Generic Medicinal Products in Russia: Legal Regulations

 

December 29, 2023

BRACE Law Firm ©

 

The invention of a new medicinal agent, from R&D and molecule creation to the finished dosage form, conducting preclinical and clinical studies, and registration, takes many years and requires significant financial investments. Therefore, manufacturers of original medicinal products in most countries are granted patent protection (exclusive rights to manufacture and sell the product for a certain period). Due to the investments made and the monopoly obtained on production, original medicinal products generally require substantial investments in R&D.

Upon expiration of the patent protection term for the inventions of original medicines, "copies" of original products containing the same active substance may be created. They have received the names "generics," "generic medicinal products," or "generic drugs." Bringing generic products to market is much simpler: conducting a significant number of studies, checks, and trials is not required, the registration procedure is simplified, and such a volume of investment is not required.

Significant growth in the generic drug market has been observed worldwide in recent years. This global trend also applies to the Russian market. According to the analytical report for the first 8 months of 2023, "Pharmaceutical Market of Russia," published by the DSM Group, sales of generics in Russia are predictably growing, the share of which is already significantly higher than the share of original products — 70.7% in value terms and 87% in packages [1].

In this article, we will analyze the legal basis for the circulation of generics used for medical use on the Russian market. At the same time, we will not examine in detail the procedures for clinical trials, registration, and other operations, as they are of a specialized nature and of interest to a narrow circle of specialists, but we will focus on legal problems arising during the market launch and circulation of these products.

Which Products are Classified as Generics?

The term "generic" (from the English "generic" (general, clan)) emerged in the 70s of the last century. At that time, it was believed that analogue products should be called by their generic name, unlike the original medicinal product, which was sold under a special trade name. For example, a well-known antispasmodic was named "No-Spa" ("No-Spa" – "No spasms"), while its generic was released under the faceless chemical name of the main active substance "Drotaverine hydrochloride." This facilitated the identification of the original medicine among analogue products. Subsequently, this practice was abandoned, and often, it is difficult for a non-specialist to determine whether it is an original or a generic.

Official documents of various countries provide different definitions of the term "generic." One of them was formulated by the European Medicines Agency (EMA) [2] – it is a medicinal product developed by copying an already registered medicinal product (the reference medicinal product). It contains the same active substances as the reference product, has the same dosage, and is used to treat the same disease; however, the name, appearance (for example, color or shape), and packaging may differ from the original medicinal product.

The concept of "generic" is unknown to Russian legislation. Instead, Federal Law No. 61-FZ dated April 12, 2010, On the Circulation of Medicinal Products (the "Law on Circulation of Medicinal Products", "Law No. 61-FZ") uses the term "generic medicinal product" (literally: reproduced medicinal product). Let us consider what the Russian legislator includes in this term and how they differ from original products.

Original medicinal product (the "MP") is a medicinal product with a new active substance that was the first to be registered in the Russian Federation or in foreign states based on the results of preclinical studies of medicinal agents and clinical studies of medicinal products confirming its quality, efficacy, and safety (Part 10.1 of Article 4 of Law No. 61-FZ).

As a general rule, the original product is used as a reference medicinal product, i.e., a product used to assess the equivalence of a generic medicinal product.

A generic medicinal product is recognized as a medicinal product that has a qualitative composition and quantitative composition of active substances equivalent to the reference MP in an equivalent dosage form, the bioequivalence or therapeutic equivalence of which to the corresponding reference medicinal product has been confirmed by appropriate studies (Part 12 of Article 4 of Law No. 61-FZ).

Thus, a generic medicinal product is characterized by the following features:

• has a qualitative and quantitative composition of active substance(s) identical to the reference MP;
• has a dosage form equivalent to the reference MP;
• has bioequivalence or therapeutic equivalence to the reference MP confirmed.

A similar definition is provided in the supranational legislation of the Eurasian Economic Union (the "EAEU"). The only exception is the absence of requirements for therapeutic equivalence, which will be discussed below.

It should be noted that only products that are chemical compounds should be considered generics. As for biological medicinal products, since their active substance is isolated from biological sources (microorganisms, blood, plasma, etc.), the creation of an absolutely identical active substance is impossible due to biological variability. For such products, the term "biosimilar products" (biosimilars) is used, which can only be similar to original products in terms of quality, biological activity, efficacy, and safety indicators.

Despite significant similarities with the original product, generics may differ from the original product. For example, they may contain different excipients (substances of inorganic or organic origin used in the manufacturing process to give the product the necessary physicochemical properties and not possessing independent pharmacological activity).

Bioequivalence Study of Generics

A mandatory condition for the release of generics into circulation is the confirmation of their bioequivalence to the reference medicinal product.

A bioequivalence study is a type of clinical study during which the rate and extent to which the active substance becomes available at its site of action when administered in the same dose and under similar conditions (bioavailability) are assessed. The reference and generic medicinal products are recognized as bioequivalent if there are no significant differences in these indicators.

Currently, bioequivalence studies in the Russian Federation are carried out according to the rules in force in the Eurasian Economic Union. The Rules for Conducting Bioequivalence Studies of Medicinal Products within the EAEU were approved on November 3, 2016, by Decision of the Council of the Eurasian Economic Commission No. 85 (the "Decision of the Council of the EEC No. 85"). They establish requirements for the plan and methods of conducting studies depending on the types of products studied, and for the analysis and reporting of their results.

Let us consider the main requirements for a bioequivalence study provided by Decision of the Council of the EEC No. 85:

• As a general rule, an original medicinal product registered in the EAEU is chosen as the reference medicinal product; in its absence, an original medicinal product registered in other countries. If it is impossible to use the original medicinal product as a reference, a generic medicinal product registered in the EAEU that has confirmed its bioequivalence to the original medicinal product is chosen. During the study and subsequent registration, the applicant is obliged to justify the choice of the reference medicinal product.
• The volume of the batch of the investigational product must be at least 1/10 of the industrial batch, or 100,000 units of dosage forms, whichever is greater.
• Studies are conducted with the participation of at least 12 healthy volunteers aged 18 years and older, who take a single dose of the studied product, and then, after several half-life periods, a similar dose of the original product.
• A report is compiled based on the results of the study.

As noted above, the Law on Circulation of Medicinal Products also provided for a study of the therapeutic equivalence (achievement of comparable therapeutic effect and efficacy and safety indicators) of the original and the generic medicinal product. However, currently, the norms of national legislation are practically not applied, and Decision of the Council of the EEC No. 85 does not contain an obligation to study therapeutic equivalence.

Confirmation of bioequivalence allows extending the results of preclinical trials and clinical studies conducted regarding the reference product to the generic product. At the same time, in the opinion of the medical community, bioequivalence is not a guarantee, but only an assumption of the therapeutic equivalence and safety of the product [3]. Thus, for example, manufacturers of generics usually use other excipients, which may cause side effects or reduce the efficacy of the product's action. To confirm complete identity in impact, it is necessary to conduct a clinical study of therapeutic equivalence, which is not mandatory under current rules.

Institute of Exclusivity of Data of Preclinical and Clinical Studies

The Law on Circulation of Medicinal Products contains the institute of exclusivity of data of preclinical and clinical studies of medicinal products (data exclusivity). However, it was introduced to implement the obligations of the Russian Federation upon accession to the World Trade Organization (WTO). In particular, according to Article 39 of the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS), members, when requiring, as a condition of approving the marketing of pharmaceutical or of agricultural chemical products which utilize new chemical entities, the submission of undisclosed test or other data, the origination of which involves a considerable effort, shall protect such data against unfair commercial use.

The institute of "data exclusivity" provides for the protection of information on the results of preclinical and clinical studies of original medicinal products for a period determined by law. Thus, according to Part 18 of Article 18 of Law No. 61-FZ, the use of information on the results of preclinical and clinical studies for commercial purposes without the consent of the owner of the original product is not permitted within 6 years from the date of its state registration in Russia. Similar rules are established in other EAEU member states.

The content of this institute was the subject of a judicial dispute between the owner of an original product and a generic manufacturer. Thus, in the case regarding the claim of Novartis Pharma AG against BioIntegrator LLC for the protection of exclusive rights by prohibiting the use for the purpose of state registration of the generic medicinal product "Neskler" of information on the results of preclinical and clinical studies of the original medicinal product "Gilenya" [4], the courts indicated that "data exclusivity" represents not a ban on the registration of a generic, but protection against the disclosure of undisclosed information on the results of preclinical and clinical studies of the original product. Thus, "data exclusivity" imposes an obligation to refrain from using data of preclinical and clinical studies within the established period for commercial purposes. It is important to understand that the institute of data exclusivity applies regardless of the presence or absence of patent protection.

At the same time, in practice, when applying this institute, a large number of questions arise regarding the scope of protection provided, and the possibility of using such results for other purposes not related to introduction into commercial circulation. Thus, in the aforementioned case, a legal position was formulated and supported by the Supreme Court of the RF that the ban on the disclosure and use of data from preclinical and clinical studies does not apply to information published in specialized printed publications. The latter conclusion, in our opinion, may negatively affect the protection of the exclusivity of clinical study data.

We note that within the framework of EAEU legislation, the indicated legal institute is not provided for. In this regard, the following situation has developed: the norms of the Law on Circulation of Medicinal Products establishing data exclusivity continue to operate, but it is not possible to apply them because the procedure for registering medicines is not regulated by national legislation.

The indicated institute is necessary to protect the rights of the owner of the original medicinal product, including compensation for their costs of bringing the product to market. In this regard, it can be concluded that there is a need to amend the EAEU registration procedures: to introduce the institute of data exclusivity and establish a unified data protection term.

Specifics of Registration of Generics

Since 2021, in all countries of the Eurasian Economic Union, the registration of new medicinal products has been carried out in accordance with the Rules for Registration and Examination of Medicinal Products for Medical Use, approved by Decision of the Council of the Eurasian Economic Commission No. 78 dated November 3, 2016 (the "Decision of the Council of the EEC No. 78").

The procedure for registering generic medicines is significantly simplified compared to reference medicines. The most important condition for registration is the confirmation of its bioequivalence to the reference product in the manner prescribed by Decision of the Council of the EEC No. 85. Bioequivalence of the generic medicinal product to the original product must be demonstrated by appropriate studies.

Decision of the Council of the EEC No. 78 details the requirements for the formation of the registration dossier of a generic product. Let us consider the main ones:

• The summary of product characteristics (SmPC) and the instructions for medical use (package leaflet) of the generic must correspond to the SmPC and instructions for medical use of the original product. If the indications for use differ in terms of expansion, or the dosage regimen or route of administration differs, the results of appropriate clinical studies must be submitted.
• Instead of clinical study reports, the results of bioequivalence studies are submitted for registration. At the same time, the report on the conduct of bioequivalence studies must indicate information about the investigator (indicating their workplace), the organization where the studies were conducted, and the duration of the studies. An official letter confirming the choice of the reference medicinal product in accordance with Decision of the Council of the EEC No. 85 must also be submitted. If the active substance of the generic medicinal product is represented by a different salt, ester, or derivative of the active substance of the reference product, additional information proving the absence of changes in the pharmacokinetics, pharmacodynamics, and (or) toxicity of the generic medicinal product is submitted.
• The applicant is obliged to submit information on intellectual rights to the medicinal product and confirm that they do not violate the rights of the owner of the original product.

At the same time, after the transition to EAEU legislation, a legal conflict arose during the registration of generics. According to Part 20 of Article 18 of the Law on Circulation of Medicinal Products, an application for state registration of a generic product can be submitted only after the expiration of four years from the date of registration of the reference medicinal product in Russia. However, EAEU legislation does not establish such bans. In this regard, despite the bans established in Russian legislation, the registering authority does not have the right to refuse to accept an application for the registration of a generic before the expiration of the established period. Bringing the norms to uniformity is obviously required.

Registration of Generics During the Patent Protection Period of the Original Product

The question of the lawfulness of registering generic products before the expiration of the patent protection term for the original product remains topical.

Thus, back in 2009, the Supreme Arbitration Court of the RF formulated a position that actions to prepare and submit documents for the state registration of a generic before the expiration of the patent term are not the use of the invention and can be qualified only as preparation for use, and, consequently, are not a violation of the exclusive right. However, the manufacture or storage of a generic is not permitted until the date of expiration of the patent validity term [5].

This position was applied by the Arbitration Court of the City of Moscow in the case of Bristol-Myers Squibb v. Nativa LLC [6]. Thus, Bristol-Myers Squibb applied to the court with a demand to oblige Nativa LLC to submit an application to the Ministry of Health of the RF to suspend the registration of the generic "Dasatinib-native" until the expiration date of the patent term. In justification of its claims, it indicated that it owns the patent for the invention "Cyclic protein tyrosine kinase inhibitors" in the medicinal product Sprycel and its pharmaceutical substance Dasatinib. During the consideration of the case, it was established that before the expiration of the patent protection term for the indicated invention, Nativa LLC conducted a bioequivalence study and submitted an application to the Ministry of Health of the RF to obtain a registration certificate for the medicinal product Dasatinib-native. The court decided that the defendant's actions in preparing and submitting documents to the Ministry of Health of the RF for the purpose of state registration of the generic are not the use of the invention and can be qualified only as preparation for the use of this agent. It refused to satisfy the claim. We note that at the stage of consideration of the dispute by the appellate instance, the plaintiff withdrew the claim in full.

This approach is also supported by some researchers of this problem. As A.S. Vorozhevich points out, such a departure from the "patent monopoly" serves the purpose of preventing the actual extension of the copyright holder's monopoly after the expiration of the legal protection term. Since, if submitting an application for registration is permissible only after the expiration of the patent validity term, the possible market entry of the generic will be delayed for several more years. During this period, the exclusivity of original products and all negative effects associated with it, primarily the overpricing of the product, will persist [7].

At the same time, it is important to understand that the immediate goal of developing and registering a generic is to bring it to market. Thus, in another case regarding the claim of Novartis AG v. Nativa LLC to suppress actions, the court recognized the actions of Nativa LLC in registering a generic product and the selling price for it several years before the expiration of the patent for the original product as a threat of violation of the exclusive right of the patent owner for the original medicinal product. It obliged the defendant to submit an application to suspend the registration of the generic [8].

Finally, when considering the case regarding the claim of AstraZeneca v. Jodas Expoim LLC, similar actions were explicitly regarded by the court as a violation of the plaintiff's exclusive right. In this case, the defendant went further: it carried out the registration of the generic product and the maximum selling price for it. The court obliged the defendant to submit to the Ministry of Health of the RF an application for the cancellation of state registration and an application for exclusion from the State Register of Maximum Selling Prices. We note that this decision was recognized as lawful and justified by the Supreme Court of the RF [9].

Thus, judicial practice on this issue is not uniform, which does not contribute to the stability of the circulation of medicinal products.

Interchangeability of Original Products and Generics

Among representatives of the medical and pharmaceutical community, there are disputes about what is better: the original or the generic. There is no unequivocal answer to this question, and we will not express a point of view on it, as we do not have special knowledge. However, let us consider how the interchangeability of medicinal products is regulated at the legislative level.

In accordance with Part 1 of Article 27.1 of Law No. 61-FZ, the interchangeability of medicinal products is determined by the Ministry of Health of Russia within the framework of one INN based on the conclusion of a commission of experts of the expert institution FSBI "SCEMP".

The procedure for determining interchangeability is defined by Decree of the Government of the Russian Federation No. 1360 dated September 5, 2020 [10]. As a general rule, the assessment of interchangeability is carried out based on the following criteria:

• equivalence of qualitative and quantitative characteristics of pharmaceutical substances;
• equivalence of the dosage form;
• equivalence or comparability of the composition of excipients of the medicinal product. At the same time, differences in the composition of excipients are not an obstacle to recognizing interchangeability if, during the bioequivalence study of the medicinal product, the absence of clinically significant differences is proven;
• identity of the route of administration and method of use;
• compliance of the medicinal agent manufacturer with the requirements of the rules of good manufacturing practice (GMP).

The establishment of interchangeability is carried out by comparing the normative documentation for medicinal products, reports on conducted bioequivalence studies, and instructions for medical use.

For certain categories of generics, such as certain aqueous solutions, powders, and lyophilisates, ear or eye medicinal products, and others [11], proof of their bioequivalence is not required.

Generic medicinal products interchangeable with respect to one reference medicinal product are recognized as interchangeable with each other.

In case of detection of differences in indications and contraindications for use in the instructions for medical use of interchangeable medicinal products, the expert institution sends the relevant information to the Ministry of Health of Russia within 3 working days from the date of discovery of such differences. In turn, the Ministry of Health sends a request to the registration certificate holder demanding the provision of reports on the results of relevant clinical studies or bringing the instruction into conformity with the instruction for medical use of the reference medicinal product. The period within which the registration certificate holder must fulfill the requirements is 6 months.

The list of interchangeable medicinal products is posted on the official website of the Ministry of Health of Russia and is subject to updating at least once a month. We note that it is quite difficult for a simple consumer, as it contains several categories of medicinal products and is primarily intended for medical and pharmaceutical specialists, as well as for the purposes of state procurement.

Summing up, we draw attention to the long-overdue necessity of amending the Law on Circulation of Medicinal Products in order to eliminate the arisen conflicts and form uniform law enforcement practice. The task of the state, in our opinion, is to ensure a balance of interests of all participants in the pharmaceutical market, where, on the one hand, effective medicinal products are available to patients and medical organizations, and on the other hand, manufacturers and suppliers of original medicinal products have not lost interest in the development and promotion of new medicinal products on the market.

_____________________

References

[1] The share of generics sold in Russia increased to 87% / October 6, 2023. Pharmznanie.

[2] Questions and answers on generic medicines. 22 November 2012. European Medicines Agency. EMA/393905/2006 Rev. 2.

[3] Tarlovskaya E.I. Generics and original drugs: the view of a practitioner. RMJ. 2008;5:333.

[4] Ruling of the Supreme Court of the RF dated May 26, 2016, No. 305-ES16-2399 in case No. A40-188378/14.

[5] Resolution dated June 16, 2009, No. 2578/09 in case No. A40-65668/08-27-569.

[6] Decision of the Arbitration Court of the Moscow Region dated May 19, 2017, in case No. A41-7505/2017.

[7] Vorozhevich A.S. Protection of exclusive rights to patent-protected objects: monograph // Statut, 2020.

[8] Resolution of the Intellectual Property Court dated April 24, 2018, No. S01-206/2018 in case No. A41-85807/2016.

[9] Resolution of the Ninth Arbitration Appeal Court dated October 18, 2018, No. 09AP-51493/2018 in case No. A40-106405/18.

[10] Decree of the Government of Russia No. 1360 dated September 5, 2020, On the Procedure for Determining the Interchangeability of Medicinal Products for Medical Use.

[11] The full list is provided in Parts 10 and 11 of Decree of the Government of Russia No. 1360 dated September 5, 2020.