Why EMA should provide clearer guidance on the authorization of NBCDs in generic and hybrid applications

KEYWORDS:

• Europe
• EMA
• procedure
• generic
• biosimilar
• non biological complex drug

1. Introduction

Health is a typical field where the economic theory of market competition does not enjoy the basic conditions to work, and pharmaceuticals are a clear example of market failure. Research is the mainstay of pharmaceutical industry and the flow of new drugs is protected by patents to remunerate investment. However, as soon as a patent expires, competition is open and any manufacturer can copy the originator product if it guarantees therapeutic equivalence and good manufacturing practice [1]. This justifies the marketing of the well-established generics and the more recent biosimilars, all off-patent medicines that can be sold at lower prices than their originators.

For more than two decades, the European Medicines Agency (EMA) has been the authority responsible for assessing the efficacy, safety and quality of all medicines on the entire European market. All products with expired data protection are subject to abbreviated procedures, although the marketer can still choose among three different applications depending on the countries where it plans to launch the product. Except for specific categories of drugs,¹ for which a centralized procedure valid throughout Europe is mandatory, a decentralized procedure is still possible for simultaneous marketing authorization in a preset sample of EU countries, and a mutual recognition procedure if the applicant wants to market a product already approved in one member State in other EU countries.

Here, we analyze the main categories of off-patent medicines and the three types of EMA-abbreviated procedures, to assess the consistency between types of products and applications. We focus in particular on the emerging issue of the so-called nonbiological complex drugs (NBCDs), a subcategory of products that seem to arouse regulatory uncertainty once patents expire and generics manufacturers can start launching follow-on versions.

2. Off-patent products

A generic product is the off-patent version of a chemically derived drug which is identical and bioequivalent to the originator in terms of dosage, form, strength, route of administration, and therapeutic effects; only the inactive ingredients (or ‘excipients’) may differ between the generic and its originator [2].

A biosimilar product is developed to be therapeutically overlapping an original biological medicine which has already been authorized, and is generally used at the same dose to treat the same conditions. The active ingredient of a biosimilar and its reference medicine are essentially the same biological substance, though there may be minor differences due to their complex nature and production methods [3].

A third ‘in-between’ category often mentioned in the literature is the follow-on NBCDs, medicinal products with an active substance that is not a homo-molecular structure [4], consisting of a multitude of closely related structures whose properties cannot be fully characterized by physicochemical analysis. The composition of a NBCD depends closely on the production of the active ingredient and on the formulation, so a well-controlled manufacturing process is fundamental to reproduce the product. It is still not really known what structural elements can affect the NBCD therapeutic performance, so the whole complex is considered the active pharmaceutical ingredient [5]. This particular class of products comprises a number of families, such as glatiramoids, iron-carbohydrate complexes, liposomes, polymeric micelles, swelling polymers, albumin–cytostatic complexes and other nano-medicines [4].

3. EMA-abbreviated procedures

The application for marketing authorization of drugs with expired data protection in the EU is disciplined by the Directive 2001/83/EC [6], which identifies three different abbreviated procedures: generic, hybrid, and biosimilar. A generic applicant has to submit evidence of the manufacturing quality of its product and its bioequivalence [7] with the reference drug for a generic procedure (Art. 10(1) of Directive 2001/83/EC).

A hybrid procedure is requested when a chemical product does not fully correspond to the definition of a generic, so its bioequivalence with a reference product cannot be demonstrated simply through bioavailability studies (Art. 10(3) of Directive 2001/83/EC). This can happen because of (slight) changes in the active substance(s), therapeutic indication, strength, pharmaceutical form, or route of administration. The results of appropriate preclinical tests and/or clinical trials to establish the properties of the follow-on version should be provided in the dossier for market approval [8].

A biological medicine is marked by a degree of natural variability, so a biosimilar dossier needs to include an extensive head-to-head comparison with the originator to ensure close resemblance in physicochemical and biologic characteristics, safety, and efficacy (Art. 10(4) of Directive 2001/83/EC). In practice, the type and amount of clinical data required for each biosimilar can vary widely, depending on many variables, starting from the complexity of the active substance and how well it can be characterized [8].

4. Policy implications

After having matched the types of off-patent medicines and EMA-abbreviated procedures, we noted some apparent inconsistency which might raise regulatory uncertainty and thus be a potential source of legal disputes by marketers after marketing authorization, particularly for reimbursement rules at national level.

The category of NBCDs does not in fact have a dedicated regulatory pathway for follow-on versions. Although NBCDs are not biological medicines, they share some general features with biologics: both are complex substances, difficult to characterize, and the production process is crucial to obtain similar products and subsequent in vivo performance [4]. Accordingly, it could be argued that a common approach should be applied for biosimilars and follow-on NBCDs, with the presentation of preclinical and clinical data showing similar quality, safety, and efficacy to the originator. The argument that NBCDs comprise very different groups of products (with differences in structure, complexity and clinical use), making it difficult to design a universal regulatory pathway, can be applied to biosimilars too; not by chance has EMA issued specific guidelines for some of them (e.g. insulin and epoetin) [9].

At present, although the market approval of similar NBCDs after the originator patent expiry calls for specific ruling (with information provided on a case-by-case basis) and EMA already tends to refer to the biosimilar framework when issues regarding follow-on NBCDs are discussed [10], a practical difference with biosimilars is that follow-on NBCDs may receive marketing authorization through a decentralized route too so do not necessarily follow a centralized procedure. Moreover, although EMA has published ‘reflection papers’ for some NBCDs [11,12] no specific regulatory pathway for follow-on versions has been set up so far. In practice, depending on the amount and type of data needed to support bioequivalence, a similar NBCD may be approved at present through either a generic or a hybrid procedure [13], although the latter was probably intended for what are called ‘super generics’ [14], i.e. generics that have been differentiated from their originators through reformulation or new combination(s) of active substances in order to claim some improvement for patients.

To sum up, this regulatory uncertainty can cause confusion and generate heterogeneous decisions for reimbursement rulings at national level, particularly for substitution and interchangeability. For instance, the Swedish Medical Products Agency recently stated that the glatiramer acetate originator is not automatically substitutable with a follow-on version approved through a hybrid application for patients with multiple sclerosis, because the active substance cannot be guaranteed identical [15].

Rather than generics, biosimilars might be the example to follow for follow-on NBCDs, maybe limiting the automatic switch with the originator until adequate post-marketing surveillance can confirm the therapeutic equivalence in real practice. This could be particularly important for off-patent drugs indicated for chronic and invalidating pathologies like multiple sclerosis, to protect – at best – severely ill patients who are responding to the ongoing treatment.

In conclusion, particularly during this apparently never-ending period of financial crisis, the European marketing authorization for drugs with expired data protection should be exhaustive and unquestionable, to discourage any legal controversy and potential reimbursement delays for products that can lead to immediate savings in pharmaceutical expenditure after their launch. Of course, this regulation should protect the most fragile patients too.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.

Notes

1. Medicines derived from biotechnology processes, orphan and anticancer drugs, actives for HIV/AIDS, diabetes, neurodegenerative disorders or autoimmune diseases.