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20 March 2015Big PharmaTrevor Cook

Market exclusivity: Lucky orphans

Since 2001, the EU has had under Regulation No. 141/2000 a modified regulatory regime that provides incentives to develop orphan medicinal products—those that treat rare diseases with patient populations of generally less than 250,000—within the EU.

The regime has been a success, with the number of marketing authorisations (MAs) for orphan medicinal products increasing at a faster rate than new MAs generally. It has attracted little controversy, and litigation has usually focused on whether medicinal products meet the eligibility criteria to be designated as an orphan medicinal product, as in cases CSL Behring v European Commission (T-264/07) and Now Pharma v European Commission (T-74/08).

One of the regime’s incentives is a special market exclusivity system, which has now become the subject of litigation. The first decision on this, given by the EU General Court in a case brought by Teva, has confirmed its strength.

Although an orphan medicinal product benefits from a range of incentives, the greatest of these is the promise, if it subsequently secures an MA, of receiving a ten-year period of true market exclusivity.

This is a different form of non-patent exclusivity than the ‘8+2+1’ form of data exclusivity that a new active substance will automatically attract in Europe when the first medicinal product to contain it as an active is granted an MA. The first difference is that the second applicant cannot avoid the effect of orphan medicinal product exclusivity by generating and filing its own clinical data, because the exclusivity is absolute (except as against a superior product), provided that one can fulfil the market for the medicinal product and that the criteria that led to its orphan designation in the first place remain valid.

The second difference is that orphan medicinal product exclusivity is keyed to a particular orphan indication, so that although it does not confer protection against the same (or a similar) product receiving an MA for other indications, it can confer a new period of protection for a new orphan indication for a medicinal product that has already been authorised for other indications, even where these may not necessarily have been other orphan indications.

The third difference is that orphan medicinal product marketing exclusivity extends so far as to prevent the grant of an MA for a ‘similar medicinal product’ for the same indication, where guidance on the interpretation of this expression is provided by Regulation No 847/2000. Under article 3(3) of this, ‘similar medicinal product’ means “a medicinal product containing a similar active substance of substances as contained in a currently authorised orphan medicinal product, and which is intended for the same therapeutic indication”.

‘Similar active substance’ means “an identical active substance, or an active substance with the same principal molecular structural features (but not necessarily all of the same molecular structural features) and which acts via the same mechanism”. Therefore a wide range of structural analogues could be regarded as ‘similar’ for this purpose.

On January 22, 2015, the General Court, in Teva Pharma & Teva Pharmaceuticals Europe v European Medicines Agency (EMA) (case T-140/12) provided the first test of the strength of this orphan medicinal product market exclusivity regime. Here, Teva failed in its application to annul the decision of the EMA not to validate its application for an MA for a generic version of the orphan medicinal product imatinib to the extent that it concerned certain indications for the treatment of chronic myeloid leukaemia (CML).

The reasoning of the EMA, upheld by the court, was that although the orphan exclusivity for imatinib in the treatment of CML had expired, another medicinal product, nilotinib, retained orphan exclusivity for such CML indications and was ‘similar’ to imatinib, so such market exclusivity for nilotinib precluded the grant of an MA for imatinib in the relevant CML indications.

The provisions for market exclusivity for orphan medicinal products and on which the EMA had relied in refusing to validate Teva’s application for an MA for a generic version of imatinib to the extent that it concerned certain indications for the treatment of CML are set out in article 8 of Regulation No. 141/2000, which, so far as relevant to this dispute, states:

8(1) Where a marketing authorisation in respect of an orphan medicinal product is granted pursuant to Regulation (EEC) No 2309/93 or where all the member states have granted marketing authorisations in accordance with the procedures for mutual recognition laid down in articles 7 and 7a of Directive 65/65/EEC or article 9(4) of Council Directive 75/319/EEC ... and without prejudice to intellectual property law or any other provision of Community law, the Community and the member states shall not, for a period of ten years, accept another application for a marketing authorisation, or grant a marketing authorisation or accept an application to extend an existing marketing authorisation, for the same therapeutic indication, in respect of a similar medicinal product.

(2) …

(3) By way of derogation from paragraph 1, and without prejudice to intellectual property law or any other provision of Community law, a marketing authorisation may be granted, for the same therapeutic indication, to a similar medicinal product if:

(a) the holder of the marketing authorisation for the original orphan medicinal product has given his consent to the second applicant, or

(b) the holder of the marketing authorisation for the original orphan medicinal product is unable to supply sufficient quantities of the medicinal product, or

(c) the second applicant can establish in the application that the second medicinal product, although similar to the orphan medicinal product already authorised, is safer, more effective or otherwise clinically superior.

Case study

The background to this dispute was as follows. In February 2001 imatinib had been designated an orphan medicinal product for the treatment of certain CML indications. In November 2001, Novartis Europharm (Novartis) was granted a centralised MA for imatinib (trademarked as ‘Glivec’). In May 2006, another product, nilotinib, was also designated an orphan medicinal product for the treatment of CML and Novartis was subsequently granted an MA for this (trademark ‘Tasigna’) in late 2007.

In its assessment recommending that the European Commission grant an MA for Tasigna, the relevant EMA committee, the Committee of Medicinal Products for Human Use (CHMP), concluded that imatinib and nilotinib, although different chemical compounds, were sufficiently similar structurally that they should be regarded as similar products. On the face of article 8(1), this would have precluded the grant of an MA for Tasigna in the orphan CML indications, had Novartis not consented to this under article 8(3)(a).

“Orphan medicinal product marketing exclusivity extends so far as to prevent the grant of an MA for a ‘similar medicinal product’ for the same indication.”

The period of orphan market exclusivity for imatinib (Glivec) in the relevant CML indications expired in November 2011, ten years after the grant of the relevant MA. Teva sought an MA for a generic version of imatinib for all indications for which it had been authorised, which the EMA refused to validate as it included the CML indications that were still the subject of marketing exclusivity for nilotinib (Tasigna). However, the EMA confirmed that it could accept applications for generic versions of imatinib in other indications.

Teva’s challenge to the EMA decision was based initially on the interpretation of article 8(1) and 8(3), although in the course of the proceedings it sought to add a challenge based on the designation of nilotinib as an orphan medicinal product under article 3(1)(b) of Regulation No. 141/2000.

This imposes a further requirement, over and above the patient population criterion of article 3(1)(a), which must also be met for designation as an orphan medicinal product where there is already a treatment for the condition in question:

3(1) A medicinal product shall be designated as an orphan medicinal product if its sponsor can establish:

(a) that it is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition affecting not more than five in ten thousand persons in the Community when the application is made, or

that it is intended for the diagnosis, prevention or treatment of a life-threatening, seriously debilitating or serious and chronic condition in the Community and that without incentives it is unlikely that the marketing of the medicinal product in the Community would generate sufficient return to justify the necessary investment; and

(b) that there exists no satisfactory method of diagnosis, prevention or treatment of the condition in question that has been authorised in the Community or, if such method exists, that the medicinal product will be of significant benefit to those affected by that condition.

This further attempted challenge under article 3(1)(b) focused on two reports in November 2007 from another EMA committee, the Committee for Orphan Medicinal Products (COMP), which is responsible for orphan designations., Before the decision by the CHMP that the European Commission grant an MA for nilotinib (Tasigna) the COMP had reviewed the orphan designation for nilotinib, and recommended its retention as it had been established that it would be of significant benefit to patients with CML, even though a satisfactory treatment existed for CML, thereby meeting the requirements of article 3(1)(b).

The General Court ruled the further challenge inadmissible as it was too late and because it was not based on matters of law or of fact that came to light in the course of the procedure. Moreover, the court said, it concerned matters (namely reports, as opposed to the decision to grant an MA) that were not susceptible to review.

Regarding article 8(1) and (3), Teva argued that the EMA had erred in law by granting a new and independent period of exclusivity to a similar second-generation product for therapeutic indications already authorised for a first orphan medicinal product, even though that first authorised orphan medicinal product existed.

Its primary basis for arguing that was that article 8(1) and (3) should be interpreted as mutually exclusive, so that the derogations in article 8(3) should provide no basis for conferring an independent ten-year period of market exclusivity under article 8(1).

In the alternative it argued that even if a similar orphan medicinal product authorised under the derogation in article 8(3) could benefit from an independent ten-year period of market exclusivity, such exclusivity should not preclude the grant of generic MAs in respect of a similar orphan product for which such exclusivity had expired.

The General Court rejected both interpretations, observing, in relation to article 8(3), that it has no bearing on the conditions under which an MA for a ‘similar’ medicinal product may be granted and has nothing to do with whether such authorisation confers market exclusivity on a similar medicinal product. Indeed, a similar medicinal product may itself be an orphan medicinal product or a non-orphan medicinal product and, in the latter case, the MA for that product will not confer on it any sort of market exclusivity under article 8(1).

The court went on to observe that “on the other hand, if it is an orphan medicinal product, the ten-year period of market exclusivity with which it is endowed by virtue of article 8(1) of the regulation cannot be curtailed as a result of the fact that there exists an orphan medicinal product which has received MA for the same therapeutic indications and which benefits from market exclusivity for those indications”.

“Similarly, the market exclusivity attaching to that product will not be extended as a result of the fact that MA has been granted for the second medicinal product. In issue are independent designations as orphan medicinal products and independent MAs, granted in accordance with separate procedures and triggering separate periods of market exclusivity, which may overlap in time.”

The General Court concluded with the observation that “the ten-year period of market exclusivity provided by Regulation No. 141/2000 as an incentive for the development and marketing of orphan medicinal products cannot be regarded as equivalent to the data protection periods enjoyed by any medicinal product which has been granted MA, as the effects and scope of each of those mechanisms are different”.

However, the decision has wider significance than the specific context of an application for a generic MA in which it arose. It confirms the broad, but literal interpretation of the market exclusivity provisions provided by Regulation No. 141/2000 and the exhaustive nature of the three derogations set out in article 8(3) of this.

It also emphasises the broad scope of such market exclusivity provisions in extending to similar medicinal products, a feature of the orphan medicinal product regime in Europe that is perhaps not sufficiently appreciated.

Trevor Cook is a partner at Wilmer Cutler Pickering Hale and Dorr LLP. He can be contacted at:  trevor.cook@wilmerhale.com

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