The same from the face

Everything you Need to know about generics and biosimilars

Oleg Lischuk, N+1

Quite often you can hear that now there are only "generics" everywhere instead of medicines. What is it? What is the difference between a generic and a biosimilar? This is our big explanatory material prepared with the participation of the biopharmaceutical company "Biocad". Read it.

How are new medicines created in general?

The development of new drugs begins with the search for candidate molecules (usually relatively small organic molecules). Traditionally, it was carried out by modifying known compounds (hormones, neurotransmitters, plant alkaloids, fungal antibiotics, available drugs, etc.) or by simple brute force. In recent decades, computer modeling (in silico design) has been actively used – virtual "synthesis" of a molecule based on the configuration of its target (protein or nucleic acid) in the body or the causative agent of infection.

New drugs are being tested, right?

Absolutely, otherwise the drug will not be registered. And this process is complex, lengthy and costly. The properties of the selected molecules are examined chemically, on cell cultures and on animals (the stage of laboratory and preclinical tests), determining potential efficacy and toxicity. Based on the results obtained, an application for clinical trials is submitted to the regulatory authorities, which are conducted after obtaining the appropriate permission. These tests take place in three phases.

During phase I, a potential drug is tested on several dozen healthy volunteers (less often on patients), determining the safety profile with a gradual increase in dose, pharmacokinetics (how the drug is absorbed into the bloodstream, distributed to various tissues, metabolized and excreted from the body) and pharmacodynamics (how the drug acts on a given target and what effect does it have).

Several hundred patients participate in phase II. Its main purpose is to determine the effectiveness of the substance with ongoing monitoring of side effects. As a rule, the second phase is divided into phase IIA, in which the required dose of the drug is selected, and phase IIB, in which the effects of the drug at a given dose are studied.

Phase III trials, as a rule, are multicenter (conducted in several medical institutions, preferably geographically remote) controlled (the drug is compared with a placebo) double-blind (neither the patient nor the doctor knows whether the drug or placebo is prescribed) randomized (the distribution of participants between the experimental and control groups is carried out randomly) studies involving hundreds and thousands of patients. In this phase, the potential benefits of clinical use of the substance and the frequency of various side effects are evaluated. According to its results, a permit for the sale of the drug is issued. After the drug is put on the market, its study continues in post-marketing research.

The whole process of developing a new drug takes on average more than 10 years and, if the drug is brought to the markets of all countries of the world, it costs hundreds of millions of dollars. Therefore, original patent-protected drugs are very expensive.

What are generics and how are they related to the original drugs?

When the patent for the original drug expires, any pharmaceutical company has the right to make a copy of it. Such copies are called generics and, since the manufacturer does not have to invest in the development and testing of the molecule, they are much cheaper than the original drugs. Competition between manufacturers also contributes to price reduction. Due to the relatively low cost, generics account for up to 80 percent of all medications consumed in kind (number of doses). So, for example, according to the FDA, in the USA, generics are prescribed in 8 out of 10 prescriptions for medicines.

So generics are worse?

Not if they are manufactured and tested properly. Generics must contain the same active substance in the same dose as the original drug, be administered in the same way (orally, intravenously, etc.) and have identical quality indicators and similar pharmacokinetic characteristics and safety based on the results of a bioequivalence study (if applicable). The molecule of the "classic" medicine should absolutely accurately reproduce the original (due to the small size of the molecule, it is relatively easy to do this). At the same time, the form of release may differ (for example, capsules instead of tablets), inactive ingredients (fillers, dyes, etc.) are not required to match, but only on condition that such changes do not affect the key characteristics of bioequivalence.

The quality of generics is confirmed in the so-called bioequivalence studies (usually involving several dozen patients), during which the identity of the parameters of the generic pharmacokinetics to the original drug is checked. The main purpose of such studies is to show that the drug enters the body and is absorbed in the same way as the original drug. If the substance is identical to the original molecule on the basis of a complex of physico-chemical and preclinical studies, enters the body in the same way, then there are no prerequisites for differences in the effect of the drug.

For some generics (for example, with an intravenous form of administration), according to international standards, registration is possible without a bioequivalence study, since in this case the route of administration of the same composition drugs enter the blood immediately, that is, the issue of absorption is irrelevant for them. Since the time spent on the development of the active substance and multiphase clinical trials is not required, generics are brought to the market much faster and make it possible to provide a large number of patients with inexpensive treatment.

As explained by Roman Ivanov, Vice President of Biocada for Research and Development, until 2010, the requirements for proving the identity of the quality and bioequivalence of generics for entering the Russian market were imperfect, which gave rise to well-founded doubts about their quality. Now the requirements for the registration of generics have been brought into line with international ones, which guarantees the quality of generics approved after the improvement of legislation.

Is it even legal? Are companies not trying to prevent generic drugs from entering the market?

Legally. Patents for medicines are different from the protection of other technologies – here we are talking about people's health, and drug provision should be affordable. Therefore, the term of the patent is limited. It differs in different countries, but in most cases it is 20 years old. In the USA and the European Union, as well as in Russia, in some cases, the patent may be extended for another five years. While the patent is valid, manufacturers in the absence of competition sell the original medicine at a high price to compensate for the costs of its development and make a profit.

Of course, pharmaceutical companies investing billions of dollars in the creation of new drugs are unhappy with the limitation of the term of patents. They use various tricks to extend the protection of their intellectual property – from obtaining a new patent, slightly changing the composition of the drug (for example, registering another salt of it), to buying a potential generic manufacturer. In English-language literature, the combination of such tricks is called evergreening (literally, it is "maintaining in an evergreen state", usually translated into Russian as "updating"). But even when such tricks work, they only allow to delay the start of generic drug production, but not to prevent it.

What is biopharmaceutics?

This is a rapidly developing field of pharmaceuticals aimed at creating targeted drugs of biological origin. Biopharmaceuticals are macromolecules produced by a genetically engineered method. The vast majority of such drugs are monoclonal antibodies ("mabs", from the English monoclonal antibody; INN (international nonproprietary names – VM) of all monoclonal antibodies end in "-mab"). Their fundamental difference from "chemical" pharmaceuticals lies in the purposeful action on a certain type of cells in the absence of interaction with all others.

Due to this selectivity, biologics are effective in diseases that are difficult to treat by traditional methods – first of all, oncological (the drug specifically binds to tumor cells) and autoimmune (the drug acts only on a certain type of immune cells or signaling molecules produced by them – cytokines).

Monoclonal antibodies have different mechanisms of action. They can facilitate the recognition of target cells by the immune system (for example, rituximab), block the receptors of target cells or capillaries to growth factors (for example, bevacizumab), deliver radioactive or chemotherapeutic drugs to cancer cells (for example, ibritumomab).

Antibody structure diagram: 1 – antigen–binding fragment (Fab), 2 – crystallizable fragment (Fc), 3 – heavy chains, 4 – light chains, 5 – antigen-binding site, 6 - hinge site (Y_tambe / Wikimedia Commons).

How are biologics developed? Is the development very different from conventional drugs?

Very much, almost nothing in common. The development of a monoclonal antibody begins with the search for a specific target inherent only in the type of cells to which the drug's action is directed – as a rule, it is a receptor or another surface protein. When a target is found, an antigen–binding site of an antibody of a certain amino acid sequence is selected for it (each antibody consists of an unchanged part specific to a specific biological species - human, mouse, etc., and an antigen-binding site responsible for the action on a specific target) and tested in silico. Then a gene encoding this amino acid sequence is synthesized, with sites providing its expression in a living cell.

The resulting gene is embedded in the cell genome (mammalian cell culture is most often used, for example, the ovaries of a Chinese hamster; it is less convenient to work with human cells). Various techniques are used for embedding, such as electroporation (a short pulse of alternating current destabilizes the cell membrane, and a gene in the form of plasmids penetrates from the medium into the cell, embedding into the desired sections of the chromosome) or a viral vector (embedding into DNA occurs using a neutralized virus containing a given gene).

"A specific technique is chosen so as to place the maximum number of active copies of the gene in the cell genome (productivity directly depends on this), while maintaining the stability of this gene in the integration sites," explained Alexander Karabelsky, head of the Advanced research department of the biopharmaceutical company Biocad.

Then one with the best properties is selected from the cell culture and is cloned. The resulting cell line will express identical antibodies (hence the "monoclonal" in the name). After checking the productivity of cells and the quality of the antibodies obtained, optimal cultivation conditions (composition of the nutrient medium, physical conditions, etc.) are selected for this cell line. When the conditions are selected, they proceed to scaling. Its goal is to maintain cell productivity while increasing the volume of culture fluid from several milliliters to liters (in the laboratory) and up to hundreds of liters (in production). This is followed by the choice of the purification technology of the drug.

After the development of all stages of the technological process and the development of a sufficient number of antibodies, their preclinical tests are carried out in vitro and in vivo. If they are successful, they proceed to clinical trials that go through the same phases as "traditional" medicines. If in the course of research it turns out that a biopreparation can radically affect the tactics of treating a serious disease (for example, cancer) and significantly prolong the life of patients, it is possible to use the so-called accelerated (conditional) registration, in which clinical use begins according to the results of phase II, and phase III is carried out after the fact.

Since biological products are obtained using living systems, and not chemical synthesis, it is impossible to achieve complete identity of their molecules in principle (all proteins in a living cell undergo modification during synthesis, the so-called posttranslational modification). Because of this, even medicines from different batches produced at the same plant using the same technology have minor differences. The main task is to prevent these differences from significantly affecting the physical and pharmacological properties of the drug and its stability during storage.

How do they ensure that these differences do not exist? That is, how is the quality control of biological products arranged?

As already mentioned, minor differences are inevitable. Therefore, in the dossier of the drug (the main document describing all its characteristics – molecular weight, density of the solution, half-life from the body, and many others) all parameters are specified not as a single digit, but as an interval of values. Each batch of medicine produced must fit into these intervals, otherwise it cannot be sold. Quality control of the drug, that is, compliance with the specified intervals of values of key characteristics, is carried out necessarily at several stages of the production process for each batch of the drug.

What are biosimilars?

Biosimilars are "generics" of original biopharmaceuticals that enter the market after the patent expires. They differ from "real" generics in that, for the reasons described above, it is not possible to fully reproduce the original molecule. Accordingly, the processes of developing and obtaining generics and biosimilars also differ. If a generic drug manufacturer is dealing with a well–known molecule, then a biosimilar developer is dealing with a gene encoding a monoclonal antibody and a target for it.

The entire technological process of biosimilar production has to be created almost from scratch, bypassing only the stages of target search and configuration of the antigen-binding site of the molecule. The manufacturer of a biosimilar (also called a biosimilar) has to independently choose the technology for creating a genetic construct, suitable cells, the method of embedding the gene in their DNA and cultivation conditions, as well as to scale and transfer the technology from the laboratory to production.

In a certain respect, the development of a biosimilar is more complex than the creation of an original biological product. The original must have acceptable parameters of efficiency, safety, immunogenicity and stability during storage; the intervals of permissible activity indicators and physical properties (usually quite narrow) are prescribed and registered de facto, after the development of production technology. The biosimilar should initially fall into these intervals of the reference drug, and to achieve this using its own technology is a separate difficult task. It happens that the developed biosimilar is even more active than the original drug, but this also serves as an obstacle to its registration. A biosimilar with the necessary activity may be rejected even due to a deviation in such an insignificant parameter as, for example, the color of the solution.

After the development of the technological process, the biosimilar undergoes a large program of preclinical tests on cell cultures and laboratory animals (this stage is not required for generics). During clinical trials, biosimilars, like generics, are checked for equivalence to the original drug, but the volume of parameters studied is significantly larger: pharmacokinetics, efficacy, safety and immunogenicity of the drug. At the same time, biosimilar tests are much more expensive due to the large volume of research conducted, as well as due to the high cost of the original drug with which the comparison is being carried out.

Due to the peculiarities of the development and production of biosimilars, they are brought to the market much slower than generics. Nevertheless, the entire cycle of their creation before the start of sales can be carried out within about five to six years (two to three years for the development of technology for obtaining and scaling, two to three years for preclinical and multicenter clinical trials, nine months for registration).

According to Timofey Nemankin, head of the Biocada antibody development Department, it is possible to meet such a short deadline using machine learning technologies, maximum automation and unification of all stages of development and independent modification of equipment to solve specific tasks. The company's development of each subsequent biosimilar is simplified compared to the previous one, since it uses already developed technologies. The same technologies can later be used to create their own original biopharmaceuticals.

Portal "Eternal youth" http://vechnayamolodost.ru  31.03.2016