1) the MHRA refers to a concept not reflected in the Medicinal Code, namely whether one active substance is “different from” another; (2) the MHRA (and the EMA) were considering the wrong comparators, when identifying any relevant “differences”, namely DMF and not MMF as against MEF; and (3) the chemical differences between MMF and MEF do not support the conclusion that they are different active substances.

I reject these contentions.

The language of Article 10(2)(b) of the Directive makes clear that the test must be whether the two active substances being compared are “different” from one another (see Teva judgment at para 57). It is not correct that the wrong test of “different substances” was applied to determine whether Tecfidera was part of the same GMA as Fumaderm. The critical issue for determining the scope of the GMA is whether the two products contain the same active substance or different active substances. Two active substances will be “different” if their “therapeutic moiety” is different. The CHMP concluded that DMF and MEF were different active substances because they each displayed independent pharmacological action and did not share the same “therapeutic moiety”. That finding was relied on by the Standing Committee and upheld by the Commission. There is, in my view, no reason to depart from the analysis of Jay J in Teva and his findings (in particular at paras 57, 59, 63, 145 and 151) that the Commission applied the correct legal test. I am satisfied that it did so.

The CHMP did make the comparison between MMF and MEF. MEF salts and MMF (as a metabolite of DMF) are not derivatives of one another and MEF salts and MMF are different therapeutic moieties. That was the scientific evidence that led to the CHMP’s conclusion that was accepted by the Standing Committee and led the Commission to conclude that Biogen was entitled to a new GMA. So even if MMF were used as a comparator to MEF (in substitution for DMF on the Claimant’s case), the outcome would not have been any different.

The Claimant’s contention that their expert reports show that transesterification is possible as between MMF and MEF is, as Ms Stratford submits, an irrelevant scientific rather than legal challenge. The CHMP was clear that MEF salts have their own independent pharmacological action and constituted a separate active substance in their own right.

In his initial refusal of permission in this case, Jay J found “at first blush” the expert evidence submitted by the Claimant to be much more impressive than the evidence that was before the MHRA and the court in Teva, however as he observed “The Claimant’s scientific arguments were not cognisable by the MHRA and are not justiciable in this forum”. He went on to observe, “This problem cannot be circumvented by conjuring up a reference to the CJEU”. I agree with those observations. This ground of challenge discloses no error of law. The Claimant is in essence challenging the factual and scientific conclusions and regulatory judgment of the relevant expert competent authorities.

The Claimant suggests that these proceedings raise novel questions of law. I am not persuaded that they do. The Claimant has not pointed to any new underlying data in the new evidence that it says should have been considered by the CHMP. The fact that the Claimant’s experts disagree in part with the conclusions to be drawn from the data does not amount to an arguable error of law for the purposes of this judicial review. I agree with the MHRA that it is not now open for the Claimant to challenge the scientific findings made by the CHMP.

The Claimant’s case is that the MHRA has failed to take into account the further expert evidence prepared by the Claimant. This evidence, the Claimant contends, identifies errors in the scientific analysis carried out by the CHMP such that the Commission Decision has erred in treating the active substance in Tecfidera as “different” from the active substance contained in Fumaderm.

The first point to be made is that on the Claimant’s own case, the MHRA acted in accordance with its legal obligations under the CRF in relying on the findings of the Commission Decision in the manner it did. As such the MHRA cannot be regarded as having erred in law.

The MHRA Decision states:

“In view of its duties and obligations under the harmonised regime and more widely under EU law, following the final decision of the Commission, the MHRA is not permitted to question the expert scientific evaluation conducted by the CHMP and the decision of the Standing Committee. The two scientific reports that you have submitted with your letter seek to do exactly that. The CHMP and Standing Committee’s determinations are conclusive on the status of the GMA and the Commission has also refused to reconsider its position in response to your specific invitation. Any attempt by the MHRA to adopt an inconsistent position to the Commission would put it in breach of its cooperation obligations under the Community Code.”

As the MHRA is bound to follow the Commission Decision unless and until it is set aside, the MHRA did not err in law in failing to take the Claimant’s allegedly new evidence into account. I agree with Ms Howard that to have done so would undermine the harmonisation and uniform outcome that is the aim of the centralised procedure under Regulation 726/2004. That being so I consider that the provision of allegedly new scientific evidence cannot form the basis of a legal ground of challenge which might form the subject of an order for a preliminary reference.

I do not consider that either ground of challenge is arguably “well founded” (R (IATA) v Dept. for Transport Case C-344/04). Accordingly there is no basis for making a preliminary reference. Permission is therefore also refused on this ground.

For the reasons I have given this application for permission to apply for judicial review is refused.