The biological drugs and their biosimilar drugs constitute a paradigm of pharmacological innovation by allowing to alter the course of a disease by acting on an aspect or very specific mechanism of a specific cell, organ or system.
For this reason, they have managed to improve the expectations and the quality of life for patients with serious illnesses such as cancer and other serious neurological diseases, endocrine or rheumatological disorders for which there were no specific and effective treatments.
Biosimilars (or similar biological medicinal products) constitute biological drugs equivalent in quality, safety and efficacy to an original bio-drug, which is called reference product.
The dosage and route of administration should be the same as those of the reference bio-drug, and the biosimilar must be authorised for all or some of the approved indications for the biological reference point.
In this way must be made clear that a biosimilar is not a generic drug, mainly due to the differences in their production systems and their molecular characteristics, as we will see later.
As for the cost of developing a biosimilar it will require between 100 to 300 million euros and takes between five to eight years. In comparison, for the development of a generic, it takes between 1 to 3 million euros and two or three years. In the same way, the process for requesting the authorization of a biosimilar is much more expensive and complicated than that of a generic, as they are needed to carry out preclinical studies and clinical trials, requiring for the approval of generics only the demonstration of bioequivalence with the reference medicinal product through studies of bioavailability.
In recent decades have been generated more than 650 biopharmaceuticals, of which 100 will lose their patent in the next 10 years, which leaves a wide open field to biosimilars.
In the game of patents healthcare systems and patients are the winners. The patent system provides a period of protection to the drugs of reference that allows biotech companies which develop them recover their investment for about 11 years. Therefore, the patent system is one way to encourage the private sector to carry out R&D activities, which will result in a greater benefit for society as a whole.
In the face of this regime of protection offered by patents, the Spanish legislation incorporates the so-called “Bolar clause”, according to which companies may begin the process of experimentation and obtaining the necessary authorizations to commercialize biosimilar drug before the patent for the original drug has expired, so that when it ceases its patent, biosimilar companies already have their own prepared and introduced into the market and enter into the dynamics of competences.
According to recent studies, biosimilar medicines will generate a saving for the Health System of 1,500 million euros by the year 2020, causing a decrease in the expected cost of acquisition of biologicals of reference that have already lost the patent, having this favorably in an increase in the access to these treatments more effective by patients.
In this same line, according to a study published in 2012 by Dr. Robert Haustein, currently Head of Governmental Affairs of VDGH, Berlin, Germany, the use of biosimilars is expected to result in a savings in health systems among the 11,800 billions of euros and 33,400 million euros between 2007 and 2020 for 8 European Union markets, since the biopharmaceuticals now account for 40% of spending on hospitals and biosimilars represent on average between a 10 to a 15% savings respects to the biopharmaceuticals .
This saving effect was observed in the same way with the arrival of the generic products, coupled with the fact that was an incentive for research of innovative products, increasing competitiveness in the pharmaceutical industry to generate best medicines that differentiate each company, as reflected in the OECD document of 2015 which reflects the conclusions of the meeting of the Competition Committee February 2014 (Ref. DAF/COMP/M(2014)2/ANN6/FINAL). Identical competitiveness and innovation race occurs with biosimilars.
Stand out for their higher levels of expected savings countries such as France, Germany and the United Kingdom followed by Poland, Romania and Sweden.
The humanised monoclonal antibodies (MAB) are biosimilar drugs which are expected to reach greater proportions of savings ranging from 1,800 million euros to the 20,400 million euros in Europe.
With regard to the biosimilar versions of erithropoyetin, used for stimulating the production of red blood cells in the treatment of anemia in patients with chronic kidney disease (CKD) and also as a complement to the dialysis and after cycles of aggressive chemotherapy in cancer treatments, it is estimated that they generate savings of between 9,400 million euros and 11,200 million euros, while the colony-stimulating factors of granulocytes could produce a savings of $0.7 billion to $1.8 billion.
The authorization of biosimilar medicines in the countries of the European Economic Area (EEA), such as Spain, is subject to a centralised procedure in which the European Medicines Agency (EMA), based in London, is responsible for evaluating the dossier (or expedient) that collects studies with the candidate for biosimilar, and is responsible for issuing a report with regard to the accreditation, or not, of biosimilarity.
The evaluators of the EMA are experts who belong to the regulatory agencies of each of the member states.
In this sense, the EMA has a special recognition in the field of regulation of biosimilars, since 2001 it became the first agency at the global level to develop guidelines about how should proceed with biosimilars: detailing the required studies to demonstrate the equivalence between biosimilars and their reference biopharmaceuticals.
So much so that the criteria of that regulatory framework, once developed, were then adopted fully by large entities such as the World Health Organization (WHO), and the regulatory agencies of reference as the US FDA, and the regulatory agencies of drugs from Canada, Japan and Australia.
It was in 2006 when the EMA approved its first biosimilar: omnitrope®, the active principle somatotropin, indicated for the treatment of dwarfism, Prader-Willi syndrome and Turner syndrome.
To date 42 biosimilar drugs have been approved by the EMA.
The membership of the European Economic Area has a special significance in the field of biosimilars, for the leadership and recognition that is attributed to the EMA with respect to the experience in the regulatory requirements required by law, and in the pre-commercial evaluation of these products.
Biosimilar drugs contain a version of the active principle of the reference biopharmaceutical, being both drugs of biological origin: manufactured synthetically or semi-synthetically, extracted from biological sources.
In this category include vaccines, blood, blood components, allergens, somatic cells, gene therapies, tissue, therapeutic proteins, monoclonal antibodies and recombinant humanized and living cells, the latter being used in cellular therapy.
The biopharmaceuticals unlike the drugs of chemical synthesis, such as ibuprofen or aspirin that have a one-dimensional and defined chemical structure , are larger and more complex molecules, arriving to have up to quaternary structures and being able to develop millions of variations at different points in their molecular structures susceptible to modification.
This is due to the nature of the own production processes of living cells, which vary the integrity of their products in relation to the conditions and characteristics of their culture media, the mutation rates of each species and cell type, etc.
In this way, the control of almost all of the parameters involved in the Bioproduction of biopharmaceuticals and biosimilars, in particular of special relevance the critical quality attributes (CQAs), allow the reproduction with broad guarantees of similarity.
In this process is crucial the correct choice of the cell line that is going to be used to produce them, thus a priori this must already have a footprint of postraduccional modifications (glycosylation, phosphorylation, acetylation, methylation and deamination) similar to that of the cell line used in the production of the reference, called biodrug original line.
In terms of its composition, the biopharmaceuticals and biosimilars can be composed of sugars, proteins, nucleic acids or complex combinations of these substances, or they may also consist of cells or tissues. These products or their derivatives are isolated from living organisms, such as humans, animals, plants, fungi or microbes.
The equivalence between biopharmaceuticals and their similar must be established through an exhaustive “exercise of comparability“. The objective of this exercise is to demonstrate that the slight physico-chemical differences existing between the two products do not significantly impact the benefit/risk profile, which allows to sustain that the active principle of both drugs is essentially the same, and are obtained similar clinical results.
Once accredited equivalence and authorized the biosimilar, this happens to be a new biological medicinal product.
The choice to use the original biological treatment or the version biosimilar rests with the criterion of the doctors. According to the current legislation, biological medicinal products are not interchangeable and do not support replacement because, from a scientific point of view, biological medicines and their biosimilar drugs can have different clinical effects. In this way, although for the administrations is a temptation for get savings, it is likely that the biosimilars are being used only in some new patients.
On the other hand, there is some level of variability in physical chemistry without therapeutic significance inherent in products of biological nature, which does not exist in the medications in chemical synthesis that reproduce identically the molecular structure of the reference drug in the generic.
In the biosimilars this variability can be identified in occasions between batches of certain biological medicinal products subject to changes in the productive process, which may require even the execution of a “exercise of comparability” to the measured between two or more batches of the same biological medicinal product, original or biosimilar, in order to verify their equivalence.
This effect also serves to underscore the need for procedures to allow the traceability of each batch and dose of biosimilars, due to that the different physico-chemical properties can be implicated in different adverse effects at the immunogenic power level. This is due to the fact that due to their biological origin, the biopharmaceuticals have the potential to activate the body’s immune response.
It stands out for the relevance of the information offered about the Spanish Association of Biosimilars (Biosim), which develops a whole series of white papers, news, events and articles that you can not lose.
And you, have you ever been left with more questions about biosimilar drugs? How do they are produced, which companies produce them, which biosimilars are available?… In Ispira Biotech we invite you to find out the answers.
Image credits: Ivan Marc, Billion Photos, Africa Studio, Krisana Antharith, YuriiHrb /shutterstock.com
Robert Haustein, Christoph de Millas, Ariane Höer, MD(2012). Saving money in the European healthcare systems with biosimilars. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(3-4).120-6. DOI: 10.5639/gabij.2012.0103-4.036
Anticuerpo monoclonal y molécula de aspirina: https://www.nejm.org/doi/10.1056/NEJMp1107285?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dwww.ncbi.nlm.nih.gov&