Registration of reproduced and hybrid drugs in the EAEU

The Eurasian Economic Union (EAEU) has created a solid methodological basis for launching replicated and hybrid drugs (DRUG) on the market. Since the concepts of reproducibility and hybridity are regulatory and serve as the basis for simplified access to the pharmaceutical market of medicines with established safety and efficacy, it is advisable to consider in detail the terminology, criteria for recognizing drugs as reproduced and hybrid, analyze the regulatory conditions for the development and registration of such medicines. European and Eurasian legal regulations governing the introduction to the market of these two important public health I DRUG categories.

The authors of the material: R.R. Niyazov, D.A. Christmas, A.N. Vasilyev, E.V. Gavrishin, M.A. Dranitsyna, D.A. Kulichev
LLC Center for Scientific Consulting
Eurasian Economic Commission
Source: Journal "Remedium" № 7-8, 2018

Introduction

The problems of regulating the circulation of reproduced drugs are inextricably linked with the peculiarities of their development, drug registration, and post-registration life cycle. The laws governing the development and registration of original medicinal products are objectively defined and are based on the determination of their safety and efficacy profile, for which a corresponding production process, a quality assurance and quality control strategy are created. In other words, as part of the development of the original drug, the characteristics of the effect of xenobiotics on the human body, as well as the consequences of such influence, are established. In the development of the reproduced drug another problem is solved. In this case, it is important to create such a production process, which, in the absence of knowledge about all the nuances of the production technology of the original drug, will produce a product comparable in effect to the human body with the original drug product. The main problem of this approach is the definition of comparability criteria, within what limits and under what conditions it can be stated. All these issues have led to the formation of various concepts and approaches to the recognition of comparability, which, with respect to reproduced drugs, is confirmed using bioequivalence approaches. As a result, a new regulatory group of drugs, called hybrid ones, emerged; concepts of pharmaceutical equivalence and alternativeness emerged; it became clear that the reproducibility approach is only limited to biological products. The limited approach also occurs when it comes to herbal, complex non-biological, homeopathic and some other drugs. All these issues from the regulatory point of view will be discussed in this article.

Terms and Definitions

It is advisable to start the analysis of the problem with consideration of definitions, since they lay the foundation for the regulation and registration of reproduced drugs in the EAEU.

The definition of bioequivalence refers to pharmaceutically equivalent and pharmaceutically alternative drugs. Let’s consider the essence of these concepts.

Pharmaceutical equivalents are drugs in identical dosage forms containing the same amount of an identical active ingredient, i.e. the same salt or ester of the same active part of the active ingredient molecule, or in the case of modified release dosage forms requiring creating a reservoir or an excess, or forms such as pre-filled syringes (in which the residual volume can vary) —that deliver an identical amount of active ingredient during identical dosing period.

Pharmaceutical equivalents do not necessarily contain the same inactive ingredients. Pharmaceutical equivalents must meet identical pharmacopoeial or [in the absence of relevant private pharmacopoeial articles] other applicable standards for authenticity, dosage, quality and purity, including activity and, in applicable cases, content uniformity, disintegration time, and dissolution rate [1].

The identity of the dosage form is evaluated in accordance with the nomenclature of dosage forms approved by the Eurasian Economic Commission (EEC) [2]. At the same time, according to the legislation of the European Union (EU), it is possible to recognize the identity of the reproduced drug and the reference drug in the dosage form, if the form of their introduction in the definition of the European Pharmacopoeia coincides [3].

It should be noted that this definition, contained in the Rules for the Bioequivalence Studies of Medicinal Products in the EAEU [1], was taken not from the EU documents, most of which are based on the rules of the pharmaceutical law of the EAEU, but from the US Food and Drug Administration (FDA) regulations Because the American definition is more complete and understandable [4].

Pharmaceutical alternative drugs (pharmaceutical alternatives) are drugs containing the same active part of the active substance molecule, or its precursor (precursor) (not necessarily in the same amount or dosage form), or the same salt or ester. Each such drug individually satisfies the identical or its own corresponding pharmacopoeial or other applicable standards for authenticity, dosage, quality and purity (including activity and, in applicable cases, content uniformity, disintegration time and / or dissolution rate) [1].

Examples of pharmaceutically alternative drugs are:

• Medicine drug of nifedipine with a prolonged release in relation to the drug nifedipine with immediate release;
• Levetiracetam for oral administration and levetiracetam for intravenous administration;
• tenofovir disoproxil fumarate at a dosage of 300 mg and tenofovir alafenamide at a dosage of 25 mg.

Note that in the last example there are differences not only in salt forms, but also in dosages. However, they show approximately the same bioavailability at their site of action, namely, in the area of DNA-dependent RNA polymerase of human immunodeficiency virus inside the cell, while due to less drug loading of tenofovir, alafenamide causes less undesirable reactions. The given example once again confirms the validity of the determination of bioavailability through the site of action, and not through systemic concentration [1].

The definition used in the Bioequivalence Research Policy of the Eurasian Economic Union (hereinafter referred to as the EAEU Bioequivalence Study Rules) is the definition of the reproduced drug taken from Article 10 (2) of the EU Directive 2001/83 / EC on the Community Code for Medicinal Drugs for Medical Use and states that the reproduced drug is , generic is a drug having the same qualitative and quantitative composition of active ingredients and the same dosage form as the reference drug, and whose bioequivalence to the reference drug is confirmed by appropriate bioavailability studies [5].

Thus, in the definition of reproduced drug, a pharmaceutically equivalent drug is actually indicated, since the reproduced drug must have the same qualitative and quantitative composition of the active ingredients and the same dosage form (which implies the same route of administration), as well as equivalent bioavailability. At the same time, confirming the equivalent bioavailability is allowed by different methods, not limited solely to pharmacokinetic studies.

However, differences in excipients and impurity profiles should also not adversely affect safety and efficacy. When registering a drug in the EAEU, applicants are required to provide justification that differences in excipients and impurity profiles, if any, are not significant for therapeutic comparability and bioequivalence of the replicated and referential drug, and the authorized bodies, in turn, are obliged to evaluate such differences in the light of all the scientific knowledge that they have [3].

Further, the definition of the reproduced drug postulates that various salts, esters, isomers, mixtures of isomers, complexes or derivatives of the active substance are recognized by the same active substance if their safety and (or) effectiveness do not significantly differ [5].

Thus, a number of pharmaceutically alternative drugs can also be reproduced if clinical criteria are met - comparable safety and efficacy with respect to reference drugs have been established. At the same time, strictly speaking, initially a new salt or a new ether cannot be recognized as reproduced drug, since additional experiments are required confirming their comparable efficacy and safety. If such additional studies are carried out, then such an drug from a regulatory point of view automatically becomes a hybrid. However, over time, after the accumulation of sufficient clinical experience confirming the absence of clinically significant differences between different salts or esters, recognition of such hybrid drugs as reproduced ones is possible. Thus, the assignment of drugs to the category of reproduced and hybrid depends, among other things, on the clinical experience of their use, which is also considered by the authorized body during process of state registration of a drug. For example, initially when marketing perindopril arginine to the market, it was considered as a hybrid, therefore additional preclinical and clinical studies (super simple bioequivalence studies) were required to confirm a comparable safety profile and efficacy [6]. As a result, the first developer was forced to incur additional costs to obtain such confirmation, but since the comparability of clinical profiles was successfully confirmed, other manufacturers of arginine salt registered their preparations solely based on the results of the bioequivalence study, and the arginine salt itself was found to satisfy the definition of reproducible drug.

Various immediate-release oral dosage forms are recognized in bioavailability studies of the same dosage form from a biopharmaceutical point of view.

This is another exception to the generic definition of reproducible drug, which is limited only by oral immediate release dosage forms. In the definition of the EEC, a clarification “from a biopharmaceutical point of view” is introduced, which, in our opinion, is somewhat superfluous, since such dosage forms are considered the same not so much from a biopharmaceutical point of view, as from a regulatory one, that is, when registering a drug. It should be noted that this clarification is missing in the original text - in Article 10 (2) of Directive 2001/83 / EC [5].

The definition of a hybrid drug is also borrowed from the aforementioned EU Directive, namely from 3 paragraph of Article 10, i.e. it immediately follows the definition of a reproduced drug and states that a hybrid drug is an drug that does not fall under the [previously] definition of a reproduced drug or for which it is impossible to confirm bioequivalence using bioavailability studies, as well as if its active substance, indications for use, dosage, dosage form or route of administration differ from those of reference drug that requires the presentation of preclinical results and (or) clinical studies [5].

Thus, in certain cases, when applying for registration of a medicinal product that is “similar” to the reference drug, it is necessary to provide the results of relevant preclinical trials or clinical studies. Such statements about drug registration will be based partly on the results of preclinical trials and clinical trials of a reference drug (the results of which are extrapolated using bioavailability studies) and partly on new / own data, i.e. the dossier will be mixed, and the degree of “similarity” is less however, as a rule, more new / own data.

The basis of this “similarity” is the identity of the active part of the active substance molecule, which need not necessarily be contained in the drug itself before its introduction. It can also be formed as a result of biotransformation directly in the body. For example, tenofovir diphosphate is formed from both tenofovir disoproxil fumarate and tenofovir alafenamide [7]. In such cases, the results of tests and studies must comply with the data requirements of Part I of Appendix No. 1 to the Rules for Registration and Expertise of Medicines for Medical Use of the EAEU [8] (hereinafter referred to as Rules for Registration and Expertise of the EAEU).

These requirements were borrowed from Part I of Annex I to Directive 2001/83 / EC [5] and are requirements for the registration dossier of the original drug.

Providing additional data when registering a drug is required to do in three cases:

• in the absence of strict compliance with the definition of “reproduced drug”, for example, due to a more favorable bioavailability profile when taking a potential reproduced drug with a sustained release with food (the tested formulation is more resistant to aggressive factors of the gastrointestinal tract when taking the drug with food);
• if it is impossible to use bioavailability studies to confirm bioequivalence (for example, if a new drug is super bioavailable or if it is some drugs for external / topical use);
• in case of changes in the active substance, indications for use, dosage, dosage form or route of administration of the reproduced drug in relation to the reference drug.

In the EU, the decision to classify a new active substance form as a new active substance is made by the authorized bodies individually during the examination [9]. At least two EMA scientific guidelines are devoted to this issue [10, 11]. The rules of drug registration and expertise in the EAEU also provide for a similar assessment of the novelty of the active substance (see Appendix No. 9) [8]. The issue of recognition or non-recognition of novelty is important from the point of view of patent protection and recognition of exclusive rights; therefore, it is settled in some detail.

Characteristics of additional studies for a hybrid drug are given in the table contained in Section 7 of Part II of Annex 1 to the Rules for Registration and Expertise of the Union [8], but its original source is still the same Chapter 1 of Volume 2A “Registration Procedures”. Explanations for applicants in the Rules of drug circulation in the EU [3]. The last line of the table characterizing the requirements for release forms modified with respect to the reference drug is only in the European document, it is not in the Rules of Registration and Expertise of the EAEU due to the unresolved issue of modified release dosage forms.

Obviously, depending on the clinical consequences of the difference between the hybrid drug and the corresponding reference drug, the amount of data required can vary greatly, limiting in the simplest cases only bioavailability, but requiring extensive preclinical and clinical development with a new route of administration or adding a new indication to use. The scope of research is determined using a risk-based approach based on the predictability of the effects of the modification on the safety profile and effectiveness of the hybrid drug.

Attributes of the reproduced drug. Inherent and permissible characteristics of reproduced drug

Having considered the definitions, we proceed to the analysis of the attributes of the reproduced drug.

Speaking about the inherent and acceptable characteristics of the reproduced drug, it should be noted that the approaches of the US and the EU are different. The EAEU usually uses EU approaches for drug registration purposes.

For example, in the US, insulins and low molecular weight heparins are recognized as replicated [12], while in the EU / EAEU they are considered as biosimilars [13, 14].

Clinical studies of bioequivalence at clinical endpoints are being conducted for US drugs for local use and local action, so dosage forms such as ointments are considered replicated. In the EU and the EAEU, it is believed that the impossibility of conducting bioequivalence studies on pharmacokinetic or pharmacodynamic endpoints in the drug registration process requires clinical trials that are not recognized as bioequivalence studies, although they are in fact. It is the impossibility of carrying out standard bioequivalence studies (i.e., the impossibility of studying bioavailability with pharmacokinetic and pharmacodynamic endpoints or the insufficiency of such an approach) for some dosage forms for local application of local action led to the classification of such drugs in the EU as hybrid. This approach actually operates in the EAEU.

Speaking of local, or external, application, we give a formalized definition contained in the Regulations on drugs for medical use from 2012 in the current edition of the United Kingdom of Great Britain and Northern Ireland [15]: external use of drug is understood to be its use by applying to the skin , teeth, mucous membrane of the mouth, throat, nose, eyes, vagina or anal canal, if only local action is required and systemic absorption is unlikely, but not involving its use with n power throat spray, nasal spray, nasal inhalation and application to the teeth or by means for throat lozenges, throat lozenges, tablets, throat and nasal drops.

The analysis of the concepts of “original drug” and “reference drug” is given as part of the discussion of the regulatory conditions for the registration in the EAEU of reproduced drug.

Inherent and permissible characteristics of reproduced drug

Let us proceed directly to the consideration of the inherent and permissible characteristics of reproduced drugs from the standpoint of EU and EAEU legislation [3]. There are 8 criteria that must be met for the possibility of registering a drug as reproduced. Consider each of them in more detail.

Criterion 1: method of obtaining

To be considered reproduced and consecutively registered by state, the active substance of the drug must be obtained by chemical synthesis. Thus, according to the approaches of the EU and the EAEU, biological drugs, plant or animal drugs, homeopathic drugs and other active ingredients that are not chemically characterized cannot be considered to be reproduced.

The separation of active substances into those obtained by chemical synthesis and obtained by another method is explained precisely by the degree of chemical characterization, and therefore, by the possibility of obtaining on an ongoing basis an active substance with highly homogeneous properties. Such a requirement is usually satisfied by low molecular weight active substances obtaine by chemical synthesis. As a rule, it is possible to apply the bioequivalence approach to them, since the comparability of their clinical properties can be confirmed by evaluating only bioavailability. Substances of biological or plant origin often require additional research, and evaluation of bioequivalence is either impossible (as with herbal preparations) or insufficient (as with biological preparations), since, in addition to absorption, the clinical characteristics of biological substances may vary under the influence of other pharmacokinetic processes and immunogenicity.

Speaking about the degree of chemical characterization, it is advisable to note the so-called non-biologic complex drugs, which today include nano-drugs, including liposomal drugs, drugs based on block-copolymer micelles and colloidal iron preparations for intravenous administration, as well as glatiramoids. Despite the fact that, in general, multisource non-biologic complex drugs are replicated, they require additional preclinical and / or clinical studies, which, as a rule, transpose them into a group of hybrid drugs, or these drugs require a complex set of pharmaceutical tests to confirm pharmaceutical equivalence for purpose of state registration of the drug.

Speaking about chemical synthesis, it is advisable to mention the draft of the new FDA manual, published in October 2017 and dedicated to a number of highly purified synthetic peptide drugs, the reference preparations of which were obtained by recombinant DNA technology [16]. The FDA believes that modern synthesis and characterization technologies have reached such heights that peptide drugs such as glucagon, liraglutide, nesiritide, teriparatide, and teduglutide, obtained by chemical synthesis, can be recorded in the reproduced path. This example once again shows that the construction of “reproduced drug” is a regulatory issue and depends on scientific and technical progress.

Criterion 2: the degree of coincidence of the active substance

The active ingredient of the reproduced PL must match the active ingredient of the original drug. However, a drug containing a salt, an ether or an ester, a complex derived from an active substance other than the active substance of the original drug may be considered reproduced for drug registration purposes if its modified active substance does not differ in safety profile and effectiveness from the active ingredient of the original drug. Thus in this case, only the active principles of therapeutic / active moiety coincide. We have examined this issue in detail earlier. Thus, if a drug containing a modified substance differs in its safety and efficacy profile from an original drug containing an unmodified substance, additional research is required when registering a drug, which automatically translates such a preparation containing a modified active ingredient into the hybrid category. Moreover, if such a drug is the first drug containing a modified active substance, then it is usually recognized as a hybrid by default and requires additional research and testing during drug registration, since in the absence of experimental data it is impossible to draw a conclusion about equivalent safety and efficacy. Such a need is directly derived from the principle laid down by pharmaceutical legislation, which consists in the fact that the drug is unsafe and ineffective until proven otherwise. The burden of proof falls on the developer of such a drug [5].

Criterion 3: Dosage Form

The dosage form of the reproduced drug must match the dosage form of the original drug. However, in certain cases of drug registration, differences are acceptable when the route of administration coincides. It is advisable to first give the definition of the dosage form, referring to the document "Standard terms" of the European Directorate for the quality of drugs and health [17]. So, a dosage form (the pharmaceutical dose form or dosage form) is the physical embodiment of a drug containing the active ingredient and inactive ingredients delivered to the patient. It is important to note that the dosage form refers both to the dosage form administered and the dosage form produced, which may differ, for example: a lyophilisate for preparing the solution and a solution ready for administration. It should be noted that the definition of the dosage form contained in the Federal Law of April 12, 2010 No. 61-ФЗ “On Circulation of Medicines” (hereinafter - FZ-61) [18], as well as in the Nomenclature of EAEU Dosage Forms [2], is incorrect and does not allow to understand the essence of this term.

From the point of view of bioequivalence, it is important to evaluate the dosage form injected into the human body, and not contained in the primary packaging, because in the case where the dosage form of the drug requires additional manipulations for administration, for example dilution or dissolution, the form contained in the primary packaging should be considered an intermediate product . Compliance with the criteria of reproduction, as well as the criteria of biowaiver while registering a drug should be assessed for the form introduced into the body. It is important to remember the following: if it is indicated in the information about the preparation that, in its final form, the preparation forms a true solution, then it is necessary to confirm that the preparation of the drug results in such a true solution, as well as validate the preparation process, since if a suspension is formed, for example, a biowaiver applicable to true solutions is not allowed for drug registration purposes.

However, in some cases, when registering a drug, reproducibility is recognized even if the dosage forms of the replicated and original drugs do not match. However, in this case there should be a coincidence of the route of administration [3]. Such an exception is made in respect of dosage forms for oral administration with immediate release. For example, topiramate capsules and tablets are considered to be reproduced if the other criteria for reproducibility are fulfilled [1, 5].

Criterion 4: the ability to assess bioavailability

It should be possible to assess the bioavailability of the active substance during process of drug registration. This criterion implies two possibilities: the active substance must be characterized physically and chemically and can be determined, or it must be possible to evaluate the pharmacodynamic effect. If, due to physicochemical or analytical reasons, bioavailability assessment by pharmacokinetic end points is impossible, such a drug is recognized as hybrid under European and Eurasian legislation [1, 5]. For these reasons, most forms for external use, other than true solutions, are recognized in the EU as hybrid. As such, they must be recognized in the EAEU. It should not be forgotten that for some drugs, such as topical corticosteroids, it is possible to estimate the bioavailability by the pharmacodynamic end point (the degree of vasoconstriction of the skin vessels).

In the United States, it is believed that bioavailability can be assessed using a clinical endpoint, i.e., this approach in the United States is applicable to replicated drugs. Thus, the problem of classifying a drug as reproduced and hybrid has a conceptual and terminological component for drug registration purposes.

Criterion 5: differences in excipients

Differences in excipients should not lead to clinical differences from the original drug. This means that the reproduced drug must contain the studied excipients, previously used with the same route of administration, in the same or comparable amounts, in the same population and with the same duration of exposure. Ideally, the qualitative and quantitative composition of excipients should be as close as possible to the original, but in many cases this is unattainable. If the reproduced preparation contains new excipients, including new ones for a given route of administration or a given target population (for example, for children), etc., then additional studies may be required for drug registration purposes. It should be noted that, depending on the route of administration, the requirements for the composition of excipients may vary. So, for parenteral and ophthalmic dosage forms, if the drug is declared as replicated, the FDA allows differences only in the composition of preservatives and antioxidants, otherwise additional safety and efficacy studies are required [19]. In the case of other dosage forms, such a rigid framework, as a rule, is absent, however, if the drug claims a biowaiver according to the biopharmaceutical classification system, the profile of auxiliary substances should be comparable to a high degree [1, 20, 21].

Criterion 6: indications for use

The indications for the use of the reproduced  drug should coincide with the indications for the use of the original drug, or their list should be narrower if the indications are protected by a patent. If the tested preparation has additional indications in relation to the original, then an appropriate complex of preclinical and clinical studies is required when registering a drug, justifying additional indications or modification of existing ones, including population expansion. In this case, the drug becomes a hybrid.

Criterion 7: accessibility of the reference drug

Original or reference drug must be available, i.e. be present on the pharmaceutical market so that comparative bioavailability tests can be carried out during drug registration process. It should be noted that for some types of biowavers it is not necessary to conduct bioavailability studies when registering a drug, however one should keep in mind the norm contained in the Bioequivalence Study Rules of the drugs in the EAEU and that the reference and reproduced drug should not differ in the quantitative content of the active substance defined in using the analytical methodology of the developer of the reproduced drug, by more than 5%, which implies conducting parallel tests, and therefore, Reference drug. In the absence of a reference / original drug on the market, it will be necessary to look for other grounds for registering drugs, i.e. the reproduced path is impossible.

Criterion 8: impurity profile

The impurity profile of the reproduced drug must be no worse than that of the reference drug. Otherwise, additional studies will be required for drug registration to qualify the profile of impurities, including studies of general toxic properties, genotoxicity, pharmacological safety, and even reproductive toxicity and carcinogenicity.
The applicant in the registration dossier must justify, and the expert during the examination must assess the compliance with all these criteria for the possibility of registering the drug as reproduced.

Alternative ways to register drugs

If one or several criteria are not met, registration of a medicinal product as reproduced is not possible, however, there are other ways to bring the drug to the market.

Firstly, if the active drug substance is a chemical compound, and the original or reference drug is available on the market, but any other reproduction criteria are not met, then such a drug is allowed to be registered as a hybrid, if additional tests and studies substantiating the hybridity are carried out. An exception is the case of registration of a medicinal product of a new indication, when a reference drug may not be required.

Secondly, it is possible to register a drug along the path of a well-studied medical application. In this case, the active substance must be obtained by chemical synthesis, the original or reference drug may not be available, however, regulatory criteria, including the degree of knowledge of the molecule, must be met, and the bibliographic description of the safety and efficacy profile should be consistent with the full dossier [8]. For example, paracetamol preparations in the EU are registered along the path of well-studied medical use [22, 23].

Thirdly, it is possible to register a medicinal product on the basis of the so-called mixed registration dossier. Such a dossier is based on a combination of literature data and the results of its own research, which could not be described bibliographically. Such a drug as a whole will be considered as original [5]. It should be noted that in the law of the EAEU such a registration path is not described, but it seems that such a path is possible.

Fourthly, if the active substance has a biological origin, then when registering a drug, it is necessary to confirm the bioanalogical nature of the potential biosimilar and reference drug. There are limitations for this path, which are described in detail in the EAEU Biological Drug Research Rules [14].

Fifthly, if the drug is of plant origin, then it must be registered as such. Herbal drugs are usually recorded on the basis of a mixed dossier. That is, as a rule, it is required to conduct clinical studies for their registration, since it is possible to confirm the safety and efficacy of a specific herbal preparation only by matching its quality profile with the profile of clinical efficacy and safety [24]. At the same time, if herbal medicinal plant falls under the criteria of simplified registration of drugs, then you can refuse to conduct clinical trials if you comply with the relevant regulatory criteria, including appropriate restrictions in the information on the drug. The relevant provisions are contained in Annex 1 to the Rules for registration and examination [8].

Sixth, if the drug is combined and there is no complete compliance with the criteria for reproduction, then such a drug can be registered on the way of the original, hybrid, well studied, or a combination of them, including with the provision of a mixed dossier. In any case, additional research will be required.

If a drug is homeopathic, then it also has no right to claim the reproduced path, even if it contains the same active ingredient in the same amount and it has a chemical origin. Each time such a drug will be registered either as an original or by a simplified procedure; comparable bioavailability of homeopathic medicines cannot be confirmed.

Regulatory conditions

We turn to the consideration of regulatory conditions.

Pharmaceutical equivalence or alternativeness

Both pharmaceutically equivalent and pharmaceutically alternative drugs may be replicated with respect to the original drug.

If the drug is pharmaceutically equivalent and bioequivalent to the reference drug, it considered to be reproduced if the active substance is obtained by chemical synthesis, and the drug information (in the general characteristics of the drug and the leaflet) matches the information on the original drug. Compliance with the remaining criteria for reproduction follows from the definition of pharmaceutical equivalence.

If the drug is pharmaceutically alternative and bioequivalent to reference drug, it can be considered as replicated, if the active substance is obtained by chemical synthesis, the pharmacological and clinical information about the drug coincides with the information about the original drug, the drugs are the same in dosage or dose (if a comparable dose can be obtained using several dosage units of a pharmaceutically alternative drug), the route of administration is identical, the drugs have the same release characteristics, and the differences in salt / ether and other forms are not clinically significant.

Otherwise, the drug in accordance with EU and EAEU norms is recognized as a hybrid with all the ensuing consequences, i.e., the potential need for additional preclinical and clinical studies with the purpose of state registration of the drug.

It should be noted that in the US, a pharmaceutically alternative reproduced drug cannot be considered therapeutically equivalent, and therefore, interchangeable with respect to the corresponding original drug, therefore in the USA it is very important to divide drugs into pharmaceutically equivalent and pharmaceutically alternative [25].

Reference drug, comparison drug and original drug

In the context of drug registration process, such concepts as the original drug, reference drug and comparison drug are used. These concepts are generally similar to each other and are often interchangeable, but in certain contexts they can have different meanings, so it is important to understand the differences between them. Consider the definitions given in the documents of the EAEU [8]. It should be noted that it is inappropriate to use the definitions given in FZ-61 [18], since they can be misleading.

The rules for drug registration and examination of the EAEU contain the following definitions:

The original drug is a drug with a new active substance, which was first registered and introduced to the global pharmaceutical market on the basis of a registration dossier containing the results of complete non-clinical (non-clinical) and clinical studies confirming its quality, safety and efficacy.

This definition as a whole reflects the essence of the original drug, but contains some legal uncertainty regarding the completeness of preclinical and clinical studies. Such completeness should be interpreted as a set of studies described in Part I of Appendix No. 1 to the Rules for registration of drugs and expertise in the EAEU. It is this legal construction that is used in the definition of the original medicinal product, given in the EU legislation, as well as in the USA [5, 26].

In addition, it is advisable to note that the word “original” is practically not used in foreign legal acts. In the United States, the original drugs are called new drugs, i.e., “new drugs,” or drugs that are registered under section 505 (b) (1) of the Federal Law on Food, Drugs, and Cosmetics. In the EU, such drugs are called preparations registered on the basis of a separate dossier, or preparations registered in accordance with paragraph 3 of Article 8 of Directive 2001/83 / EC.

According to the Rules for drug Registration and Expertise of the EAEU, a reference drug is a medicinal product, which is used as a comparison drug and is the standard by which the properties of a drug are determined (normalized). At the same time, the English word “reference” is translated into Russian as “reference”, “standard”, “reference point”. In European legislation, the concept of "reference" is used specifically in relation to reproducible, hybrid, and bioanalogical drugs. In the case of the development of such drugs, the original drug is the reference for them.

It should be noted that the reference drug in the EAEU documents is equal to the drug for comparison, which is certainly correct and eliminates the legal conflict that is contained in the FZ-61, since the reference drug does not have to be original. In particular, when conducting research that is not less effective, reference drug may be a drug containing a completely different medicinal substance, a similar situation may be found in studies of superiority over active control or when changing the production process of the bioanalogue of a drug — the reference in this case is the bioanalogue produced before changes.

In the case of replicated, hybrid and biosimilar drug in the case when the corresponding original medicinal product is available on the market, the original and reference drugs are the same. If there is no original drug on the market, then the drug chosen by the authorized body is the reference. The principle of choice is determined by the maximum proximity of the reference drug to the original. In the US and the EU, this choice is not arbitrary. The pharmaceutical legislation of these regions provides for the obligation of the holder of a registration certificate for the original drug to notify the authorized body of their intention to withdraw original drug from the market [5, 25]. In this case, the authorized body instructs to transfer the production technology of the original drug to another manufacturer, in this situation it becomes the reference drug.

If for some reason the transfer of technology did not take place and the original and reference drugs are different, it is necessary to remember the following: on the one hand, the reproduced medicinal product must “reproduce” the original drug, but, on the other hand, the bioequivalence must be confirmed by the reference drug.

The developer of the reproduced drug does not have a direct task to reproduce the reference drug.

In addition, when choosing an original / reference drug for registration of a medicinal product, it is necessary to take into account that:

• Original / reference drug may be produced at different production sites for markets in different countries, with possible differences in compositions;
• The composition of the original / reference drug may change over time, including process of pharmaceutical development of reproduced medicinal products. In some cases, a change in the composition of the original drug formulation during the development of the reproduced material may require further development of the composition of the latter to take into account the biopharmaceutical changes in the original preparation with the new composition. A possible scenario: laboratory development was carried out using a reference preparation with the same composition, but when proceeding to conducting registration studies of the bioequivalence of the reproduced preparation, a reference preparation with a new composition was introduced to the market.

Choosing a reference drug for bioequivalence studies in the EAEU

It is advisable to consider the principles of choosing a reference drug for bioequivalence studies in the EAEU for the registration of drugs and the resulting difficulties.

In accordance with paragraph 18 of the Rules for the Study of the Bioequivalence of the Union, when choosing a reference LP, proceed from the following sequence:

• The best option is the original drug, the quality, safety and effectiveness of which were established during registration in the EAEU (this is the so-called “original drug registered in the EAEU”).
• In the absence of an original drug registered in the EAEU, the original drug must be used, registered in the country, the level of regulatory requirements for the pharmaceutical market in which it is not lower than the level established in the EAEU.
• If the original drug is not available either in the EAEU or abroad, then a replicated drug is selected that is registered in each of the Member States and confirms its bioequivalence to the original drug. The choice is agreed upon by the Expert Committee on Medicinal Products for Medical Use, established as part of the EEC.
• If it is not possible to resort to the first three options, it is allowed to use a drug that has been used in one of the Member States for at least 25 years. It also requires the prior approval of the Expert Committee.

It is advisable to consider the legal and regulatory implications of the proposed approach to choosing a reference drug for registration purposes.

It is obvious that the use of the original drug, registered in at least one of the Member States of the EAEU, is the optimal strategy. At the same time, developers and experts need to take into account that the original medicinal product can be made at different sites, with different compositions for different markets. This question must be taken into account at the stage of both development and examination during the registration of medicines. In this variant of the choice of the reference drug, the drug must be reproduced in relation to the original, the composition, technology and place of production of which are registered for the EAEU market.
If an original product is selected with a composition, technology or place of production different from those registered in the EAEU, then the choice is actually made in accordance with paragraph (b) of paragraph 18, which may be a violation of the Rules if option (a) is possible.

The original drug may not be available on the EAEU market. Absence may be temporary or permanent. Temporary absence may be due to various reasons. Unfortunately, EAEU legislation does not provide for the mandatory notification by holders of registration certificates of authorized bodies about the absence of drugs on the market, which not only hinders the development of replicated drugs, but can also lead to a shortage of drugs and problems in drug provision. In the EU, holders of drug registration certificates must inform regulators of supply problems, as well as their withdrawal from the market [5, 25].

The constant lack of a reference drug may be due, among other things, to commercial and pharmacovigilance reasons. In the case of pharmacovigilance reasons, obviously, the development of replicated drugs cannot be allowed.

If the original drug is not available on the EAEU market for commercial reasons, paragraph (b) of paragraph 18 provides for the use of the original drug registered abroad. At the same time, the country of origin of the original drug must have strict regulation of drugs. Obviously, the permanent members of the ICH should be counted as such (i.e. the EU, the USA, Japan, Canada and Switzerland), but in 2017 Brazilian, South Korean and Chinese regulators also became members of the ICH. The procedure for classifying a country as having a regulation at least equivalent to that of the EAEU has not been defined. It should be noted that, for example, in the EU there are special documents and procedures for determining the compliance of other countries with the EU criteria for the level of regulation, including conducting on-site inspections of foreign regulators, as well as analyzing legislation [5].

By itself, the option of using a foreign original drug as a reference when registering a drug is also quite controversial. In case of successful development and state registration of the reproduced drug, the regulator actually recognizes the safety and effectiveness of not only such a reproduced drug, but also the corresponding original drug not registered in the EAEU, without an examination of the latter. Then a natural question arises: if the manufacturer of the original drug then submits an application for registration of the drug in the EAEU, does it need expertise? If the examination was nevertheless carried out and a decision was made to refuse registration, should all generics be withdrawn from the market? Moreover, if the registration made in the EU or the USA is recognized, is it necessary to conduct an examination of drugs registered in these regions? Would it not be more expedient then to concentrate resources in other areas of drug regulation? Perhaps, in the case of simplifying the registration of original drugs registered in the ICH member states, it would be possible to increase the availability of generics, since the period of exclusivity of data in the member states of the EAEU is rather short or is completely absent.

In addition, for this option it is also necessary to take into account different compositions, technologies and places of production. Obviously, the use of original drugs of European origin is optimal for the EAEU.

This reasoning applies to biosimilars.

The third option, i.e., the use of reproduced drug, which confirmed its bioequivalence to the original, in the absence of the original preparation on the world market, is also controversial. As mentioned earlier, in the USA, for example, the originator cannot simply leave the market without transferring the production technology to another manufacturer (assuming the drug is important for health needs) so that you can get a reference drug as close as possible to the original one. This is possible in the EAEU. The criteria for the third option are not fully scientifically justified. For example, why do we need to register a potentially referential replicated drug in all five Member States if its bioequivalence to the original drug is confirmed. It is probably enough that under this option the reference drug was chosen by the Expert Committee. The mention of the confirmation of bioequivalence with the original medicinal product is redundant, because the confirmation of bioequivalence is an integral element of the legal definition of the reproduced drug. At the same time, it is strongly recommended to consider alternative grounds for drug registration (other than reproduction), discussed earlier.

Finally, the fourth option as a whole also has no scientific basis for the choice. The requirement of a 25-year experience in the use of drugs is also arbitrary, in this case there is no mention of confirmation of safety and efficacy. The only positive rational criterion is the coordination of the choice of the reference drug with the Expert Committee when registering a drug in the EAEU. Obviously, this provision concerns heritage products, however, a special procedure would be appropriate, implemented under the authority of the Expert Committee, to assess the safety profile and effectiveness of such drugs with possible determination of the conditions for further presence in the market.

Thus, the approaches to the choice of the reference medicinal product for the purpose of state registration of the reproduced drugs require a deeper understanding. In addition, we believe that it is advisable to refer to the concept of "international comparator" (international comparator pharmaceutical products), supported by the World Health Organization [27].

Which drug to use - original or reference?

It should be noted that the current legislation of the EAEU provides for two definitions of the reproduced drug. The first is contained in the Rules for Registration and Expertise of Medicines in the EAEU, the second is in the Rules for the Conduct of Bioequivalence Studies of the EAEU. The rules for registration and examination of the EAEU state that the reproduced drug is a drug that has the same quantitative and qualitative composition of the active ingredients and the same dosage form as the original drug, and whose bioequivalence to the original drug is confirmed by appropriate bioavailability studies. Whereas, the rules for conducting bioequivalence studies of the EAEU establish that the reproduced drug is a drug having the same qualitative and quantitative composition of active ingredients and the same dosage form as the reference drug and whose bioequivalence reference drug is confirmed by appropriate bioavailability studies.

Since the Rules for Registration and Expertise of Medicines in the EAEU distinguish between the notions of “reference” and “original” (we defined definitions earlier), it remains unclear whether such distinctions are deliberate, or they are random, and whether state registration of reproduced drugs in the EAEU is possible using reference drug, different from the original?

Ability to conduct bioequivalence studies

Conducting a bioequivalence study for the purpose of state registration of drugs is associated with the ability to determine either the exposure of the analyte (systemic or in the site of action), or the effect of the analyte on the body (biomarker evaluation) or the ability to simulate the exposure of the analyte in vitro.

It should be noted that the inappropriateness of conducting a bioequivalence study when registering medicines, for example, for intravenous administration, is not identical to the impossibility of conducting a bioequivalence study. This is especially important to understand in Russia, since many continue to believe that the FZ-61 norm on the impossibility of conducting a bioequivalence study applies to injectable dosage forms. In fact, a biowaiver is carried out for injectable dosage forms, and a bioequivalence study is possible, but not feasible, since the bioequivalence of such aqueous solutions is self-evident.

Strictly speaking, a bioequivalence study can always be carried out, only the end points vary: pharmacokinetic, pharmacodynamic, clinical or in vitro. However, in some cases, such a study is difficult due to the complexity of the design (limited population size, for example, in case of replicated oncological drugs; difficulty in recording pharmacodynamic / clinical effects when it is impossible to estimate pharmacokinetic / in vitro parameters, for example, in local dosage forms of chondroprotectors; finally, the final the point can be very distant) or ethical restrictions (for example, in the case of the study of certain oncological drugs). For example, in the EU, Glatiramer acetate was registered at the surrogate endpoint - the dynamics of changes in the number of inflammatory foci in the brain after 9 months of using the compared drugs, but in fact it was a bioequivalence study [28], while in the USA the reproduced Glatiramer was registered on the basis of pharmaceutical equivalence (in-depth studies were conducted, comparability of production technology was shown) [29].

Comparability of the structural organization of the dosage form is a new FDA / EMA requirement for a number of replicated drugs that are complex in structure. This is due to the fact that in some cases the combination of pharmaceutical equivalence and bioequivalence, sufficient for many generic products, is not capable of providing clinical comparability, therefore, it is necessary to confirm the comparability of the structural organization of active and auxiliary substances within the limits of the drug. Such compatibility is referred to as Q3-compatibility [30]. Often this also implies the comparability of production technology.

Bioequivalence Research Program

Several studies often required to confirm bioequivalence. Additional research may be associated with the need to assess the effect of food intake on bioavailability in addition to its assessment in fasting conditions. It should be noted that in the United States it is much more often required to conduct research after meals [30].

A single vision of this issue in the world is not yet available.

It should also take into account the need for in vivo bioequivalence studies for additional dosages if it is not possible to add additional dosages to the biowaiver.

As for single-unit modified-release dosage forms, each dosage, according to EU requirements, should be assessed in at least one bioequivalence study [31].

Finally, in the EU, under certain conditions, bioequivalence studies are provided for with multiple dosing [31].

In the registration dossier of a drug, it is necessary to substantiate the program of conducted bioequivalence studies, including to motivate the uselessness of conducting research in appropriate conditions and for additional dosages.

Biowaiver in the Eurasian Economic Union

Documents of the EAEU allow 4 types of biowaiver:

• bioequivalence is self-evident, for example, in the case of true solutions, gases;
• biowaiver for additional dosages;
• biowaiver on biopharmaceutical classification system;
• biowaiver with established in vitro / in vivo correlation.

In the registration dossier of the medicinal product it is necessary to provide a justification for the fulfillment of all conditions of the biowaiver.

Bioequivalence, therapeutic equivalence and interchangeability

In conclusion, let us consider the question of how bioequivalence, therapeutic equivalence and interchangeability correlate, since these concepts are used differently in different regions, which can cause confusion.

Bioequivalence is the comparability of the rate and extent of the receipt of the same active ingredient or active principle to the place of its action from different drugs. Understanding the essence of bioequivalence in the world as a whole is the same, whereas the interpretation of therapeutic equivalence has regional differences. In the USA, it is a scientific concept underlying interchangeability; Bioequivalence is one of the criteria for therapeutic equivalence. In the EU, therapeutic equivalence is mentioned in a number of scientific guidelines on the development of replicated drugs as an alternative to bioequivalence. The European notion of therapeutic equivalence in the United States corresponds to “bioequivalence at clinical endpoints”. However, in European legislation there is no definition of therapeutic equivalence, therefore it is difficult to characterize what is meant by it.

In Russia, the study of therapeutic equivalence is perceived as an alternative to the study of bioequivalence, since the study of bioequivalence is conceived only in the pharmacokinetic framework, whereas the study of therapeutic equivalence, according to Federal Law 61, is a study on pharmacodynamic or clinical end points.

This perception is not conceptually worked out. In particular, the study examines only one end point, the choice of which is usually not justified. Security is studied on a small sample for a short time. In fact, it is supposed to extrapolate the comparability of one clinical endpoint to all the others. However, any analysis of the concept is missing; it is taken for granted, that is, it is unscientific. In this context, it can easily be confused with such clinical and statistical constructions as equal efficiency and equivalence.

The difference in the bioequivalence study for the clinical endpoint from the therapeutic equivalence study in this case is that evidence of comparability across a single clinical trait is recognized as confirmation of comparable bioavailability, and comparable bioavailability allows for extrapolation of comparability to all other clinical properties of the reproduced drug.

In the United States, therapeutic equivalence is a scientific concept to confirm the equivalent safety and efficacy of replicated drugs, based on scientific criteria such as pharmaceutical equivalence, bioequivalence, GMP, adherence to quality standards, and uniformity of drug information [25].

Interchangeability in the classical sense is a socio-economic category, which is a combination of therapeutic equivalence and pharmacoeconomics, a large role is played here by the issues of price and availability of interchangeable drug products. Interchangeable drug may not be as optimal in terms of secondary characteristics (for example, shelf life, composition of excipients, structure and internal organization of the dosage form, if they are not significant for pharmaceutical equivalence and bioequivalence) than the original drug, but this is allowed in exchange for price affordability .
In Russia, the recognition of interchangeability pursues purely economic goals, leaving no room for scientific criteria for confirming therapeutic equivalence, which eliminates social orientation, since with this approach, patients do not need to receive equivalent alternatives to the original drug. Failure to comply with scientific criteria makes drugs therapeutically nonequivalent, and therefore non-interchangeable. Failure to comply with pharmacoeconomic criteria does not make drugs therapeutically nonequivalent, but the issues of interchangeability are determined by socio-economic factors.

Conclusion

Within the framework of the EAEU, a system has been created that provides a solid scientific basis for access to the market of the Member States of the EAEU of safe, effective and high-quality, replicated and hybrid drugs, which is a great achievement in the field of public health. The system is based on European and global standards, it is quite deeply developed and requires effort to understand it, as well as additional resources for its implementation. However, one cannot fail to note a number of methodological problems, which we hope can be solved by finalizing the existing documents by the working group on the formation of common approaches to the regulation of drug circulation within the EAEU, operating under the EEC.

1. Formulation refers to a finished product having a certain composition and production technology. For example, a drug with the same composition, but with different pressing efforts will represent two different formulations, which may differ in dissolution, disintegration, stability, and bioavailability.
2. It should be noted that representatives of the Pharmacokinetic Working Group of the European Medicines Agency recognize the fallacy of the approach of not using pharmacodynamic and clinical endpoints to confirm bioequivalence, but have to reckon with it, since it is enshrined in legislation.

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