Conventional medicinal products derived from chemical processes can generally be divided into innovative and generic. Innovative medicinal products are those that have no equivalent on the market, carry patents, and a decision to market them depends to a great extent on an analysis of clinical trial results. However, a generic medicinal product is the equivalent of an innovative reference medicine and any scientific assessment thereof is based in the majority of cases on the results of bioequivalence tests that are aimed at demonstrating the similarity or minor therapeutic differences between the generic product and the reference product. In the legal opinion of pharmaceutical inspectorate supervision authorities, innovative products and their corresponding generics are generally treated as the same.  A good example here is the numerous questions raised in the past about the so-called antigeneric campaign, i.e. communications of innovative manufacturers in which the quality of generic products is challenged, they are shown to be worse or deviating in some other way from an innovative medicine.

Biological and biosimilar products are a category separate from the above division of conventional products. Applicable regulations do not contain a statutory definition of these product categories, which means that each time it is construed, we need to resort to the definitions given in scientific literature, in documents issued, e.g. by the European Medicines Agency, which constitute guidelines or procedures, or interpret it from applicable regulations.

According to an annex to Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use, a biological medicinal product is a product, the active substance of which is a biological substance. A biological substance is a substance that is produced by or extracted from a biological source and that needs for its characterisation and the determination of its quality a combination of physico-chemical-biological testing, together with the production process and its control. These products can then be divided into those that are: (i) natural – their active substances come from human blood or living organisms such as micro-organisms, animals and plants and were not genetically engineered, and also (ii) obtained from genetic engineering.

However, according to the proposed amendment to Directive 89/105, a biological medicinal product is a medicinal product that is similar to a reference biological medicinal product. The word „similar” is of great importance here since, as opposed to conventional medicinal products, manufacturing a copy of a biological medicinal product is almost impossible. This is due to several factors, among which are:

  • these products are never manufactured using the same ingredients as they arise as a result of complex biotechnological processes and living cells;
  • biological products are manufactured by genetically engineering living cells in a controlled environment, this means that each product is manufactured in unique conditions;
  • each manufacturer uses different processes which also give rise to differences between products and consequently variations between those that later translate into the final product which will be marketed.

Such material differences arising during manufacture arise from legal regulations. In this context, we can list three main facets:

  • biological products made using specified technologies must be registered by the European Medicines Agency in a central procedure. These medicines are listed in the annex to Regulation no. 726/2004 which lists, e.g. those arising from using the following biotechnological processes: (i) recombinant DNA technology; (ii) controlled expression of genes coding for biologically active proteins in prokaryotes and eukaryotes including transformed mammalian cells; (iii) hybridoma and monoclonal antibodies methods;
  • there is a modified pharmacovigilance system, the proper functioning of which in relation to biological and biosimilar medicinal products is specified as a priority of the European Medicines Agency. In this context it should be pointed out that marketing authorisation holders have to file a wide scope of registration documentation containing, e.g. a description of details of all recommended conditions and limitations as regards safe and efficacious application of a medicinal product (including those that should be included in the Risk Management Plan); recommendations to carry out post-registration efficacy and safety studies; and also a report assessing the results of pre-clinical and clinical trials and the pharmacovigilance system for a given medical product. According to Regulation 726/2004/EC, the marketing authorisation holder has to include in the Summary of Product Characteristics and on the leaflet accompanying the packet a black equilateral triangle symbol with the words: This medicinal product is subject to additional monitoring;
  • reasonable doubts are raised by the possibility of automatically making a substitution and reimbursement of a biological medicinal product by a biosimilar, which results directly from their obvious differences and was also already raised many times in discussions between pharmaceutical firm business organisations and public authorities.

The issue of biological and biosimilar medicinal products and their differences is extremely extensive and has undergone many valuable scientific studies. At the same time, this is that facet of the pharmaceutical market that in the next few years in connection with expiry of patents for reference medicinal products may see a very dynamic rise, which is often compared to events in the 1990s in the case of conventional innovative and generic products.

Krzysztof Kumala

Krzysztof Kumala


krzysztof.kumala@dzp.pl

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