18 June 2009

Biopharmaceuticals: originals and analogues

Biosimilars – analogues of pharmaceutical products of biological originJ.A.Satybaldieva, R.S.Kuzdenbaeva, A.T.Kabdenova, A.A.Mamadalieva, O.T.Tugambayeva

RSE "National Center for Expertise of Medicines, Medical Devices and Medical Equipment" of the Ministry of Health of the Republic of Kazakhstan, Almaty
The journal "Remedium" No. 10-2008.

Biotechnology is a rapidly developing branch of modern natural science, which is increasingly being used in various fields of activity, and especially in medicine. New biopharmaceuticals are increasingly being developed and introduced into medical practice – medicines obtained with the help of modern biotechnologies.

So, if in 2004 the share of biopharmaceuticals in the total volume of medicines circulating on the world market was 20%, then by 2010, according to forecasts of leading experts in the world, it is expected to increase to 50%. The list of biological products is quite wide and contains biological proteins (hormones, cytokines, blood clotting factors, monoclonal antibodies, enzymes, colony-stimulating factors, vaccines and preparations based on cells and tissues) obtained using genetically engineered and hybridomic technologies.

In recent years, the expiration of marketing exclusivity patents for a number of original biological products obtained with the help of biotechnologies has been noted in the USA and the EU. This mainly concerns biological products, the active substance of which are recombinant somatotropin, insulin, urokinase, interferons, erythropoietins, filgrastim, IL-2, alteplase, tenecteplase. This circumstance has prompted many companies to start the development and subsequent production of biopharmaceuticals.

A distinctive feature of the reproduced analogues of chemical drugs, or generics, is the exact coincidence of the chemical structure with the original drug. It should be noted that chemically identical drugs should have the same pharmacokinetic profile and the same clinical efficacy with the original drugs. Therefore, clinical trials of generics with proven bioequivalence to their original drugs are not required by regulatory authorities.

The situation is different with biopharmaceuticals, which are much more complex and heterogeneous than traditional drugs. Biopharmaceuticals, unlike traditional drugs with a well-established chemical formula, have a three-dimensional complex spatial high-molecular protein structure. The molecular weight of biological products is 100-1000 times greater than that of chemical drugs.

Analogues of biopharmaceutical drugs are called biosimilars or bioengineers, in the USA they are called modified biopharmaceuticals. Reproduced biopharmaceuticals are also called "biosimilars" ("biosimilars"), and this term has been used most frequently in recent years.

Obtaining biosimilars that are completely identical to the original is very problematic. According to the Provisions of the Committee on Patented Medicines (CPMP), the comparability analysis should show that biosimilars are completely identical in quality, safety and clinical efficacy to the original biopharmaceutical drug. However, even with full compliance with the production technology, the clinical efficacy and activity of biosimilars may differ even from series to series. At the same time, producers use the same recombinant genetic constructs, host cells, observe the same conditions of cultivation, isolation and purification, control the composition and quality of excipients. These and other features of biosimilars encourage the manufacturer to require preclinical and clinical trials and a complete presentation of safety data, because conventional bioequivalence studies are not enough.

Since biosimilars are complex protein preparations, they also have a complex effect on the body: the ways they affect the organs and systems of the body are extremely diverse, markers of the effectiveness of biologics are uncertain, in addition, their quantitative content is difficult to accurately characterize (the results are ambiguous).

It should also be noted that one of the main criteria for the safety of biological products is immunogenicity. Thus, in the process of repeated use of recombinant drugs, antibodies are produced in the body of patients that neutralize the drug. As an example, an increase in the number of cases of so-called partial erythrocyte aplasia, which occurs as a result of the production of neutralizing antibodies to erythropoietin. These cases of aplastic anemia were noted when taking the drug Eprex. Immunogenicity should be predicted at the stage of preclinical study of the safety of biosimilars, as well as studied in the process of post-marketing observation of the clinical use of the drug.

Regulatory authorities face a serious task of correctly assessing the safety and effectiveness of biosimilars during the procedure of state registration and pharmacovigilance. It is necessary to require from the manufacturer of the biosimilar complete data on preclinical and clinical studies, not limited to bioequivalence data.

Taking into account the fact that in the coming years about 50% of all drugs will belong to biological products, it is necessary to develop a system of measures for an objective and adequate assessment of the safety and effectiveness of biosimilars in the process of analytical and specialized expertise. To do this, first of all, it is necessary to amend the regulatory framework regulating their introduction into medical practice, organize training of specialists in new methods of evaluating biological products, as well as widely popularize new knowledge among specialists of various profiles.


  1. The chemical structure and technology of biosimilars is much more complex than generics of traditional chemical medicines.
  2. When conducting state registration of biosimilars, in addition to bioequivalence data, it is necessary to require data on preclinical and clinical studies (etc.), i.e. the requirements for biosimilars should be similar to the requirements for original drugs.
  3. One of the main criteria for the safety of biosimilars is the absence of immunogenicity, which is especially important for biosimilars intended for long-term use (for example, erythropoietins).
  4. The principles of biosimilar approval established by the regulatory authorities of the USA and EU countries are constantly being refined with the inclusion of new and improved methods for analyzing the characteristics of the drug, including the prediction of immunogenicity.
  5. Due to the increase in the number of biological products, state regulatory authorities should be ready to conduct analytical and specialized expertise of biological products for an objective assessment of their quality, safety and effectiveness.

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