Biological products: originals and analogues
Biological medicinal products and their biosimilars:
definition, quality, identity and security issues.
N.N.Khasabov, Department of Nephrology and Hemodialysis, RMAPO,
N.A.Zemskova, Department of Pharmacy Management and Economics, RUDN
No. 6-2008
Introduction
Various medicines of biological origin were widely used for treatment at the dawn of the development of medicine – bear bile, mummy pieces, various animal organs. At the beginning of the XX century. the first vaccines, bovine insulin, streptokinase and other drugs appeared. Biological medicines have been widely used since the 1980s. The first human protein, growth hormone, produced by genetic engineering using microorganisms (E. coli), was obtained in 1977 and was intended for children with its deficiency; in 1986, for the first time in the clinic for the correction of anemia in patients with chronic renal failure erythropoietin (EPO) was used; in 1985-1986, recombinant interferon-alpha, an effective remedy against viral infections, in particular chronic hepatitis, was introduced to the market (it is also used in oncology as an additional therapy) [3].
Currently, we can talk about a revolution, or at least a turning point in the creation of biological medicines – up to 10% of the pharmaceutical market volume falls on biotechnological drugs; their share is constantly increasing and, according to a number of experts, may reach 50% by 2015. Today, more than 150 drugs in the world (84 proteins) are widely used for the treatment of patients: insulins and glulisin, human growth hormone, interferons, colony stimulating factor, antihemophilic factor VIII, antithrombotics; more than 400 drugs are under development. It is safe to say that the invention of innovative drugs largely follows the path of creating biological medicines and that the further progress of medicine will depend precisely on the possibility of using biological medicines that are more effective and safe, selectively acting on pathological processes in the body.
However, the widespread use of biological medicines may be limited by their relatively high cost, which raises questions, primarily of an economic nature: will the health budget withstand the use of expensive biological medicines? How will these financial problems affect modern treatment options? Is it permissible to use reproduced biological medicines in order to reduce the financial burden on the healthcare budget, and what consequences can the widespread introduction of analogues into practice have? Will the use of biosimilars make modern treatment more accessible to the majority of the population?
Definition of a biological medicinal product and a reproduced biological medicinal product (biosimilar). Clinical problems.
Currently, there are no regulatory documents regulating the circulation of biological medicines in Russian legislation. At the same time, the features of the structure, production, action and immunogenicity of medicines of this group significantly distinguish them from other medicines.
A biological medicinal product, as defined by the European Medicines Agency (EMEA – European Medicines Agency), is an immunobiological medicinal product produced by biotechnological processes using:
- recombinant DNA technologies;
- controlled expression of genes encoding the production of biologically active proteins;
- the method of hybrid and monoclonal antibodies, as well as gene therapy and somatotherapy drugs.
The need for strict compliance with the production technology and the huge costs of pharmaceutical companies in the high-tech development of the molecule lead to a high cost of biological products.
A reproduced biological medicinal product (biosimilar) is a biological medicinal product that has entered circulation after the expiration of the exclusive patent rights for the original biological medicinal product.
Since the first innovative biopharmaceutical molecules released on the market 20-25 years ago lost patent protection, along with original biological drugs, their reproduced analogues have become increasingly used in clinical practice. Only until 2010, drugs with a market volume of 10-15 billion US dollars will be released from patent protection. The production and sale of high-quality biosimilars leads to a reduction in the cost of treatment and is a stimulant of healthy competition among pharmaceutical manufacturers. In some cases, the replacement of original biological products with their analogues may be justified: the effectiveness and safety of a number of drugs is comparable to the original drug.
It is believed that the original and reproduced drugs are identical to each other, have the same efficacy and safety, so they are safely prescribed by many specialists. Biosimilars, as well as other generic drugs, are the most attractive in terms of their price, which increases the availability of their use not only for the population, but also for the state. However, despite the economic advantages, biosimilars are rarely comparable with the original in terms of their effectiveness and safety, because it is impossible to create two absolutely identical banks of cells serving to produce an active molecule and repeat exactly the long-term high-tech production process. For example, the usual process of synthesis and subsequent isolation of the active substance erythropoietin takes 9 months [1]. Any deviation from the production process, especially violation of cell culture conditions and simplification of the purification process, entails deviations in the structure of the final product and the ratio of isoforms, is the cause of the presence of additional bacterial endotoxins and, as a consequence, the cause of increased immunogenicity – one of the main problems associated with the development of biosimilars.
The following variants of immunogenicity are possible:
- generalized immune reaction (allergy);
- neutralization of exogenous protein (absence or decrease in therapeutic efficacy of the drug);
- neutralization of endogenous (own) protein (a serious undesirable phenomenon).
The immunogenicity of biopharmaceuticals can increase due to many factors, including variations in the sequence of technological processes, glycosylation, the presence of pollutants and the ingress of impurities. Preparation of dosage forms, storage and transportation are also important.
The above is confirmed by studies of erythropoietin preparations. EPO is a glycoprotein with side carbohydrate chains consisting of a mixture of isoforms due to the different spatial structure of the molecule and differences in glycosylation. The degree of glycosylation of epoetin and the presence of free sialic acid residues changes the pharmacokinetics of the molecule and affects the rate of excretion from the body. Different isoforms of EPO have different biological and therapeutic activity [6]. In particular, the presence of more alkaline isoforms can change the activity of drugs, which is associated with a reduced half-life.
Immunogenicity is a particularly urgent problem when using epoetin, since antibodies to EPO have a neutralizing effect on EPO, which leads to progressive resistant anemia due to the development of true erythrocyte bone marrow aplasia (PCCA) [2]. The presence of pollutants and the ingress of impurities associated with the technological process can significantly change the quality of the drug, its effectiveness and safety profile. The following clinical observation shows the consequences of using the erythropoietin biosimilar.
A 24-year-old young man suffering from chronic nephritis in the stage of chronic renal failure was admitted to the nephrology department with a low hemoglobin level (6g/dl). Therapy with a weekly dose of 8,000 units with a good effect has been started. Subsequently, in order to save money, the patient was transferred to the erythropoietin biosimilar (epokin), which led to a decrease in hemoglobin levels, the development of skin allergic reactions. He was again transferred to the hormone, prednisone was prescribed – without effect. Antibodies to erythropoietin were detected.
2 studies were conducted in Europe and the USA (study 1: Schellekens H. Eur J Hosp Pharm 2004; 3:43-7; and Study 2: Singh A. K., Renal Division, Brigham and Women's hospital & Harvard Medical School, Boston, USA. World Congress of Nephrology – Apr 22, 2007.). In particular, the first study compared 11 erythropoietin preparations (obtained from 8 manufacturers) presented on markets outside the EU and the USA, according to the content of the active substance, activity and isoform composition. Bioactivity in vitro ranged from 71-226%, while the indicators of 5 samples did not meet the specifications. Among the deviations in the isoform composition are: the presence of one or more additional acidic and/or basic isoforms, as well as an altered quantitative ratio of various isoforms. Inter-series differences were also identified; some products did not meet their own specifications, that is, manufacturers did not provide adequate control of production processes. The amount of the active substance also did not always correspond to the declared amount. As the authors concluded, such deviations from the stated parameters may have important clinical significance, since they can lead to an overdose or, conversely, the introduction of a lower dose [5, 6].
In the second study, the authors show that the products of EPO manufacturers outside Europe and the USA differ greatly in composition [6]. Although this does not necessarily mean that these products are clinically inferior to the original drugs, some of them do not meet the specifications attached to them; this situation indicates at least that some manufacturers do not control the production process sufficiently. In addition, the contents of the ampoules often exceeded the permissible values for the activity indicated on the label. Incorrect labeling can lead to an excess dosage and cause undesirable clinical consequences.
Many analogues of biological drugs are heterogeneous in terms of the distribution of isoforms. Since it is difficult to determine the effect of various isoforms on the overall degree of activity and toxicity of the drug, regulatory standards require uniformity between different batches of the product. In view of the above, the variability of different batches of the same product is of particular concern. The discrepancy between the batches indicates the presence of major shortcomings in the production process or, even worse, gives reason to imply different sources of what is positioned as an identical product
Thus, taking into account the large volumes of the biopharmaceutical market, the existing risk of the appearance of biosimilars of questionable quality in clinical practice, the use of which poses a threat to the life and health of patients, has been confirmed. This makes it especially careful to choose between the original and the reproduced biological preparation.
What to do?
The increasing number of reproduced biological drugs on the Russian market – there are already about 10 of them for erythropoietin alone (vero-eropoietin, epostim, etc.) – causes some concern about the effectiveness and safety of these drugs. However, in Federal Law No. 86 "On Medicines" there is no concept of "biological medicinal product", "reproduced medicinal product". Biosimilars are registered according to the same rules as generics. Additional studies on their effectiveness and safety are currently not required. Thus, our pharmaceutical market does not have a regulatory framework for a more thorough selection and control of these drugs [1,2].
In 2003, the concepts of a biological medicinal product, a reproduced medicinal product (biosimilar) were introduced into the legislation of the European Union, while it was specifically stipulated that the concept of a biosimilar does not correspond to the concept of a generic. In 2006, EMEA approved new requirements for the registration of biosimilars, including preclinical and clinical comparative studies, and also introduced additional monitoring for adverse events during the first year of their use in the clinic.
Thus, in Russia there is also a need to correct existing regulatory documents taking into account the experience of international legislation.:
- introduction of new concepts of "biological medicinal product", "reproduced biological medicinal product";
- introduction of new rules for registration and control, prohibition of the use of facilitated registration of reproduced biological medicines;
- introduction of new rules for accounting for complications;
- the prohibition of replacing biological drugs in the pharmacy within the framework of one INN without the consent of a doctor, because there is a therapeutic lack of equivalence of biosimilars, their use may entail a serious risk of the patient receiving an insufficient or too large dose of the drug and lead to the development of side effects. Therefore, the transfer of a patient from one biopreparation to another can pose a serious risk to the patient.
Thus, the question of whether the use of biosimilars will make modern treatment more accessible to the majority of the population remains open. Any potentially low cost of a drug, especially when it comes to a biological drug, may be due to certain losses in its quality and, consequently, effectiveness and safety. It is necessary that manufacturers of a new reproduced biological agent confirm the effectiveness and safety of their drug in large-scale clinical trials.
Literature
1. Belousov D. Yu. Biosimilars – how similar are they? Qualitative Clinical Practice, 2006, No. 2, pp. 80-83.
2. V.Y.Shilo. Biosimilars in the treatment of anemia in chronic kidney disease: potential benefit or unjustified risk? – Attending physician, 2007, No. 9-10, pp. 56-64.
3. Federal Law No. 86-FZ of 22.06 1998 "On Medicines" (as amended by: Federal Law No. 5-FZ of 02.01. 2000; Federal Law No. 196-FZ of 30.12.2001; Federal Law No. 15-FZ of 10.01.2003; Federal Law of 30.06.2003 No. 86-FZ; Federal Law No. 122-FZ of 22.08.2004; Federal Law No. 160-FZ of 16.10.2006).
4. V.V. Breder. Biosimilars: copies or similar, but different medicines? Medical Bulletin, 2007, No. 26-27, pp. 411-412.
5. Schellekens H. Biosimilar epoetin: how similar are they? Eur J Hosp Pharm 2004; 3: 43 -7.
6. Singh A. K., Renal Division, Brigham and Women’s hospital & Harvard Medical School, Boston, USA. World Congress of Nephrology – Apr 22, 2007.
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