Search

Evolution of knowledge about pharmacokinetics and pharmacodynamics of locally acting products, and an increase in the number of generics and medicines under development have laid the ground for the development of new scientific approaches to planning and conducting of therapeutic equivalence studies of medicinal products acting locally in the gastrointestinal (GI) tract. To date, many international guidelines on planning and conducting of bioequivalence (BE) studies of locally acting GI products have been updated, however, there are still no such guidelines in the Russian Federation and the Eurasian Economic Union (EAEU). Therefore, elaboration of common methodological approaches to the planning of clinical studies of these products is of particular relevance for the EAEU. The aim of the study was to analyse foreign approaches to planning, conducting, and evaluation of therapeutic equivalence studies of locally acting GI products. The paper analyses the guidelines of the European Medicines Agency and the US Food and Drug Administration on the planning, conduct, and evaluation of BE studies of locally acting GI products. The analysis demonstrated that BE clinical trials are giving way to in vitro studies providing a sensitive and accurate assessment of the differences between a locally acting GI product and the reference product, based on careful consideration of the medicine’s mechanism of action, dosage form, and site of action. The paper gives examples of test methods applied to medicinal products with a complex biopharmaceutical profile whose bioequivalence assessment is challenging, with a special focus on mesalazine products. The results of the analysis may be used for elaboration of a harmonised methodological approach to planning and conducting therapeutic equivalence studies of locally acting GI products in the Russian Federation and EAEU.

A bioequivalence (BE) study is one of the key stages of investigations required for the registration of oral generic drugs. The planning of this type of study is determined by many factors, including the linearity of the pharmacokinetics of the active substance. The choice of the drug dose for a BE study will depend on this property in registering several drug strengths. Regulatory requirements for planning BE studies of drugs with non-linear pharmacokinetics are considered using atazanavir and valaciclovir as examples. An analysis of protocols and reports of BE studies received by the SCEEMP according to the State Drug Registry and open published data on BE revealed differences in both the tested drug dosages and the number of tests performed. All characteristics of the given active substance, available literature data, international experience, and current regulatory requirements should be taken into account in planning and evaluating BE studies of drugs with non-linear pharmacokinetics.

The coronavirus (COVID-19) pandemic, which began in 2020, has affected all spheres of life, including clinical trial processes. Health authorities around the world issued recommendations aimed at minimising the risks of virus spreading and ensuring the safety of study participants. One of the types of clinical trials is bioequivalence studies of generic medicines. The aim of the study was to analyse current foreign approaches to planning and conduct of bioequivalence studies of medicines in the context of the COVID-19 pandemic, and to develop recommendations for planning of studies conducted in the Eurasian Economic Union and evaluation of their results. The paper discusses the main provisions of the current guidelines of the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) on the planning, conduct and evaluation of clinical trials and, in particular, bioequivalence studies of generic medicines. The paper substantiates the necessity of detailing the recommendations of the Ministry of Health of the Russian Federation, published in an open letter to all market stakeholders and regulating the conduct of clinical trials of medicines in the context of the coronavirus pandemic. The results of the analysis helped to develop recommendations aimed at ensuring the protection of clinical trial participants, as well as maintaining an acceptable level of quality and reliability of study results.

Issues with planning bioequivalence studies of lopinavir/ritonavir (LPV/RTV) preparations are discussed. LPV is an antiviral (HIV) medicine and HIV protease inhibitor that was developed in a fixed-dose combination with RTV. According to existing RF legislation, results from bioequivalence studies with a reference drug must be submitted to register generics. Protocols and reports of bioequivalence studies of LPV/RTV film-coated tablet dosage forms that were submitted for review to the SCEEMP, MHRF, are analyzed. The number of administered tablets and duration of sample collection differed slightly in the study designs. The number of volunteers included in the study differed more substantially and was calculated based on the intra-subject coefficient of variation of LPV/RTV. A search of the internet for data on the variability of LPV/RTV found several results indicating that LPV/RTV was highly variable (30%). Recommendations for planning bioequivalence studies of LPV/RTV preparations are formulated based on the analysis.

Angiotensin II receptor antagonists (ARAs) are one of the most promising classes of antihypertensive drugs. They are most widely represented on the Russian market by losartan drugs which total 24 items. Therefore, it is crucial to analyse the factors that may affect the results of comparison of generic and reference losartan drugs.The aim of the study was to perform a retrospective analysis of bioequivalence studies of generic losartan drugs in order to develop approaches to expert evaluation of research protocols and reports.Materials and methods: the retrospective analysis covered the results of 27 bioequivalence studies of losartan and included the calculation of the pharmacokinetic parameters Cmax and AUC0-t, their intra-individual variability, and the weighted average of intra-individual variability. The calculations were made for the pooled population of men and women, as well as separately for each gender.Results: the data obtained indicate borderline high variability of losartan in bioequivalence studies (for Cmax in 50 % of the studies). It was demonstrated that losartan drugs may have different pharmacokinetics in men and women in terms of Cmax and AUC0-t. The retrospective analysis of the data made it possible to formulate relevant expert approaches to evaluation of protocols and reports of bioequivalence studies of losartan drugs.Conclusions: Bioequivalence of losartan should be evaluated in three- or four-period, double crossover, two-sequence replicate design studies. The study has to determine the pharmacokinetic parameters of the starting compound and its active metabolite; the period of determination of analytes should be at least 36 hours; the washout period of 7 days is sufficient; blood sampling should be more frequent during the first hour after administration for losartan and during the first 3–4 hours for the metabolite. When determining the sample size, the weighted average of the coefficient of intra-individual variability of Cmax of losartan (33 %) should be taken into account. The bioequivalence margins for Cmax can be scaled up.

Results of a retrospective analysis of bioequivalence studies of generic angiotensin II receptor antagonists are presented. Losartan, valsartan, and telmisartan medicines can be considered highly variable with respect to the pharmacokinetic parameter for maximum blood-plasma concentration. Candesartan, irbesartan, and olmesartan medicines do not demonstrate high intra-individual variance in bioequivalence studies. Current regulatory recommendations and approaches to bioequivalence studies of highly variable medicines are discussed. Recommendations for the design and evaluation of test results of angiotensin II receptor antagonists are formulated.

Generic drugs are widely discussed in the scientific literature. Their key advantage is high availability in the medical practice due to the possibility of a significant reduction in developer costs. In most cases the efficacy and safety of generic oral drugs are confirmed based on the acceptable results of pharmacokinetic evaluation of their bioequivalence with the reference drug. However, generic drugs are not directly compared with one another, and this calls into question the validity of the conclusion about the interchangeability of the generic drugs.The aim of this study was to evaluate the results of indirect comparison of generic drugs by the ratios of their AUC0-t and Сmax based on the information obtained in bioequivalence studies involving the reference drug.Materials and methods: the authors performed an indirect comparison of the results of bioequivalence studies of generic drugs containing one active pharmaceutical ingredient. The analysis was based on bioequivalence study reports over the last 7 years dealing with risk/benefit assessment of imatinib and tacrolimus products.Results: the results of indirect assessment of 90 % confidence intervals of the ratios of imatinib products’ geometric means show that in 46.7 % of cases the intervals fall outside the generally accepted limits (80–125 %) for at least one of the estimated parameters. As for tacrolimus products, the intervals did not go beyond the generally accepted limits (80–125 %) for the AUC0-t ratio, but a discrepancy was found in 10 % of cases for the Cmax ratio. However, when narrower limits of 90–111 % were used to assess the AUC0-t ratio, 90 % of the compared pairs did not meet the recommended standards. Conclusions: thus, conclusions on the acceptable degree of bioequivalence of two generic drugs to the reference product cannot constitute a scientifically sufficient reason for regarding these generic drugs as clinically equivalent.

The introduction of the «therapeutic equivalence» concept into the Russian legislation is critical for evaluation of medicines interchangeability and for recognising them as generics. It is stipulated by the legislation that therapeutic equivalence has to be evaluated using a special instrument — «therapeutic equivalence study». The aim of this work was to analyse the validity of considering a therapeutic equivalence study as the only study that allows for confirmation of therapeutic equivalence of medicines. The term «therapeutic equivalence» has been adopted by the leading world regulators, but there is no clear concept of what is a therapeutic equivalence clinical study. The key distinctive features of the foreign approach, as compared to the Russian one, are comparison of medicines with one active pharmaceutical ingredient, and additional conditions for the establishment of therapeutic equivalence. The clinical trial methodology, which is based on the use of statistical analysis methods, also imposes constraints on evaluation of «similarity» of properties, efficacy and safety of medicines in a single study. Hence, there are several reasons why the results of comparative clinical trials can not be used as a sole basis for the establishment of therapeutic equivalence. These results have to be substantiated by confirmation of comparable composition and pharmacokinetic parameters of medicines in order for them to be considered therapeutically equivalent. This does not contradict the existing regulatory framework and is consistent with the current scientific methodology for conducting clinical trials.

There are no specific requirements and recommendations in the Russian Federation for evaluation of bioequivalence of modified-release medicinal products. Until recently, modified-release products were regulated in a similar manner as immediate-release products, which is unacceptable considering the active ingredient release profile and its pharmacokinetics. The modified release characteristics require a more complex approach to the assessment of equivalence of generic medicines as compared with the reference product. The number of parameters to be assessed and the scope of testing depend on many factors (release mechanism, specific features of the dosage form, linearity of pharmacokinetics, potential for ingredient accumulation, dependence on food intake, dose-dumping effects, and the number of dosage strengths to be registered). The aim of this paper was to develop recommendations for the national procedure of modified-release products authorisation based on the analysis of international regulatory experience in this field. The paper reviews the current European Medicines Agency (EMA) guidelines on evaluation of bioequivalence of generic modified-release dosage forms for oral use that were taken as a basis for the development of Eurasian Economic Union regulations on bioequivalence assessment. The analysis of the above-mentioned documents made it possible to develop recommendations for the national procedure of modified-release products authorisation. In the case of modified-release products for oral use it is recommended to perform bioequivalence studies by comparing the test product with the reference product. The authors developed a procedural algorithm for bioequivalence studies of modified-release medicinal products.

The Government of the Russian Federation approved the State strategy of combating the spread of HIV aimed at prevention of HIV epidemic. One of the goals of the Strategy is to increase the coverage of antiretroviral therapy for people infected with HIV, which includes extensive use of generic drugs. In order for a generic drug to be authorised, the applicant has to submit a report on the results of the bioequivalence studies in which the generic product was compared to the reference product. Atazanavir is an antiretroviral drug, which is also the drug of choice for the treatment and prevention of mother-to-child transmission of HIV. The aim of this study was to analyze the protocols and reports of atazanavir products bioequivalence studies, which were submitted for expert examination to the FSBI “SCEEMP” of the Ministry of Health of the Russian Federation, and to prepare recommendations for planning of bioequivalence studies of atazanavir products. The analysis of a number of studies revealed significant differences in the study design and number of subjects. The main reason for these differences is the conflicting data on the intrasubject coefficient of variation of atazanavir, which means that atazanavir may be considered a highly variable drug. The analysis helped to formulate recommendations for the design of bioequivalence studies of atazanavir products, including studies of the maximum dose, studies under fed conditions, and consideration of atazanavir variation when planning the study design.

Planning issues for darunavir (DRV) bioequivalence studies are considered. DRV is an antiviral (HIV) agent classified as an HIV protease inhibitor. Bioequivalence test results must be submitted for registration of generic drugs in the RF according to Federal Law 61-FZ. Bioequivalence study protocols and reports for DRV preparations that were submitted for review to the SCEEMP were analyzed. Differences in study designs including administration after fasting or meals, with or without a low dose of ritonavir, numbers of volunteers included in the study, and intra-subject variability were found. The internet was also searched for data on DRV variability. Recommendations for planning bioequivalence studies of DRV preparations were formulated based on the analysis.

Background. Evidence of the effect of sex on the pharmacokinetics of drugs and, accordingly, on the clinical response is significantly accumulated, because of a growing number of clinical studies of the early development of original drugs, which include female subjects. The number of bioequivalence studies of replicated drugs involving both sexes is also growing. Of particular importance for the bioavailability of oral medications are differences in the anatomy and physiology of the digestive system. Along with this factor, the differences may be due to the dosage form of the reproduced drug, which may differ from that of the reference (original). The aim of the study was to identify the effect of sex differences on the pharmacokinetics of drugs and to propose an algorithm for assessing their detection. Materials and methods. The article presents a general analysis of the works devoted to the pharmacokinetics of medicines in men and women and includes literature data. Results. The main factors influencing the pharmacokinetics of drugs (absorption, distribution, metabolism, excretion) are identified. Examples of medicinal products for which differences in pharmacokinetics in men and women are revealed are given. The article describes the main international requirements for conducting clinical trials and bioequivalence studies with regard to the choice of gender of subjects and their number to be included in the clinical study. It is suggested that there is a need to further study of the effect of sex differences on bioequivalence results in carrying out relevant studies. Conclusion. An algorithm for estimating the detection of sex differences and their effect on the results of bioequivalence studies of generic drugs is proposed.

The article analyses regulatory documents and requirements for statistical principles of planning and evaluation of results of bioequivalence studies. It describes current statistical approaches to bioequivalence evaluation and relevant recommendations for the planning of studies of conventional medicinal products, medicinal products with a narrow therapeutic range, and analogues of endogenous compounds. The article analyses such statistical approaches as average Bioequivalence (ABE), Average Bioequivalence with Expanding Limits (ABEL), Reference-Scaled Average Bioequivalence (RSABE). It describes specific aspects of statistical analysis of insufficiently studied medicinal products. The article also describes acceptable algorithms of planning and performing two-stage bioequivalence study designs, since such studies call for multiple testing of the bioequivalence hypothesis which leads to an increased probability of type i error (consumer risk). The article offers recommendations for the choice of statistical approaches and describes some aspects of statistical analysis methods depending on the design of the study and the type of generic medicines.

The article demonstrates that bioequivalence studies of generic drugs whose active substances are analogues of endogenous compounds found in the human body in natural concentrations present a major challenge as compared to other products and call for a specific regulatory approach. In the absence of available scientific data demonstrating that the product intake can increase the general concentration of the endogenous compound, conducting bioequivalence studies can be economically impractical in contrast to a standard comparative clinical trial, because first it would be necessary to demonstrate a significant increase in the compound concentration in blood plasma. The article analyses Russian legislation and international law with respect to evaluation of medicinal products that are analogues of endogenous compounds, i.e. vitamins, hormones, enzymes, amino acids and salts. It was demonstrated that correction for endogenous compound concentration in blood plasma and control of its dietary intake are required in order to obtain accurate bioequivalence results. The article summarises the experience gained at the FSBI «SCEEMP» of the Ministry of Health of the Russian Federation with respect to evaluation of medicines that are analogues of endogenous compounds, and outlines the most frequent mistakes in testing protocols. It substantiates the need for an individual approach tailored for each particular product, since there is no single solution to the problem of background concentration of endogenous compounds. The authors of the article developed some key solutions that can help minimize the impact of background concentrations of test samples on the results of bioequivalence assessment. Based on the results of the analysis performed and accumulated experience the authors of the article suggested some ways to resolve the problem.

The article analyses regulatory documents containing requirements for clinical (trials) documentation for orally inhaled products, including requirements for the demonstration of therapeutic equivalence of medicinal products for the treatment of bronchial asthma and chronic obstructive pulmonary disease in adults and children. The article summarises the main approaches to the assessment of inhalers equivalence. It also systematizes and describes dosage forms and inhalation devices, as well as the necessary stages of inhaler evaluation, looks into the methodology of conducting therapeutic equivalence studies with due regard to the therapeutic class of the drug, duration of its action and proposed nosology. The methodology includes requirements for the selection of the study population, study design and conditions, and recommendations for the selection of drug dose, study duration, primary and secondary efficacy and safety endpoints in the context of orally inhaled products.

At present a specific group of medicines - highly variable medicines - is distinguished based on intraindividual variability data (CVintra > 30%). It is quite difficult to confirm therapeutic equivalence of highly variable medicines by pharmacokinetic bioequivalence studies, and quite a large number of subjects need to be included into the study in order to confirm bioequivalence within standard limits of 80-125%. Variability may be caused by many factors which include physiological and pathophysiological differences in absorption and metabolism processes; factors associated with properties of the active substance and factors associated with the finished product. In general factors impacting variability in bioequivalence studies could be divided into controllable and uncontrollable. The influence of controllable factors can be neutralized by proper performance of the bioequivalence study or proper development of the finished product. The influence of uncontrollable factors cannot be neutralized, and due to these factors medicines can be recognized as highly variable. This article provides a definition of a highly variable medicine, describes reasons for high variability and outlines current regulatory recommendations for and approaches to studying bioequivalence of highly variable medicines, proposes recommendations for designing such studies.

The principles for assessing therapeutic equivalence based on bioequivalence studies as accepted in Russia are significantly different from those adopted abroad, in particular with respect to drugs with narrow therapeutic indices (NTI). Certification of these drugs based on bioequivalence studies with commonly recognized limits is unacceptable in practice because drugs in this concentration range can cause serious adverse side effects and be more dangerous than the reference drug. The situation becomes especially critical when the reference drug is replaced by a generic. This circumstance creates the need to develop stricter regulations for NTI drugs. This article analyzes possible approaches to planning bioequivalence investigations for NTI drugs as adopted by leading world regulatory institutions in order to harmonize them with bioequivalence studies of NTI drugs in the Russian Federation. General recommendations for planning bioequivalence studies of NTI drugs were formulated based on the analysis.