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.