Shady European Commission policy is leaving pharma industry in the dark
This article was originally published in SRA
Maria Isabel Manley
The pharmaceutical industry has operated on the basis of a long-held understanding that, where a company unconnected with the original marketing authorization (MA) holder develops a product under the hybrid-abridged procedure set out in Article 10(3) of Directive 2001/83/EC (as amended1, referred to hereafter as the Medicinal Code), the pre-clinical tests and clinical trials supporting the product development will be entitled to indefinite protection. However, EU member states and the European Commission consider that indefinite protection is unacceptable from a policy perspective and are therefore allowing cross-reference to be made to the bridging studies supporting these product developments.
The purpose of this article is not to advocate what would be the appropriate protection for these studies. Rather, it is argued that the authorities’ approach is contrary to the current legal framework and that the commission is acting beyond its powers by amending the legislation by the backdoor. In doing so, the commission violates the legitimate expectation of innovative pharmaceutical companies, which may have made a substantial investment in developing and improving existing medicinal products by bringing to the market new therapeutic indications, strengths, pharmaceutical forms and administration routes. That outcome is ultimately adverse to the patient population.
Analysis of the legal framework
The legal regime providing for regulatory data protection (RDP) is intended to strike a balance between different interests at stake. In broad terms, this balance is intended to take into account: the interest of the innovative industry to partially recoup its substantial investment in R&D; the interest of the generics industry to gain access to the market quickly (and therefore without submitting a complete dossier); and the public interest of having safe and efficacious medicinal products whilst avoiding unnecessary clinical trials. These different interests are reflected in recitals 9 and 10 of the Medicinal Code:
Experience has shown that it is advisable to stipulate more precisely the cases in which the results of toxicological and pharmacological tests or clinical trials do not have to be provided with a view to obtaining authorisation for a medicinal product which is essentially similar to an authorised product, while ensuring that innovative firms are not placed at a disadvantage.
However, there are reasons of public policy for not conducting repetitive tests on humans or animals without over-riding cause.
Regulatory data protection and marketing protection
The legislation provides that, in order to obtain an MA, it is necessary to submit the results of pharmaceutical tests, pre-clinical tests and clinical trials (Article 8(3)(i) of the Medicinal Code).
A medicinal product authorized on the basis of a full application under Article 8 will benefit from an eight-year period of RDP, during which time a generic applicant cannot make reference to the pre-clinical tests and clinical trials contained in the originator’s dossier. However, after the expiry of eight years, a generic applicant may rely on the derogation provided for in Article 10(1) in order to apply for an MA:
...the applicant shall not be required to provide the results of 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.
Although a generic applicant may make reference to the originator’s data after the expiry of eight years, Article 10(1) further provides that:
A generic medicinal product authorised pursuant to this provision shall not be placed on the market until 10 years have elapsed from the initial authorisation of the reference product.
This means that, following the expiry of RDP, the originator product benefits from a two-year period of marketing protection, during which time the generic product may not be placed on the market. This two-year period may be increased to three years "if, during the first eight years... the [MA] holder obtains an authorisation for one or more new therapeutic indications which... are held to bring a significant clinical benefit in comparison with existing therapies". The additional year of marketing protection, which can be claimed only once, relates to the full set of data. Accordingly, if the +1 year is obtained for a new therapeutic indication, generics may not be placed on the market until the expiry of 11 years (whether with or without that new indication). The duration of RDP and marketing protection is often expressed as the 8+2+1 formula.
Is there an additional period of RDP for "line extensions"?
It is important to note that the possibility of obtaining the +1 year marketing protection represents an exception to the "global MA concept". Essentially, the global MA concept means that "line extensions" granted to the original MA holder (or to a company connected with the original MA holder) will not trigger any further period of RDP. Specifically, Article 6 (second paragraph) of the Medicinal Code, which reflects the judgment of the Court of Justice of the European Union in Case C-106/01 (Novartis)2, provides as follows:
When a medicinal product has been granted an initial marketing authorisation in accordance with the first paragraph, any additional strengths, pharmaceutical forms, administration routes, presentations, 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). (Emphasis added)
This means that a generic applicant may make reference not only to the data of a product authorized on the basis of full application (in which RDP has expired), but also to the data supporting the line extension. We refer to the respective products as Product A, Product B and Product C in this article. The global MA concept may be illustrated as follows:
Whilst the Medicinal Code does not explicitly state that the global MA concept is limited to MAs held by the same entity, it is very apparent that this was the intention behind the provision. This may be clearly inferred from the words "in particular for the purpose of the application of Article 10(1)". As explained above, Article 10(1) provides for a period of RDP to be afforded to the originator medicinal product. On a systematic interpretation of the legislation, Article 6 (2nd paragraph) is very clearly saying that line extensions granted to the same entity shall not be entitled to an additional period of RDP, but shall rather fall within the global MA of the reference medicinal product. Indeed, the purpose of the global MA concept was to ensure that an MA holder benefits from a single period of RDP in respect of a particular active substance; in other words, each new product development does not trigger a separate period of RDP (with the exception of the +1 year for a new therapeutic indication). This interpretation is expressly confirmed by the Notice to Applicants3, in which the commission confirms that the global MA concept is limited to MAs held by the same entity:
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. [Notice to Applicants, Chapter 1, Section 2.3, p. 9; emphasis added]
What it means to be the same MA holder for the purposes of the global MA concept is set out in the Notice to Applicants, which further clarifies the definition of "applicant" provided for in the 1998 Commission Communication [98/C 229/03]4. Specifically, MA holders belonging to the “same company group or that are controlled by the same physical or legal entity” are to be considered as one entity; as are MA holders which have "concluded tacit or explicit agreements concerning the marketing of the same medicinal product for the purposes of the application of the pharmaceuticals rules regarding that medicinal product" [Notice to Applicants, Chapter 1, Section 2.8, p 14].
What does the law say about product developments by a different MA holder?
Line extensions, discussed above, refer to the situation where the original MA holder develops its own product.
However, in some cases, innovative companies will develop a new therapeutic indication, strength, pharmaceutical form or route of administration for an "old" medicinal product where they are entirely unconnected with the original MA holder. In these circumstances, it will be important to ascertain whether there is any RDP in respect of the pre-clinical and clinical data supporting the product development.
Where a company submits a full or full-mixed application for MA under Article 8, the studies generated in respect of the product development will benefit from RDP, even in the case of a product development where the active substance is "old". Of course, the value of that protection will depend on how difficult/onerous it would be for another company to do exactly the same studies (thus by-passing that RDP).
However, the position is less clear-cut in cases where the company follows the hybrid-abridged procedure under Article 10(3) of the Medicinal Code. Article 10(3) provides a partial derogation to the requirement to submit the results of pre-clinical tests and clinical trials, as follows:
In cases where the medicinal product does not fall within the definition of a generic medicinal product... or where the bioequivalence cannot be demonstrated through bioavailability studies or in case of changes in the active substance(s), therapeutic indications, strength, pharmaceutical form or route of administration, vis-à-vis the reference medicinal product, the results of the appropriate pre-clinical tests or clinical trials shall be provided.
An applicant under Article 10(3) can therefore rely on the pre-clinical tests and clinical trials submitted in respect of the original medicinal product to the extent relevant. However, to the extent that there are changes in particular aspects of the product, the applicant must submit bridging studies (ie "the results of the appropriate pre-clinical tests or clinical trials").
The law does not expressly state what protection shall be available for these bridging studies. In the case of a line extension (ie a product developed by the original MA holder), the position is clear: Product B will fall within the global MA of Product A. This means that there shall be no additional protection (save for, potentially, the +1 year marketing protection). However, in the case of unconnected entities the global MA does not apply, as explained above.
Further, it is apparent that a medicinal product authorized under Article 10(3) cannot serve as a reference medicinal product for the purposes of a generic application. The term "reference medicinal product" is defined in Article 10(2)(a) as: "a medicinal product authorised under Article 6, in accordance with the provisions of Article 8". Article 6 stipulates that no medicinal product may be placed on the market of a member state without an MA. Article 8 provides that, in order to obtain an MA, an application shall be made to the competent authority on the basis of a full dossier. Accordingly, in order to qualify as a reference medicinal product, it is necessary that the product has been authorized on the basis of a complete dossier. This is recognized by the commission in the Notice to Applicants:
Reference can be made to the dossier of a reference medicinal product for which a marketing authorisation has been granted in the Union in accordance with Articles 8(3), 10a, 10b or 10c of Directive 2001/83... On the contrary, reference cannot be made to a dossier of a medicinal product for which a marketing authorisation has been granted in the Union in accordance with Article 10(1). [Notice to Applicants, Chapter 1, Section 188.8.131.52, p. 29]
This principle of "no generic of a generic" was more clearly explained in the previous version of the Notice to Applicants, which stated that reference to a well-established use, combination or informed consent dossier (respectively, articles 10a, 10b and 10c of the Medicinal Code) is acceptable because "all relevant information is in the dossier of the original medicinal product" (ie as it also is for a full or full-mixed dossier). Although not expressly stated in the Notice to Applicants, it is clear that a product authorized under the hybrid-abridged procedure (Article 10(3)) cannot serve as the reference medicinal product because the dossier is not complete.
Accordingly, where the MA holders of products A and B are entirely unconnected entities, the law does not provide any mechanism for reference or cross-reference to be made to the bridging studies supporting Product B. Product B cannot serve as the reference medicinal product, nor does it fall within the global MA of Product A. Consequently, on the basis of the current legal framework, the industry has in the past operated on the understanding that the bridging studies undertaken by an independent company in support of an application under the hybrid-abridged procedure are, de facto, entitled to indefinite protection. However, it appears that the authorities do not favor that approach from a policy perspective and are seeking to override the law by way of guidance.
For the sake of completeness, it is also important to analyze whether the legislation provides for any middle-ground, between indefinite protection on the one hand and no protection on the other. The relevant question here is whether the MA holder of the product authorized under Article 10(3) is able to rely on Article 10(5) of the Medicinal Code to claim a one-year period of RDP. Article 10(5) provides as follows:
In addition to the provisions laid down in paragraph 1 [i.e. relating to the 8-year period of RDP and the 2 or 3-year period of marketing protection], where an application is made for a new indication for a well-established substance, a non-cumulative period of one year of data exclusivity shall be granted, provided that significant pre-clinical or clinical studies were carried out in relation to the new indication. (Emphasis added)
The scope of Article 10(5) is as yet untested. However, it appears to be limited to cases where the application is made for a new therapeutic indication for a well-established substance. This is apparent from the commission’s Guidance on a New Therapeutic Indication for a Well-Established Substance (November 2007). Therefore, whilst a one-year period of "data exclusivity" may be available in cases where an independent entity develops a well-established substance for a new therapeutic indication in accordance with Article 10(3), it would not be available where such an entity develops (for example) a new formulation.
The approach of the regulatory authorities
In 2007, the CMD(h) – which comprises representatives from the EU member states as well as from Norway, Iceland and Liechtenstein and which considers matters relating to the mutual recognition and decentralized procedures for human medicines under the auspices of the Heads of Medicines Agencies group – published specific guidance on the possibility of making cross reference to the bridging studies undertaken by an MA holder which is unconnected from the original MA holder. This guidance was incorporated into its Questions and Answers on Generic Applications and the current version (October 2012)5 reads as follows:
Is it possible in an application for marketing authorisation based on an abridged dossier to refer both to the complete dossier of a reference product and to clinical studies contained in a hybrid dossier according to Article 10(3) of Directive 2001/83/EC, from a Marketing Authorisation Holder (MAH) different from the MAH of the reference product?
Answer: The EC has confirmed the admissibility of an application for marketing authorisation based on an abridged dossier, which refers both to the complete dossier of a reference product and to clinical studies contained in a hybrid dossier, authorised according to Article 10(3) of Directive 2001/83/EC.
The non-admissibility of such an application, referring to new clinical studies developed for a medicinal product authorised as a hybrid would entail an indefinite protection of these studies, which is not intended in the Community legislation.
Applicants are advised to discuss the dossier requirements in such situations with the Reference Member State.
Applicants should indicate in the application form only one reference medicinal product that has to be either approved under Article 8(3) or 10a and make reference in the cover letter to the studies in the Article 10(3) application.
The CMD(h) does not cite any legal basis for its position. Rather, it makes the assumption that indefinite protection of the bridging studies is unacceptable and that the only alternative is to allow (immediate) cross reference to that data.
The CMD(h) guidance expressly states that the approach has been "confirmed" by the commission. Further, in June 2013 the commission amended the Notice to Applicants to include some wording which appears to go in the same direction as the CMD(h) guidance, although it is highly unclear:
...in those cases where a medicinal product authorised under Article 10(1) has been developed through an application submitted in accordance with Article 10(3) of Directive 2001/83/EC leading to a new indication, strength, pharmaceutical form, a marketing authorisation application of a subsequent generic of this medicinal product can include the new indication, strength, pharmaceutical form, etc. To this effect, it will also be possible to refer to the data submitted to support the development. [Notice to Applicants, Chapter 1, Section 184.108.40.206, p. 29]
Reading between the lines, it seems that the above wording is referring to the situation where a product (Product A) is developed by an unconnected entity via the hybrid-abridged procedure (Product B). In that case, according to the commission, a subsequent generic of Product A (Product C) may also refer to Product B’s bridging data (which may concern a new indication, strength, pharmaceutical form etc). This may be illustrated as follows:
However, the wording of the Notice to Applicants is unclear.
First of all, it is not apparent what is meant by the words: “where a medicinal product authorised under Article 10(1) has been developed through an application submitted in accordance with Article 10(3)...” (emphasis added). A medicinal product authorized under Article 10(1) could never be "developed" as there can be no "generic of a generic". It would appear that the commission instead intended to refer to the situation where a product authorized on the basis of a complete application (Product A) is developed by way of a hybrid-abridged application (Product B). If that is correct, the text should have read: "where a medicinal product authorised [under Article 8(3)/on the basis of a complete application] has been developed through an application submitted in accordance with Article 10(3)..." (emphasis added). That revised wording would also be consistent with the reference to "a subsequent generic of this medicinal product" (emphasis added). Reading the text as a whole, "this medicinal product" must refer to Product A which, for the reasons explained above, must have been authorized on the basis of a complete application.
Secondly, the Notice to Applicants does not make explicit that its position extends to the situation where the MA holders of Product A and Product B are unconnected. However, this seems to be the commission’s meaning in light of the guidance of the CMD(h), and considering also that the point would not have to be made at all if the intention was simply to refer to the same MA holder (ie because the global MA concept would apply).
It is understood that the commission is currently reviewing the wording of this section of the Notice to Applicants with the member states. In the meantime, however, it has been unwilling to confirm in correspondence what it intends by the current wording. The confusion evident from the current wording suggests that the commission is not itself certain of its approach. It is highly unsatisfactory that it should have issued guidance in these circumstances. In any event, the industry is faced with the fact that the authorities are already applying the approach set out in the CMD(h) guidance.
Discussion: is there any legal basis for the authorities’ position?
In allowing cross-reference to the bridging studies supporting Product B in circumstances where the MA holders of products A and B are unconnected entities, the authorities have effectively applied a fiction; namely that Product B falls within the global MA of Product A. However, this compromises the principles of legitimate expectation and legal certainty, particularly considering that the commission has still failed to articulate a coherent policy and guidance.
The position expressed in the CMD(h) guidance and apparently endorsed by the commission is dictated purely by policy considerations; namely that indefinite protection is unacceptable, presumably because it would prevent generic applicants from ever relying on the data and would therefore lead to repetitive testing.
However, there is no legal basis for the authorities’ policy-driven approach. As explained above, a product authorized under Article 10(3) of the Medicinal Code (Product B) can never serve as a reference medicinal product because it is not authorized on the basis of a complete dossier. Further, cross-reference cannot be made to the bridging studies supporting Product B because it does not fall within the global MA of Product A in cases where the MA holders are entirely unconnected. Quite simply, there is no mechanism in the EU legal framework for the authorities to allow cross-reference to the additional data supporting Product B. The absence of a specific period of RDP for products authorized under Article 10(3) does not entitle the authorities to simply invent such a mechanism that is entirely inconsistent with what the law says. If the commission considers that the existing wording of the legislation is not appropriate, then it has the power to propose an amendment to the legislation (see Bayer Adalat); it cannot unilaterally "amend" the law via the Notice to Applicants and ignore the legislative process established by the Treaty on European Union and the Treaty on the Functioning of the European Union.
Further, the authorities’ position is entirely unfair for innovative companies, which may have made a substantial investment in generating valuable data by way of bridging studies in order to develop an old medicinal product (and who have not benefitted from the RDP for the original product). Without adequate protection, there may be no incentive to develop and improve existing medicinal products and to bring to the market new therapeutic indications, strengths, pharmaceutical forms and administration routes. That outcome is ultimately adverse to the patient population.
Ultimately, whether or not the commission is correct in its position is a matter of debate. However, that debate is for another forum. The critical point here is that, based on the current wording of the legislation, the authorities are not entitled to allow cross-reference to the bridging studies supporting a product authorized under Article 10(3) in cases where the MA holders of products A and B are unconnected entities. The commission may not agree with what the law says, but this does not entitle it to "amend" the existing legislation via the backdoor route of the Notice to Applicants, thus circumventing the appropriate legislative process. In doing so, the commission violates the legitimate expectation of stakeholders that the data they generated in support of their application for an MA would be protected.
If the commission believes that the protection afforded to the data submitted under Article 10(3) needs to be revisited, then it is submitted that this should be done in accordance with the legislative framework, which will ensure that the interests of all stakeholders are taken into account in a fair and balanced manner. In the meantime, it is understood that the commission is reviewing the section of the Notice to Applicants regarding applications under Article 10(3), and it is very much hoped that it will reconsider the legality of its approach and clarify its guidance accordingly.
1. Directive 2001/83/EC on the Community Code relating to medicinal products for human use  OJ L311/67, as amended, http://ec.europa.eu/health/files/eudralex/vol-1/dir_2001_83_consol_2012/dir_2001_83_cons_2012_en.pdf
2. Case C 106/01 Novartis Pharmaceuticals UK Ltd v the Medicines Control Agency  ECR I-4429, http://curia.europa.eu/juris/showPdf.jsf?text=&docid=49137&pageIndex=0&doclang=EN&mode=lst&dir=&occ=first?=1&cid=36241
3. Notice to Applicants, Volume 2A: Procedures for Marketing Authorisation, Chapter 1: Marketing Authorisation, June 2013 (Revision 4), http://ec.europa.eu/health/files/eudralex/vol-2/a/vol2a_chap1_2013-06_en.pdf
4. Commission Communication on the Community marketing authorisation procedures for medicinal products, 98/C 229/03, http://ec.europa.eu/health/files/eudralex/vol-1/com_1998/com_1998_en.pdf
5. CMDh questions & answers generic applications, Doc Ref: CMDh/272/2012, Rev0 October 2012,
Maria Isabel Manley is a partner heading the IP regulatory practice at the law firm Bristows, in London, UK and Marina Vickers is a senior associate at the firm. Emails: firstname.lastname@example.org and email@example.com.