1) Introduction - the naming of pharmaceutical products
Pharmaceutical products are part of a heavily regulated market. Their commercialization needs to be authorized by a regulatory authority which will scrutiny inter alia the choice of the name for the drug.
The application for marketing authorization shall contain the indication of the brand chosen for the product. This can be a completely or partial fanciful sign, or a scientific name together with the general brand or the name of the holder of the marketing authorization. Regulatory authorities typically approve the names of medicinal products based on guidelines which establish inter alia requirements for the use of INNs in the registration of pharmaceutical trademarks. Regulatory authorities take into consideration, on top of the traditional requirements for the registration of a trademark, other issues such as consumer safety and health protection.
All pharmaceutical products are also identified by an INN (International Non-Proprietary Name). This is intended to indicate to the public of consumers the presence of an active ingredient, and helps healthcare professionals to recognize the properties of the product. INNs cannot be used as pharmaceutical trademarks, since this would create confusion in the market. However many pharmaceutical trademarks make reference to the active ingredient since this helps to make the product more easily to be distinguished by the prescribers and patients. Reference to the INN is often made in combination with a name of fantasy or with the name of the owner of the AIC.
The fact that the brand of a pharmaceutical product makes reference to the INN (and to the active ingredient) makes this less distinctive. Unlike in other sectors, for medicinal products it is accepted that even slight modifications to the generic name of gives origin to a valid (weak) trademark. If this is the case even slight modifications, amendments or additions of the resulting brand can create a new valid trademark, and avoid infringement of the previous registered brand. In other cases pharmaceutical brands are names of fantasy, having nothing to do with the active ingredient: those are strong trademarks. In this case slight modifications, amendments or additions cannot create a new valid trademark.
2) Biological products and biosimilars
A biological medicine (biologic) is a product that contains one or more active substances made by a biological process or derived from a biological source (human, animal, plant, fungus or microbe) rather than chemical synthesis. Biological products includes vaccines, gene therapies and recombinant therapeutic proteins. They can be relatively small molecules (as for example human insulin) or complex medicines, such as monoclonal antibodies. The structures of biologics are highly dependent on the processes by which they are manufactured: for example post-translational modifications (e.g. glycosylation) are highly sensitive to processing conditions.
Biologics are manufactured in cell culture, with typical stages of:
- Creating cellular 'clone';
- Cell propagation and scale up;
- Protein production;
- Protein harvest and purification;
- Characterisation and analysis;
- Formulation of the biological medicine.
Biologics are typically larger in size and more complex than drugs of chemical synthesis. In contrast to chemically synthetized medicines, it is impossible to exactly replicate the structure of a biological product. For this reason, generic versions of biologics are called 'biosimilars'. Biosimilars are biological products "similar" to an already authorized reference biological medicine.
The complex nature of biological molecules and biosimilars requires specific nomenclature guidelines. Naming biological products has further increased its complexity and, to date, several different conventions have been applied in the world.
3) The naming of biosimilars in Europe and in the United States
In Europe the naming of biosimilar products is governed by EU Directive 2001/83/EC and follows the same rules of other pharmaceutical products. No specific naming conventions have been provided by the EMA.
The brand of a biosimilar product is therefore either a fantasy name or an INN accompanied by company identifier (i.e. the trade name of the holder of the marketing authorization). In any event, in all labelling of biosimilars there shall be a clear distinction between the brand and the INN, as the first identifies the producer while the latter the active substance in the medicinal product.
INNs, brand names and batch numbers are intended to facilitate identification of the product in case of an adverse event report.
There is empiric evidence that this naming system works well. In fact, the EU has taken the lead in the approval of biosimilar products acquiring significant experience with regard to their use and safety. In particular, based on the available studies more than 95 per cent of adverse events regarding biosimilars are reported using brand names. No differences in the nature, severity or frequency of adverse effects between biosimilars and their reference medicine have been traced so far.
The situation is different in the United States. In 2017 FDA issued Guidelines called "Nonproprietary naming of biological products". The procedure to give the name to biosimilars is now as follows: the name of the biosimilar is constituted by a core name, assigned by the USAN Council (United States adopted names) and distinguishing suffix deprived of any meaning and composed of four lowercase letters. The core and suffix shall be connected by an hyphen.
According to the FDA, those FDA-designated suffixes should prevent inadvertent substitution of products. In fact, only products that have been approved as interchangeable biologicals for a particular indication should replace innovator treatment for that indication. The naming system adopted by the FDA is therefore intended to facilitate accurate identification of the biosimilars by the healthcare professionals and patients, at the same time preventing accidental alternation between different biological products that share the same core name.
Biosimilars with different INNs in Europe and in the US cause confusion for physicians and make the collection of post approval data and its analysis for adverse events associated to a given active ingredient more difficult. It is therefore essential to adopt a global unified naming system is essential to ensuring safe use of biological products. In this regard, in 2015 the WHO proposed the adoption of a unique identification code (called Biological Qualifier, BQ) to be used for biosimilars. The BQ would consist of a four-letter code assigned randomly. In the WHO proposal, the BQ should apply retrospectively to all biological products assigned with an INN on a global scale, be complimentary to national systems and be adopted on a voluntary basis.
However, considering the contrast between Europe and US and the adoption of different approaches in other regions it will be not easy to find a solution universally accepted.